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WO2005040112A1 - Composes a activite antagoniste de pgd2 - Google Patents

Composes a activite antagoniste de pgd2 Download PDF

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Publication number
WO2005040112A1
WO2005040112A1 PCT/GB2004/004337 GB2004004337W WO2005040112A1 WO 2005040112 A1 WO2005040112 A1 WO 2005040112A1 GB 2004004337 W GB2004004337 W GB 2004004337W WO 2005040112 A1 WO2005040112 A1 WO 2005040112A1
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WO
WIPO (PCT)
Prior art keywords
methyl
indol
fluoro
acetic acid
benzenesulfonyl
Prior art date
Application number
PCT/GB2004/004337
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English (en)
Inventor
David Middlemiss
Mark Richard Ashton
Edward Andrew Boyd
Frederick Arthur Brookfield
Richard Edward Armer
Eric Roy Pettipher
Original Assignee
Oxagen Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0324083A external-priority patent/GB0324083D0/en
Priority claimed from GB0403334A external-priority patent/GB0403334D0/en
Priority claimed from GB0406963A external-priority patent/GB0406963D0/en
Application filed by Oxagen Limited filed Critical Oxagen Limited
Publication of WO2005040112A1 publication Critical patent/WO2005040112A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to compounds which are useful as pharmaceuticals, to methods for preparing these compounds, compositions containing them and their use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D 2 (PGD 2 ) acting at the CRTH2 and/or the DP receptor on cells including eosinophils, basophils and Th2 lymphocytes.
  • PPD 2 prostaglandin D 2
  • PGD 2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD 2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. I. Med. 315: 800-804). Instillation of PGD into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl.
  • the first receptor specific for PGD 2 to be discovered was the DP receptor which is linked to elevation of the intracellular levels of cAMP.
  • PGD 2 is thought to mediate much of its proinflammatory activity through interaction with a G protein- coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) /. Exp. Med. 193: 255-261, and EP0851030 and EP-A- 1211513 and Bauer et al, EP-A-1170594).
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) I. Allergy Clin. Immunol. 108: 982-988). Based on this evidence, antagonising PGD 2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.
  • EP-A-1170594 suggests that the method to which it relates can be used to identify compounds which are of use in the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmune disease, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD at the CRTH2 receptor.
  • WO-A-03066046 and WO-A-03066047 teach that the compounds to which they relate are modulators of CRTH2 receptor activity and are therefore of use in the treatment or prevention of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease (COPD) and a number of other diseases including various conditions of bones and joints, skin and eyes, GI tract, central and peripheral nervous system and other tissues as well as allograft rejection.
  • COPD chronic obstructive pulmonary disease
  • Indole derivatives are also disclosed in WO-A-9950268. These compounds have a carboxylic acid moiety attached to the indole nitrogen atom. These compounds are said to be of use in the treatment of complications arising from diabetes mellitus.
  • PL 65781 and GB 1172320 also relate to indole derivatives which are similar in structure to indomethacin and, like indomethacin, are said to have anti-inflammatory and antipyretic activity.
  • the compounds they describe are COX inhibitors, an activity which is quite different from that of the compounds of the present invention. Indeed, COX inhibitors are contraindicated in the treatment of many of the diseases and conditions, for example asthma and inflammatory bowel disease for which the compounds of the present invention are useful, although they may sometimes be used to treat arthritic conditions.
  • the present invention relates to compounds similar to those of PL 65781 and GB 1172320 which are antagonists of PGD 2 .
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, -C ⁇ -C 6 alkyl, -O(C ⁇ -C 6 alkyl), -C C 6 alkyl(C 3 -C 7 cycloalkyl), -CON(R 9 ) 2 , -SOR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R 9 ) 2 , -NR 9 COR 9 , -CO 2 R 9 , COR 9 , -SR 9 , -OH, -NO 2 or -CN; each R 9 is independently hydrogen or -C ⁇ alkyl; R 5 and R 6 are each independently hydrogen, or d-C 6 alkyl or together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group;
  • R 7 is hydrogen or C C 6 alkyl
  • R 8 is C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo,
  • R 14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R 9 , -OR 9 , -CON(R 9 ) 2 , -SOR 9 -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R 9 ) 2 , - NR9COR 9 , -CO 2 R 9 , -COR 9 , -SR 9 , halo, -NO 2 or -CN; wherein R 9 is as defined above; provided that when R 1 , R 3 and R are hydrogen and R 2 is hydrogen, halogen or -O(C !
  • R is not unsubstituted phenyl or phenyl substituted by halo, Ci-C ⁇ alkyl, -O(C 1 -C 6 )alkyl, -S(C ⁇ -C 6 )alkyl or -CO(Ci-C 6 )alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.
  • the compounds of general formula (I) are antagonists of PGD 2 . Some of the compounds of general formula (I) act at the CRTH2 receptor, others have dual activity at the CRTH2 and DP receptors and yet others act selectively at the DP receptor. The compounds will be useful in the treatment of conditions which are mediated by PGD 2 binding to the CRTH2 and/or DP receptors.
  • allergic diseases include allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD 2 -mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
  • autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury
  • Q-Q alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms and optionally substituted with one or more halo substituents or with one or more C 3 -C cycloalkyl groups. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, mefhylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.
  • C 1 -C 4 alkyl and “Q-Qs alkyl” have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively.
  • C -C 6 alkenyl and “C ⁇ -C 6 alkynyl” refer to straight or branched carbon chains having from one to six carbon atoms and containing respectively a carbon-carbon double bond and a carbon-carbon triple bond.
  • the groups are optionally substituted with one or more halo substituents or with one or more C 3 -C 7 cycloalkyl groups. Examples include ethenyl, ethynyl, 2-propenyl and 2-propynyl.
  • C 3 -C 7 cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring.
  • Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halo refers to fluoro, chloro, bromo or iodo.
  • aromatic moiety and "aryl” in the context of the present specification refer to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings, one or more of which may be replaced by a nitrogen, oxygen or sulphur atom.
  • aromatic moieties are benzene, pyridine, naphthalene, biphenyl, quinoline, isoquinoline, quinazoline, benzthiazole, benzoxazole, benzimidazole indole, indazole and imidazole ring systems.
  • Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (I) and (II) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine and other well known basic addition salts.
  • pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesul, 2-
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo.
  • Examples of prodrugs include alkyl esters of the compounds of general formula (I), for example the esters of general formula (LI) below.
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • R 1 is C ⁇ -C 4 alkyl, halo or hydrogen
  • R 2 is C 1 -C 4 alkyl, CN, halo, hydrogen or -CON(R 9 ) 2 , (where R 9 is hydrogen or C ⁇ -C 4 alkyl);
  • R 3 is Q-C 4 alkyl, halo or hydrogen
  • R 4 is C 1 -C 4 alkyl, halo or hydrogen.
  • R 1 , R 3 and R are hydrogen, while R 2 is halo, particularly fluoro.
  • R 5 and R 6 are each independently hydrogen or C 1 -C 4 alkyl. However, in more active compounds, at least one, and preferably both of R 5 and R 6 are hydrogen.
  • Compounds of general formula (I) preferably have an R 7 group chosen from H or Q- C 6 alkyl; most suitably R 7 is methyl.
  • the compounds of general formula (I) have the additional advantage that the selectivity of the compound can be manipulated by making changes to the R 8 substituent.
  • a high selectivity at the CRTH2 receptor is advantageous and the inclusion of certain R 8 substituents give rise to compounds in which binding selectivity at the CRTH2 receptor is more than 200 times greater than DP or TP binding.
  • other compounds of general formula (I) bind selectively to the DP receptor and yet others bind strongly to both CRTH2 and DP receptors and this is preferable for some medical uses such as allergic rhinitis.
  • R is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(C C 4 alkyl), -SO 2 (C ⁇ -C 4 alkyl), -R 14 , -N(R 14 ) 2 and -OR 14 ; where R 14 (or one R 14 if two are present) is preferably aryl, optionally substituted as described above.
  • R 8 groups include an aromatic moiety having one or two rings, and especially phenyl or pyridyl, substituted with -SO 2 R 14 , -N(R 14 ) 2 or -OR 14 ; where R 14 (or one of the R 14 groups if two are present) is preferably aryl, optionally substituted as described above.
  • substituents for the R 14 moiety are Q-C 4 alkyl, -0(0 ⁇ 0 4 alkyl), -CN, -SO 2 NH 2 , -SO 2 (C 1 -C 4 alkyl) or halo.
  • R , ⁇ 1 , R ⁇ R ⁇ R 4 , R D , R°, R' and R B are as defined for general formula (I);
  • R 11 is hydrogen or methyl
  • R 12 is Ci-Ci ⁇ alkyl; provided that when R 1 , R 3 and R 4 are hydrogen and R 2 is hydrogen, halogen or - O(C ⁇ -C 6 )alkyl, R 8 is not unsubstituted phenyl or phenyl substituted by halo, Q-C O alkyl, -O(C ⁇ -C 6 )alkyl, -S(C 1 -C 6 )alkyl or -CO(d-C 6 )alkyl.
  • Compounds of general formula (II) are novel and may be used as prodrugs for compounds of general formula (I).
  • the compound of general formula (TT) acts as a prodrug, it is later transformed to the drug by the action of an esterase in the blood or in a tissue of the patient.
  • compounds of formula (II) wherein R 10 is d-C 6 alkyl may be used in a process for the preparation of a compound of general formula (I), the process comprising reacting the compound of general formula (LI) with a base such as sodium hydroxide or lithium hydroxide.
  • a base such as sodium hydroxide or lithium hydroxide.
  • the reaction may take place in an aqueous solvent or an organic solvent or a mixture of the two.
  • a typical solvent used for the reaction is a mixture of tetrahydrofuran and water.
  • R 1 , R 2 , R 3 , R 4 R 5 , R 6 and R 7 are as defined for general formula (I) and R 10 is as defined for general formula (II); by reaction with a compound of general formula (IV): X-SO 2 -R 8 (TV)
  • R 8 is as defined for general formula (I) and X is a leaving group in particular a halo group, for example chloro.
  • the reaction is conducted under strongly basic conditions, for example in the presence of a metal alkoxide, in particular a potassium or sodium alkoxide such as potassium tert-butoxide.
  • a metal alkoxide in particular a potassium or sodium alkoxide such as potassium tert-butoxide.
  • the reaction may be carried out in a polar organic solvent such as tetrahydrofuran and the alkoxide may be solubilised using a polyether, particularly a crown ether. If a potassium alkoxide is used, 18-crown-6 is a particularly suitable solvating agent as it complexes very effectively with potassium ions.
  • R is a trifluoromethanesulfonyl- substituted aryl group (for example trifluoromethylsulfonylbenzene)
  • R is a trifluoromethanesulfonyl- substituted aryl group
  • the reaction may be conducted at elevated temperature, for example 50 to 150°C.
  • the trifluoromethanesulfonyl-substituted aromatic compound may be prepared by oxidising the corresponding sulfide, for example using ruthenium trioxide and sodium periodate. Trifluoromethylsulfonylbenzene may be prepared in this way from phenyltrifluoromethylsulfide.
  • the precursor sulfonyl chloride derivative of general formula (IV) may be prepared by reacting the corresponding pyridyloxyaryl compound with chlorosulfonic acid.
  • the reaction is preferably carried out in a chlorinated organic solvent at a low temperature, for example from -5 to 30°C.
  • Examples of intermediates of general formula (IV) which can be prepared in this way include: 4-(pyridine-2-yloxy) benzene sulf onyl chloride; 4-(pyridine-3-yloxy) benzene sulfonyl chloride; and 4-(pyridine-4-yloxy) benzene sulfonyl chloride.
  • the most suitable method for the preparation of the aryloxy aryl group depends upon the required substitution pattern on the aryloxy group.
  • Some of these compounds can be prepared by the reaction of the corresponding halopyridine with a hydroxyaryl group in the presence of a strong base such as sodium hydride. The reaction is carried out under an inert atmosphere, for example nitrogen in an aprotic organic solvent such as dioxane. This method is appropriate for the preparation of 2- phenyoxypyridine from phenol and 2-fluoropyridine.
  • a hydroxyaryl compound such as a pyridinol
  • a base such as sodium or potassium hydroxide and a halo-substituted aromatic compound in a copper catalysed reaction.
  • This method is suitable for the preparation of compounds such as 3-phenoxypyridine and 4-phenoxypyridine.
  • compounds of general formula (II) in which R 8 is chloro-, bromo- or iodo-substituted aryl may be converted to other compounds of general formula (II) in which R is arylaminoaryl by reaction with an aryl amino compound in a palladium (0) mediated cross-coupling reaction.
  • This reaction may be used to convert o compound in which R is haloaryl (for example bromophenyl or bromopyridyl) to compounds in which R is arylaminoaryl (such as arylaminophenyl or arylaminopyridyl, for example Compounds 109-153).
  • Compounds of general formula (LI) in which R 8 is aryl aminoaryl can be converted into compounds of general formula (LI) in which R 8 is aryl-N-alkylaminoaryl by reaction with an alkyl iodide in the presence of a strong base.
  • R 8 is aryl-sulfinyl-aryl or aryl-sulfonyl- aryl
  • R 8 is aryl- sulfanyl-aryl by oxidation using an appropriate oxidising agent to give either partial or complete oxidation as appropriate.
  • a suitable oxidising agent for the aryl sulfinyl compounds is mCPBA and a suitable oxidising agent for the aryl-sulfonyl compounds is OxoneTM.
  • the precursor sulfonyl chloride derivative of general formula (TV) may be prepared by reacting the corresponding diaryl sulfide compound with chlorosulfonic acid under standard conditions.
  • Compounds of general formula (I) are antagonists of PGD 2 at the CRTH2 and/or DP receptors and compounds of general formula (II) are prodrugs for compounds of general formula (I).
  • Compounds of general formulae (I) and (LI) are therefore useful in a method for the treatment of diseases and conditions mediated by PGD 2 at the CRTH2 and/or DP receptors, the method comprising administering to a patient in need of such treatment a suitable amount of a compound of general formula (I) or
  • a compound of general formula (I) or (II) for use in medicine particularly for use in the treatment or prevention of diseases and conditions mediated by PGD 2 at the CRTH2 and/or DP receptor. Examples of such diseases and conditions are listed above.
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, halo, -C ⁇ -C 6 alkyl, -O(d-C 6 alkyl), -d-C 6 alkyl(C 3 -C 7 cycloalkyl), -CON(R 9 ) 2 , -SOR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , -N(R ) 2 , -NR 9 COR 9 , -CO 2 R 9 , COR 9 , -SR 9 , -OH, -NO 2 or -CN; each R 9 is independently hydrogen or d-C 6 alkyl; R 5 and R 6 are each independently hydrogen, or d-C 6 alkyl or together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group; R 7 is hydrogen or d-C 6 alkyl;
  • R 8 is d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, -SOR 13 -SO 2 R 13 , -R 14 , -OR 14 , -CON(R 14 ) 2 , -SOR 14 , -SO 2 R 14 , -SO 2 N(R 14 ) 2 , -N(R 14 ) 2 , -NR 14 COR 14 , -CO 2 R 14 , -COR 14 , -SR 14 , -NO 2 or -CN; wherein R 13 is a 5 to 7 membered heterocyclic ring; and each R 14 is independently hydrogen, alkyl or aryl, the aryl being optionally substituted by -R 9 , -OR 9 , -CON(R 9 ) 2 , -SOR 9 -SO 2 R
  • autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease; as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
  • Preferred compounds are as set out above for the first aspect of the invention.
  • a pharmaceutical composition comprising a compound of general formula (I) or (II) together with a pharmaceutical excipient or carrier.
  • Other active materials may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.
  • each of the carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
  • compositions for oral, nasal, bronchial or topical administration.
  • the composition may be prepared by bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of general formula (I) or (II) in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
  • the term "acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth
  • pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia
  • mouthwashes comprising the active agent in a suitable liquid carrier.
  • compounds of general formula (I) or (LT) may be made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British
  • Compounds of general formula (I) or (LT) may be used for the treatment of the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension.
  • Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and or diluents.
  • Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser.
  • compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
  • Parenteral formulations will generally be sterile.
  • the dose of the compound will be about 0.01 to 100 mg kg; so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit PGD 2 at the CRTH2 and/or DP receptor.
  • the precise amount of a compound of general formula (I) or (H) which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • Compounds of general formula (I) or (II) may be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although these active agents are not necessarily inhibitors of PGD at the CRTH2 and/or DP receptor.
  • the pharmaceutical composition described above may additionally contain one or more of these active agents.
  • additional active agents which may have a completely different mode of action include existing therapies for allergic and other inflammatory diseases including: ⁇ 2 agonists such as salmeterol; corticosteroids such as fluticasone; antihistamines such as loratidine; leukotriene antagonists such as montelukast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease.
  • ⁇ 2 agonists such as salmeterol
  • corticosteroids such as fluticasone
  • antihistamines such as loratidine
  • leukotriene antagonists such as montelukast
  • anti-IgE antibody therapies such as omalizumab
  • CRTH2 and or DP antagonists may also be combined with therapies that are in development for inflammatory indications including: other antagonists of PGD 2 acting at other receptors such as CRTH2 (for compounds of general formula (I) which are DP antagonsists) or DP (for compounds of general formula (I) which are CRTH2 antagonists); inhibitors of phoshodiesterase type 4 such as cilonilast; drugs that modulate cytokine production such as inhibitors of TNF converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines LL-4 and LL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR- ⁇ agonists such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton.
  • other antagonists of PGD 2 acting at other receptors such as CRTH2 (for compounds of general formula (I) which are DP antagonsists) or DP (for compounds of general formula (I) which are CRTH
  • a product comprising a compound of general formula (I) or (LT) and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD 2 at the CRTH2 and/or DP receptor.
  • Tr 1.63 min (91%), m/z (ES + ) (M+H) + 362.1.
  • Tr 1.73 min (100%), m/z (ES + ) (M+H) + 426.1.
  • Tr 1.55 min (85%), /z (ES + ) (M+H) + 416.01.
  • Tr 1.66 min (100%), m/z (ES + ) (M+H) + 432.15.
  • Tr 1.60 min (100%), m/z (ES + ) (M+H) + 412.14.
  • Tr 1.28 min (100%), m/z (ES + ) (M+H) + 300.25.
  • Tr 1.50 min (100%), m/z (ES + ) (M+H) + 374.16.
  • Tr 1.60 min (100%), m/z (ES + ) (M+H) + 450.11.
  • Tr 1.45 min (100%), m/z (ES + ) (M+H) + 393.13.
  • Tr 1.46 min (100%), m/z (ES + ) (M+H) + 382.17.
  • Tr 1.40 min (100%), m/z (ES + ) (M+H) + 373.16.
  • Tr 1.41 min (100%), m/z (ES + ) (M+H) + 373.20.
  • Tr 1.30 min (100%), m/z (ES + ) (M+H) + 445.08.
  • Tr 1.49 min (100%), m/z (ES + ) (M+H) + 431.16.
  • Tr 1.66 min (97%), /z (ES + ) (M+H) + 410.22.
  • Tr 1.31 min (100%) m/z (ES + ) 389.12 (M+H) + .
  • sodium hydride 60% dispersion in mineral oil
  • 2-fluoro-pyridine 2.9 g, 29.9 mmol
  • Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 2-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Three other treatments with chlorosulfonic acid (3 x 0.38 mL, 3 x 5.84 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL).
  • Chlorosulfonic acid (0.77 mL, 11.69 mmol) was added dropwise to a stirred solution of 3-phenoxy-pyridine (500 mg, 2.92 mmol) in chloroform (10 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Another treatment with chlorosulfonic acid (0.77 mL, 11.69 mmol) was required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (250 mL). The aqueous layer was extracted with dichloromethane (250 mL).
  • Chlorosulfonic acid (1.55 mL, 23.38 mmol) was added dropwise to a stirred solution of 4-phenoxy-pyridine (1 g, 5.85 mmol) in chloroform (20 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. Four extra treatments with chlorosulfonic acid (4 x 1.55 mL, 4 x 23.38 mmol) were required to give complete conversion to the sulfonyl chloride. The resulting mixture was then poured slowly onto a mixture of ice and water (500 mL). The aqueous layer was extracted with dichloromethane (500 mL).
  • 1,4-Dioxane (5.0 ml) was added to a flask containing [l-(4-bromo-benzenesulfonyl)- 5-fluoro-2-methyl-2H-indol-3-yl]-acetic acid ethyl ester (227 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (46 mg, 0.044 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.025 mmol), cesium carbonate (813 mg, 2.50 mmol) and 3-methylaniline (64 mg, 0.60 mmol) under a nitrogen atmosphere.
  • Examples 155 to 169 were prepared using a similar method to Compound 154 but with appropriately chosen starting materials
  • Chlorosulfonic acid (0.70 mL, 10.74 mmol) was added dropwise to a stirred solution of diphenyl sulfide (2 g, 10 mmol) in chloroform (5 mL) at 0°C. The mixture was left at 0°C for 30 minutes, and then left overnight stirring at room temperature. The resulting mixture was concentrated in vacuo to give a yellow oil which crystallised on standing. The resulting product was dissolved in toluene and treated with phosphorus pentachloride (2.23 g, 10.71 mmol) at 90°C for one hour. The resulting mixture was concentrated in vacuo and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was used directly in the next step.
  • Oxone (190 mg, 0.31 mmol) was added to a solution of [5-fluoro-2-methyl-l-(4- phenylsulfanyl-benzenesulfonyl)-2H-indol-3-yl]-acetic acid ethyl ester (100 mg at 50% purity, 0.10 mmol) in 5 mL of dioxane : water (4:1). The resulting mixture was stirred at room temperature overnight and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Monopoly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 microbeads were from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD). Poly-D- lysine coated 96-well plates were obtained from Greiner (Gloucestershire, UK). [ 3 H]PGD 2 was from Amersham Biosciences (Buckinghamshire, UK). [ 3 H]SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma-Aldrich (Dorset, UK), unless otherwise stated.
  • Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors (CHO/CRTH2 and CHO/DP) and were maintained in culture in a humidified atmosphere at 37°C (5% CO 2 ) in Minimum Essential Medium (MEM) supplemented with 10% foetal bovine serum, 2 mM glutamine, and 1 mg ml "1 active G418. The cells were passaged every 2-3 days.
  • MEM Minimum Essential Medium
  • radioligand binding assay cells were prepared in triple-layer flasks or in 175 cm square flasks (for membrane preparation).
  • calcium mobilisation assay cells were grown in a 96 well plate 24h prior to the assay at a density of 80,000 cells per well.
  • Membranes were prepared either from CHO/CRTH2 and CHO/DP cells, or from platelets (as a source of TP receptors). CHO cells grown to confluency were washed with PBS and detached using a Versene solution (15 ml per flask). When the cells were grown in 175 cm 2 square flask, they were collected by scrapping in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 min, 4°C) and resuspended in 15 ml of buffer (lxHBSS, supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were then homogenised using an Ultra Turrax at setting 4-6 for 20 s.
  • the homogenate was centrifuged at 1,700 rpm for 10 min and the supernatant was collected and centrifuged at 20,000 rpm for lh at 4°C. The resulting pellet was resuspended in buffer and stored at -80°C in aliquots of 200-500 ⁇ l.
  • the protein concentration was determined by the method of Bradford (1976), using bovine serum albumin as standard.
  • the platelets were washed by centrifugation at 600xg for 10 min and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM Glucose, 120 mM NaCl, 10 ⁇ M indomethacin) and directly centrifuged at 20,000 rpm for 30 min at 4°C. The resulting pellet was treated as described above. Radioligand binding assays
  • [ 3 H]PGD 2 (160 Ci/mmol) binding experiments were performed on membranes prepared as described above. Assays were performed in a final volume of 100 ⁇ l of buffer (1XHBSS/HEPES 10 mM, pH 7.3). Cell membranes (15 ⁇ g). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 min. [ 3 H]PGD2 (mol, final concentration) was then added and the incubation continued for a further one hour at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 ⁇ l of ice- cold buffer.
  • the Unifilter plates were dried at room temperature for at least lh and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40 ⁇ l of Optiphase Hi-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 ⁇ M unlabelled PGD 2 . Assays were performed in duplicate.
  • TP receptor radioligand binding was done on membranes prepared from platelets. 15-40 ⁇ g of protein were pre-incubated with varying concentrations of competing ligand for 15 min at room temperature in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM NaCl, 10 ⁇ M indomethacin). [ 3 H]SQ29548 (38 Ci/mmol, 10 nM final concentration) was then added and the incubation continued for a further 30 min at room temperature.
  • the reaction was terminated by the addition of 200 ⁇ l ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/C glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) followed with six washes of 300 ⁇ l of ice-cold buffer.
  • the radioactivity was determined as described above.
  • Cells were seeded onto poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated at 37 °C overnight to allow the cells to adhere. Cells were washed twice with HBSS and incubated for lh at 37°C in lOO ⁇ l HBSS and lOO ⁇ l calcium-3-dye (Molecular Devices), supplemented with 4mM probenecid. Changes in fluorescence were monitored over a 50s time course with agonist addition at 17s using a Flexstation (Molecular Devices).

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Abstract

L'invention concerne les composés représentés par la formule générale (I); dans laquelle R1, R2, R3 et R4 représentent séparément hydrogène, halo, -alkyle C1-C6, -O(alkyle C1-C6), -alkyle C1-C6 (cycloalkyle C3-C7), -CON(R9)2, -SOR9, -S02R9. -S02N(R9)2, -N(R9)2, -NR9OR9, -C02R9, COR9, -SR9, -OH, -N02 ou -CN; chaque R9 représente séparément hydrogène ou alkyle C1-C6; R5 et R6 représentent chacun séparément hydrogène, ou alkyle C1-C6, ou forment conjointement avec l'atome de carbone auquel ils sont liés un groupe cycloalkyle C3-C7; R7 représente hydrogène ou alkyle C1-C6; R8 représente alkyle C1-C6, alcényle C2-C6, alcynyle C2-C6 ou une fraction aromatique, qui peuvent chacun être éventuellement substitués par un ou plusieurs substituants choisis parmi halo, -SOR13 -S02R13, -R14, -OR14, -CON(R14)2 -SOR14, -S02R14, -S02N(R14) -SO2N(R14)2, -N(R 14)2, NR14COR14, -CO2R14, COR14, -SR14, -N02 or CN, R13 représentant un noyau hétérocyclique comportant de 5 à 7 chaînons; et chaque R14 représente séparément hydrogène, alkyle ou aryle, l'aryle étant éventuellement substitué par -R9, -OR9, -CON(R9)2, -SOR9 -S02R9, -S02N(R9)2, -N(R9)2, NR9COR9, -C02R9, -COR9, -SR9, halo, -N02 ou CN, R9 étant conforme à la définition ci-dessus; avec la restriction suivante: lorsque R1, R3 et R4 représentent hydrogène et que R2 représente hydrogène, halogène ou alkyle -O(C1-C6), R8 n'est pas phényle non substitué ou phényle substitué par halo, alkyle C1-C6, -O alkyle (C1-C6), -S-alkyle (C1-C6) ou CO-alkyle (C1-C6); ou des sels, des hydrates, des solvates, des complexes ou des promédicaments pharmaceutiquement acceptables de ces composés, convenant pour le traitement des maladies allergiques telles que l'asthme, les rhinites allergiques et les dermatites atopiques.
PCT/GB2004/004337 2003-10-14 2004-10-13 Composes a activite antagoniste de pgd2 WO2005040112A1 (fr)

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GB0324083A GB0324083D0 (en) 2003-10-14 2003-10-14 Compounds
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GB0403334.6 2004-02-14
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