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Definitions

• This invention relates to octahydropyrrolo[3,4-c]pyrrole derivatives and to processes for the preparation of, compositions containing and the uses of, such derivatives.
• the octahydropyrrolo[3,4-c]pyrrole derivatives of the present invention are histamine H 4 receptor ligands and have therefore a number of therapeutic applications, particularly in the treatment of asthma and allergic rhinitis.
• the histamine H 4 receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40 % homology to the histamine H 3 receptor. In contrast to the H 3 receptor, which is primarily located in the brain, the H 4 receptor is expressed at greater levels in eosinophils and mast cells, among other inflammatory cells. H 4 receptor ligands should thus be suitable for the treatment of various inflammatory disorders.
• diseases where treatment with H 4 ligands are inflammatory bowel disease, Crohn's disease, colitis ulcerosa, dermatitis, psoriasis, conjunctivitis, rheumatoid arthritis, respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
• respiratory diseases such as adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic r
• Histamine H 4 receptor ligands have been developed. An overview of the current advance in H 4 ligand research and patenting is given in Expert OpIn. Ther. Patents (2003) 13(6). Examples of Histamine H 4 receptor ligands can be found in WO 02/07548, WO 04/022537 and in Terzioglu et al., J. Bioorg. Med. Chem. Lett. 14 (2004), 5251-5256.
• H 4 ligands are known there is still a need to further provide new H 4 ligands that are good drug candidates.
• preferred compounds should bind potently to the histamine H 4 receptor whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects.
• the present invention thus relates to octahydropyrrolo[3,4-c]pyrrole derivatives of formula (I): or pharmaceutically acceptable salts and solvates thereof, wherein:
• R 1 is H or (C 1 -C 4 ) alkyl optionally substituted with a hydroxy
• X is N or C-R 9 wherein R 9 is H or methyl
• R 6 is H or methyl
• R 2 , R 3 , R 4 and R 5 are independently selected from H, halo, cyano, (C r C 4 )alkyl, (C 1 -CJaIkOXy, trifluoromethyl, trifluoromethoxy, hydroxy, (CH 2 ) n -C(O)O-R 7 , (CH 2 ) n -O-(CH 2 ) m -R 8 and (CH 2 ) n -R 8 , wherein n and m are both independently 0 or 1 , R 7 is H or (d-CJalkyl and R 8 is phenyl.
• halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro.
• (d-CJalkyl radicals denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents such as a hydroxy substitutent or occur as substituents of other radicals, for example in (C 1 -C 4 )alkoxy radicals
• substituents such as a hydroxy substitutent or occur as substituents of other radicals, for example in (C 1 -C 4 )alkoxy radicals
• suitable (CrC 4 )alkyl radicals are methyl, ethyl, ⁇ -propyl, /so-propyl, n-butyl, /sobutyl, seobutyl and terf-butyl.
• Examples of suitable (d-C 4 )aIkoxy radicals are methoxy, ethoxy, n-propyloxy, /sopropyloxy, n-butyloxy, /so-butyloxy, sec-butyloxy and terf-butyloxy.
• Examples of suitable (CrC 4 )alkyl radicals substituted by a hydroxy radical are hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl etc.
• the compound of formula (I) where Y is O may be prepared by coupling an acid of formula (II)
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are as previously defined.
• the coupling of the acid (II) to the amine (III) is generally carried out in an excess of said amine, with a conventional coupling agent (e.g. 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O- benzotriazo-1 -yl- ⁇ /, ⁇ /,/VW-tetramethyluronium hexafluorophosphate or ⁇ /./V-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g.
• a conventional coupling agent e.g. 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O- benzotriazo-1 -yl- ⁇ /, ⁇ /,/VW-tetramethyluronium hexafluorophosphate or ⁇ /./V-dicyclohexylcarbodiimide
• a catalyst
• a tertiary amine base e.g. /V-methylmorpholine, triethylamine or ⁇ /, ⁇ /-diisopropylethylamine.
• the reaction may be undertaken in a suitable solvent such as pyridine, ⁇ /, ⁇ /-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 1 O 0 C and 40°C (room temperature).
• the coupling is carried out using an excess of the amine (1.2-1.5 equivalents), with O- benzotriazo-i-yl-A/./V./V/V-tetramethyluronium hexafluorophosphate as the coupling agent.
• the reaction is also preferably undertaken using ⁇ /, ⁇ /-dimethylformamide as solvent.
• the amine of formula (III) may be prepared as described in the literature (J. Heterocyclic. Chem 1983, 20, 321).
• R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined.
• the oxidation is generally carried out using a conventional oxidising agent (e.g. potassium permanganate) optionally in the presence of a base (e.g. NaOH) in a suitable solvent (e.g. water) at a temperature comprised between 40 0 C and 100 0 C.
• a suitable solvent e.g. water
• the oxidation is carried out using potassium permanganate in the presence of sodium hydroxide using water as solvent with a reaction temperature of 100 0 C for 1 hour and 30 minutes.
• the alcohol of formula (IV) may be prepared by condensation of an aniline of formula (V) with glycolic acid :
• R , R , R , R and R are as previously defined.
• the condensation is generally carried out in the presence of an acid catalyst (e.g. HCI) in a suitable solvent (e.g. water) at a temperature comprised between 40 0 C and 100 0 C.
• an acid catalyst e.g. HCI
• a suitable solvent e.g. water
• condensation is carried out using 6N aqueous hydrochloric acid as solvent at a temperature of 100 0 C with a reaction time of 16 hours.
• aniline of formula (V) is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. nitration, reduction, alkylation, chlorination) from commercially available material as detailed in the experimental section.
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined.
• the coupling is generally carried out with an excess of the amine (III), optionally in the presence of a base (e.g. triethylamine, N,N-diethylisopropylamine, potassium carbonate) in a suitable aqueous solvent or mixture of solvents (e.g. acetonitrile, tetrahydrofuran, water) at a temperature comprised between 10 0 C and 40°C (room temperature).
• a base e.g. triethylamine, N,N-diethylisopropylamine, potassium carbonate
• solvents e.g. acetonitrile, tetrahydrofuran, water
• the compound of formula (Vl) may be prepared by condensation of an aniline of formula (V):
• R is methyl or ethyl and R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined.
• the coupling is generally carried out with an excess of the acetimidate in a suitable solvent (e.g. AcOH) at a temperature comprised between 10 0 C and 40 0 C (room temperature).
• a suitable solvent e.g. AcOH
• aniline of formula (V) is prepared as described previously and the trichloroacetimidate of formula (VII) is commercially available.
• the compound of formula (I) where Y is NH and X is N may be prepared by condensing a trichloromethylbenzimidazole of formula (Vl):
• the condensation is generally carried out with equimolar amounts of the amine (III) and the source of ammonia (e.g. ammonia in dioxan, ammonium acetate), optionally in the presence of a base (e.g. triethylamine, N,N-diisopropylethylamine, potassium carbonate) in a suitable solvent (e.g. acetonitrile, tetrahydrofuran) at a temperature comprised between 10°C and 40°C (room temperature).
• a base e.g. triethylamine, N,N-diisopropylethylamine, potassium carbonate
• a suitable solvent e.g. acetonitrile, tetrahydrofuran
• the amine of formula (III) is allowed to react with the trichloromethylbenzimidazole (Vl) for a period of 0.5 to 2 hours prior to the addition of the ammonia equivalent.
• the compound of formula (I) where X is N and Y is NH may be prepared by reaction of an amine of formula (III) with a nitrile of formula (VIII):
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined.
• the reaction is generally carried out with an excess of the amine (III) in a suitable solvent (isopropanol, methanol, tetrahydrofuran) and a temperature comprised between 60°C and 85°C (reflux temperature of solvent).
• a suitable solvent isopropanol, methanol, tetrahydrofuran
• a temperature comprised between 60°C and 85°C (reflux temperature of solvent).
• the reaction is carried out with 1.2 equivalents of the amine in isopropanol at reflux for a period of 3 hours.
• the nitrile of formula (VIII) may be prepared by reacting the trichloromethylbenzimidazole of formula (Vl) with aqueous ammonia followed by treatment with aqueous acid.
• the reaction is generally carried out with an excess of aqueous ammonia in a suitable solvent (e.g. ethanol, tetrahydrofuran) at a temperature comprised between -7°C and 0 c C for a period of 0.5-2 hours.
• aqueous hydrochloric acid at a temperature comprised between 0 0 C and 5°C.
• the reaction is carried out using tetrahydrofuran as solvent.
• the compound of formula (I) where X is CR 9 and Y is NH may be prepared by condensation of a thioamide of formula (IX) :
• R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as previously defined.
• the condensation is generally carried out in the presence of an activating agent (e.g. methyl iodide, mercuric acetate) with an excess of ammonia in a suitable solvent (acetonitrile, tetrahydrofuran) at a temperature between -78 0 C and 50°.
• an activating agent e.g. methyl iodide, mercuric acetate
• ammonia e.g. methyl iodide, mercuric acetate
• acetonitrile, tetrahydrofuran acetonitrile, tetrahydrofuran
• the thioamide of formula (IX) may be prepared from an amide of formula (I) where X is CR 9 and Y is O.
• the conversion is generally carried out using an excess of Lawesson's reagent (2,4-bis(4- methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4-disulfide) in suitable solvent (toluene, tetrahydrofuran) at a temperature comprised between 50°C and 110°C
• any compatible protecting radical can be used.
• methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
• the preferred compounds are those of formula (I) wherein: R 1 is H or methyl, preferably methyl; and/or
• - R 6 is H
• - X is N or CH; and/or - R 2 , R 3 , R 4 and R 5 are independently selected from H, halo, methyl, hydroxy, phenyl, and COOH, preferably from H, fluoro, chloro, bromo, methyl, hydroxy, phenyl, and COOH and more preferably from H, fluoro, chloro, bromo, hydroxy and methyl.
• the compounds of formula (I) wherein R 1 is H or methyl and R 2 , R 3 , R 4 and R 5 are independently selected from H, halo, methyl, hydroxy, phenyl, and COOH are preferred.
• the compounds of formula (I) wherein R 1 is methyl, R 6 is H, X is N or CH a anndd R R 22 ,, R R 33 ,, R R 44 a and R 5 are independently selected from H, fluoro, chloro, bromo, hydroxy and methyl are more preferred.
• the compounds of formula (I) wherein Y is NH, R 1 is methyl, R 6 is H, X is N or CH and R 2 , R 3 , R 4 and R 5 are independently selected from H, fluoro, chloro, bromo, hydroxy and methyl are most preferred.
• the compounds of formula (I) as here above described have the cis configuration, i.e. the (3af?,6aS) configuration as follows:
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined above.
• More preferred compounds are those selected from the examples 1 to 68 and 6-bromo-4-methyl-2- ⁇ [(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]carbonyl ⁇ -1 H-benzimidazole and 6-fluoro-4- methyl-2- ⁇ [(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]carbonyl ⁇ -1 H-benzimidazole.
• Most preferred compounds are those selected from the compounds of examples 1 , 3, 7, 15, 16, 17, 21 , 22, 25, 26, 27, 41, 48, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 and 68.
• Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
• Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluor
• Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• compositions of formula (I) may be prepared by one or more of three methods:
• the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
• the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
• the compounds of the invention may exist in both unsolvated and solvated forms.
• '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.
• complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
• complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
• the resulting complexes may be ionised, partially ionised, or non-ionised.
• references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
• the compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (I).
• 'pro-drugs' of the compounds of formula (I) are also within the scope of the invention.
• certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
• Such derivatives are referred to as 'prodrugs'.
• Further information on the use of prodrugs may be found in Pro ⁇ drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
• Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
• prodrugs in accordance with the invention include:
• metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug are also included within the scope of the invention.
• Some examples of metabolites in accordance with the invention include:
• Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
• the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
• a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
• the resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
• Chiral compounds of the invention may be obtained in enantiomerically- enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
• chromatography typically HPLC
• a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
• Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
• the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
• isotopically labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Isotopically labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed.
• solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMS0.
• the compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
• excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
• excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
• compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).
• the compounds of the invention may be administered orally.
• Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
• Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
• Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
• the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ⁇ [Q), 981 -986, by Liang and Chen (2001).
• the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
• tablets generally contain a disintegrant.
• disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
• the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
• Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
• lactose monohydrate, spray-dried monohydrate, anhydrous and the like
• mannitol xylitol
• dextrose sucrose
• sorbitol microcrystalline cellulose
• starch dibasic calcium phosphate dihydrate
• Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
• surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
• Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
• Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
• ingredients include anti-oxidants, colorants, flavouring agents, preservatives and taste- masking agents.
• Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
• Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
• the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
• Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent.
• Some components of the formulation may perform more than one function.
• the compound of formula (I) may be water-soluble or insoluble.
• a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
• the compound of formula (I) may be in the form of multiparticulate beads.
• the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
• Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
• Solid formulations for oral administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1 -14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
• the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
• Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
• Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
• Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
• excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
• a suitable vehicle such as sterile, pyrogen-free water.
• parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
• solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.
• Formulations for parenteral administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
• examples of such formulations include drug-coated stents and poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
• the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
• Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
• Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
• topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
• Formulations for topical administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
• the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
• the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• Capsules made, for example, from gelatin or hydroxypropyl-methylcellulose
• blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
• the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
• Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
• a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
• a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
• Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
• Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
• Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the dosage unit is determined by means of a valve, which delivers a metered amount.
• Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 1 ⁇ g to 4000 ⁇ g of the compound of formula (I).
• the overall daily dose will typically be in the range 1 ⁇ g to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
• the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
• Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
• Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
• Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
• a polymer such as crossed-Iinked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
• a preservative such as benzalkonium chloride.
• Such formulations may also be delivered by iontophoresis.
• Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
• the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
• soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
• Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
• the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma- cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
• compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
• the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
• a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
• the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
• the kit typically comprises directions for administration and may be provided with a so-called memory aid.
• the total daily dose of the compounds of the invention is typically in the 0.001 mg to 2000 mg depending, of course, on the mode of administration.
• oral administration may require a total daily dose of from 0.1 mg to 2000 mg, while an intravenous dose may only require from 0.01 mg to 100 mg.
• the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
• These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
• references herein to "treatment” include references to curative, palliative and prophylactic treatment.
• the compounds of the formula (I) or pharmaceutically acceptable salts, derived forms or compositions thereof can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result.
• the second and more additional therapeutic agents may also be a compound of the formula (I) or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more histamine H 4 receptor ligands known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
• co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to the compounds of formula (I) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following: • simultaneous administration of such combination of compound(s) of formula (I) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,
• Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (I), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to :
• Histamine H 1 receptor antagonists in particular loratidine, desloratidine, fexofenadine and cetirizine
• Histamine H 2 receptor antagonists • Histamine H 2 receptor antagonists • Leukotriene antagonists, including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , in particular Montelukast
• Phosphodiesterase inhibitors namely PDE4 inhibitors and PDE5 inhibitors
• neurotransmitter re-uptake inhibitors in particular fluoxetine, setraline, paroxetine, ziprasidone
• 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists • OC 1 - and ⁇ 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, • Muscarinic M3 receptor antagonists or anticholinergic agents,
• Anti-tumor necrosis factor (anti-TNF- ⁇ ) agents Anti-TNF- ⁇
• Adhesion molecule inhibitors including VLA-4 antagonists, • Kinin-B-i - and B 2 -receptor antagonists,
• MMPs matrix metalloproteases
• cytokine signaling pathways such as p38 MAP kinase inhibitors, syk tyrosine kinase inhibitors or JAK kinase inhibitors
• Prostaglandin D2 receptor antagonists DP1 and CRTH2
• Histamine H 1 receptor antagonists in particular loratidine, desloratidine, fexofenadine and cetirizine, • Histamine H 3 receptor antagonists,
• Leukotriene antagonists including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , in particular Montelukast, and
• H 4 ligands are meant to include H 4 receptor antagonists, agonists and inverse agonists.
• H 4 antagonists are believed to be most suitable.
• a further aspect of the present invention relates to the compounds of formula (I) or pharmaceutically acceptable salts, derived forms or compositions thereof, for use as medicaments, more particularly in the treatment of diseases, disorders, and conditions in which the H 4 receptor is involved. More specifically, the present invention also concerns the compounds of formula (I), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of: • inflammatory diseases;
• respiratory diseases e.g. adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis
• allergy allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion;
• cardiac dysfunctions such as myocardial ischaemia and arrythmia
• the compounds of formula (I) according to the present invention are particularly suitable for the treatment of asthma, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion and allergic congestion.
• a still further aspect of the present invention also relates to the use of the compounds of formula (I), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug being a H 4 ligand.
• the present inventions concerns the use of the compounds of formula (I), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of H 4 mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
• the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a H 4 mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising administering to said mammal an effective amount of a compound of formula (I), its pharmaceutically acceptable salts and/or derived forms.
• Preparation 28 3-Fluoro-5-methylbenzene-1 ,2-diamine
• a solution of the nitroaniline from preparation 27 (124mg, 0.72mmol) in ethanol (5ml) was treated with 10%Pd/C and hydrogenated at 50psi for 4 hours at room temperature.
• the reactions mixture was filtered and the solvent removed in vacuo to give a colourless solid (79mg).
• reaction mixture was purified directly by SCX resin, eluting non-basic compounds with methanol and the basic compounds with 1 N ammonia in methanol.
• the basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 880 ammonia (99:1 :0.1 changing to 90:10:1 , by volume) to give the title compound as a pale yellow solid (499mg).
• the reaction mixture was diluted with ethyl acetate (20ml) and water (20ml) and the organic phase separated, dried (sodium sulphate) and the solvent reduced in vacuo.
• the residue was treated with a 1 M solution of HCI in methanol (15ml) and left to stir at room temperature for 16 hours.
• the solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 880 ammonia (99:1 :0.1 changing to 90:10:1 , by volume) to give the title compound as a colourless solid (50mg).
• the reaction mixture was diluted with ethyl acetate (20ml) and water (20ml) and the organic phase separated, dried (sodium sulphate) and the solvent reduced in vacuo.
• the residue was treated with a 1 M solution of HCI in methanol (15ml) and left to stir at room temperature for 16 hours.
• the solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 880 ammonia (99:1:0.1 changing to 90:10:1 , by volume) to give the title compound as a pale yellow solid (42mg).
• Example 11 6-IVlethyl-2-fr(3a/7,6aS)-5-methylhexahvdropyrrolor3,4-cipyrrol-2(1 / ⁇ fl-ylicarbonyll-i H- indole
• Example 12 4-Methoxy-2-fr(3a/?,6aS)-5-methylhexahvdropyrrolor3,4-cipyrrol-2(1 /fl-ylicarbonyl ⁇ - 1 H-indole
• Example 14 5-Methoxy-2- ⁇ r(3afl,6aS)-5-methylhexahvdropyrrolor3,4-cipyrrol-2(1 /fl-ylicarbonyl)- 1 H-indole
• Example 18 S ⁇ -Dimethyl- ⁇ -f r(3afl,6aS)-5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 HWUcarbonyll- 1H-indole
• Example 22 7-Fluoro-2-f r(3af?,6aS)-5-methylhexahvdropyrrolor3,4-c
• Example 25 ej-Difluoro- ⁇ -frOaflJa ⁇ -S-metriylhexahvdropyrrolorS ⁇ -cipyrrol- ⁇ dffl-vncarbonyl)- 1 H-benzimidazole
• Example 27 S.e-Difluoro- ⁇ -frOaB.eaSi-S-methylhexahvdropyrrolorS ⁇ -clpyrrol- ⁇ d /fl-v ⁇ carbonvIV 1 H-benzimidazole
• Example 30 y-Chloro-S-methyl- ⁇ -fflSaReaS ⁇ -S-methylhexahvdropyrrolore ⁇ -ciPyrrol- ⁇ H)- v ⁇ carbonyl)-1 H-benzi imidazole
• Example 32 Methyl a-irOaR ⁇ a ⁇ -S-methylhexahvdropyrrolors ⁇ -clpyrrol- ⁇ d/fl-yllcarbonyll-I H- benzimidazole-5-carboxylate
• Example 34 S.S-Dimethyl-Z-irOaR ⁇ a ⁇ -S-methylhexahvdropyrrolorS ⁇ -cipyrrol- ⁇ d Afl-vncarbonyl)- 1 H-benzimidazole
• Example 36 a-irOaReaSVS-methylhexahvdropyrrolorS ⁇ -cipyrrol- ⁇ d ffl-vncarbonvD-S-
• Example 38 4-chloro-6-fluoro-2-fr(3aR6aS)-5-methylhexahvdropyrrolo r3,4-clpyrrol-2(1 H)- yllcarbonyll-1 /-f-benzimidazole
• Example 48 5-Chloro-4-methyl-2- ⁇ r(3a/7.6aS)-5-methylhexahydro pyrrolor3,4-clpyrrol-2(1 H)- vHcarbonyl)-1 H-benzimidazole
• Example 49 4-Fluoro-2-fr(3a/?.6aS)-5-methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)-vncarbonyl)-1 H- benzimidazole
• Example 51 4,5,6,7-Tetrafluoro-2-fr(3a/?,6aS)-5-methylhexahydro pyrrolor3.4-clpyrrol-2(1H)- ylicarbonylVI H-benzimidazole
• Example 52 6-Fluoro-2-(rf3a/?,6aS)-5-methylhexahvdropyrrolor3,4-c1 pyrrol-2f1 /fl-yllcarbonyl)-4- (trifluoromethyl)-I W-benzimidazole
• Example 54 6-Chloro-4-fluoro-2- ⁇ r(3af?,6aS)-5-methylhexahvdro pyrrolor3,4-clpyrrol-2(1 H)- yllcarbonyl)-1 H-benzimidazole
• Example 58 4,5,6-Trifluoro-2-fr(3afl,6aS)-5-methylhexahvdropyrrolo r3,4-c
• Example 59 1 -(5.6-Dif luoro-1 H-benzimidazol-2-v0-1-r(3afl,6aS)-5-methylhexahvdropyrrolor3,4- cipyrrol-2(1 Aft-ylimethanimine
• Example 59 1-(5,6-Difluoro-1H-benzimidazol-2-yl)-1-r(3af?,6aS)-5- methylhexahvdropyrrolor3,4-clpyrrol-2(1 H)-vnmethanimine
• Example 60 1-(5-Fluoro-1 Afbenzimidazol-2-yl)-1-r(3afl,6aS)-5-methylhexahvdropyrrolor3,4- clpyrrol-2(1 /fl-ylimethanimine
• 6-bromo-4-methyl-2- ⁇ [(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl]carbonyl ⁇ -1 H- benzimidazole and 6-fluoro-4-methyl-2- ⁇ [(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)- yl]carbonyl ⁇ -1 H-benzimidazole have also been prepared using identical or similar methods.
• Examples 61-64 were prepared from the trichloromethylbenzimidazole precursors indicated in the table below according to the following procedure : A solution of the trichloromethylbenzimidazole (0.75mmol) in ethanol (3ml) was cooled to 0°C and treated with a solution of 880 ammonia (3ml) in water (3ml). The resulting mixture was then allowed to warm gradually to room temperature. After 2 hours the pH was adjusted to pH1 by addition of 2N hydrochloric acid. The reaction mixture was extracted with dichloromethane (2 x 20ml) and the combined extracts reduced in vacuo.
• the resulting solid was dissolved in methanol (3ml) and treated with N-acetyl cysteine (1mmol) and (3afl,6aS)-2- methyloctahydropyrrolo[3,4-c]pyrrole (O. ⁇ mmol) and heated to 40 0 C for 2.5 hours.
• the reaction was cooled to room temperature and purified on a strong cation exchange resin, eluting non-basic impurities with methanol, and basic products with 2M ammonia in methanol.
• Examples 65-68 were prepared from the bis-aniline precursors indicated in the table below according to the following procedure : A solution of the aniline precursor (79mg, 0.50mmol) in acetic acid (3ml) was treated with methyl-2,2,2-trichloroacetimidate (0.55mmol) and the resulting solution was left to stir at room temperature for 16 hours. Water (10ml) was added and the reaction stirred for a further hour. The trichloromethylbenzimidazole intermediate was filtered off and dried in vacuo, prior to processing as described for examples 61-64 to give the desired compounds.
• Cell pellets from CHO cells expressing the histamine H 4 receptor were homogenised in ice-cold 5OmM Tris-HCI/0.5mM CaCI 2 buffer containing a protease inhibitor cocktail (Roche®, United Kingdom) using a ground glass homogeniser. Homogenates were centrifuged at 4800Og for 30min at 4°C. The membrane pellet was resuspended in fresh buffer and the centrifugation step was repeated as described above. The membrane pellet was resuspended in 5OmM Tris-HCI in the same volume as the original cell pellet. Aliquots of membrane preparations were stored at -80°C and were used for [ 3 H]-Histamine binding experiments.
• the compounds of the Examples have been tested in the H 4 binding assay described above and were found to have a K 1 value of less than 13 ⁇ M in the H 4 cell based binding assay.
• Preferred examples have a K 1 value of less than 1 ⁇ M in the H 4 binding assay.
• Most preferred examples have a K 1 value of less than 120 nM in the H 4 cell based binding assay as indicated in the table below:

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• 2005
  • 2005-11-10 JP JP2007542155A patent/JP2008520644A/ja active Pending
  • 2005-11-10 CA CA002587141A patent/CA2587141A1/en not_active Abandoned
  • 2005-11-10 EP EP05824102A patent/EP1846409A1/en not_active Withdrawn
  • 2005-11-10 WO PCT/IB2005/003478 patent/WO2006056848A1/en active Application Filing
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