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WO1996033997A1 - Derives de benzimidazole qui sont des antagonistes doubles de l'histamine (h1) et du facteur d'activation des plaquettes (paf) - Google Patents

Derives de benzimidazole qui sont des antagonistes doubles de l'histamine (h1) et du facteur d'activation des plaquettes (paf) Download PDF

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Publication number
WO1996033997A1
WO1996033997A1 PCT/GB1996/000680 GB9600680W WO9633997A1 WO 1996033997 A1 WO1996033997 A1 WO 1996033997A1 GB 9600680 W GB9600680 W GB 9600680W WO 9633997 A1 WO9633997 A1 WO 9633997A1
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Prior art keywords
pyridin
compound
alkyl
methyl
formula
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PCT/GB1996/000680
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English (en)
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Fionna Mitchell Martin
Christopher David Floyd
Zoe Marie Spavold
Andrew Paul Ayscough
Mark Whittaker
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British Biotech Pharmaceuticals Limited
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Publication of WO1996033997A1 publication Critical patent/WO1996033997A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to compounds which are dual histamine (H 1 ) and platelet activating factor (PAF) antagonists, to therapeutic compositions containing such compounds, and to methods for their preparation.
  • H 1 histamine
  • PAF platelet activating factor
  • Potent H 1 antagonists of various structural types are known, and are useful in treating the symptoms of inflammatory conditions such as allergic rhinitis, and allergic conditions of the skin, which are mediated at least in part by the release of histamine.
  • histamine release plays a causative role
  • PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a wide variety of physiological responses, including hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), and accumulation of inflammatory cells in the lower airways.
  • agents which have dual hh and PAF antagonistic activity for the improved treatment of conditions mediated by histamine and PAF release.
  • Such conditions include allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis.
  • EP-A-515158 (Schering), EP-A-463873 (Sankyo), EP-A-549364 (Sankyo), WP-A-577957 (Uriach) and Japanese patent application published under no 4-226993 (Yoshitomi) all disclose compounds which possess both histamine (H 1 ) and PAF antagonist activity
  • One possible strategy for the design of compounds having both Hi and PAF antagonist activity might be to couple a H 1 antagonist molecule to a PAF antagonist molecule via a flexible linker chain, with little or no structural modification of the parent H 1 and PAF antagonist molecules, such that the "Hi fragment" of the combined molecule may bind to the H 1 receptor without distortion or interference from the "PAF fragment", and and vice versa.
  • Disadvantages of such a strategy include the inevitable high molecular weight of the combined molecule and probable resultant poor oral bioavailability, and the difficulty of designing a linker chain which is capable of permitting the specific receptor interactions at each end of the combined molecule without substantial mutual interference
  • the present invention makes available a class of compounds in which the structure as a whole provides a desirable balance of H 1 and PAF antagonist activity.
  • the invention thus includes compounds having reduced molecular weight and hence bioavailability, compared with compounds consisting of separate PAF and Hi antagonist molecules joined through a flexible linking chain.
  • R represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halogen or C 1 - C 6 alkoxy;
  • R 2 represents hydrogen, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 1 - C 6 alkoxy, C 1 - C 6
  • alkylsulphanyl cyclopropyl, C 1 -C 6 hydroxyalkyl, N(C 1 -C 6 alkyl) 2 , C 1 -C 6 N(C 1 - C 6 alkyl) 2 and -CF 3 ;
  • R 3 represents hydrogen, C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -CO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkoxy, C 1 -C 6 alkylsulphanyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, (C 1 -C 6 alkylsulphanyl)C 1 -C 6 alkyl, (phenyl)C 1 -C 6 alkyl, orphenylsulphanyl;
  • R 4 and R 5 independently represent hydrogen or C 1 -C 6 alkyl; or R 4 and R5 taken together with the carbon atom to which they are attached form a 3-8 membered carbocyclic or heterocyclic ring;
  • X represents -O-, -S- or -N(R9)- where R 9 represents hydrogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 3 -C 8 cycloalkyl optionally substituted in the cycloalkyl ring with one or more C 1 -C 6 alkyl groups, HOOC-(C 1 -C 6 alkyl) and ester and amide derivatives thereof, hydroxy(C 1 -C 6 alkyl) or C 1 -C 6 alkyloxy(C 1 -C 6 alkyl);
  • Y represents a carbonyl or sulphonyl group
  • Z represents bivalent C 1 - C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group, or a single bond;
  • R 6 represents hydrogen, halogen, hydroxy, cyano, C 1 -C 4 alkyl, trifluoromethyl, or C 1 -C 4 alkyloxy;
  • R 7 and R 8 independently represent hydrogen or C 1 -C 4 alkyl, or R 7 and R 8 taken together with the nitrogen atom to which they are attached form a heterocyclic ring containing 4-7 ring atoms, which ring may contain one or more heteroatoms other than the nitrogen to which R7 and R8 are attached; and n and m independently represent 0 or 1 ; or a pharmaceutically or veterinarily acceptable acid addition salt or hydrate thereof.
  • halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
  • C 1 -C 6 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • C 2 -C 6 alkenyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1 -propenyl, 1 - and 2-butenyl and 2-methyl-2- propenyl.
  • C 2 -C 6 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1 -propynyl, 1 - and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
  • C 1 -C 6 alkoxy refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
  • C 1 -C 6 alkylsulphanyl refers to straight chain or branched chain alkylsulphanyl groups having from one to six carbon atoms. Illustrative of such alkyl groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio.
  • C 3 -C 8 cycloalkyl refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • pharmaceutically or veterinarily acceptable acid addition salt refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human or animal consumption.
  • Examples of pharmaceutically and/or veterinarily acceptable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and tartrate salts.
  • Preferred compounds of formula (II) include those in which, independently or in any compatible combination:
  • A N- ;
  • R represents hydrogen
  • R 2 represents methyl;
  • R 3 representshydrogen;
  • R 4 and R 5 independently represent hydrogenor C 1 -C 6 alkyl, and in particular both R 4 and R 5 may represent hydrogen or R 4 may represent hydrogen and R 5 may represent methyl;
  • X represents-O-or-N (R 9 )-, where R 9 represents hydrogen, C 1 -C 6 alkyl,C 3 - C 8 cycloalkyl or C 3 -C 8 cycloalkyl optionally sustituted in the cycloalkyl ring with one or more C 1 -C 6 alkyl groups, and in particular R 9 may represent hydrogen, methyl or cyclohexyl;
  • Y represents carbonyl;
  • Z represents C 1 -C 6 alkyl or C 2 -C 6 alkenyl, in particular ethyl or E-ethenyl;
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, Z, m, n, A, B and D are as defined in formula (I).
  • the esterification may be facilitated by using a carbodiimide condensing agent, such as (N)-3-dimethylaminopropyl-N'-ethyl-carbodiimide.
  • a carbodiimide condensing agent such as (N)-3-dimethylaminopropyl-N'-ethyl-carbodiimide.
  • an activated derivative of the acid (II) may be employed for the esterification, such as the acid chloride or pentafluorophenyl ester. Dimethylaminopyridine added to the reaction mixture may facilitate the esterification reaction.
  • R, R 2 , R 3 , R 4 , R 5 , R 9 , Z, m, n, A are as defined in formula I.
  • the amidation may be facilitated by using a carbodiimide condensing agent or an activated derivative of the acid (II) as for the esterification.
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , W, X, Y, m, n, A, B and D are as defined in formula (I) and K represents a halide (preferably bromide).
  • the reaction is typically performed in the presence of palladium acetate and a triaryl phosphine such as triphenyl phosphine.
  • the reaction may be performed at room temperature or may require heating at up to 200°C in a sealed vessel.
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , W, X, Y, Z, m, n, and A are as defined in formula I.
  • This reaction may be performed in the presence of a suitable base (eg. N-butyl lithium) in an appropriate solvent (eg. toluene)
  • a suitable base eg. N-butyl lithium
  • an appropriate solvent eg. toluene
  • Compounds of formula (I) may also be prepared by a process comprising reaction of a diamino compound of formula (IX), with an acid of formula (X) or an activated derivative thereof.
  • the starting carboxylic acids of formula (II) for routes 1 and 2 may be prepared by routes previously described in the literature eg EP-085959-A2 (Wellcome).
  • Corresponding sulphonic acids which may be used to prepare compounds of formula (I) where Y represents a sulphonyl group, may be prepared using similar chemistry.
  • the sulphonic acid group may be introduced using the Wittig reaction (C. Gennari, B. Salom, D. Potenza, A. Williams; Angew Chem. Int. Ed. Engl., 33 (20), 2067-2069, 1994).
  • the sulphonic acids may be converted to sulphonyl chlorides, for example by treatment with triphenylphosphine and sulphuryl chloride and then coupled to amines of formula (IV).
  • R, R 2 , R 3 , m, and A are as defined in formula (I) and R 10 represents C 1 -C 6 alkyl or benzyl,
  • Compounds of formula (XI) may be prepared using methods described in the literature eg WO-A-93/16075 (British Biotechnology), WO-A-90/1 1280 (Pfizer), WO- A-92/14734 (Pfizer).
  • alcohols of formula (III) may be oxidized with for example manganese dioxide to provide aldehydes or ketones of formula (XII)
  • Aldehydes and ketones of formula (XII) may be reduced or treated with alkyl lithium and grignard reagents as above to provide a range of alcohols of formula (III).
  • compounds of formula (XII) may be subjected to a reductive amination reaction with an amine of formula R 9 NH 2 either in the presence of a reducing agent such as sodium cyanoborohydride or using a palladium catalyst under an atmosphere of hydrogen gas to provide compounds of formula (IV).
  • a reducing agent such as sodium cyanoborohydride or using a palladium catalyst under an atmosphere of hydrogen gas to provide compounds of formula (IV).
  • R 4 and R 5 are equivalent (but not hydrogen) they may be prepared by the reaction of esters of formula (XI) with alkyl lithium or alkyl grignard reagents.
  • R 4 , R 5 and R 9 are hydrogen these compounds may be prepared by reaction of the mesylate of the alcohol (III) with sodium azide followed by reduction either by hydrogenation over a palladium catalyst or in the presence of triphenylphosphine.
  • the invention makes available a class of compounds having a desirable balance of H 1 and PAF antagonist activity.
  • this invention concerns:
  • a method of management by which is meant treatment or prophylaxis of diseases or conditions mediated by histamine and/or PAF in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (I) above, or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical or veterinary formulation comprising a compound of general formula (I) and a pharmaceutically and/or veterinarily acceptable carrier.
  • One or more compounds of general formula (I) may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • compositions containing compounds of general formula (I) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occuring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or
  • condensation products of ethylene oxide with long chain aliphatic alcohols for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as
  • polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium
  • any bland fixed oil may be employed including synthetic mono-or diglyce ⁇ des.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the invention may also be administered in the form of
  • compositions for rectal administration of the drug
  • suppositories for rectal administration of the drug
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • 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 Pharmacopoeia.
  • compounds of the invention may be made up into a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle.
  • Additives for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hypromellose may also be included.
  • Compounds of the invention may be administered parenterally in a sterile medium.
  • the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Compounds of the invention may be used for the treatment of the respiratory tract by nasal or buccal administration of, for example, aerosols or sprays which can disperse the pharmacologic al 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.
  • Dosage levels of the order olfrom about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 1.0 mg to about 3.5 g per patient per day).
  • the dosage employed for the topical administration will, of course, depend on the size of the area being treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the drug.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • Finely ground, degassed, ammonium chloride (1.48g, 27.6mM) was added followed by a solution of methyl-(E)-3-(6-[3-pyrrolidin-1 -yl- ⁇ 4-tolyl ⁇ -prop-1 E- enyl]-pyridin-2-yl)-acrylate (1.00g, 2.76mmol) in ethanol (10mL).
  • the reaction was allowed to stir at room temperature for 18 hours under an inert atmosphere and then for a further 2 hours open to the atmosphere.
  • the reaction mixture was filtered through a pad of kieselguhr and the titrate concentrated under reduced pressure.
  • reaction mixture was partitioned between DCM and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and concentrated to a brown gum. The product was purified by column chromatography on silica gel eluting with 20 %
  • Manganese (IV) dioxide (6.3g, 72mmol) was added to a solution of 4-(1 H-2-methyl- imidazo[4,5-c]pyridin-1 -ylmethyl)-benzyl alcohol (Example 1 , step a, 1.90g, 7.51 mmol) in DCM (30mL). The reaction was stirred at room temperature for 24 hours. The reaction mixture was filtered through kieselguhr and concentrated to a colourless oil. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM.
  • Palladium catalyst (150mg, 10% on charcoal) was added to a solution of 4-(1 H-2- methyl-imidazo[4,5-c]pyridin-1 -ylmethyl)-benzaldehyde (1.50g, 5.98mmol) in ethanol (20mL) under an inert atmosphere. A solution of methylamine in ethanol (1 mL, excess of a 33% solution) was added and the reaction stirred under an atmosphere of hydrogen gas for 18 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to leave a colourless oil.
  • the reaction mixture was poured into water (100mL) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine before drying over magnesium sulphate, titration and removal of solvent to yield a pink oil.
  • the product was purified by column chromatography on silica gel eluting with 25% methanol/DCM.
  • mice Female Dunkin-Hartley guinea pigs (350-400g) were anaesthetised by intrapentoneal injection of 60mg.kg -1 sodium pentobarbitone (Sagatal, May & Baker UK). Through a midline incision of the neck, the trachea was cannulated and connected to a small animal respirator (Harvard, UK). Animals were artificially ventilated at a rate of 30 breaths per minute with a tidal volume of 8-10ml to give a resting tracheal inflation pressure of 15mmHg as measured by a physiological pressure transducer (type P23XL, Spectramed USA) connected to a side arm of the respiratory circuit.
  • a physiological pressure transducer type P23XL, Spectramed USA
  • the left jugular vein was cannulated for the administration of propranolol and for the infusion of histamine.
  • a carotid artery was cannulated for the measurement of arterial blood pressure via a physiological pressure transducer (type P23XL, Spectramed USA). Blood pressure and tracheal inflation pressure were recorded on a thermal array chart recorder (type TA4000, Gould Electronics UK).
  • propranolol (1 mg.kg -1 i v. & 3mg.kg -1 s.c. Sigma Chemical Co. UK) was administered to inhibit any resulting catecholamme release following histamine administration.
  • Histamine infusion (10 ⁇ g.kg -1 .min -1 at a rate of 10ml.hr -1 using a perfusion pump type Perfuser securer FT, B. Braun Germany) was started at the one hour time point following oral administration of the test compound or vehicle. Changes in tracheal inflation pressure and blood pressure of drug treated animals were compared with changes from vehicle treated animals and ED 50 values determined.
  • One dose of test compound was investigated per animal.
  • trachea 60mg.kg -1 sodium pentobarbitone (Sagatal, May & Baker UK).
  • the trachea was cannulated with a length (3cm) of nylon tubing which was connected to a small animal respirator (Harvard, UK). Animals were artificially ventilated at a rate of 30 breaths per minute with a tidal volume of 8-10ml to give a resting tracheal inflation pressure of 15mmHg as measured by a physiological pressure transducer (type P23XL, Spectramed USA) connected to a side arm of the respiratory circuit.
  • a physiological pressure transducer type P23XL, Spectramed USA
  • a jugular vein was cannulated with an intraveinous catheter (type 3F with blue luer fitting, Portex UK) for the administration of a bolus dose of propranolol and for the later administration of bolus PAF.
  • a carotid artery was exposed and cannulated with an intraveinous catheter (type 3F with pink luer fitting, Portex UK) for the measurement of arterial blood pressure via a physiological pressure transducer (type P23XL, Spectramed USA).
  • a physiological pressure transducer type P23XL, Spectramed USA.
  • the catheter was filled with saline containing heparin (lithium heparin, 50U.ml -1 v/v). Blood pressure and tracheal inflation pressure were recorded on a thermal array chart recorder (type TA4000, Gould Electronics UK).
  • PAF 100ng.kg -1 i.v. bolus
  • PAF 100ng.kg -1 i.v. bolus

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Abstract

Composés de formule (I) dans laquelle les substituants et groupes variables sont tels que définis dans la demande, qui sont des antagonistes doubles de l'histamine (H1) et du facteur d'activation des plaquettes (PAF).
PCT/GB1996/000680 1995-04-28 1996-03-22 Derives de benzimidazole qui sont des antagonistes doubles de l'histamine (h1) et du facteur d'activation des plaquettes (paf) WO1996033997A1 (fr)

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GBGB9508748.2A GB9508748D0 (en) 1995-04-28 1995-04-28 Benzimidazole derivatives

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1000935A1 (fr) * 1997-07-25 2000-05-17 TSUMURA & CO. Derives de pyridylacrylamide, remedes contre la nephrite et inhibiteurs de tgf-beta contenant lesdits elements
JP2005533809A (ja) * 2002-06-19 2005-11-10 シェーリング　コーポレイション カンナビノイドレセプタアゴニスト
US7504393B2 (en) 2001-01-26 2009-03-17 Btg International Limited Benzylamine analogues

Citations (11)

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