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WO1995013064A1 - Derives de l'acide 4-(1h-2-methylimidazo 4,5-c pyridinylmethyle)phenyle sulfonamide carboxylique en tant qu'antagonistes - Google Patents

Derives de l'acide 4-(1h-2-methylimidazo 4,5-c pyridinylmethyle)phenyle sulfonamide carboxylique en tant qu'antagonistes Download PDF

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Publication number
WO1995013064A1
WO1995013064A1 PCT/GB1994/002460 GB9402460W WO9513064A1 WO 1995013064 A1 WO1995013064 A1 WO 1995013064A1 GB 9402460 W GB9402460 W GB 9402460W WO 9513064 A1 WO9513064 A1 WO 9513064A1
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WIPO (PCT)
Prior art keywords
alkyl
methylimidazo
pyridinylmethyl
phenylsulphonyl
methyl
Prior art date
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PCT/GB1994/002460
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English (en)
Inventor
Mark Whittaker
Andrew Miller
Stephen Arthur Bowles
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British Biotech Pharmaceuticals Limited
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Filing date
Publication date
Application filed by British Biotech Pharmaceuticals Limited filed Critical British Biotech Pharmaceuticals Limited
Priority to JP7513680A priority Critical patent/JPH09505040A/ja
Priority to AU81125/94A priority patent/AU8112594A/en
Priority to EP95900227A priority patent/EP0727995A1/fr
Priority to GB9606996A priority patent/GB2298138B/en
Publication of WO1995013064A1 publication Critical patent/WO1995013064A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to the use of certain 4-(1 H-2-Methylimidazo[4,5-c]pyridinylmethyl)
  • PAF platelet activating factor
  • R represents hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, halogen or -OC 1 -C 6 alkyl; each of R 1 and R 2 independently represents hydrogen, - C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, halogen, -CN, -CO 2 H, - CO 2 C 1 -C 6 alkyl, -CONH 2 , -CHO, -CH 2 OH, -CF 3 , -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -SOC 1 -C 6 alkyl, -SO 2 C 1 -C 6 alkyl, -NH 2 , -NHCOMe or -
  • R3 represents hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -OC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -CF 3 , -(C 1 -C 6 alkyl)phenyl, -C 3 -C 8 cycloalkyl, -C 4 -C 8 cycloalkenyl, -(C 1 -C 6 alkyl)C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)C 4 -C 8 cycloalkenyl or thiophenyl;
  • R4 represents hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -CO 2 C 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)phenyl or thiophenyl;
  • R5 represents hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -COC 1 -C 6 alkyl, -CO 2 C 1 -C 6 alkyl, -(COC 1 -C 6 alkyl)phenyl, -(CO 2 C 1 -C 6 alkyl)phenyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)CO 2 C 1 -C 6 alkyl, -C 3 -C 8 cycloalkyl, -C 4 -C 8 cycloalkenyl or a group -D wherein D
  • n is an integer from 0 to 3
  • each of R 8 and R 9 is independently hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, halogen, -CN, -CO 2 H, -CO 2 C 1 -C 6 alkyl, -CONH 2 .
  • R 6 and R 7 independently represents hydrogen, halogen, -C 1 -C 6 alkyl optionally substituted by one or more halogen atoms, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(C 1 -C 6 alkyl)CO 2 C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)
  • compounds of formula (I) wherein B is a group -CONR 11 R 12 where R 11 and R 12 are as defined in formula (I) may be prepared by treatment of a compound of formula (I) wherein B is a -CO 2 R 10 group wherein R 10 is a benzyl group with hydrogen in the presence of a noble metal catalyst (eg 10% palladium on charcoal) to give a carboxylic acid which is then treated with an amine of formula HNR11R12 in the presence of a coupling reagent (eg 1 ,3-dicyclohexylcarbodiimide).
  • a noble metal catalyst eg 10% palladium on charcoal
  • Example 77 of WO 92/03423 discloses the carboxylic acid N-methyl-N-4-(1 H-2- methylimidazo[4,5-c]pyridylmethyl)phenylsulphonyl-L-leucine, used as an
  • WO 92/03423 discloses the use of compounds of formula (I) wherein B is a carboxylic acid group -CO 2 H as intermediates for the synthesis of PAF antagonists of formula (I) wherein B is an esterified or amidated carboxylic acid group.
  • B is a carboxylic acid group -CO 2 H
  • the present invention is based on the discovery that carboxylic acids known from WO 92/03423 to be useful as intermediates for the preparation of PAF antagonists disclosed therein, have PAF antagonist activity in their own right.
  • the invention therefore relates to the use of such carboxylic acids in human and veterinary medicine and to pharmaceutical and veterinary compositions comprising them.
  • the present invention provides a compound of formula (II):
  • R 1 represents hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl,
  • -COC 1 -C 6 alkyl -CO 2 C 1 -C 6 alkyl, -(COC 1 -C 6 alkyl)phenyl, - (CO 2 C 1 -C 6 alkyl)phenyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)CO 2 C 1 -C 6 alkyl, -C 3 -C 8 cycloalkyl, -C 4 -C 8 cycloalkenyl or a group -D wherein D represents a group:
  • n is an integer from 0 to 3
  • each of R 3 and R 4 is independently hydrogen, -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, halogen, -CN, -CO 2 H, -CO 2 C 1 -C 6 alkyl, -CONH 2 , -CONHC 1 -C 6 alkyl, -CONH(C 1 -C 6 alkyl) 2 , -CHO, -CH 2 OH, -CF 3 , -OC 1 -C 6 alkyl, - SC 1 -C 6 alkyl, -SOC 1 -C 6 alkyl, -SO 2 C 1 -C 6 alkyl, -NH 2 or -NHCOMe;
  • R 2 represents hydrogen, halogen, -C 1 -C 6 alkyl optionally substituted by one or more halogen atoms, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -(C 1 -C 6 alkyl)CO 2 C 1 -C 6 alkyl, -(C 1 -C 6 alkyl)SC 1 -C 6 alkyl, -(C 1 -C 6 alkyl)OC 1 -C 6 alkyl, -(C 1 -C 6
  • compound of formula (II) will be used to refer to a compound as defined in the preceeding paragraph, and is to be understood as referring to the pharmaceutically or veterinarily acceptable salts thereof.
  • pharmaceutical is to be understood as including both human and veterinary applications.
  • PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema). It is known that these
  • intravascular alterations or disorders and to regulate the activation or coagulation of platelets, to correct hypotension during shock, the pathogenesis of immune complex deposition and smooth muscle contractions.
  • they have applications in the treatment of inflammatory disorders; such as rheumatoid arthritis, osteoarthritis and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia and any other condition in which PAF is implicated.
  • inflammatory disorders such as rheumatoid arthritis, osteoarthritis and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria,
  • the invention includes the use of a compound of formula (II) in the preparation of a pharmaceutical composition adapted for oral, topical, rectal or parenteral
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • Such compositions will include, as is conventional, pharmaceutically acceptable carriers for the active compound, and may contain other conventional pharmaceutical excipients.
  • compositions in dosage unit form for the management of diseases or conditions mediated by PAF, comprising a compound of formula (II) and one or more pharmaceutically acceptable carriers.
  • Pharmaceutical dosage units are of course known in the art in general, but are primarily characterised in that the active compound is substantially free of impurities, and present in the dosage unit in a predetermined unit dose amount.
  • dosage units include tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups elixirs, phials containing sterile injectable suspensions or solutions of the active ingredient, nebulisers containing solid micronised, or atomisable solutions or suspensions of the active ingredient,
  • Each dosage unit may comprise from about 0.1 mg to about 1g of active ingredient, for example from 10mg to 500 mg, more particularly from 100 to 300mg.
  • each dosage unit will be chosen to deliver to the patient from about 0.1 mg to abou 0.5 mg to about 7 g per patient per day.
  • the administration of from about 1.0 mg to about 3.5 g per patient per day may be appropriate.
  • the dosage employed for 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.
  • Another aspect of the invention is a method for the management of diseases or conditions mediated by PAF, comprising administering to the patient an effective amount of a compound of formula (II) or a pharmaceutically salt thereof.
  • Suitable base addition salts include the sodium, potassium, magnesium, lithium, and calcium salts
  • Suitable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and tartrate salts.
  • 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 4 perfluoroalkyl refers to straight chain or branched chain groups having from one to four carbon atoms and substituted by more than one fluorine atom. This term would include for example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoro-n-propyl, sexafluoro-i-propyl, septafluoro-n-propyl, septafluoro-i-propyl, 4,4,4-trifluoro-n-butyl, nonafluoro-n-butyl, nonafluoro-sec-butyl and nonafluoro-i-butyl.
  • OC 1 -C 6 alkyl 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.
  • SC 1 -C 6 alkyl refers to straight chain or branched chain alkylthio 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.
  • C 4 -C 8 cycloalkenyl refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds.
  • Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • side chain of a naturally occurring amino acid includes the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine, ornithine, pipecolic acid, and thyroxine.
  • Preferred compounds for use according to the invention include those in which, independently or in any compatible combination:
  • R 1 represents a hydrogen atom, a -C 1 -C 6 alkyl (for example methyl, ethyl or propyl) group, a -C 2 -C 6 alkenyl (for example allyl) group or a group -D;
  • R 2 represents a hydrogen atom, a -C 1 -C 6 alkyl (for example ethyl, n-butyl, t- butyl or neopentyl) group, a -C 2 -C 6 alkenyl (for example allyl) group, a -(C 1 -C 6 alkyl)C 3 -C 8 cycloalkyl (for example cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl) group, a side chain of a naturally occurring amino acid (for example the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine) or a group D; in the group D, R3 represents a hydrogen atom, a -C 1 -C 6 alkyl (for example methyl) group, a halogen (for example fluorine, chlorine or bromine) atom, a -
  • a compound of formula (II) which is at present particularly preferred for use in accordance with the present invention is N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]-pyridylmethyl)phenylsulphonyl-L-leucine and its pharmaceutically acceptable salts.
  • Triphenylphosphine (101.80 g, 0.388 mol) was added to a solution of N-methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (71.5 g, 0.194 mol) in a mixture of THF and water (4:1 , 200 ml), and the reaction mixture stirred overnight at ambient temperature. The THF was removed under reduced pressure, and the product extracted with ethyl acetate, dried, filtered and concentrated to an orange oil.
  • the title compound was prepared from N-4-(1 H-2-methyiimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine ethyl ester by base hydrolysis in an analogous manner to that for preparation of the compound of Example 2 above.
  • Examples 5-24 are prepared as their hydrochloride acid addition salts by the method of Example 1 employing the appropriate amino acid derivative in lieu of L-leucine ethyl ester hydrochloride in Step (b) and for certain compounds missing out the methylation Step (d) or employing a different alkyl halide in lieu of methyl iodide in Step (d).
  • SORVALL is a trade mark.
  • the supernatant was subsequently centrifuged at 3,000 rpm in a SORVALL RC3B centrifuge to pellet the platelets present.
  • the platelet rich pellets were resuspended in a minimum volume of buffer (150 mM NaCl, 10 mM Tris,
  • the pelleted platelets were resuspended in buffer (10 mM Tris, 5mM MgCl 2 , 2 mM EDTA, pH 7.0), snap freezed in liquid N2 and allowed to thaw slowly at room temperature in order to lyse the platelets. The latter step was repeated at least
  • the lysed platelets were centrifuged at 3,000 rpm for 10 minutes in a SORVALL RT6000 centrifuge and resuspended in buffer. The latter step was repeated twice in order to remove any cytoplasmic proteins which may hydrolyse the platelet activating factor (PAF) receptor.
  • the prepared platelet membranes may be stored at -70°C. After thawing the prepared membranes were centrifuged in a SORVALL RT6000 at 3,000 rpm for 10 minutes and resuspended in assay buffer.
  • the assay was conducted by preparing a series of Tris-buffered solutions of the selected antagonist of predetermined concentrations. Each of these solutions contained [ 3 H]-PAF (0.5 nM; 1-O-[ 3 H]octadecyl-2-acetyl-sn-glycero-3-phosphoryl choline with a specific activity of 132 Ci/mmol), unlabelled PAF (1000 nM), a known amount of the test antagonist, and a sufficient amount of Tris-buffer solution (10mM Tris, 5mM MgCl 2 , pH 7.0, 0.25% BSA) to make the final volume 1 ml.
  • Tris-buffer solution 10mM Tris, 5mM MgCl 2 , pH 7.0, 0.25% BSA
  • the activity of the compounds of general formula I is also demonstrated in vivo by their ability to reverse the hypotension caused by an infusion of PAF in rats.
  • Male Sprague-Dawley rats 300-350 g were anaesthetised with a mixture of sodium pentobarbitone, 22.5 mg/kg and thiopental 62.5 mg/kg. Through a midline incision in the neck, the trachea was cannulated and the animals breathed spontaneously. A carotid artery was cannulated for the measurement of blood pressure and this signal was used to trigger a rate meter to measure heart rate. Both jugular veins were cannulated: one for the infusion of PAF and the other for the bolus administration of test compounds.
  • Example ED 50 ( ⁇ g/kg i.v.) 2 32

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Abstract

L'invention se rapporte à des composés de la formule (II) ainsi qu'à leurs sels acceptables sur les plans pharmacologiques et vétérinaires, qui sont des inhibiteurs du facteur d'activation plaquettaire (PAF). Dans cette formule, R1 représente hydrogène, alkyle C¿1?-C6, alcényle C2-C6, alcynyle C2-C6, alkyle COC1-C6, alkyle CO2C1-C6, (alkyle COC1-C6)phenyle, (alkyle CO2C1-C6)phényle, (alkyle C1-C6)alkyle OC1-C6, (alkyle C1-C6)alkyle SC1-C6, (alkyle C1-C6)alkyle CO2CO1-C6, cycloalkyle C3-C8, cycloalcényle C4-C8 ou un groupe D dans lequel D représente un groupe de la formule (A) dans laquelle n est un nombre entier compris entre 0 et 3, et chacun des R?3 et R4¿ est indépendamment hydrogène, alkyle C¿1?-C6, alcényle C2-C6, alcynyle C2-C6, halogène, CN, CO2H, alkyle CO2C1-C6, CONH2, alkyle CONHC1-C6, (alkyle C1-C6)2 CONH, CHO, CH2OH, CF3, alkyle OC1-C6, alkyle SC1-C6, alkyle SOC1-C6, alkyle SO2C1-C6, NH2 ou NHCOMe; R?2¿ représente hydrogène, halogène, alkyle C¿1?-C6 facultativement substitué par un ou plusieurs atomes d'halogène, alcényle C2-C6, alcynyle C2-C6, (alkyle C1-C6)alkyle CO2C1-C6, (alkyle C1-C6)alkyle SC1-C6 (alkyle C1-C6)alkyle OC1-C6, (alkyle C1-C6)N(alkyle C1-C6)2, cycloalkyle C3-C8, cycloalcényle C4-C8, (alkyle C1-C6)cycloalkyle C3-C8, (alkyle C1-C6)cycloalcényle C4-C8, (alkyle C1-C6)cycloalkyle OC3-C8, (alkyle C1-C6)cycloalcényle OC4-C8, (alkyle C1-C6)cycloalkyle SC3-C8, (alkyle C1-C6)cycloalcényle SC4-C8, une chaîne latérale d'un aminoacide survenant naturellement, un groupe D tel que défini ci-dessus ou un groupe (alkyle C1-C6)OD dans lequel D est tel que défini ci-dessus.
PCT/GB1994/002460 1993-11-10 1994-11-09 Derives de l'acide 4-(1h-2-methylimidazo 4,5-c pyridinylmethyle)phenyle sulfonamide carboxylique en tant qu'antagonistes WO1995013064A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP7513680A JPH09505040A (ja) 1993-11-10 1994-11-09 アンタゴニストとしての４−（１ｈ−２−メチルイミダゾ４．５−ｃピリジニルメチル）−フェニルスルホンアミドカルボン酸誘導体
AU81125/94A AU8112594A (en) 1993-11-10 1994-11-09 4-(1h-2-methylimidazo 4,5-c pyridinylmethyl)phenyl sulphonamide carboxylic acid derivatives as antagonists
EP95900227A EP0727995A1 (fr) 1993-11-10 1994-11-09 Derives de l'acide 4-(1h-2-methylimidazo 4,5-c pyridinylmethyle)phenyle sulfonamide carboxylique en tant qu'antagonistes
GB9606996A GB2298138B (en) 1993-11-10 1994-11-09 4-(1h-2-methylimidazo 4,5-c pyridinylmethyl)phenyl sulphonamide carboxylic acid derivatives as antagonists

Applications Claiming Priority (2)

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GB9323162.9 1993-11-10
GB939323162A GB9323162D0 (en) 1993-11-10 1993-11-10 4-(1h-2-methylimidazo(4,5-c)pyridinylmethyl)phenylsulphonamid e derivatives as antagonists of paf

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WO (1) WO1995013064A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033997A1 (fr) * 1995-04-28 1996-10-31 British Biotech Pharmaceuticals Limited Derives de benzimidazole qui sont des antagonistes doubles de l'histamine (h1) et du facteur d'activation des plaquettes (paf)
US6013649A (en) * 1996-07-22 2000-01-11 Monsanto Company Thiol sulfone metalloprotease inhibitors
EP0950656A4 (fr) * 1996-01-23 2003-04-16 Shionogi & Co Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
US6919375B1 (en) 1996-01-23 2005-07-19 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
WO2010051245A1 (fr) 2008-11-03 2010-05-06 Merck Sharp & Dohme Corp. Benzimidazole et aza-benzimidazole carboxamides

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003423A1 (fr) * 1990-08-15 1992-03-05 British Bio-Technology Limited Derives benzimidazoliques, procede de preparation et applications

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003423A1 (fr) * 1990-08-15 1992-03-05 British Bio-Technology Limited Derives benzimidazoliques, procede de preparation et applications

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033997A1 (fr) * 1995-04-28 1996-10-31 British Biotech Pharmaceuticals Limited Derives de benzimidazole qui sont des antagonistes doubles de l'histamine (h1) et du facteur d'activation des plaquettes (paf)
US6881727B2 (en) 1996-01-23 2005-04-19 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
EP1486207A3 (fr) * 1996-01-23 2011-01-05 Shionogi & Co., Ltd. Dérivés d'acides aminés sulfonés et inhibiteurs de metalloprotéinases les contenant
EP0950656A4 (fr) * 1996-01-23 2003-04-16 Shionogi & Co Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
US6919375B1 (en) 1996-01-23 2005-07-19 Shionogi & Co., Ltd. Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
US6013649A (en) * 1996-07-22 2000-01-11 Monsanto Company Thiol sulfone metalloprotease inhibitors
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
US7067670B2 (en) 1999-02-08 2006-06-27 Warner Lambert Company Sulfamato hydroxamic acid metalloprotease inhibitor
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
WO2010051245A1 (fr) 2008-11-03 2010-05-06 Merck Sharp & Dohme Corp. Benzimidazole et aza-benzimidazole carboxamides
EP2358202A4 (fr) * 2008-11-03 2012-07-25 Merck Sharp & Dohme Benzimidazole et aza-benzimidazole carboxamides
US8470819B2 (en) 2008-11-03 2013-06-25 Merck Sharp & Dohme Corp. Benzimidazole and aza-benzimidazole carboxamides

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GB9323162D0 (en) 1994-01-05
EP0727995A1 (fr) 1996-08-28
CA2176124A1 (fr) 1995-05-18
JPH09505040A (ja) 1997-05-20
AU8112594A (en) 1995-05-29

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