WO1995001170A2 - Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux - Google Patents

Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux Download PDF

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Publication number
WO1995001170A2
WO1995001170A2 PCT/EP1994/002106 EP9402106W WO9501170A2 WO 1995001170 A2 WO1995001170 A2 WO 1995001170A2 EP 9402106 W EP9402106 W EP 9402106W WO 9501170 A2 WO9501170 A2 WO 9501170A2
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WIPO (PCT)
Prior art keywords
group
groups
alkyl
defined below
substituted
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Application number
PCT/EP1994/002106
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English (en)
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WO1995001170A3 (fr
Inventor
Richard Storer
Michael Walter Foxton
Charles David Hartley
Richard Howard Green
Stuart Travers
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Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP7503267A priority Critical patent/JPH08512038A/ja
Priority to AU73840/94A priority patent/AU7384094A/en
Priority to EP94923697A priority patent/EP0706386A1/fr
Publication of WO1995001170A2 publication Critical patent/WO1995001170A2/fr
Publication of WO1995001170A3 publication Critical patent/WO1995001170A3/fr

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to a new medical use for certain phenethanolamine derivatives and to pharmaceutical compositions containing them.
  • the invention relates to the use of such compounds which act as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors).
  • beta-adrenoceptors also known as beta-3-adrenoceptors.
  • Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).
  • Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline.
  • Sub-types of the adrenoceptors, - -, ⁇ -2-, ⁇ , &2" and &3- can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not >2) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
  • Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Compounds which act as agonists at atypical beta- adrenoceptors may be identified using standard tests (see for instance C Wilson et. al., supra).
  • R° is a hydrogen atom, a methyl group or a hydroxymethyl group
  • R 1 is a substituted C ⁇ alk l group which group is substituted by at least one of the substituents A, defined below
  • R 2 and R 3 are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C.,.. 5 alkoxy group, a carboxy group, a C 2 _ 7 alkoxycarbonyl group, a Chalky!
  • R 4 is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C ⁇ alkoxy group, a C ⁇ alkyl group, an aliphatic carboxylic C 1 ⁇ acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC ⁇ alkyl group;
  • R 5 is a hydrogen atom, a halogen atom, a hydroxy group, a C- ⁇ alkoxy group, a Chalk ! group, or a nitro group;
  • R 6 is a hydrogen atom, a halogen atom, a hydroxy group, a C- ⁇ alkoxy group, or a C ⁇ alkyl group; said aralkyl part is a C ⁇ alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C 6 _ 10 aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C 2 _7alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C ⁇ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic
  • substituents B are selected from halogen atoms, C 1. alkyl groups, C- ⁇ alkoxy groups, nitro groups, haloC ⁇ alkyl groups, and hydroxy groups; and pharmaceutically acceptable salts thereof.
  • atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents.
  • Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiathereosclerotic agents, and as being useful in the treatment of glaucoma.
  • the compounds of general formula (I) which act as agonists at atypical beta-adrenoceptors may be useful for the treatment of gastrointestinal disorders, especially inflammatory gastrointestinal disorders including peptic ulceration, oesophagitis, gastritis and duodenitis (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, especially, ulcerative colitis, ileitis, Crohn's disease and proctitis) and gastrointestinal ulcerations, especially when induced by non-steroidal anti- inflammatory drugs (NSAIDs) or corticosteroids.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • a preferred sub-class of the compounds of the general formula (I) for use according to the present invention is that defined by formula (II)
  • R 11 and R 12 represents a hydrogen atom and the other of R 11 and R 12 represents the group -CH 2 CO 2 H;
  • R 14 represents a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group.
  • R 11 represents the group -CH 2 CO 2 H.
  • a particularly preferred compound of general formula (I) for use according to the present invention is:
  • Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballyates.
  • the compounds may also form salts with suitable bases. Examples of such salts include alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium, or magnesium), ammonium and substituted ammonium.
  • salts referred to above will be physiologically acceptable, but other salts may find use, for example, in the preparation of the compounds of general formula (I) and the physiologically acceptable salts thereof.
  • the present invention provides a method of treatment of a human or non-human mammal, suffering from or susceptible to a inflammatory gastrointestinal disorder, such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
  • a inflammatory gastrointestinal disorder such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations
  • a method of treatment of a human or non-human mammal suffering from a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease, such as ulcerative colitis, ileitis, Crohn's disease or proctitis, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
  • a method of treatment of a human or non-human mammal, suffering from a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
  • references in this specification to treatment include prophylactic treatment as well as the alleviation of symptoms.
  • the present invention provides a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in medicine, particularly human medicine, for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
  • a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in medicine, particularly human medicine, for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
  • a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.
  • a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.
  • the invention provides for the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.
  • NSAID non-steroidal anti- inflammatory drugs
  • the active ingredients may be employed in the form of separate pharmaceutical formulations or a combined formulation may be used. In such a combined formulation, the active ingredients must of course be stable and mutually compatible in the particular formulation employed.
  • compositions which comprise at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof and at least one non-steroidal anti-inflammatory drug, together with at least one physiologically acceptable carrier or excipient are believed to be novel compositions and constitute a further aspect of the present invention.
  • compositions comprising at least one compound of general formula (1) or a physiologically acceptable salt or solvate thereof adapted for use in human or veterinary medicine.
  • Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • the carrier(s) or excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compounds for use according to the present invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- ⁇ -hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds for use according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds for use according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a proposed dose of the compounds for use according to the present invention for administration to a human is 0.1 mg to 1g, preferably to 1mg to 100mg of the active ingredient per unit dose, expressed as the weight of free base.
  • the unit dose may be administered, for example, 1 to 4 times per day.
  • the dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the compounds of general formula (I) for use according to the present invention may be prepared by a number of processes which are well known in the art for the preparation of phenethanolamine derivatives. Suitable methods are described, for instance, in European Patent Specification No. 0 543 662-A.
  • Atypical beta-adrenoceptor agonists are compounds which demonstrate a pharmacological response (in vitro or in vivo) mediated at atypical beta-adrenoceptors. This activity has been be measured as the ability to stimulate lipolysis by rat adipocytes at sub-micromolar concentrations, in a response that is resistant to blockade by standard beta-adrenoceptor blocking drugs such as propranolol.
  • Another useful means of identifying an atypical beta-adrenoceptor agonist involves the measurement of agonist activity at atypical beta-adrenoceptors in the rat isolated lower oesophagus.
  • a suitable assay is .described below as Method 1.
  • a compound of general formula (I) for use according to the present invention has an equipotent molar ratio (EPMR) relevant to isoprenaline of less than 30.
  • the rat oesophagus assay is based upon that described by Ford et. al., Br. J.
  • the lower oesophagus is removed from male AH/A rats (100-150g).
  • the overlying serosal muscle is removed from the oesophagus to leave the tunis muscularis mucosa.
  • Tissues are then placed in Kreb's solution containing the ⁇ 2-antagonist ICI 118,551 (lO ⁇ M), the ⁇ -
  • tissues are contracted with a submaximal concentration of carbachol (10 " ⁇ M) and, when a stable increase in tension has been achieved, a cumulative concentration effect curve to isoprenaline is constructed.
  • tissues are recontracted with carbachol (lO ⁇ M) and a cumulative concentration effect curve to test agonist is constructed.
  • EC50 is the molar concentration of agonist which produces 50% of the maximum possible response for that agonist.
  • compounds selective for atypical beta-adrenoceptors should preferably be a minimum of 10-30 times less potent than isoprenaline at or ⁇ 2 ⁇ adrenoceptors and, more preferably, 300-1000 times less potent than isoprenaline at ⁇ -
  • Method 2 Food (but not water) is withheld from female random hooded rats (70-120g) for 24 hours and then the rats are re-fed with Rat and Mouse No. 1 Maintenance Diet. After 1 hour of access to food, the rats are dosed orally with either the test compound or solvent (0.5% w/v methyl cellulose in water). 30 minutes later, indomethacin (60mg/kg; dissolved in 1 % w/v NaHCO ⁇ in saline) is administered as a single subcutaneous injection at the back of the neck. Subsequently, the rats are allowed food, but water is withheld, and the animals are humanely killed by cervical dislocation at 6 hours post dose. Control animals received a single subcutaneous dose of the appropriate solvent.
  • the rat's stomach is removed (with a small amount of duodenum attached), opened along the greater curvature and the contents removed by washing with 0.9% w/v sodium chloride solution (saline).
  • the opened stomach is pinned out (mucosal surface uppermost) on a polystyrene mat and the area of damage assessed by placing a grid (composed of 1 mm squares) over the antral region. Antral damage appears as discrete black or dark brown ulcers. The total area of antral damage is then expressed as a percentage of the total surface area of the antrum.
  • Tablets may be prepared by the normal methods such as direct compression or wet granulation.
  • the tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques.
  • suitable film forming materials such as hydroxypropyl methylcellulose, using standard techniques.
  • the tablets may be sugar coated.
  • the active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate.
  • the resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled edge punches.
  • the active ingredient is passed through a 60 mesh sieve, and blended with the lactose, pregelatinised starch and magnesium stearate.
  • the resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 7.5mm normal concave punches.
  • SYRUP This may be either a sucrose or sucrose free presentation.
  • the active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.
  • the hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation.
  • the resultant solution is adjusted to volume and mixed.
  • the syrup is clarified by filtration.
  • the active ingredient is dissolved in a suitable volume of Sodium Chloride Injection BP, the pH of the resultant solution is adjusted to pH3.5 with dilute hydrochloric acid BP then the solution is made to volume with sodium chloride injection BP and thoroughly mixed.
  • the solution is filled into Type I clear glass 5ml ampoules which are sealed under a headspace of air, by fusion of the glass then sterilised by autoclaving at 120 ⁇ for not less than 15 minutes.
  • Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient.
  • suitable buffer salts may be used.
  • the solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass.
  • the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
  • the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
  • the solution may be packed under an inert atmosphere of nitrogen or other suitable gas.
  • a suspension of the active ingredient in molten Witepsol is prepared and filled using suitable machinery, into 1g size suppository moulds.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) dans laquelle: R0 est hydrogène, méthyle ou hydroxyméthyle; R1 est un alcoyle substitué; R2 et R3 sont chacun un groupe hydrogène, halogène, hydroxy, alcoxy, carboxy, alcoxycarbonyle, alcoyle, nitro, haloalkyle, ou un alcoyle substitué; X est oxygène ou soufre, et Ar est soit un phényle substitué, soit un naphtyle substitué. L'invention concerne également les sels pharmaceutiquement acceptables de ces composés servant dans le traitement des troubles gastro-intestinaux.
PCT/EP1994/002106 1993-07-01 1994-06-29 Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux WO1995001170A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7503267A JPH08512038A (ja) 1993-07-01 1994-06-29 胃腸障害の治療に関するフェネタノールアミン誘導体の用途
AU73840/94A AU7384094A (en) 1993-07-01 1994-06-29 Use of phenethanolamine derivatives in the treatment of gastrointestinal disorders
EP94923697A EP0706386A1 (fr) 1993-07-01 1994-06-29 Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939313574A GB9313574D0 (en) 1993-07-01 1993-07-01 Medicaments
GB9313574.7 1993-07-01

Publications (2)

Publication Number Publication Date
WO1995001170A2 true WO1995001170A2 (fr) 1995-01-12
WO1995001170A3 WO1995001170A3 (fr) 2002-02-14

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PCT/EP1994/002106 WO1995001170A2 (fr) 1993-07-01 1994-06-29 Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux

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EP (1) EP0706386A1 (fr)
JP (1) JPH08512038A (fr)
AU (1) AU7384094A (fr)
GB (1) GB9313574D0 (fr)
WO (1) WO1995001170A2 (fr)

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US5635534A (en) * 1991-11-20 1997-06-03 Sankyo Company, Limited Aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses
US5786356A (en) * 1995-09-21 1998-07-28 Eli Lilly And Company Selective β3 adrenergic agonists
US5808080A (en) * 1996-09-05 1998-09-15 Eli Lilly And Company Selective β3 adrenergic agonists
WO1998043953A1 (fr) * 1997-04-02 1998-10-08 Glaxo Group Limited Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur
US6046227A (en) * 1997-12-05 2000-04-04 Eli Lilly And Company Selective β3 adrenergic agonists
US6140352A (en) * 1996-09-05 2000-10-31 Eli Lilly And Company Carbazolyl-substituted ethanolamines as selective β-3 agonists
US7045658B2 (en) 2001-03-22 2006-05-16 Glaxo Group Limited Formailide derivatives as beta2-adrenoreceptor agonists
US7135600B2 (en) 2001-02-14 2006-11-14 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7144908B2 (en) 2001-03-08 2006-12-05 Glaxo Group Limited Agonists of beta-adrenoceptors
US7361787B2 (en) 2001-09-14 2008-04-22 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7402598B2 (en) 2002-07-25 2008-07-22 Glaxo Group Limited Arylethanolamine β2-adrenoreceptor agonist compounds
US7425639B2 (en) 2001-01-31 2008-09-16 Smithkline Beecham Corporation Process
US7538127B2 (en) 2003-02-14 2009-05-26 Glaxo Group Limited Medicinal compounds
US7709677B2 (en) 2001-01-31 2010-05-04 Glaxosmithkline Llc Process of preparing arylethanoldiamines

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EP0473285A1 (fr) * 1990-07-30 1992-03-04 Imperial Chemical Industries Plc Utilisation d'acide acétique et 2-(phénoxypropanolamino)éthoxyphénoxy et ses dérivés pour l'inhibition de la motilité gastro-intestinale
EP0516349A2 (fr) * 1991-05-28 1992-12-02 Zeneca Limited Dérivés de 2-hydroxy-2-phényléthylamine comme agonistes des bêta-3-adrénoceptors
EP0543662A2 (fr) * 1991-11-20 1993-05-26 Sankyo Company Limited Dérivés d'aminoalcohol aromatique avec propriétés antidiabétiques et antiobésité, leur préparation et utilisation thérapeutique
EP0556880A2 (fr) * 1992-01-22 1993-08-25 Glaxo Group Limited L'utilisation médicale des agonistes de bêta adrénoceptor atypique

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EP0516349A2 (fr) * 1991-05-28 1992-12-02 Zeneca Limited Dérivés de 2-hydroxy-2-phényléthylamine comme agonistes des bêta-3-adrénoceptors
EP0543662A2 (fr) * 1991-11-20 1993-05-26 Sankyo Company Limited Dérivés d'aminoalcohol aromatique avec propriétés antidiabétiques et antiobésité, leur préparation et utilisation thérapeutique
EP0556880A2 (fr) * 1992-01-22 1993-08-25 Glaxo Group Limited L'utilisation médicale des agonistes de bêta adrénoceptor atypique

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Cited By (33)

* Cited by examiner, † Cited by third party
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EP0706386A1 (fr) 1996-04-17
WO1995001170A3 (fr) 2002-02-14
AU7384094A (en) 1995-01-24
JPH08512038A (ja) 1996-12-17
GB9313574D0 (en) 1993-08-18

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