WO1994024090A1 - Arylethanolamine derivatives and their use in the treatment of obesity and hyperglycaemia - Google Patents

Arylethanolamine derivatives and their use in the treatment of obesity and hyperglycaemia Download PDF

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Publication number
WO1994024090A1
WO1994024090A1 PCT/GB1994/000829 GB9400829W WO9424090A1 WO 1994024090 A1 WO1994024090 A1 WO 1994024090A1 GB 9400829 W GB9400829 W GB 9400829W WO 9424090 A1 WO9424090 A1 WO 9424090A1
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Prior art keywords
formula
compound
ester
pharmaceutically acceptable
amide
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PCT/GB1994/000829
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English (en)
French (fr)
Inventor
Lee James Beeley
John Michael Berge
Richard Anthony Godwin Smith
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Smithkline Beecham Plc
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Priority to AU65418/94A priority Critical patent/AU6541894A/en
Publication of WO1994024090A1 publication Critical patent/WO1994024090A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/32—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to acyclic carbon atoms and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Definitions

  • This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.
  • European patent application, publication number 0023385 discloses certain arylethanolamine derivatives which are stated to have anti-obesity and/or anti- hyperglycaemic activity.
  • These compounds are also indicated to have potential in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids.
  • These compounds also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock.
  • These compounds may also be of use in increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.
  • HDL high-density- lipoprotein
  • R° represents a substituted or unsubstituted aryl group
  • R.1 represents hydrogen or an alkyl group
  • R. represents a moiety of formula (a): *** _S
  • R 5 (a) wherein R 4 represents a moiety (CH2) n CO2H wherein n is zero or an integer in the range of from 1 to 3 and R ⁇ represents a moiety (CH.2)p CO2H, (CH2)pOH, (CH2) p CN, (CH2) p COCH3 or (CH2> p NH2 wherein p is zero or an integer in the range of from 1 to 3; and
  • R3 represents hydrogen, halogen, alkyl or alkoxy.
  • R° is a 3-chlorophenyl group
  • R* is an alkyl group
  • R! is alkyl, it is favourably a C g alkyl group, especially a methyl group.
  • R ⁇ represents hydrogen
  • R ⁇ is a CO2H group, or a pharmaceutically acceptable salt or ester thereof; an example of an ester is an ethyl ester, an example of a salt is a sodium salt.
  • An example of R ⁇ is a CO2H group, or a pharmaceutically acceptable salt or ester thereof; an example of an ester is an ethyl ester, an example of a salt is a sodium salt.
  • n is zero.
  • p is zero.
  • the compounds of formula (I) have two or more asymmetric carbon atoms, for example those marked with asterisks in the formula. These compounds may therefore exist in different stereoisomeric forms.
  • the present invention encompasses all stereoisomers of the compounds of the general formula (I) whether free from other isomers, or admixed with other isomers in any proportion, such as mixtures of diastereoisomers and racemic mixtures of enantiomers. Of particular interest are those carbon atoms marked with one (*) or two (**) asterisks in the formula.
  • the asymmetric carbon atom indicated by a single asterisk (*) is in the R-configuration.
  • the asymmetric carbon atom indicated by two asterisks (**) is in the R-configuration.
  • a suitable form of a compound of formula (I) is a mixture of the R(*)R(**) and S(*)S(**) enantiomers, such as a racemic mixture.
  • a preferred form of a compound of formula (I) is the R(*)R(**) enantiomer.
  • 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
  • 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, nitrile, carboxy and pharmaceutically acceptable salts, esters and amides thereof, sulphonamide, alkylsulphonamide, dialkylsulphonamide, alkoxycarbonylalkyl, alkylcarbonyloxy and alkylcarbonyl groups or two substituents on adjacent carbon atoms together with the carbon atoms to which they are attached may form a heterocyclic group.
  • a preferred aryl group is a substituted or unsubstituted phenyl group.
  • Preferred optional substituents for the aryl group include up to three substituents selected from halogen, hydroxy, alkoxy, hydroxyalkyl and amino.
  • Suitable heterocyclic groups are single ring heterocyclic groups having 4 to 7, generally 5 or 6, ring atoms including 1 or 2 hetero atoms selected from O or N.
  • Examples of such heterocyclic groups include imidazoline and imidazolone, especially 2-imidazolone.
  • Suitable esters are pharmaceutically acceptable esters.
  • Esters of compounds of formula (I) include esters of the carboxyl group of formula (I). In addition the hydroxy group present in the moiety
  • -CH(OH)CH2NH ('the ethanolamine hydroxyl group') or any hydroxyl group present in the compound of formula (I) may also be derivatised as an ester.
  • Suitable pharmaceutically acceptable esters of the carboxyl group of formula (I) include alkyl esters, especially Cj.g alkyl esters such as methyl.
  • Suitable pharmaceutically acceptable esters of hydroxyl groups are those provided by an aryl carboxy lie acid, an arylalkyl carboxylic acid or a C ⁇ -g alkyl carboxylic acid.
  • Suitable pharmaceutically acceptable esters also includes in-vivo hydrolysable esters.
  • in-vivo hydrolysable ester relates to a pharmaceutically acceptable ester which readily breaks down in the human or non-human animal body to leave the free hydroxy group and free carboxyl group.
  • Suitable in-vivo hydrolysable ester groups are those used conventionally in the art, for example those provided by C ⁇ . alkyl carboxylic acids.
  • the ethanolamine hydroxyl group is present as a free hydroxyl group.
  • Suitable amides are pharmaceutically acceptable amides.
  • Suitable pharmaceutically acceptable amides include those of formula CO.NR s R l wherein R s and R l each independently represent hydrogen, alkyl or alkoxyalkyl.
  • Suitable salts are pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include acid addition salts and salts of carboxy groups.
  • Pharmaceutically acceptable acid addition salts may be, for example, salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulophonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C ⁇ _6 alkylamines such as triethylamine, hydroxy-Ci.g alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b- phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts
  • Suitable solvates are pharmaceutically acceptable solvates.
  • Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.
  • esters, amides, salts and solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be used to prepare the corresponding pharmaceutically acceptable esters, amides, salts and solvates and hence they also form a useful part of the present invention.
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide or a pharmaceutically acceptable solvate thereof, which process comprises reducing a compound of formula (II):
  • R°, R 1 , R ⁇ and R ⁇ are as defined in relation to formula (I), and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and (ii) preparing a pharmaceutically acceptable salt, ester or amide of a compound of formula (I) or a pharmaceutically acceptable solvate thereof.
  • the reduction of the compound of formula (II) may be carried out using any suitable reduction procedure, for example by using catalytic reduction in the presence of hydrogen.
  • Suitable catalysts include platinum oxide and palladium on charcoal.
  • Suitable reduction conditions include using an alkanol solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example ambient temperature, under a pressure of 1-5 atmospheres of hydrogen.
  • an alkanol solvent such as methanol
  • the compound of formula (II) may be prepared by reacting a compound of formula (III):
  • R° is as defined in relation to formula (I) with a compound of formula (IN):
  • R , R ⁇ and R ⁇ are as defined in relation to formula (I).
  • the reaction between compounds of formulae (III) and (IV) may be carried out under conventional amination conditions, for example in a solvent such as methanol or toluene.
  • the compound of formula (II) is prepared in-situ by reacting a compound of the above defined formula (III) with a compound of the above defined formula (IV) under reductive amination conditions.
  • Suitable reductive amination conditions include reacting the compounds of formula (III) and (IV) in an alkanolic solvent, such as methanol, in the presence of a suitable reduction catalyst, such as platinum oxide or palladium on charcoal, at any temperature providing a convenient rate of formation of the required product, generally ambient temperature, under hydrogen at a pressure of 1-5 atmosphere.
  • an alkanolic solvent such as methanol
  • a suitable reduction catalyst such as platinum oxide or palladium on charcoal
  • a compound of formula (TV) may be prepared by reducing a compound of formula (V):
  • R*, R ⁇ and R ⁇ are as defined in relation to formula (I).
  • the reduction of the compound of formula (V) may be carried out using any appropriate reduction procedure, for example by using iron powder in the presence of acetic acid in an aqueous solvent such as aqueous methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent.
  • an aqueous solvent such as aqueous methanol
  • a compound of formula (V) may be prepared by reacting a compound of formula (VI):
  • R ⁇ and R ⁇ are as defined in relation to formula (I), with a nitroalkane, such as nitroethane; for compound (V) wherein R* is CH3.
  • the carbon atom of the -CHO group of compound of formula (VI) is in an activated form, a suitable activated form being provided by forming an imine of the said carbonyl group:
  • the i ine may be prepared by reacting the compound of formula (VI) with an amine, suitably a primary alkyl amine such as n-butylamine.
  • reaction of the compound of formula (VI) and the amine may be carried out in any suitable solvent, such as toluene, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; and preferably in the presence of a catalytic amount of toluenesulphonic acid.
  • suitable solvent such as toluene
  • the reaction between the compound of formula (VI) and nitroalkane may be carried out in glacial acetic acid, preferably in the presence of an ammonium acetate catalyst, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C.
  • an ammonium acetate catalyst generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C.
  • the reaction with nitroalkane may be carried out in glacial acetic acid, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C.
  • a compound of formula (VI) may be prepared from a compound of formula (Nil):
  • R ⁇ and R ⁇ are as defined in relation to formula (I) and 1?- is a leaving group or atom, such as a halogen atom, for example a chlorine atom.
  • the compound of formula (VII) is in an activated form, such as a salted form.
  • An activated form of a compound of formula (VII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (VII) with a base such as an alkali metal hydride, for example sodium hydride, or an alkali metal hydroxide, for example potassium hydroxide.
  • a base such as an alkali metal hydride, for example sodium hydride, or an alkali metal hydroxide, for example potassium hydroxide.
  • the reaction between the compounds of formulae (VII) and (VIII) may be carried out in any suitable solvent, for example ethanol at any suitable temperature which provides a convenient rate of formation of the required product, generally being an elevated temperature and conveniently the boiling point of the solvent; as stated preferably the reaction is carried out in the presence of a base, such as potassium hydroxide.
  • Suitable conversions of one compound of formula (I) into another compound of formula (I) include:
  • Conversion (1) may be carried out using any conventional means for hydrolysing esters, such as alkali metal hydroxide hydrolysis in aqueous medium.
  • Conversion (2) may be carried out using conventional amidation methods such as tiiose mentioned hereinafter.
  • Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected. Protecting groups may be prepared and removed using the appropriate conventional procedure.
  • a leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy groups and tosyloxy groups.
  • the compounds of formulae (III), (VII) and (VIII) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example the compounds of formula (III) may be prepared according to methods disclosed in J.Org.Chem., 1974, 39, 914; the compounds of formula (VII) may be prepared according to methods disclosed in Org. Synthesis 1967, 47,1 and the compounds of formula (VIII) may be prepared according to methods disclosed in Synthesis 1987, 188 or Org. Synthesis, Collective Vol. IV 1963, 590.
  • the salts, esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art:
  • acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.
  • Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid widi the appropriate alkanol, generally under acidic conditions.
  • Amides may be prepared using conventional amidation procedures, for example amides of formula CONR s R l may be prepared by treating the relevant carboxylic acid with an amine of formula HNR S R 1 wherein R s and R l are as defined above, in the presence of a suitable dehydrating agent, for example dicyclohexylcarbodiimide.
  • a C ⁇ . alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR s R to provide the required amide.
  • mixtures of isomers of the compounds of the invention may be separated ⁇ Rto individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • optically active acids which maybe used as resolving agents are described in Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971, Allinger, N.L. and Eliel, W.L. Eds.
  • any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
  • the absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques.
  • the compounds of the present invention have valuable pharmacological properties:
  • the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia in human or non-human animals.
  • the present invention further provides a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-huma animals.
  • a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • the term "pharmaceutically acceptable” embraces compounds, compositions and ingredients for both human and veterinary use: for example the term “pharmaceutically acceptable salt” embraces a veterinarily acceptable salt.
  • the composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.
  • Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof.
  • the present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
  • the present invention further provides a method for treating gastrointestinal disorders or for the treatment of gastrointestinal ulcerations in a human or non-hum mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
  • the active ingredient may be administered as a pharmaceutica composition herein before defined, and this forms a particular aspect of the present invention.
  • the compound of formula (I), o pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, o to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
  • the treatment regimens for atherosclerosis, gastrointestinal disorders or gastrointestinal ulcerations are generally as described for hyperglycaemia.
  • the active ingredient may be administered by mouth, usually once or twice a day and in an amount in the ran of from about 0.025 mg/kg to 25 mg kg, for example 0.1 mg/kg to 20 mg/kg.
  • the present invention also provides a method for increasi weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptab salt, ester or amide thereof, or a veterinarily acceptable solvate thereof.
  • the compounds of formula (I) and the veterinarily acceptable salt, es or amides thereof or a veterinarily acceptable solvate thereof may be administered any livestock in the above mentioned method, ti ey are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and decreasing birth mortality rate and increasing post-natal survival rate; in poultry, especially turkeys and chickens, cattle, pigs and sheep.
  • the compounds of formula (I) or veterinarily acceptable salt, ester or amides thereof will normally be administered orally althou non-oral modes of administration, for example injection or implantation, are also envisaged.
  • the compounds are administered in the feed-stuff or drinking water provided for the livestock.
  • these are administered in the feed-stuff at from 10-3 ppm - 500ppm of total daily fed intake, more usually 0.01 ppm to 250ppm, suitably less than lOOpp .
  • the particular formulations used will of course depend upon the mode of administration but will be those used conventionally in the mode of administration chosen.
  • the drugs are conveniently formulated as a premix in association with a suitable carrier.
  • the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable salt, ester or amide thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.
  • Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/GB1994/000829 1993-04-21 1994-04-19 Arylethanolamine derivatives and their use in the treatment of obesity and hyperglycaemia WO1994024090A1 (en)

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GB939308178A GB9308178D0 (en) 1993-04-21 1993-04-21 Novel compounds
GB9308178.4 1993-04-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031357A1 (fr) * 1997-01-21 1998-07-23 Sanofi-Synthelabo Utilisation des agonistes des recepteurs beta-3 adrenergiques pour la preparation de medicaments cicatrisants
WO2010052563A3 (en) * 2008-11-07 2010-09-16 Aston University Glycoproteins having lipid mobilizing properties and therapeutic uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0023385A1 (en) * 1979-06-16 1981-02-04 Beecham Group Plc Ethanamine derivatives, their preparation and use in pharmaceutical compositions
EP0198412A1 (de) * 1985-04-16 1986-10-22 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Phenäthanolaminderivate
EP0262785A1 (en) * 1986-08-29 1988-04-06 Beecham Group Plc N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethane amine, the methyl ester, salt and stereoisomeric forms thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0023385A1 (en) * 1979-06-16 1981-02-04 Beecham Group Plc Ethanamine derivatives, their preparation and use in pharmaceutical compositions
EP0198412A1 (de) * 1985-04-16 1986-10-22 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Phenäthanolaminderivate
EP0262785A1 (en) * 1986-08-29 1988-04-06 Beecham Group Plc N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethane amine, the methyl ester, salt and stereoisomeric forms thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031357A1 (fr) * 1997-01-21 1998-07-23 Sanofi-Synthelabo Utilisation des agonistes des recepteurs beta-3 adrenergiques pour la preparation de medicaments cicatrisants
FR2758460A1 (fr) * 1997-01-21 1998-07-24 Sanofi Sa Utilisation des agonistes des recepteurs beta-3 adrenergiques pour la preparation de medicaments cicatrisants
US6235793B1 (en) 1997-01-21 2001-05-22 Sanofi-Synthelabo Use of agonists of adrenergic β-3 receptors for preparing wound-healing medicines
WO2010052563A3 (en) * 2008-11-07 2010-09-16 Aston University Glycoproteins having lipid mobilizing properties and therapeutic uses thereof
AU2016204169B2 (en) * 2008-11-07 2018-02-01 Aston University Glycoproteins having lipid mobilizing properties and therapeutic uses thereof

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TW282452B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1996-08-01
GB9308178D0 (en) 1993-06-02
AU6541894A (en) 1994-11-08

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