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WO1993010074A1 - Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques - Google Patents

Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques Download PDF

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Publication number
WO1993010074A1
WO1993010074A1 PCT/GB1992/002135 GB9202135W WO9310074A1 WO 1993010074 A1 WO1993010074 A1 WO 1993010074A1 GB 9202135 W GB9202135 W GB 9202135W WO 9310074 A1 WO9310074 A1 WO 9310074A1
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WO
WIPO (PCT)
Prior art keywords
formula
pharmaceutically acceptable
compound
ester
amide
Prior art date
Application number
PCT/GB1992/002135
Other languages
English (en)
Inventor
Barrie Christian Charles Cantello
Lee James Beeley
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1993010074A1 publication Critical patent/WO1993010074A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54Compounds 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
    • C07C217/56Compounds 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
    • C07C217/60Compounds 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 Number 0023385 discloses certain compounds which are described as having activity as an anti-obesity and/or anti-hyperglycaemic agents.
  • HDL high-density-lipoprotein
  • R represents hydrogen, halogen or CF 3 .
  • R is substituted in the 3-position on the phenyl ring.
  • R represents halogen, especially chlorine or bromine, or CF 3 .
  • R represents chlorine, especially 3-chloro.
  • the compounds of formula (I) have an asymmetric carbon atom, marked with an asterisk in the formula. These compounds may, therefore, exist in one of two 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, and thus includes for instance, racemic mixtures of enantiomers.
  • the assymmetric carbon is in the R-configuration.
  • 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
  • Suitable esters are 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.
  • Suitable in-vivo hydrolysable ester groups are those used conventionally in the art, for example those provided by C 1-6 alkyl carboxylic acids.
  • esters of compounds of formula (I) are esters of the carboxyl group of formula (I).
  • the hydroxy group present in the moiety -CH(OH)CH 2 NH ('the ethanolamine hydroxyl group') or any hydroxyl group present in the compound of formula (I) may be derivatised as an ester.
  • Suitable esters of the carboxyl group of formula (I) include alkyl esters, especially C 1-6 alkyl esters such as methyl.
  • Suitable esters of hydroxyl groups are those provided by an aryl carboxylic acid, an arylalkyl carboxylic acid or a C 1-6 alkyl carboxylic acid.
  • the ethanolamine hydroxyl group is present as a free hydroxyl group.
  • Suitable pharmaceutically acceptable amides are those of formula NR s R t wherein R s and R t each independently represent hydrogen, alkyl or alkoxy alkyl.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkahne earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C 1-6 alkylamines such as triethylamine, hydroxy- C 1-6 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.
  • Compounds of formula (I) also form acid addition salts.
  • 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 solvates are conventional solvates, preferably hydrates.
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, which process comprises reacting an activated form of a compound of formula (II):
  • R is as defined in relation to formula (I), R x represents hydrogen or a hydroxy protecting group and R y represents hydrogen or a nitrogen protecting group; with a compound of formula (III): L-CH 2 COOR z (III) wherein R z is hydrogen or a protecting group and L represents a leaving group; and thereafter if necessary carrying out one or more of the
  • a suitable leaving group L is a halogen atom, preferably a bromine atom.
  • a suitable activated form of a compound of formula (II) is an anionic form.
  • reaction between an activated form of a compound of formula (II) and a compound of formula (III) may be carried out in any suitable solvent, generally an aprotic solvent such as acetone, tetrahydrofuran or
  • dimethylformamdde at any temperature providing a suitable rate of formation of the required product at an ambient temperature or at an elevated temperature, such as in the range of from 20°C to 150°C, for example 60°C; conveniently when acetone is the solvent a suitable temperature is the reflux temperature.
  • An activated form of a compound of formula (II) may be prepared by the appropriate conventional procedure.
  • an anionic form may be prepared by treating a compound of formula (II) with a base such as sodium carbonate.
  • the activated form of compound (II) is prepared in situ.
  • R is as defined in relation to formula (I)
  • R x and R y are as defined in relation to formula (II)
  • R z is as defined in relation to formula (II), providing that at least one of R x , R y or R z represents a protecting group; and thereafter if necessary carrying out one or more of the following optional steps:
  • Suitable protecting groups R x include trialkyl silyl groups.
  • R x is hydrogen.
  • R y is a nitrogen protecting group, for example a tert-butyloxy carbonyl group
  • Suitable protecting groups R z include conventional carboxyl protecting groups, such as C 1-6 alkyl groups.
  • R z is hydrogen
  • the deprotection of the compound of formula (IA) may be carried out using any suitable, conventional procedure appropriate to the particular protecting group chosen.
  • R y is a tert-butyloxycarbonyl group
  • the compound of formula (IA) is deprotected using mild acidic hydrolysis, using for example trifluoroacetic acid in an inert, solvent such as dichloromethane, preferably under an inert atmosphere such as nitrogen and preferably under anhydrous conditions.
  • R x represents a trialkyl silyl group it may be removed by mild acid hydrolysis.
  • R z represents a C 1-6 alkyl group then it may be removed by mild basic hydrolysis.
  • the compounds of formula (IA) may be prepared as described above by reaction between the compounds of formulae (II) and (III).
  • the compounds of formula (II) may be prepared by reacting a compound of formula (IV):
  • R and R x are as defined in relation to formula (II) with tyramine, and subsequently reducing the resulting amide; and thereafter, if
  • reaction between a compound of formula (IV) and tyramine may be carried out under conventional amidation conditions, for example in an inert solvent, such as dry dichloromethane, in the presence of a coupling agent, at any temperature which provides a suitable rate of formation of the required product, conveniently at low to ambient temperature, for example 0°C or ambient temperature; and preferably in an inert
  • atmosphere such as nitrogen.
  • Suitable coupling agents are conventional coupling agents such as N,N'- dicylohexylcarbodiimide, benzotriazol-1-yloxy tris(dimethylamino)- phosphoniumhexafluorophosphate and benzotriazol-1-yloxy tripyrrolidinophosphoniumhexafluorophosphate.
  • the reduction of the resulting amide may be effected by use of any appropriate, conventional reducing method, for example by using a borane such as boranedimethylsulphide in refluxing tetrahydrofuran, preferably under nitrogen.
  • a borane such as boranedimethylsulphide in refluxing tetrahydrofuran, preferably under nitrogen.
  • Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected, for example those mentioned hereinbefore.
  • Protecting groups may be prepared and removed using the appropriate conventional procedure: For example, tert-butyloxycarbonyl protecting groups may be prepared by treating the appropriate compound of formula (II) with di-tert-butyl dicarbonate in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • tert-butyloxycarbonyl protecting groups may be removed by mild acidic hydrolysis, such as by treatment with trifluoroacetic acid.
  • R z is a C 1-6 alkyl group, it may be removed using mild, basic hydrolysis.
  • a leaving group is any group that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups are halogen atoms, mesyloxy groups and tosyloxy groups.
  • Compounds of formula (IA) and (II) are considered to be novel and thus form a further aspect of the invention.
  • Compounds of formulae (III) and (IV) are either known compounds or can be prepared from known compounds by known processes or processes analogous to known processes for example those disclosed in Organic Synthesis, Collective Vol. 3 p. 381 (for compounds of formula (III) and p. 538 (for compounds of formula (IV)).
  • Tyramine is a known compound.
  • a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may also be prepared according to methods disclosed in EP 0023385, such methods are incorporated herein by reference.
  • the salts, esters, amides and solvates of compounds of formula (I) 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 compounds of formula (I) maybe prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required compound of formula (I) with the appropriate alkanol under acidic conditions.
  • One convenient process for preparing C 1-6 alkyl esters of compounds of formula (I), and especially a methyl ester is provided by treating a compound of formula (II) with a compound of formula (III) wherein R z represents C 1-6 alkyl, especially methyl.
  • Amides of compounds of formula (I) may be prepared using conventional amidation procedures, for example amides of formula CONR s R t of a compound of formula (I) may be prepared by treating a compound of formula (I) with an amine of formula HNR s R t wherein R s and R t are as defined above.
  • a C 1-6 alkyl ester such as a methyl ester, of a compound of formula (I) may be treated with an amine of the
  • optically active acid as a resolving agent.
  • Suitable optically active acids which maybe used as resolving agents are described in 'Topics in
  • any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting
  • an enantiomer of the compound of formula (I) may be prepared by reaction of an enantiomer of the compound of formula (II) with a compound of formula (III), for example the R-enantiomer of compound (I) would be prepared from the R- enantiomer of compound (II).
  • the relevant enantiomeric substrates are conveniently prepared using methods discussed above, for example the R- enantiomer of compound of formula (II) may be prepared from the R- enantiomer of the compound of formula (IV).
  • the absolute configuration of any compound of the general formula (I) 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
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a
  • Suitable non-human animals include non-human mammals especially pets such as dogs and cats.
  • the present invention further provides a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for tile manufacture of a medicament for the treatment of hyperglycaemia in human or non-human animals.
  • the present invention also provides the use a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a
  • hyperinsulinaemia in human or non-human animals is hyperinsulinaemia in human or non-human 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.
  • 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.
  • 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 from 2 to 100 mg or from 0.1 to 500 mg, and more especially from 0.1 to 250 mg.
  • the present invention further provides a method for treating
  • hyperglycaemia in a human or non-human animal 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 animal 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 animal, which comprises administering an effective,
  • the active ingredient may be administered as a
  • the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one 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 that is a total daily dosage in the range of from 1.4. 10 -3 mg/kg to 86 mg/kg , more usually in the range of from 0.014 mg/kg to 21.4 mg/kg.
  • the treatment regimens for atherosclerosis are generally as described for hyperglycaemia.
  • the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range 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 increasing 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 acceptable salt, ester or amide thereof; or a veterinarily acceptable solvate thereof.
  • the compounds of formula (I) and the veterinarily acceptable salts, ester or amide thereof may be administered to any livestock in the abovementioned method, they are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and/or 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 salts, ester or amide thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged.
  • the compounds are also envisaged.
  • the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a
  • Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed.
  • Lipolysis Rat white adipocytes were prepared by collagenase digestion as described by Rodbell (1964) with the modification of Honnor et al. (1985), in that adenosine (200nM) was included in the preparation to inhibit basal lipolysis.
  • lipolysis stimulated by ⁇ -agonists was measured over 30 minutes in medium where the adenosine concentration was controlled; the medium included (-)-N 6 -(2-phenylisopropyl)adenosine (100nM) + deaminase as decribed by Honnor et al. (1985).
  • the incubation was stopped by addition of trichloracetic acid (0.2ml of 10% w/v) to 1ml of cells.
  • Glycerol was measured by the fluorimetric method of Boobis and Maugham (1983).
  • Rat uterine horns were removed and bisected longitudinally. Each tissue was tied to a glass tissue holder and placed in Krebs-Henseleit solution in a 30 ml organ bath as before. Tissues were placed under a resting tension of lg and allowed to equilibrate. Each uterine strip was pre-contracted by the addition of 40mM K + to the bath to produced a steady tonic

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de la formule (I) ou un sel acide pharmaceutiquement acceptable, un ester ou amide de celui-ci, ou un solvate de celui-ci pharmaceutiquement acceptable, dans laquelle R représente hydrogène, halogène ou CF3; l'invention concerne également un procédé de préparation de ce composé, une composition pharmaceutiquement le contenant et l'utilisation de ce composé ou composition en médécine et en agriculture.
PCT/GB1992/002135 1991-11-19 1992-11-19 Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques WO1993010074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919124512A GB9124512D0 (en) 1991-11-19 1991-11-19 Novel compounds
GB9124512.6 1991-11-19

Publications (1)

Publication Number Publication Date
WO1993010074A1 true WO1993010074A1 (fr) 1993-05-27

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Application Number Title Priority Date Filing Date
PCT/GB1992/002135 WO1993010074A1 (fr) 1991-11-19 1992-11-19 Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques

Country Status (8)

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AU (1) AU2949192A (fr)
GB (1) GB9124512D0 (fr)
MX (1) MX9206614A (fr)
NZ (1) NZ245157A (fr)
PT (1) PT101066A (fr)
TW (1) TW222619B (fr)
WO (1) WO1993010074A1 (fr)
ZA (1) ZA928859B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541197A (en) * 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5561142A (en) * 1994-04-26 1996-10-01 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
EP0659737A3 (fr) * 1993-12-21 1997-03-05 Bristol Myers Squibb Co Substituts pour Catécholamines utiles comme agonistes B3.
WO2007011065A3 (fr) * 2005-07-22 2007-08-16 Mitsubishi Pharma Corp Compose intermediaire utilise pour la synthese d'un agent pharmaceutique, procede de production de ce dernier
WO2008015558A3 (fr) * 2006-08-04 2008-07-10 Univ Bari Ligands du récepteur bêta-3 et leurs utilisation thérapeutique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0023385A1 (fr) * 1979-06-16 1981-02-04 Beecham Group Plc Dérivés d'éthanamines, leur préparation et leur utilisation dans des compositions pharmaceutiques
EP0099707A1 (fr) * 1982-07-16 1984-02-01 Beecham Group Plc Dérivés d'éther 2-aminoéthyles, leurs procédés de préparation et compositions pharmaceutiques les contenant
WO1984004091A1 (fr) * 1983-04-19 1984-10-25 Beecham Group Plc Derives de 2-phenylethylamine pharmaceutiquement actifs
EP0386603A2 (fr) * 1989-03-07 1990-09-12 F. Hoffmann-La Roche Ag Bisphénéthanolamine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0023385A1 (fr) * 1979-06-16 1981-02-04 Beecham Group Plc Dérivés d'éthanamines, leur préparation et leur utilisation dans des compositions pharmaceutiques
EP0099707A1 (fr) * 1982-07-16 1984-02-01 Beecham Group Plc Dérivés d'éther 2-aminoéthyles, leurs procédés de préparation et compositions pharmaceutiques les contenant
WO1984004091A1 (fr) * 1983-04-19 1984-10-25 Beecham Group Plc Derives de 2-phenylethylamine pharmaceutiquement actifs
EP0386603A2 (fr) * 1989-03-07 1990-09-12 F. Hoffmann-La Roche Ag Bisphénéthanolamine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0659737A3 (fr) * 1993-12-21 1997-03-05 Bristol Myers Squibb Co Substituts pour Catécholamines utiles comme agonistes B3.
US5541197A (en) * 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5561142A (en) * 1994-04-26 1996-10-01 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
WO2007011065A3 (fr) * 2005-07-22 2007-08-16 Mitsubishi Pharma Corp Compose intermediaire utilise pour la synthese d'un agent pharmaceutique, procede de production de ce dernier
US7994315B2 (en) 2005-07-22 2011-08-09 Mitsubishi Tanabe Pharma Corporation Intermediate compound for synthesizing pharmaceutical agent and production method thereof
WO2008015558A3 (fr) * 2006-08-04 2008-07-10 Univ Bari Ligands du récepteur bêta-3 et leurs utilisation thérapeutique
US8017613B2 (en) 2006-08-04 2011-09-13 Universita' Degli Studi Di Bari Beta-3 receptor ligands and their use in therapy
US8354412B2 (en) 2006-08-04 2013-01-15 Universita' Degli Studi Di Bari Beta-3 receptor ligands and their use in therapy
CN101516826B (zh) * 2006-08-04 2015-03-04 巴里学习大学 β-3受体配体

Also Published As

Publication number Publication date
GB9124512D0 (en) 1992-01-08
ZA928859B (en) 1994-05-05
AU2949192A (en) 1993-06-15
TW222619B (fr) 1994-04-21
MX9206614A (es) 1994-02-28
NZ245157A (en) 1995-03-28
PT101066A (pt) 1994-02-28

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