WO1997034905A1 - Derives d'amine d'aryloxy et d'arylthiopropanol contenant du phosphore, utiles en tant qu'agonistes du beta adrenorecepteur - Google Patents

Derives d'amine d'aryloxy et d'arylthiopropanol contenant du phosphore, utiles en tant qu'agonistes du beta adrenorecepteur Download PDF

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WO1997034905A1
WO1997034905A1 PCT/EP1997/001286 EP9701286W WO9734905A1 WO 1997034905 A1 WO1997034905 A1 WO 1997034905A1 EP 9701286 W EP9701286 W EP 9701286W WO 9734905 A1 WO9734905 A1 WO 9734905A1
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hydroxy
formula
compound
pharmaceutically acceptable
propylamino
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PCT/EP1997/001286
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English (en)
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Helen Kate Ann Morgan
Robert William Ward
Mervyn Thompson
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Smithkline Beecham Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5304—Acyclic saturated phosphine oxides or thioxides

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.
  • 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.
  • gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome
  • These compounds may also be of use in increasing the high-density-lipoprotein
  • HDL hyperinsulinaemia
  • depression depression
  • R° represents an aryl group optionally substituted with one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido wherein the alkyl group is optionally substituted with one, two or three substituents selected from: halogen, haloalkyi, hydroxy, alkoxy, or arylsulphonamido wherein the aryl group is optionally substituted, providing that R° is not 3-methylsulphonylaminophenyl;
  • X represents O or S;
  • Rl and R a each independently represents hydrogen or an alkyl group.
  • R2 represents a moiety of formula (a):
  • R° represents a moiety of formula (b):
  • Y represents hydrogen, hydroxy, hydroxymethyl, alkylsulphonamido or phenylsulphonamido wherein the phenyl group is optionally substituted with one or two halogen atoms and ⁇ l represents hydrogen, hydroxy or hydroxymethyl.
  • Favoured aryl substituents for any arylsuphonamido group include one, two or three of halogen, alkyl, alkoxy and allyl.
  • R° is 4-hydroxyphenyl, 4-hydroxy-3-alkylsulphonmidophenyl, especially 4-hydroxy-3-methanesulphonamidophenyl.
  • R s an alkyl group and R ⁇ a represents hydrogen.
  • Rl and R ⁇ a each represents hydrogen.
  • Rl is alkyl, it is favourably a C ⁇ . alkyl group, especially a methyl group.
  • R-* is hydrogen.
  • R ⁇ represent phenyl.
  • R ⁇ represents phenyl.
  • X represents O.
  • a preferred compound of formula (I) is a compound wherein:R° is 4- hydroxyphenyl-3-methanesulphonamido; X is O;R is methyl; R l a is hydrogen; R 2 is a moiety of formula (a) wherein R ⁇ and R ⁇ each represent phenyl; and R ⁇ is hydrogen.
  • the compounds of formula (I) have one or two asymmetric carbon atoms, marked with an asterisk (*) or two asterisks (**) in the formula.
  • the substituents on the phosphorous atom of moiety (a) are different, then the phosphorous atom is chiral: These compounds may therefore exist in up to eight stereoisomeric forms.
  • the present invention encompasses all stereoisomers ofthe compounds ofthe 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.
  • the asymmetric carbon atom indicated by a single asterisk (*) is in the S- configuration.
  • aryl' suitably includes phenyl or naphthyl groups, especially phenyl.
  • Suitable substitutents for any aryl group one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, halogen, alkoxy, alkyl and allyl.
  • '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, iso-propyl, n-butyl, wo-butyl or tert-butyl group.
  • 'cycloalkyl' includes C ⁇ .g cycloalkyl groups, especially C5 or Cg cycloalkyl groups.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably bromine or chlorine.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • Suitable pharmaceutically acceptable acid addition salts include 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, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
  • inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid
  • organic acids such, for example as methanesulphonic acid, toluenesulphonic 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 or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II):
  • Rl and R ⁇ a are as defined in relation to formula (I), R 2 ' represents R 2 or a protected form thereof, R ⁇ ' represents R ⁇ or a protected form thereof and T° represents hydrogen or a protecting group; and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group;
  • the reaction between compounds of formulae (II) and (III) is suitably carried out in an aprotic solvent such as acetonitrile or a chlorinated solvent such as dichloromethane, at any temperature providing a suitable rate of formation ofthe required product, suitably at ambient temperature and suitably in the presence of a perchlorate, such as lithium perchlorate; preferably the reaction is carried out under an inert atmosphere such as nitrogen or argon.
  • the reaction can be carried out in an alkanolic solvent such as methanol at any temperature providing a suitable rate of formation ofthe final product, suitably at ambient temperature or at an elevated temperature, such as the reflux temperature ofthe solvent, preferably the reaction is carried out in an inert atmosphere such as nitrogen or argon.
  • R 0 ' represents a protected form of R°, protected in accordance with conventional chemical practice using such groups as defined herein, for example when R° comprises a hydroxy group it may be protected as a benzyloxy group.
  • Suitable protecting groups represented by T° are benzyl, p-methoxybenzyl and silyl groups.
  • T° is hydrogen.
  • R 2 ' is R 2 .
  • a compound of formula (II) may be prepared by reacting an activated form of a compound of formula (IV):
  • L° represents a leaving group
  • a suitable activated form of a compound of formula (IV) is an ionic form, such as an alkali metal salted form, for example a potassium salted form.
  • An activated form of a compound of formula (IV) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (IV) with a base such as an alkali carbonate, for example potassium carbonate.
  • L° represents 3-or 4-nitrobenzenesulphonyloxy group, preferably 3- nitrobenzenesulphonyloxy.
  • reaction between the compounds of formulae (IV) and (V) may be carried out in an aprotic solvent such as acetone or dimethylformamide at any temperature providing a suitable rate of formation ofthe required product, generally at an ambient to elevated temperature, suitably an elevated temperature, for example the reflux temperature of acetone
  • an aprotic solvent such as acetone or dimethylformamide
  • L° also represents OH.
  • the compound of formula (V) is oxiranyl-methanol and the reaction between it and the compound of formula (IV) is conveniently effected using a Mitsunobu reaction, according to methods disclosed in Tetrahedron Letters., 1994, 35, 5997-6000 and Organic Reactions 1992, 42, 335-656.
  • a compound of formula (III), wherein Rl is alkyl, is suitably prepared by the hydrogenolysis of a
  • R 2 ' is a group convertible into a group R 2
  • Y 2 represents hydrogen or a moiety -B(OH)2 and the **CH carbon and ***CH carbon atoms are chiral carbon atoms; and thereafter converting the group R 2 ' into a group R 2 .
  • catalytic hydrogenolysis is used, using for example 10% palladium on charcoal, optionally in the presence of ammonium formate,_suitably in an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example at ambient temperature or at an elevated (eg, 50°C)temperature
  • a compound of formula (VI) wherein Y 2 is H and R* is alkyl may be prepared by stereoselective reduction of a compound of formula (VII):
  • the reduction ofthe compound of formula (VII) may be carried out using catalytic reduction in the presence of hydrogen.
  • a preferred catalyst is platinum oxide.
  • Suitable reduction conditions include using an alkanol solvent such as methanol or ethanol, at any temperature providing a convenient rate of formation ofthe required product, conveniently at ambient temperature using a pressure of 1-5 atmospheres of hydrogen.
  • the compound of formula (VII) may be prepared by reacting a compound of formula (VIII):
  • the reaction between compounds of formulae (VIII) and R- ⁇ -methylbenzylamine may be carried out under conventional reductive amination conditions, for example in a solvent such as methanol or toluene.
  • the compound of formula (VII) is prepared in-situ by reacting a compound ofthe above defined formula (VIII) with R-or S-(as appropriate) ⁇ - methylbenzyl amine and thereafter reducing the compound of formula (VII) so formed using reaction conditions and catalysts as described above.
  • R' , R ⁇ a and R ⁇ are as defined in relation to formula (I) and T ⁇ is a protecting group, by reaction with a compound of formula (X):
  • R ⁇ and R ⁇ are as defined in relation to formula (I) and L 2 is a leaving group or atom; and thereafter, as necessary removing any protecting group.
  • T ⁇ is a t-butoxycarbonyl group.
  • L 2 represents a 4-chlorobenzenesulphonyloxy group or a 3-or 4- nitrobenzenesulphonyloxy group.
  • the compound of formula (IX) is usually in an activated form, such as an anionic form.
  • the activated form is conveniently prepared im situ prior to addition ofthe compound of formula (X).
  • the activated form ofthe compound of formula (IX) is prepared by reaction ofthe compound of formula (IX) with a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction between compounds of formulae (IX) and (X) is carried out in an aprotic solvent, such as dimethylformamide or dimethylsulphoxide at any temperature which provides a suitable rate of reaction, conveniently at ambient temperature.
  • R ⁇ is a group convertible into a moiety of formula -OCH2R 2 .
  • R ⁇ is a methoxy group, thus preferably R2' represents hydrogen.
  • R6 may be converted into a group of formula -OCH2R 2 by any conventional means, for example when R > is a methoxy group, by treatment with a Lewis acid, such as boron tribromide, followed by reaction ofthe phenol so formed with a compound ofthe above defined formula (X) under conditions analogous to those described above for the reaction between the compounds of formulae (IX) and (X).
  • a Lewis acid such as boron tribromide
  • the compounds of formula (IX) wherein R ⁇ and R' a each represent hydrogen are known compounds or they are prepared according to methods used to prepare known compounds, such as those disclosed for such compounds when T* is t-butoxycarbonyl in Can. J. Chem. 1985, 62, 153.
  • a compound of formula (X) may be prepared by hydroxymethylation of a compound of formula (XI):
  • R ⁇ and R ⁇ are as defined in relation to formula (I),; and thereafter reacting the product so formed with a source of leaving group L 2 .
  • the hydroxymethylation is carried out using formaldehyde, generally in the form of paraldehyde, using conventional procedures depending upon the exact nature ofthe substrate, such as those disclosed by Houben-Weyl in Phosphor Verbinungen p28, J. Amer. Chem.-Soc. 1955, 77, 3522, Phosphorus and Sulphur 1978, 5_, 455 or in Aust. J. Chem. 1979, 32, 463 or in Tet. Lett. 1986, 27, 1477.
  • the conditions of reaction ofthe hydroxymethylated compound with the source of the leaving group will depend upon the nature ofthe leaving group L 2 but the appropriate conventional conditions are employed.
  • L 2 represents a 4- chlorobenzenesulphonyloxy group
  • the literature method of J. Cornforth et al J.C.S. Perkin 1, 1994, 1897 may be employed.
  • R 1 , R l a , R 2 , R ⁇ and X are as defined in relation to formula (I), R° is as defined in relation to formula (II), and thereafter, if required, carrying out one or more ofthe following optional steps:
  • the deprotection ofthe compound of formula (XII) may be carried out using conventional deprotection procedures depending upon the nature ofthe protection in R 0 ', for example when R° comprises a protected OH group such as a benzyloxy group, then the hydroxy group is reformed by using catalytic hydrogenolysis with hydrogen and a 5% or 10% Palladium-on-carbon catalyst.
  • the compounds of formula (IV) are either known commercially available compounds or they are prepared according to published methods or by use of analogous methods to the published methods, for example those disclosed in J.Chem. Soc. Perkin I;
  • the compounds of formula (V) are known commercially available compounds.
  • the compounds of formula (XI) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example may be prepared according to methods disclosed in Phosphorus and Sulphur, 1978, 5_, 455, J.
  • any reactive group or atom may be carried out at any appropriate stage in the aforementioned processes.
  • 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, for example OH groups, including diols, may be protected as the silylated derivatives by treatment with an appropiate silylating agent, for example diols are protected by use of di-tert-butylsilylbis(trifluoromethanesulphonate):
  • the silyl group may then be removed using conventional procedures such as treatment with hydrogen fluoride, preferably in the form of a pyridine complex.
  • benzyloxy groups may be used to protect phenoxy groups, the benzyloxy group may be removed using catalytic hydrogenolysis using such catalysts as palladium (II) chloride or 10% palladium on carbon.
  • Amino groups may be protected using any conventional protecting group, for example tert-butyl esters of carbamic acid may be formed by treating the amino group with di-lsU-butyldicarbonate, the amino group being regenerated by hydrolysing the ester under acidic conditions, using for example hydrogen chloride in ethyl acetate or trifluoroacetic acid in methylene dichloride.
  • the aminoboronic acid may be removed using catalytic hydrogenolysis, using for example a palladium on carbon catalyst.
  • an amino group may be protected as a benzyl derivative, prepared from the appropriate amine and a benzyl halide under basic conditions, the benzyl group being removed by catalytic hydrogenolysis, using for example a palladium on carbon catalyst, or by treatment with a dilute mineral acid.
  • 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 are halogen atoms, mesyloxy groups and tosyloxy groups, 3 -or 4-nitrobenzenesulphonyloxy and 4- chlorobenzenesulphony loxy .
  • salts, esters, amides and solvates ofthe compounds mentioned herein may be produced by methods conventional in the art: For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.
  • Compounds of formula (I) and pharmaceutically acceptable salts thereof; or a pharmaceutically acceptable solvate thereof, produced by the above processes, may be recovered by conventional methods.
  • mixtures of isomers ofthe compounds ofthe invention may be separated into individual stereoisomers and diastereoisomers by conventional means, for example by the use ofan optically active acid as a resolving agent.
  • optically active acids which may be 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 ofthe 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
  • the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable salt 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 thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia and Type II diabetes in human or non-human animals.
  • the present invention further provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-human animals.
  • the present invention provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use 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.
  • the present invention provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum, especially human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression.
  • HDL high-density-lipoprotein
  • a compound of formula (I), or a pharmaceutically acceptable salt 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 thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • 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.
  • compositions ofthe present invention may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • pharmaceutical compositions ofthe present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.
  • 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.
  • the composition will be formulated in unit dose form.
  • Such unit dose will normally contain an amount ofthe 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 or Type II diabetes 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 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 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 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, 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 thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
  • gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome
  • gastrointestinal ulcerations especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids
  • the present invention provides a method for treating for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum, especially human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression, 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 thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
  • HDL high-density-lipoprotein
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of: hyperglycaemia, Type II diabetes, obesity, 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, for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum, especially human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression.
  • HDL high-density-lipoprotein
  • the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect ofthe present invention.
  • 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.
  • the treatment regimens for treating the abovementioned gastrointestinal disorders atherosclerosis, hyperinsulinaemia and depression 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 ofan effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate thereof.
  • the compounds of formula (I) and the veterinarily acceptable salts thereof or a veterinarily acceptable solvate 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 thereof will normally be administered orally although 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--> ppm - 500ppm of total daily fed intake, more usually O.Olppm to 250ppm, suitably less than lOOppm.
  • 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 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.
  • Trifluoracetic acid (5ml) was added to a stirring solution of (R)-3-[4- (diphenylphosphinylmethyl)phenoxy]-2-propylcarbamic acid, tert-butyl ester (l .Og, 2.15mmol) in dichloromethane (25ml). After stirring for 1 hour, the mixture was evaporated and the residue re-dissolved in dichloromethane. Washed with aqueous sodium bicarbonate solution (x3) and brine. After drying (Na 2 SO ), the solution was evaporated to afford the title compound as a pale yellow oil (0.74g, 94%):
  • the title compound was prepared from (R)-2-[4-(diphenylphosphinyl- methyl)phenoxy]ethylcarbamic acid, tert-butyl ester (0.86g, 1.91mmol) employing a method similar to that used in procedure 9, isolating the compound as a pale yellow oil (0.65g, 97%) after evaporation.
  • Procedure 12 (S,R) Diphenyl-4- ⁇ 2-l2-hydroxy-3-(4-benzyI oxyphenoxy)propylamino] propyl ⁇ phenoxymethylphosphine oxide.
  • Lithium perchlorate (213mg, 2.0mmol) was added to a stirring solution of 2-(4- benzyloxyphenoxyrnethyl)-oxirane (512mgs, 2.0mmol) in acetonitrile (8ml). After 10 minutes a solution of (R)-4-(2-aminopropyl)phenoxymethyldiphenyl phosphine oxide (0.73g, 2.0mmol) in acetonitrile (7ml) was added. The reaction mixture was allowed to stir under argon atmosphere at room temperature for 2 days. Diluted with ethyl acetate and washed (water, then brine), dried (anhydrous MgSO 4 ), filtered and evaporated.
  • the title compound was prepared from [4-(2-aminoethyl)phenoxymethyl] diphenyl phosphine oxide (0.64g, 1.82mmol) and 2-(4-benzyloxy-phenoxymethyl)oxirane (0.47g, 1.83mmol) by stirring together in methanol solution (35ml) at room temperature and under argon atmosphere for 7 days. The mixture was evaporated and subjected to column chromatography to afford the product as a colourless oil (0.36g, 33%).
  • a solution of l-bromo-3-phenylpropane (6.0g, 30.1 mmol) in diethyl ether was added to a stirring mixture of magnesium metal turnings (0.73g, 30.0mmol) in diethyl ether (40ml). cooling in a cold water bath at 10°C and under argon atmosphere. Stirring was continued at 10°C for 20 mins and then at room temperature for 2 hours. After re-cooling a solution of diethyl phosphite (1.73g, 12.5mmol) in ether (10ml) was added dropwise resulting in the formation of a thick, gelatinous precipitate which was left for ' ⁇ hour.
  • Procedure 15 Hydroxymethyl, di(3-phenylpropyl)phosphine oxide.
  • Procedure 16 4-Chlorophenylsulphonic acid, di(3-phenyIpropyl)-phosphinylmethyl ester.
  • the title compound was prepared from 4-chlorophenylsulphonic acid, di(3- phenylpropyl)phosphinylmethyl ester (1.1 Og, 2.24mmol) and tert-butyl (R)-3-(4- hydroxyphenyl)-2-propyl carbamate (563mgs, 2.24mmol) using a method similar to that 0 in procedure 3. After chromatography a colourless gum was obtained (0.97g, 79%).
  • Procedure 18 (R)-4-(2-Aminopropyl)phenoxymethyldi(3-phenylpropyl)phosphine oxide.
  • the title compound was prepared from (R)-3- ⁇ 4-[di(3- 0 phenylpropyl(phosphinylmethyl]phenoxy ⁇ -2-propylcarbamic acid, tert-butyl ester (0.96g, 1.75mmol) and trifluoroacetic acid (4ml) in a manner similar to that employed for procedure 9, the product being isolated as a pale yellow oil (0.76g, 97%).
  • the title compound was prepared from acetic acid, (3-amino-4-benzyloxy phenyl)ester (3.67g, 14.28mmol) and benzenesulphonyl chloride using a method similar to that described in procedure 26.
  • the compound was isolated as a white solid after chromatography (2.31 g, 41 %).
  • the title compound was prepared from 4-benzyloxy-3-(N-tert-butoxy carbonyl)phenylsulphonylamino phenol (2.33g, 4.90mmol) and (2S)-(+)-glycidyl-3- nitrobenzenesulphonate (1.27g, 4.90mmol) using a method similar to that in procedure 29.
  • the compound was isolated as a white solid (2.32g, 93%) after chromatography.
  • Aqueous sodium hydrogen carbonate (4ml of a saturated solution) was added to a stirring solution of acetic acid, 4-benzyloxy-3-[N-ter/-butoxycarbonyl, (4- chloropheny l)sulphony lamino]pheny 1 ester (0.91 g, 1.71 mmol) in methanol (6ml) and dichloromethane (10ml). After stirring at room temperature for 4 days, the mixture was diluted with dichloromethane and washed with dilute aqueous citric acid. The organic phase was separated and the aqueous re-extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and then evaporated in vacuo to afford the title compound as a white foam (0.76g, 91%)r
  • Potassium carbonate (0.62g, 4.48mmol) was added to a stirring solution of 4-benzyloxy- 3-[N-tert-butoxycarbonyl, (4-chlorophenyl)sulphonylamino]phenol (0.73g, 1.49mmol) in dry acetone (50ml). The mixture was refluxed for 10 minutes under argon atmosphere and then re-cooled to room temperature. (2S)-(+)-Glycidyl-3-nitrobenzene sulphonate (0.50g, 1.93mmol) was added and the mixture was then refluxed for 19 hours under argon. Poured onto a half-saturated aqueous solution of ammonium chloride and extracted into ethyl acetate ( ⁇ 2).
  • Acetic acid, (3-amino-4-benzyloxyphenyl)ester (1.70g, 6.61 mMol) in dichloromethane (35ml) was treated with triethylamine (0.802g, 7.93mMol) and methanesulphonyl chloride (0.832g, 7.27mMol) and the mixture stirred at room temperature under argon for 20 minutes.
  • the solution was washed with water (3x10ml), dried and the solvent evaporated in vacuo. Trituration with diethyl ether gave the title compound as an off- white solid.
  • Procedure 33 (5)-2-[4-Beiizyloxy-3-(N-tert , -butoxycarbonyl)- methanesulphony lamino] phenoxy methy loxirane
  • Lithium perchlorate (83mgs, 0.78mmol) was added to a stirring solution of (S)-(2- ben2yloxy-5-oxiranylmethoxyphenyl)-N(tert-butoxycarbonyl)-methanesulphonamide (350mgs, O ⁇ mmol) in dry acetonitrile (6ml). After 10 mins a solution of (R)-4-(2- aminopropyl)-phenoxymethyl di(3-phenylpropyl)phosphine oxide (350mgs, 0.78mmol) in dry acetonitrile (3ml) was added. The mixture was stirred under argon atmosphere at room temperature for 4 days.
  • Lithium perchlorate (lOOmgs, 0.94mmol) was added to a stirring solution of (S)-2- ⁇ 4- benzyloxy-3-[N-tert-butoxycarbonyl, (4-chlorophenyl)- sulphonylaminojphenoxymethyl ⁇ oxirane (0.48g, 0.88mmol) in dry acetonitrile (12ml). After 15 minutes a suspension of [4-(2-aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.33g, 0.94mmol) in dry acetonitrile (8ml) was added, and the mixture allowed to stir at room temperature for 4 days under an atmosphere of argon.
  • the title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert- butoxycarbonyl)phenylsulphonylamino]phenoxymethyl oxirane (0.49g, 0.96mmol) and [4-(2-aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.40g, 1.14mmol) employing a method similar to that in procedure 35, isolating the compound as a dirty- white foam (0.25g, 34%).
  • Procedure 37 (S,R)-Diphenyl-4- ⁇ 2-[3-(4-benzyloxy-3-methane sulphonylaminophenoxy)-2-hydroxypropylamino)propyl ⁇ -phenoxymethyI phosphine oxide.
  • the title compound was prepared from (S)-(2-benzyloxy-5-oxiranylmethoxyphenyl)-N- (tert-butyoxycarbonyl)methansulphonamide and (R)-4-(2-aminopropyl)phenoxymethyl diphenyl phosphine oxide in a manner similar to that employed for Procedure 35, to give a beige foam.
  • the title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert-butoxy carbonyl)methanesulphonylamino]phenoxymethyl oxirane (0.45g, l.Ommol) and [4-(2- aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.39g, 1.1 lmmol) using a method similar to that in procedure 35.
  • the compound was isolated as an off-white gum (0.2 lg, 30%).
  • Procedure 40 Acetic acid, 4-benzyloxy-3-(N-/.?rf-butoxycarbonyl)-w ⁇ -propyl- sulphonylatninophenyl ester
  • the title compound was prepared from acetic acid, (4-benzyloxy-3-w ⁇ - propylsulphonylaminophenyl) ester (2.95 g, 8.13 mmol) and di-tert-butyldicarbonate employing a method similar to that used in procedure 27, isolating the compound as a lemon-yellow coloured foam (2.95g, 78%).
  • the title compound was prepared from acetic acid, 4-benzyloxy-3-(N-/ert- butoxycarbonyl)-wo-propylsulphonylaminophenyl ester (2.92g, 6.31 mmol) using a method similar to that in procedure 24, isolating a brown foam (2.59g, 98%).
  • the title compound was prepared from 4-benzyloxy-3-(N-tert-butoxycarbonyl) iso propylamino phenol (2.56 g, 6.08 mmol) and (2S)-(+) glycidyl-3-nitrobenzene sulphonate (2.05 g) employing a method similar to that used in procedure 29. After chromatography the compound was isolated as a yellow oil (2.62g, 90%).
  • the title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert-butoxycarbonyl)- w ⁇ -propylsulphonylamino]phenoxymethyl oxirane (0.63 g, 1.32 mmol) and [4-(2- aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.50 g, 1.42 mmol) employing a method similar to that used in procedure 35. The compound was isolated as a white foam (0.40 g, 42%).
  • the title compound was prepared from 4-chlorophenylsulphonic acid, dimethylsphosphinylmethyl ester (0.69 g, 2.44 mmol) and tert-butyl [2-(4- hydroxyphenyl)ethyl]carbamate (0.58 g, 2.45 mmol) using a method similar to that used in procedure 3, the product being isolated as a beige-coloured solid (0.68 g, 85%).
  • the title compound was prepared from 2-[4-(dimethylphosphinylmethyl)phenoxy]ethyl- carbamic acid, tert-butyl ester (0.67 g, 2.05 mmol) employing a method similar to that of procedure 9, but using n-butanol to extract the product. This gave the product as a white semi-solid (0.50 g, still containing some n-butanol) after evaporation.
  • the title compound was prepared from [4-(2-aminoethyl)phenoxymethyl]dimethyl phosphine oxide (0.37 g, 1.63 mmol) and 2-(4-benzyloxyphenoxymethyl)oxirane (0.41 g, 1.60 mmol) in a manner similar to that used in procedure 13. After chromatography, a white foam (0.23 g, 30%) was isolated.
  • the title compound was prepared from acetic acid, (3-amino-4-benzyloxyphenyl) ester (6.97 mmol) and 1-naphthylsulphonyl chloride using a method similar to that described in procedure 26.
  • the compound was isolated as a pale pink solid (1.94g, 62%).
  • Procedure 50 Acetic acid, 4-benzyloxy-3-[(N-/er/-butoxycarbonyI)-l- naphthylsulphonylaminoj-phenyl ester
  • the title compound was prepared from acetic acid (4-benzyloxy-3-(l- naphthylsulphonylamino)phenyl ester (1.91g, 4.27 mmol) and di-tert-butyl dicarbonate employing a method similar to that of procedure 27, isolating the compound as a light brown foam (2.34g, 100%) that was used without further purification.
  • the title compound was prepared from acetic acid 4-benzyloxy-3-[(N-tert- butoxycarbonyl)-l-naphthylsulphonylamino] phenyl ester (2.39g, 4.37 mmol) and sodium hydroxide by a method similar to that of procedure 24. After purification by column chromatography the title compound (2.09g, 95%) was obtained as a pale brown solid.
  • the title compound was prepared from 4-benzyloxy-3-[(N-tert-butoxycarbonyl)-l- naphthylsulphonylamino]phenol (2.03g, 4.02 mmol) and (S)-(+)-glycidyl-3- nitrobenzenesulphonate (1.35g, 5.21 mmol) by a method similar to that employed in procedure 29.
  • the compound was isolated as a white solid (0.96g, 42%) after chromatography.
  • Procedure 55 Acetic acid, [4-Benzyloxy-3-[N-(4-methoxybenzyl)- trifluoromethanesulphonylamino]phenyl] ester.
  • Acetic acid, [4-benzyloxy-3-trifluoromethanesulphonylaminophenyl]ester (lg, 2.57 mmol) was alkylated with 4-methoxybenzyl chloride under standard alkylating conditions (potassium carbonate in acetone at reflux ovemight). The title compound was obtained as a white solid (1.26g, 96%) after purification by column chromatography.
  • the title compound was obtained as a white solid (0.52g, 42%) from 4-benzyloxy-3-[N- (4-methoxybenzyl)-trifluoromethanesulphonylamino]phenol (1.12g, 2.4 mmol) and (2S)- (+)-glycidyl-3-nitrobenzenesulphonate (0.8 lg, 3.13mmol) using a method similar to that of procedure 29.
  • the title compound (0.58g, 70%) was obtained was a white gum from [4-(2- aminoethyl)phenoxymethyl]diphenylphosphine oxide (2g, 5.7 mmol) and (S)-2-[4- benzyloxy-3-[(N-4-memoxybenzyl)-rrifluoromemanesulphonylamino]phenoxymethyl oxirane (0.49g, 0.936 mmol) by a method similar to that of procedure 53 using ethanol as a cosolvent.
  • the title compound was prepared from 4-fluoro-3-nitroacetophenone (1.07g) and 3- chloroperoxybenzoic acid (approximately 60% purity) (5mol. equivalents) employing a method similar to that of procedure 20. Pure product as an amber solid (0.6g, 52%) was obtained by suction chromatography eluting with ethyl acetate (from 5% to 10%) in hexane.
  • Procedure 63 Acetic acid, 4-fluoro-3-phenylsulphonyIaminophenyl ester.
  • the title compound was prepared from acetic acid, 3-amino-4-fluorophenyl ester (0.59g), phenylsulphonyl chloride (0.53g) and pyridine (0.47g) employing a method similar to that of procedure 26. Pure product was obtained as a colourless solid (0.39g).
  • the title compound was prepared from acetic acid, 4-fluoro-3- phenylsulphonylaminophenyl ester (0.69g), di-tert-butyl dicarbonate (0.54g) and 4- dimethylaminopyridine (5mg) employing a method similar to that of procedure 27. Pure product as a colourless solid (lg) was obtained by suction chromatograhpy eluting with ethyl acetate (from 10% to 30%) in hexane.
  • Procedure 65 3-[(N-tert-Butoxycarbonyl)-phenylsulphonylamino]-4-fluorophenol.
  • the title compound was prepared from acetic acid, 3-[(N-ter/-butoxycarbonyl)- phenylsulphonylamino]-4-fluorophenyl ester (1.75g) and potassium hydroxide (0.23 g) employing a method similar to that of procedure 24. Pure product was obtained as a colourless solid (1.54g).
  • the title compound was prepared from 3-[(N-tert-butoxycarbonyl)- ⁇ henylsulphonylamino]-4-fluorophenol (1.54g), (2S)-(+)-glycidyl-3- nitrobenzenesulfonate (1.2g) and potassium carbonate (0.95g) employing a method similar to that of procedure 29. Pure product as a colourless solid (lg) was obtained by suction chromatography eluting with ethyl acetate (from 15% to 50%) in hexane.
  • the title compound was prepared from 4-(2-amino-2,2-dimethylethyl)phenol,(as described in. B. Renger., Arch Pharm. 1983, 316, 193.) triethylamine and di-tert- butylcarbonate using a method similar to that described in Procedure 7, as a colourless solid.
  • the title compound was prepared from 2-(4-hydroxyphenyl)- 1,1 -dimethylethylcarbamic acid, tert-butyl ester and 4-chlorophenylsulphonic acid, diphenylphosphinylmethyl ester using a method similar to that described in Procedure 3, as a colourless solid.
  • the title compound was prepared from 2-[4-(diphenylphosphinylmethyl) phenoxy]- 1,1- dimethylethylcarbamic acid, tert-butyl ester and trifluoroacetic acid using a method similar to that described in Procedure 9 as a gum. This material was used directly in Example 14.
  • Example 3 (S,R)Di(3-phenyIpropyl)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]-propyl ⁇ phenoxymethyl phosphine oxide.
  • the title compound was prepared from (S)-diphenyl-4- ⁇ 2-[2-hydroxy-3-(4-benzyloxy-3- methanesulphonylaminophenoxy)propylamino]ethyl ⁇ -phenoxymethyl phosphine oxide (180mg, 0.26mmol) by hydrogenolysis, employing a method similar to that used in example 5.
  • the compound was isolated as a white foam (80mg, 51%) after silica-gel chromatography.
  • the title compound was prepared from (S)-diphenyl-4- ⁇ 2-[2-hydroxy-3-(4-benzyloxy-3- wo-propylsulphonylaminophenoxy)propylamino]ethyl ⁇ phenoxymethyl phosphine oxide (0.37 g, 0.51 mmol) using a method similar to that of Example 5. After chromatography the compound was isolated as a white foam (0.20 g, 62%).
  • ⁇ iH 250 MHz, CDCI3 + CD3OD: 1.35 (6H, d); 2.76 - 3.01 (6H, m); 3.13 (4H, broad s, exchangeables, overlapping with H2O - signal); 3.21 (IH, m, partially obscured by H 2 O - signal); 3.81 (2H, d); 4.07 (IH, m); 4.68 (2H, d); 6.35 (IH, dd); 6.78 (3H, m); 7.04 (IH, d); 7.11 (2H, d); 7.54 (6H, m) and 7.83 (4H. m).
  • the title compound was prepared from (S)-dimethyl-4- ⁇ 2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino]ethyl ⁇ phenoxymethyl phosphine oxide (210 mgs, 0.43 mmol) in a manner similar to that used in example 5, isolating the compound as a white foam (170 mgs, quant).
  • Example 10 (S)-Diphenyl-4- ⁇ 2-[2-hydroxy-3-(3-(l-naphthylsulphonylamino)-4- hydroxy)phenoxy)propylamino] ethyl ⁇ phenoxy methyl phosphine oxide, trifluoroacetate salt.
  • the title compound was prepared by hydrogenation of (S)-diphenyl-4- ⁇ 2-[2-hydroxy-3- (4-benzyloxy-3-(l-naphthylsulphonylamino)phenoxy)propylamino]ethyl ⁇ phenoxy- methylphosphine oxide, trifluoroacetate salt (0.38g, 0.41 mmol) at atmospheric pressure by a method similar to that employed in Example 5. Purification by column chromatography on silica gel and freeze drying gave the title compound as an off-white foam (0.10g, 29%).
  • the title compound was prepared by hydrogenation of (S)-diphenyl-4- ⁇ 2-[2-hydroxy-3- (4-benzyloxy-3-[(N-4-methoxy benzyl)- trifluoromethanesulphonylamino]phenoxy )- propylaminojethyl ⁇ phenoxymethyl phosphine oxide (0.44g, 0.503mmol) at atmospheric pressure by a method similar to that employed in Example 5. After freeze drying the title compound was obtained as a very pale violet foam (0.127g, 38%).
  • the title compound was prepared from (S)-diphenyl-4- ⁇ 2-[3-(2,2-di-tert-butyl-4H- 1,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]ethyl ⁇ -phenoxymethyl phosphine oxide (0.48g, 0.7mmol) by treatment with hydrogen fluoride/pyridine using a method similar to example 4 of W96/04233.
  • Example 13 (S)-Diphenyl-4-(2- ⁇ 2-hydroxy-3-[(3-phenylsulfonylamino-4-fluoro)- phenoxy]-propylamino ⁇ -ethyl)-phenoxymethylphosphine oxide hydrochloride.
  • Antagonist and Agonist Activity at Human ⁇ j, ⁇ 2» and ⁇ 3-Adrenoceptors Subclones of CHO cells are stably transfected with each of the human ⁇ i , ⁇ 2 and ⁇ 3-adrenoceptorsl. c e u s ⁇ g gn disrupted by immersion in ice-cold lysis buffer (10 mM TRIS, 2mM EDTA , pH 7.4) containing protease inhibitors leupeptin and benzamidine (5 mg / ml) and soyabean trypsin inhibitor (10 mg / ml). Membranes are prepared by the method of Bouvier et. al.2 and stored in 1 ml aliquots in liquid N2 for future use.
  • Adenylyl cyclase activity is assayed by the method of Kirkham et. al.3 by the addition of 40 ml (70 -80 mg protein) to the incubation medium ofthe above CHO cell plasma membranes transfected with the human b3 -adrenoceptor .
  • cAMP produced over 20 minutes is separated from ATP by the method of Salomon et alA
  • Agonist EC50 values and intrinsic activities are expressed as the concentration of agonist producing 50 % activation of adenylyl cyclase and the maximum response produced by each agonist relative to that produced by (-) isoprenaline respectively.
  • Displacement of [125i]_i 0 docyanopindolol fro CHO cell plasma membranes transfected with either the human ⁇ i , or ⁇ 2-adrenoceptors is carried out by the method of Blin et.
  • alA Ki values (nM) are calculated from the binding IC50 values for each agonist, using the Cheng -Prusoff equation.

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Abstract

Composés représentés par la formule (I) ou un de ses sels acceptable sur le plan pharmaceutique ou un de ses solvates acceptable sur le plan pharmaceutique. Dans la formule (I), Ro représente un groupe aryle éventuellement substitué par un, deux ou trois substituants sélectionnés dans la liste constituée par hydroxy, hydroxyméthyle, nitro, amino, alkylamino, dialkylamino, alkylsulfonamido, le groupe alkyle étant éventuellement substitué par un, deux ou trois substituants sélectionnés parmi halogène, haloalkyle, hydroxy, alcoxy ou arylsulfonamido, le groupe aryle étant éventuellement substitué, à condition que Ro ne soit pas 3-méthylsulfonylaminophényle quand X représente O ou S; R?1 et R1a¿ représentent chacun indépendamment hydrogène ou un groupe alkyle; R2 représente une fraction représentée par la formule (a): dans laquelle R4 et R5 représentent chacun indépendamment hydrogène, alkyle, cycloalkyle, aryle ou aralkyle ou R5 et R4 représentent -(CH¿2?)n-, n valant 3, 4 ou 5; R?3¿ représente hydrogène, halogène, alkyle ou alcoxy; composition pharmaceutique contenant ce composé, procédé servant à préparer ce composé et l'utilisation de ce composé et de cette composition en médecine.
PCT/EP1997/001286 1996-03-15 1997-03-12 Derives d'amine d'aryloxy et d'arylthiopropanol contenant du phosphore, utiles en tant qu'agonistes du beta adrenorecepteur WO1997034905A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004047A1 (fr) * 1993-07-31 1995-02-09 Smithkline Beecham Plc Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique
WO1996004233A1 (fr) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Derives d'aryloxy- et d'arylthiopropanolamine utiles en tant qu'agonistes d'adrenorecepteurs beta 3 et qu'antagonistes des adrenorecepteurs beta 1 et beta 2 et composition pharmaceutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004047A1 (fr) * 1993-07-31 1995-02-09 Smithkline Beecham Plc Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique
WO1996004233A1 (fr) * 1994-07-29 1996-02-15 Smithkline Beecham Plc Derives d'aryloxy- et d'arylthiopropanolamine utiles en tant qu'agonistes d'adrenorecepteurs beta 3 et qu'antagonistes des adrenorecepteurs beta 1 et beta 2 et composition pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BEELEY L J ET AL: "A simplified template approach towards the synthesis of a potent beta-3 adrenoceptor agonist at the human receptor", BIOORG. MED. CHEM. LETT. (BMCLE8,0960894X);97; VOL.7 (2); PP.219-224, DEPARTMENT OF MEDICINAL CHEMISTRY, SMITHKLINE BEECHAM PHARMACEUTICALS;EPSOM; KT18 5XQ; UK (GB), XP000675569 *

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