WO1998037056A1 - Derives de phenoxypropanolamine et compositions pharmaceutiques les contenant - Google Patents

Derives de phenoxypropanolamine et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1998037056A1
WO1998037056A1 PCT/GB1998/000514 GB9800514W WO9837056A1 WO 1998037056 A1 WO1998037056 A1 WO 1998037056A1 GB 9800514 W GB9800514 W GB 9800514W WO 9837056 A1 WO9837056 A1 WO 9837056A1
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Prior art keywords
formula
compound
hydroxy
pharmaceutically acceptable
phenoxymethyl
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PCT/GB1998/000514
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English (en)
Inventor
Harshad Kantilal Rami
David Kenneth Dean
Lee James Beeley
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Smithkline Beecham Plc
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Publication of WO1998037056A1 publication Critical patent/WO1998037056A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton

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 also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock.
  • X represents -O-
  • X I represents -O(CH2) n - wherein n is zero or an integer in the range of from 1 to 4;
  • RI and R ⁇ each independently represents hydrogen or alkyl or Rl together with R2 and the carbon atom to which they are attached represent a C3_g cycloalkyl group;
  • R3 represents hydrogen, halogen, alkyl or alkoxy; and R represents a moiety of formula (a):
  • Suitable optional substitutents for R° include one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, alkylsulphonamido, arylsulphonamido and halogen.
  • R° represents a phenyl group optionally substituted with hydroxy and/or hydroxymethyl and/or halogen, especially fluoro and/or alkylsulphonamido and/or arylsulphonamido.
  • R° include 4-hydroxy-3-hydroxymethylphenyl, 4- hydroxyphenyl, 3- and 4-(N-methanesulfonylamino)phenyl.
  • Rl or R ⁇ represents alkyl
  • the alkyl group is favourably C ⁇ . alkyl, especially methyl.
  • R and R ⁇ each independently represents alkyl.
  • R* is an alkyl group and R ⁇ represents hydrogen.
  • R* and R ⁇ each represents hydrogen.
  • R ⁇ is hydrogen
  • acidic groups includes sulphonate groups, alkylsulphonamides and arylsulphonamides.
  • Suitable acidic groups also include phosphinamide and cyanoamide groups.
  • Acidic groups R ⁇ further include optionally substituted monocyclic heterocyclic groups having 5 or 6 ring atoms which ring atoms comprise 1, 2, 3 or 4 hetero atoms or moieties selected from N, NH, O or S and wherein optional substituents are selected from hydroxy, amino or thiol.
  • R is selected from groups of formula:
  • Suitable esters are alkyl esters, especially C ⁇ _ 6 alkyl esters.
  • Suitable amides are those of formula -CO.NR s Rt wherein R s and R* each independently represent hydrogen or alkyl.
  • X 2 R 5 is attached at the 2 position.
  • n is an integer 1.
  • m is zero.
  • the compounds of formula (I) comprise asymmetric carbon atoms, (for example those carbon atoms marked with an asterisk (*) or two asterisks (**) in formula (I)). These compounds may therefore exist in several 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.
  • the asymmetric carbon atom indicated by a single asterisk (*) is in the S -configuration.
  • the asymmetric carbon atom indicated by two asterisks (**) is in the R-configuration.
  • One suitable form of a compound of formula (I) is a mixture of the SR and RS enantiomers.
  • SR enantiomer One favoured form of a compound of formula (I) is the SR enantiomer.
  • 'hydrolysable derivative' includes derivatives hydrolysable under post -administration pharmacological conditions.
  • '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 fluorine or chlorine.
  • Suitable pharmaceutically acceptable salts include acid addition salts or salts of carboxy groups.
  • 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.
  • alkylamines such as triethylamine, hydroxy-C ⁇ _6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, 1,4-dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
  • pyridine type such as pyridine, collidine or quinoline.
  • Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.
  • Rl, R ⁇ , R ⁇ and x e as defined in relation to formula (I)
  • R ⁇ a is R ⁇ as defined in relation to formula (I) or a group convertible to R ⁇ 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
  • R° represents a protected form of R° such as those defined herein, for example when R° comprises an OH group it may be protected as a silylated derivative.
  • Suitable protecting groups represented by T° are benzyl or p- methoxybenzyl groups or, preferably, the amine group is present as the trifluoroacetate salt.
  • Suitable groups R a which are convertible to R include moieties of formula (b):
  • R 5a is R 5 as defined in relation to formula (I) or a group convertible into R .
  • R 5a is usually a protected form of R 5 such as an esterified form, for example a methyl ester.
  • R 5a is either the required ester or an alternative ester, for example a methyl ester, which may be first converted into a carboxyl group, by conventional hydrolysis, followed by appropriate esterification or said alternative ester may be converted directly into the required ester using conventional trans-esterification methods.
  • R a is a group convertible into an amide by conventional methods, for example a nitrile group or a carboxylic acid or ester.
  • R 5a is usually a sulfonyl chloride derived from the corresponding sulfonic acid.
  • R 5a is usually a phosphoryl chloride derived from the corresponding phosphonic acid or ester.
  • R 5a is usually the corresponding carboxylic acid or ester.
  • 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 metal hydride or an alkali metal carbonate, for example sodium hydride or potassium carbonate.
  • a base such as an alkali metal hydride or an alkali metal carbonate, for example sodium hydride or potassium carbonate.
  • L,l represents a tosylate or a 3-nitrobenzenesulphonyloxy group.
  • 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 suitable activated form of a compound of formula (VI) is an ionic form, such as an alkali metal salted form, for example a potassium salted form.
  • an activated form of the compound of formula (VI) is conveniently prepared by treating the compound of formula (VI) with a base such as an alkali metal carbonate, for example potassium carbonate; the subsequent reaction between the compounds of formulae (VI) and (VII) may be carried out in an aprotic solvent such as acetone, dimethylformamide or butanone at any temperature providing a suitable rate of formation of the required product, generally at an ambient to elevated temperature, suitably an elevated temperature, such as the reflux temperature of the solvent; or (ii) when variable n in the compound of formula (VII) is zero, an activated form of the compound of formula (VI) is prepared by treating the compound of formula (VI) with a base such as an alkali metal hydride, for example sodium hydride; the subsequent reaction between the compounds of formulae (VI) and (VII) may be carried out in an aprotic solvent such as pyridine at any temperature providing a suitable rate of
  • Compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds, such as those disclosed in Journal of Organic Chemistry, 1988, 53(3), 487 or in International Patent Application, publication number W096/04233.
  • Compounds of formula (VI) are known compounds or they are prepared according to methods used to prepare known compounds, such as those disclosed in W096/04233.
  • R , Rla, R ⁇ and R ⁇ a are as defined in relation to formula (I); and thereafter, as required, protecting the amino group so formed.
  • a compound of formula (VIII) is prepared from a compound of formula
  • R ⁇ is as defined in relation to formula (I).
  • reaction between the compounds of formulae (IX) and (X) is suitably carried out in tetrabutyl ammonium fluoride at an elevated temperature, for example 130°C and preferably in an inert atmosphere, such as argon.
  • the compounds of formula (X) are known compounds or they are prepared by use of analogous processes to those used to prepare known compounds, for example those methods disclosed by P. Claus et al, Monatsh. Chem., 1972, 103 (4), 1178-93.
  • Suitable conversions of any group R a into a group R 4 are carried out using the appropriate conventional procedure depending upon the specific nature of the group R 4 required; generally the conversion involves the conversion of R 5a into the required group R 5 in themoiety of formula (b).
  • Suitable conversion of R ⁇ a into R ⁇ include: (i) converting R ⁇ a when representing CO2 11 , wherein R u is C g alkyl, into R-> as a carboxyl group;
  • the conversion of nitrile into the above defined amide CO.NR s Rt may be effected by: a) treating the nitrile with hydrogen peroxide/potassium carbonate for compounds wherein R s and R* each independently represent hydrogen; or b) for amides wherein one or both of R s and R* represents alkyl, by first hydrolysing the nitrile to a carboxyl group and thereafter coupling with a suitable amine in the presence of a coupling agent such as dicyclohexylcarbodiimide.
  • the conversation of amine into a sulphonamide may be carried out by reaction of the amine with an appropriate alkyl- or aryl-sulphonyl halide, suitably a sulphonylchloride.
  • 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-Jert-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.
  • 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.
  • Carboxyl groups may be protected as alkyl esters, for example methyl esters, which esters may be prepared and removed using conventional procedures, one convenient method for converting carbomethoxy to carboxyl is to use aqueous lithium hydroxide.
  • 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.
  • salts, esters, amides and solvates of the compounds mentioned herein may as required 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.
  • Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions.
  • Amides may be prepared using conventional amidation procedures, for example amides of formula CONR s R t may be prepared by treating the relevant carboxylic acid with an amine of formula HNR s R t ' wherein R s and R* are as defined above.
  • a Cj.6 alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR s R t to provide the required amide.
  • the absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques. As previously indicated, the compounds of formula (I) have been discovered to possess valuable pharmacological properties.
  • the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable acid addition 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 acid addition salt 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 acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-human mammals.
  • the present invention provides a compound of formula (I), or pharmaceutically acceptable acid addition 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 acid addition 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 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 acid addition 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 acid addition salt 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.
  • 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.
  • 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 acid addition 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 acid addition 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 acid addition 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 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 acid addition 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 acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of: hyperglycaemia, 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 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 of the 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 title compound was prepared from 2-(4-hydroxyphenyl)ethylcarbamic acid, t- butyl ester and methyl 2-bromomethylbenzonitrile according to the method described in Procedure 2.
  • the title compound was prepared from N-(4-benzyloxyphenyl) methanesulfonamide and di-t-butyldicarbonate according to the method described in procedure 27.
  • the title compound was prepared from N-(4-benzyloxyphenyl)-N-(t- butoxycarbonyl)methanesulfonamide according to the method described in procedure 22.
  • Lithium aluminium hydride (0.235g, 6.2mMol) was suspended in tetrahydrofuran (25ml) and cooled to 0°C.
  • 5-Benzyloxy-2-hydroxy benzoic acid methyl ester (2g, 7.75mMol) in tetrahydrofuran (10ml) was added dropwise, v/ ' ⁇ cannula.
  • the mixture was warmed to room temperature and stirred for 20 minutes.
  • the reaction was then cooled to 0°C and cautiously quenched by the addition of water (0.5ml), 2M sodium hydroxide solution (0.5ml), and water (1ml).
  • the resulting mixture was stirred at room temperature for 30 minutes and filtered.
  • the filtrate was evaporated in vacuo to yield 4-benzyloxy-2 -hydroxymethyl phenol as a clear oil which was used in the next step without further purification.
  • Subclones of CHO cells are stably transfected with each of the human ⁇ ⁇ 2 and ⁇ 3-adrenoceptorsl. Cells are then disrupted by immersion in ice-cold lysis buffer (10 mM TRIS, 2mM EDTA , pH 7.4) containing protease inhibitors leupeptin and benzamidine (5 ⁇ g / ml) and soyabean trypsin inhibitor (10 ⁇ g / 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 ⁇ l (70 -80 ⁇ g protein) to the incubation medium of the above CHO cell plasma membranes transfected with the human ⁇ 3-adrenoceptor .
  • cAMP produced over 20 minutes is separated from ATP by the method of Salomon et al
  • a 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 [125 _j oc iocyanopindolol from CHO cell plasma membranes transfected with either the human ⁇ j, 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de la formule (I) (ou un sel pharmaceutiquement acceptable ou un solvate pharmaceutiquement acceptable dudit composé) dans laquelle R0 est un groupe aryle éventuellement substitué par un, deux ou trois substituants sélectionnés dans la liste constituée par hydroxy, hydroxyméthyle, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, formamido, halogène, alcoxy et allyle; X est -O-; X1 est -O(CH¿2?)n- (n étant zéro ou un entier compris entre 1 et 4); R?1 et R2¿ sont chacun, indépendamment, hydrogène ou alkyle, ou R1 et R2 constituent ensemble, avec l'atome de carbone auquel ils sont liés, un groupe cycloalkyle C¿3-8; R?3 est hydrogène, halogène, alkyle ou alcoxy; et R4 est une fraction de la formule (a) dans laquelle X2 est -(CH¿2?)m (m étant zéro ou un entier compris entre 1 et 4); et R?5¿ est un groupe acide comprenant au moins un hydrogène acide ou un dérivé hydrolysable dudit groupe acide. L'invention concerne également une méthode de préparation desdits composés, une composition pharmaceutique contenant lesdits composés et l'utilisation d'un tel composé ou d'une telle composition dans des médicaments.
PCT/GB1998/000514 1997-02-20 1998-02-18 Derives de phenoxypropanolamine et compositions pharmaceutiques les contenant WO1998037056A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006519196A (ja) * 2003-02-27 2006-08-24 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Ｐｐａｒ受容体モジュレーターとしての分枝側鎖を有するアリールシクロアルキル誘導体、その製造方法および医薬としてのその使用
WO2008090140A1 (fr) 2007-01-22 2008-07-31 4Sc Ag Aryloxypropanolamines, procédé de fabrication de celles-ci et utilisation d'aryloxypropanolamines comme médicaments

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0140243A2 (fr) * 1983-10-19 1985-05-08 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Phénoxypropanolamines
EP0328251A2 (fr) * 1988-01-21 1989-08-16 Imperial Chemical Industries Plc 2-(2-hydroxy-3-phénoxypropylamino)éthylphénoxyacétamides, procédés et intermédiaires de leur préparation
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
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0140243A2 (fr) * 1983-10-19 1985-05-08 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Phénoxypropanolamines
EP0328251A2 (fr) * 1988-01-21 1989-08-16 Imperial Chemical Industries Plc 2-(2-hydroxy-3-phénoxypropylamino)éthylphénoxyacétamides, procédés et intermédiaires de leur préparation
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
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A. J. SHUKER ET AL: "The application of high-throughput synthesis and purification to the preparation of ethanolamines", TETRAHEDRON LETTERS, vol. 38, no. 35, 1 September 1997 (1997-09-01), OXFORD GB, pages 6149 - 6152, XP002065960 *
ANN. PHARM. FR, vol. 45, no. 5, 1987, pages 379 - 387 *
CHEMICAL ABSTRACTS, vol. 110, no. 7, 13 February 1989, Columbus, Ohio, US; abstract no. 57222t, J. BOMPART ET AL: "Synthesis of new beta-blocker analogs of bevantolol or alprenolol" page 645; XP002065961 *
M. L. HOEFLE ET AL: "Cardioselective beta-adrenergic blocking agents. 1. 1-((3,4-Dimethoxyphenyl)amino)-3-aryloxy-2-propanols", JOURNAL OF MEDICINAL CHEMISTRY, vol. 18, no. 1, 1975, WASHINGTON US, pages 148 - 152, XP002065959 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006519196A (ja) * 2003-02-27 2006-08-24 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Ｐｐａｒ受容体モジュレーターとしての分枝側鎖を有するアリールシクロアルキル誘導体、その製造方法および医薬としてのその使用
WO2008090140A1 (fr) 2007-01-22 2008-07-31 4Sc Ag Aryloxypropanolamines, procédé de fabrication de celles-ci et utilisation d'aryloxypropanolamines comme médicaments

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