WO1995004047A1 - Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique - Google Patents

Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique Download PDF

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WO1995004047A1
WO1995004047A1 PCT/EP1994/002434 EP9402434W WO9504047A1 WO 1995004047 A1 WO1995004047 A1 WO 1995004047A1 EP 9402434 W EP9402434 W EP 9402434W WO 9504047 A1 WO9504047 A1 WO 9504047A1
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formula
compound
pharmaceutically acceptable
hydroxy
alkyl
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PCT/EP1994/002434
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English (en)
Inventor
Lee James Beeley
John Michael Berge
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Smithkline Beecham Plc
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Priority claimed from GB939315930A external-priority patent/GB9315930D0/en
Priority claimed from GB939321875A external-priority patent/GB9321875D0/en
Priority claimed from GB939323982A external-priority patent/GB9323982D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU75322/94A priority Critical patent/AU7532294A/en
Priority to JP7505545A priority patent/JPH09502166A/ja
Priority to EP94925381A priority patent/EP0711284A1/fr
Publication of WO1995004047A1 publication Critical patent/WO1995004047A1/fr

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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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • 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
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

  • This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to die 5 use of such compounds and compositions in medicine and agriculture.
  • Offenlegungschrift 2905877 discloses certain 1-amino heterocyclyloxy-2- propanol derivatives which are stated to have inter alia beta adrenergic blocking activity.
  • United Kingdom Patent Application, Publication Number 2014146 A 10 discloses certain etherified hydroxy - benzodiheterocyclic derivatives which are stated to have long lasting cardioselective beta - receptor blocking activity and alpha receptor blocking activity.
  • United States Patent Number 4367235 discloses certain 2-benzimidazolinone compounds which are stated to have marked beta - receptor blocking activity.
  • International Patent Application, Publication Number 94/02493 discloses certain phosphonated arylethanolamine derivatives which are stated to have inter alia good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects.
  • 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 30 when induced by non-steroidal anti-inflammatory drugs or corticosteroids.
  • These compounds may also be of use in increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful 35 for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.
  • HDL high-density- lipoprotein
  • R° represents a moiety of formula (a):
  • X represents O or S
  • R! and R ⁇ a each independently represents hydrogen or an alkyl group
  • R2 represents OCH2CO2H, or an ester or amide thereof, or R ⁇ represents a moiety of formula (b):
  • R ⁇ represent hydrogen, alkyl, hydroxyalkyl or cycloalkyl and R ⁇ represent hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R ⁇ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl or R ⁇ together with OR'* represents O(CH2>nO wherein n is 2, 3 or 4; and
  • R3 represents hydrogen, halogen, alkyl or alkoxy or R ⁇ together with R ⁇ represents a moiety of formula (c):
  • R ⁇ is an alkyl group.
  • R! is alkyl
  • it is favourably a Cj.g alkyl group, especially a methyl group.
  • R ⁇ a represents hydrogen.
  • X* represents NH.
  • X ⁇ represents NH.
  • X ⁇ and X ⁇ each represents NH.
  • T represents hydrogen.
  • R ⁇ represents OCH2CO2H, or an ester or amide thereof.
  • R ⁇ represents a moiety of formula (b).
  • R ⁇ together with R ⁇ represents a moiety of formula (c).
  • R ⁇ is a moiety of formula (b).
  • R ⁇ is hydrogen
  • R ⁇ represent hydrogen or alkyl, especially alkyl.
  • R ⁇ represents hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy.
  • R ⁇ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl.
  • R ⁇ represents hydroxy, alkoxy or hydroxyalkyloxy.
  • the hydroxy group is substituted on the terminal carbon atom of the alkyl group, for example as in a 2- hydroxypropyloxy group.
  • R ⁇ represents alkoxy.
  • R ⁇ represent alkyl, especially C .Q alkyl, for example ethyl, and
  • R5 represent alkoxy, -especially C ⁇ . alkoxy, for example ethoxy.
  • R ⁇ is alkyl, for example ethyl, and R ⁇ is hydrogen.
  • X represents O.
  • the compounds of formula (I) have one or two asymmetric carbon atoms, marked with an asterisk (*) or two asterisks (**) in the formula. These compounds may therefore exist in up to four 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-conf ⁇ guration.
  • One suitable form of a compound of formula (I) is a mixture of the SR and RS enantiomers.
  • the present invention provides a compound selected from the list consisting of: (S,R)4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxy)acetic acid, methyl ester, S,R) 4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol- 4- yloxy)propylamino]propyl)phenoxy)acetic acid; (S,R)-4-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxymethylphosphonic acid, diethyl ester; and especially,
  • '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.
  • 'cycloalkyl' includes C3_g cycloalkyl groups, especially C5 or Cg cycloalkyl groups.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
  • Suitable pharmaceutically acceptable esters of carboxyl groups include alkyl esters, especially Cj.g alkyl esters such as methyl.
  • Suitable pharmaceutically acceptable amides are those of formula -CONR s R t wherein R s and R l each independently represent hydrogen, alkyl or alkoxyalkyl.
  • Suitable pharmaceutically acceptable salts include acid addition salts, salts of carboxy groups and salts of phosphonic acid 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, toluenesulophonic 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, toluenesulophonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
  • Suitable pharmaceutically acceptable salts of carboxy groups or phosphonic acid groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C ⁇ .
  • alkylamines such as triethyla ine, hydroxy-Cj.g alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
  • 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 acid addition salt or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II) with phosgene:
  • R , R a , R ⁇ , R3 and X are as defined in relation to formula (I), one of X ⁇ or X ⁇ represents NH2 and the other of X ⁇ or X ⁇ is selected from NH2 > OH or SH and T * represents T as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and (ii) preparing a pharmaceutically acceptable acid addition salt of a compound of formula (I) or a pharmaceutically acceptable solvate thereof.
  • reaction between the compound of formula (II) and phosgene may be carried out in any suitable solvent, generally an aqueous solvent such as aqueous hydrogen chloride, at any temperature providing a suitable rate of formation of the required product, usually at a low to ambient temperature, such as in the range of from 0°C to 15°C, for example at 5°C.
  • a suitable solvent generally an aqueous solvent such as aqueous hydrogen chloride
  • a compound of formula (II) may be prepared by reducing a compound of formula (III):
  • R 1 , R la , R 2 , R 3 , T' and X are as defined in relation to the compounds of formula (II), one of X 5 or X 6 represents NO2 and the other of X 5 and X > represents NH2, ORPl or SRPi, wherein RPl represents hydrogen or a protecting group, and thereafter removing any protecting group RP .
  • the reduction of the compound of formula (III) may be carried out using any suitable reduction procedure, usually catalytic hydrogenation for example by using a 10% palladium on carbon catalyst optionally in the presence of ammonium formate.
  • Suitable reduction conditions include using an alkanol solvent such as methanol, preferably deoxygenated with for example carbon dioxide, at any temperature providing a suitable rate of formation of the required product, usually at a low to ambient temperature, conveniently at ambient temperature.
  • RP represents a protecting group such as a benzyl group or, especially when either of X ⁇ or X ⁇ is ORPl or SRP , a substituted benzyl group such as a 4-methoxybenzyl group, which may be removed using any conventional procedure, for example catalytic hydrogenolysis, for removal of benzyl from oxygen, or treatment with mercuric acetate, for removal of 4-methoxybenzyl from sulphur.
  • the compound of formula (III) may be prepared by reacting a compound of formula (IV):
  • reaction between compounds of formulae (IV) and (V) may be carried out in any suitable solvent, such as methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; preferably under an inert atmosphere such as nitrogen.
  • suitable solvent such as methanol
  • a compound of formula (IV) may be prepared by reacting an activated form of a compound of formula (IVA):
  • L ⁇ represents a leaving group
  • a suitable activated form of a compound of formula (IVA) 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 (IVA) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (IVA) with a base such as an alkali bicarbonate, for example potassium bicarbonate.
  • L represents a tosylate or a 3-nitrosulphonyl group.
  • the reaction between the compounds of formulae (IVA) and (IVB) may be carried out in an aprotic solvent such as acetone 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.
  • a compound of formula (V) may be prepared by the hydrogenolysis of a compound of formula (VI):
  • R 1 , R 2 and R 3 are as defined in relation to formula (I) and the **CH carbon and ***CH carbon atoms are chiral carbon atoms.
  • catalytic hydrogenolysis is used, using for example 10% palladium on charcoal 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; preferably the reaction is ca ⁇ ied out in an inert atmosphere, generally under nitrogen .
  • the compound of formula (VI) may be prepared by stereoselective reduction of a compound of formula (VII):
  • Rl, R 2 and R 3 are as defined in relation to formula (I) and the
  • the reduction of the 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 of the 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):
  • Rl, R 2 and R 3 are as defined in relation to formula (I), with R- ⁇ -methylbenzylamine.
  • reaction between compounds of formulae (VIII) and R- ⁇ -methylbenzylamine may be carried out under conventional 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 of the above defined formula (VIE) with R- ⁇ -methylbenzyl amine and thereafter reducing the compound of formula (VII) so formed using reaction conditions and catalysts as described above.
  • a compound of formula (VIII) such as those wherein R 2 represents a moiety of the above defined formula (b) wherein R ⁇ represent hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl may be prepared by reducing a compound of formula (IX):
  • R* and R 3 are as defined in relation to formula (I) and as stated R 2 is as defined in relation to the required compounds of of formula (VIII).
  • the reduction of the compound of formula (IX) may conveniently be carried out using iron powder in the presence of acetic acid in an aqueous solvent such as aqueous methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent.
  • an aqueous solvent such as aqueous methanol
  • a compound of formula (IX) may be prepared by reacting a compound of formula (X):
  • the carbon atom of the -CHO group in the compound of formula (X) is in an activated form, a suitable activated form being provided by forming an imine of the said carbonyl group:
  • the imine may be prepared by reacting the compound of formula (X) with an amine, suitably a primary alkyl amine such as n- butylamine.
  • the reaction of the compound of formula (X) and the amine may be carried out in any suitable solvent, such as toluene, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; and preferably in the presence of a catalytic amount of toluenesulphonic acid.
  • reaction between the compound of formula (X), and when it is in the form of an imine and nitroalkane may be carried out in glacial acetic acid, preferably in the presence of an ammonium acetate catalyst, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C.
  • a compound of formula (X) may be prepared from a compound of formula
  • R ⁇ is as defined in relation to formula (IX) and L ⁇ is a leaving group or atom, generally a fluorine atom, with an activated form of a compound of formula
  • R ⁇ and R ⁇ are as defined in relation to formula (I).
  • a suitable activated form of a compound of formula (XII) is an ionic form, such as a salted form, for example an alkali metal salted form.
  • An activated form of a compound of formula (XII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (XII) with a base such as an alkali metal hydride, for example sodium hydride.
  • a base such as an alkali metal hydride, for example sodium hydride.
  • reaction between the compounds of formulae (XI) and (XII) may be carried out in any suitable solvent, generally an aprotic solvent such as dimethylformamide or N-methylpyrrolidinone at a low to ambient temperature, for example in the range of from - 15°C to 20°C, such as 5°C.
  • aprotic solvent such as dimethylformamide or N-methylpyrrolidinone
  • a compound of formula (I), wherein R* a represents hydrogen, or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof, may also be prepared by reducing a compound of formula (XIII):
  • R°, Rl, R3 and X are as defined in relation to formula (I) and R 2 ' represents R 2 as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps:
  • the reduction of the compound of formula (XIII) may be carried out using any suitable reduction procedure, for example by using catalytic reduction.
  • Suitable catalysts include platinum oxide or 10% palladium on charcoal.
  • Suitable reduction conditions include using an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example when using the platinum catalyst the reaction may conveniently be carried out at ambient temperature or when using the palladium catalyst the reaction may be carried out at a medium temperature such as 50°C, under a pressure of 1-5 atmospheres of hydrogen.
  • an alkanolic solvent such as methanol
  • R 2 represents a moiety of the above defined formula (b)
  • R 2 ' generally represents a protected form of R 2 , for example a benzylated form, which may be removed by use of any conventional method, thus the benzylated form may be removed by use of hydrogenolysis using ammonium formate in the presence of a 10% palladium on carbon catalyst.
  • the compound of formula (XIII) may be prepared by reacting a compound of formula (XIV):
  • reaction between compounds of formulae (VIII) and (XIV) may be carried out under conventional amination conditions, for example in a solvent such as toluene or, preferably, methanol.
  • the compound of formula (XIII) is prepared in-siru by reacting a compounds of the above defined formulae (VIII) and (XIV) under reductive amination conditions which includes reaction in an alkanolic solvent, such as methanol, in the presence of a suitable reduction catalyst, for example those described above for the reduction of the compound of formula (XIII).
  • a suitable reduction catalyst for example those described above for the reduction of the compound of formula (XIII).
  • a compound of formula (XIV) may be prepared by reacting a compound of formula (XV) with phosgene:
  • RP represents a protecting group, such as a benzyl group which may conveniently be removed by use of catalytic hydrogenolysis, for example by use of ammonium formate in the presence of a 10% palladium on carbon catalyst, as described above.
  • T in the required compound of formula (XIV) represents OH or NH2
  • T' represents a protected form thereof, such as a benzylated hydroxy group or an acylated amino group.
  • the conversion of T * to the corresponding T, by removal of the protecting group, is carried out using the appropriate conventional procedure.
  • the reaction of the compound of formula (XV) with phosgene may be carried out under analogous conditions to those disclosed above for the reaction of the compound of formula (II) with phosgene.
  • a compound of formula (XV) may be prepared by reducing a compound of formula (XVI):
  • RPl represents a protecting group such as a benzyl group which may be removed using any conventional procedure, for example catalytic hydrogenolysis, for removal of benzyl from oxygen, or treatment with mercuric acetate, for removal of benzyl from sulphur.
  • the compounds of formula (XVI) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those methods disclosed in United Kingdom Patent Application, Publication Number
  • the compounds of formula (IVA) are either known commercially available compounds or known compounds prepared according to published methods or by use of analogous methods to the published methods, thus the compounds wherein X ⁇ is
  • the compounds of formula (IVB) are known commercially available compounds.
  • the compounds of formula (XII) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example the compounds of formula (XII) may be prepared according to methods disclosed in Phosphorus and Sulphur, 1978, 5, 455.
  • Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting one group OR 4 into another group OR 4 and/or converting one group R ⁇ into another group R ⁇ .
  • Suitable conversions of one group OR 4 into another group OR * include: (i) converting OR'* as hydroxy into OR 4 as alkoxy; (ii) converting OR** as alkoxy into OR * as hydroxy; (iii) convening OR 4 as alkoxy into OR** as another alkoxy group.
  • the abovementioned conversion (i) may be carried out under conventional phosphonate alkylation methods, using for example the appropriate alcohol (R 4 OH) in the presence of hydrogen chloride.
  • the abovementioned conversion (ii) may be carried out using conventional phosphonate hydrolysis methods, for example by treating the appropriate compound of formula (I) with an alkaline metal hydroxide, such as sodium hydroxide.
  • an alkaline metal hydroxide such as sodium hydroxide.
  • the abovementioned conversion (iii) may be carried out by first converting OR' as alkoxy into OR 4 as hydroxy using the conditions set out in respect of the abovementioned conversion (ii), followed by converting the hydroxy group so formed into another alkoxy group, using the conditions set out in respect of the abovementioned conversion (i).
  • Suitable conversions of one group R ⁇ into another group R ⁇ include analogous conversions to those mentioned above in regard to converting one group OR 4 into another group OR 4 .
  • Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected. Protecting groups may be prepared and removed using the appropriate conventional procedure.
  • a leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless othewise specified are halogen atoms, mesyloxy groups and tosyloxy groups.
  • the salts, esters, amides and solvates of the 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.
  • 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 l may be prepared by treating the relevant carboxylic acid with an amine of formula HNR s R l » wherein R s and R l are as defined above. Alternatively, a C ⁇ . alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR s R l to provide the required amide.
  • mixtures of isomers of the compounds of the invention may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • optically active acids which maybe used as resolving agents are described in Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971 , Allinger, N.L. and Eliel, W.L. Eds.
  • any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
  • the absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques.
  • the compounds of the present invention have valuable pharmacological properties:
  • the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable 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 animals.
  • 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.
  • the term "pharmaceutically acceptable” embraces compounds, compositions and ingredients for both human and veterinary use: for example the term “pharmaceutically acceptable salt” embraces a veterinarily acceptable salt.
  • the composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.
  • Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
  • Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • the composition will be formulated in unit dose form.
  • Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable 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.
  • 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 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 acid addition salt thereof, or a veterinarily acceptable solvate thereof.
  • the compounds of formula (I) and the veterinarily acceptable acid addition 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 acid addition 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 10-3 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 acid addition 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.
  • the title compound was prepared by an analogous method to that described in Procedure 1 from (S)-3-(2-amino-3-nitrophenoxy)-l,2-epoxypropane (140mg, 0.67mMol) and (R)-diethyl 4-(2-aminopropyl)phenoxymethylphosphonate (200mg, 0.66mMol) by heating under reflux in methanol (20ml) for 24h. The solvent was removed under reduced pressure, the residue was taken into ethyl acetate and washed with water (2 x 15ml) and the aqueous extracts back extracted with ethyl acetate (2 x 10ml). The organic extracts were combined, washed with brine (2 x 15ml), dried and the solvent removed under reduced pressure. The crude product was purified by column chromatography eluting with 0-8% methanol in dichloromethane.
  • the unstable brown oil obtained was used in the next step without further purification.
  • Example 2 from (S, R) 4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propyl)amino]propylphenoxymethylphosphonic acid, diethyl ester (1 lOmg, 0.22mMol) and 1M lithium hydroxide (10ml) in 1,4-dioxan (10ml) at room temperature for 24 hours under argon. The solution was adjusted to pH 9 by addition of solid carbon dioxide, and the solvents evaporated. The residue was purified by reverse phase chromatography over Cjg silica eluting with 0-10% isopropanol in water to give a white powder.
  • Agonist Activity at Rat ⁇ j and ⁇ 2 Adrenoceptors In Vitro ⁇ j-Adrenoceptor Agonism Female Sprague-Dawley rats (150-250g) are killed by a blow to the head and exsanguinated. Spontaneously beating right atria are removed by the method of Broadley and Lumley (1977) and mounted on a glass tissue holder. Each tissue is placed in 30 ml organ baths at 37°C containing Kreb's- Henseleit solution. Each atrium is attached to an isometric transducer by cotton and placed under an initial resting tension of lg. Rate recordings from the spontaneous beating atria are obtained from the tension signal using a Lectromed Type 4522 ratemeter.
  • ⁇ -adrenoceptor agonists are then added to the Krebs medium in a cumulative fashion and the results expressed as a percentage increase in atrial rate.
  • ⁇ 2-Adrenoceptor Agonism Rat uterine horns are removed and bisected longitudinally. Each tissue is tied to a glass tissue holder and placed in Krebs- Henseleit solution in a 30 ml organ bath as before. Tissues are placed under a resting tension of lg and allowed to equilibrate. Each uterine strip is pre-contracted by the addition of 40mM K + to the bath to produced a steady tonic contraction, ⁇ -agonists are then added to the bath in a cumulative manner and results expressed as percentage inhibition of contraction.
  • Subclones of CHO cells were stably transfected with each of the human ⁇ i, ⁇ 2 and ⁇ 3-adrenoceptors .
  • Cells were 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 were prepared by the method of Bouvier et. al. 2 and stored in 1 ml aliquots in liquid N2 for future use.
  • Adenylyl cyclase activity was 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 was separated from ATP by the method of Salomon et al. 4 .
  • Agonist EC50 values and intrinsic activities were 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.

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Abstract

Dérivés de 2-benzohétérocyclyloxy ou thiopropanolamine répondant à la formule (I), ou leur sel ou solvate pharmaceutiquement acceptable, formule dans laquelle Ro représente une fraction répondant à la formule (a), dans laquelle X¿1? et X2 représentent pour l'un NH et pour l'autre NH, O ou S, et T représente hydrogène ou un, deux ou trois substituants choisis dans la liste dans laquelle figurent: hydroxy, amino, alkylamino, dialkylamino, alkylsulfonamido, arylsulfonamido, amidoformyle, halogène et alcoxy; X représente O ou S; R?1 et R1a¿, indépendamment l'un de l'autre, représentent hydrogène ou un groupe alkyle; R2 représente OCH¿2?CO2H ou son ester ou amide, ou R?2¿ représente une fraction répondant la formule (b), dans laquelle R4 représente hydrogène, alkyle, hydroxyalkyle ou cycloalkyle et R5 représente hydroxy, alcoxy, hydroxyalkyloxy ou cycloalkyloxy ou R5 représente hydrogène, alkyle, alkyle substitué, cycloalkyle ou aryle, ou R?5 et OR4¿, pris ensemble, représentent O(CH¿2?)nO où n vaut 2, 3 ou 4; et R?3¿ représente hydrogène, halogène, alkyle ou alcoxy ou R3, pris ensemble avec R2, représentent une fraction répondant à la formule (c), ou son ester ou amide; procédé de préparation d'un composé de ce type; composition pharmaceutique le comportant; et utilisation médicale dudit composé. Les composés revendiqués sont des agonistes du récepteur adrénergique.
PCT/EP1994/002434 1993-07-31 1994-07-22 Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique WO1995004047A1 (fr)

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AU75322/94A AU7532294A (en) 1993-07-31 1994-07-22 2-benzoheterocyclyloxy or thiopropanolamine derivatives with adreno receptor agonist activity
JP7505545A JPH09502166A (ja) 1993-07-31 1994-07-22 アドレナリン受容体作動薬活性を有する２−ベンゾヘテロシクリルオキシまたはチオプロパノールアミン誘導体
EP94925381A EP0711284A1 (fr) 1993-07-31 1994-07-22 Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique

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Cited By (9)

* Cited by examiner, † Cited by third party
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WO1996032369A1 (fr) * 1995-04-14 1996-10-17 Tokyo Tanabe Company Limited Nouveaux composes aryloxypropanolamino(phenyl)propanol
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques
WO1997034905A1 (fr) * 1996-03-15 1997-09-25 Smithkline Beecham Plc Derives d'amine d'aryloxy et d'arylthiopropanol contenant du phosphore, utiles en tant qu'agonistes du beta adrenorecepteur
US5677321A (en) * 1996-02-29 1997-10-14 Synaptic Pharmaceutical Corporation 5- and 6-(2-imidazolin-2-ylamino) and -(2-thiazolin-2-ylamino)-benzothiazoles as alpha-2 adrenergic ligands
WO1998022480A1 (fr) * 1996-11-18 1998-05-28 Smithkline Beecham Plc Derives de propanolamine aryloxy ou arylthio contenant du phosphore
US5808080A (en) * 1996-09-05 1998-09-15 Eli Lilly And Company Selective β3 adrenergic agonists
US6046227A (en) * 1997-12-05 2000-04-04 Eli Lilly And Company Selective β3 adrenergic agonists
US6140352A (en) * 1996-09-05 2000-10-31 Eli Lilly And Company Carbazolyl-substituted ethanolamines as selective β-3 agonists
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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EP0000784A1 (fr) * 1977-08-12 1979-02-21 Roche Diagnostics GmbH Dérivés de 4-hydroxy benzimidazolin-2-one, procédé de préparation et leurs compositions pharmaceutiques
EP0003758A1 (fr) * 1978-02-09 1979-09-05 Ciba-Geigy Ag Hydroxy-benzodihétérocycles éthérifiés et leurs sels d'addition acides, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0014951A2 (fr) * 1979-02-16 1980-09-03 Roche Diagnostics GmbH Dérivés hétérocycliques d'oxypropanolamine, procédé pour leur préparation et médicaments contenant ces composés
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Cited By (27)

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WO1996032369A1 (fr) * 1995-04-14 1996-10-17 Tokyo Tanabe Company Limited Nouveaux composes aryloxypropanolamino(phenyl)propanol
US5939443A (en) * 1995-09-21 1999-08-17 Eli Lilly And Company Selective β3 adrenergic agonists
EP0764640A1 (fr) * 1995-09-21 1997-03-26 Eli Lilly And Company Agonistes adrénergiques bêta-3 spécifiques
US6093735A (en) * 1995-09-21 2000-07-25 Eli Lilly And Company Selective β-3 adrenergic agonists
US6265581B1 (en) 1995-09-21 2001-07-24 Eli Lilly And Company Selective β3 adrenergic agonists
US6060492A (en) * 1995-09-21 2000-05-09 Eli Lilly And Company Selective β3 adrenergic agonists
US5786356A (en) * 1995-09-21 1998-07-28 Eli Lilly And Company Selective β3 adrenergic agonists
US5977154A (en) * 1995-09-21 1999-11-02 Eli Lilly And Company Selective β3 adrenergic agonist
US6723741B2 (en) 1996-02-29 2004-04-20 Synaptic Pharmaceutical Corporation Benzimidazoles and benzothiazoles and uses thereof
US5948804A (en) * 1996-02-29 1999-09-07 Synaptic Pharmaceutical Corporation Substituted indoles and uses thereof
US6498177B2 (en) 1996-02-29 2002-12-24 Synaptic Pharmaceutical Corporation Indole and benzothiazole derivatives
US6040451A (en) * 1996-02-29 2000-03-21 Synaptic Pharmaceutical Corporation Substituted indoles and uses thereof
US6303643B1 (en) 1996-02-29 2001-10-16 Synaptic Pharmaceutical Corporation Substituted indoles and uses thereof
US6159998A (en) * 1996-02-29 2000-12-12 Synaptic Pharmaceutical Corporation Substituted indoles and uses thereof
US5677321A (en) * 1996-02-29 1997-10-14 Synaptic Pharmaceutical Corporation 5- and 6-(2-imidazolin-2-ylamino) and -(2-thiazolin-2-ylamino)-benzothiazoles as alpha-2 adrenergic ligands
WO1997034905A1 (fr) * 1996-03-15 1997-09-25 Smithkline Beecham Plc Derives d'amine d'aryloxy et d'arylthiopropanol contenant du phosphore, utiles en tant qu'agonistes du beta adrenorecepteur
US5808080A (en) * 1996-09-05 1998-09-15 Eli Lilly And Company Selective β3 adrenergic agonists
US6140352A (en) * 1996-09-05 2000-10-31 Eli Lilly And Company Carbazolyl-substituted ethanolamines as selective β-3 agonists
US6075040A (en) * 1996-09-05 2000-06-13 Eli Lilly And Company Selective β3 adrenergic agonists
US6413991B1 (en) 1996-09-05 2002-07-02 Eli Lilly And Company Selective β3 adrenergic agonists
US5840738A (en) * 1996-09-05 1998-11-24 Eli Lilly And Company Selective β-3 adrenergic agonists
US6686372B2 (en) 1996-09-05 2004-02-03 Eli Lilly And Company Selective β3 adrenergic agonists
US7041684B2 (en) 1996-09-05 2006-05-09 Eli Lilly And Company Selective β3 adrenergic agonists
WO1998022480A1 (fr) * 1996-11-18 1998-05-28 Smithkline Beecham Plc Derives de propanolamine aryloxy ou arylthio contenant du phosphore
US6046227A (en) * 1997-12-05 2000-04-04 Eli Lilly And Company Selective β3 adrenergic agonists
US6617347B1 (en) 1997-12-05 2003-09-09 Eli Lilly And Company Selective β3 adrenergic agonists
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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