EP0772585A1 - Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof - Google Patents

Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof

Info

Publication number
EP0772585A1
EP0772585A1 EP95929029A EP95929029A EP0772585A1 EP 0772585 A1 EP0772585 A1 EP 0772585A1 EP 95929029 A EP95929029 A EP 95929029A EP 95929029 A EP95929029 A EP 95929029A EP 0772585 A1 EP0772585 A1 EP 0772585A1
Authority
EP
European Patent Office
Prior art keywords
formula
acid
compound
procedure
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95929029A
Other languages
German (de)
English (en)
French (fr)
Inventor
Lee J. SmithKline Beecham Pharmaceuticals BEELEY
Mervyn Smithkline Beecham Pharmaceut. Thompson
David K. SmithKline Beecham Pharmaceuticals DEAN
Nikesh R. SmithKline Beecham Pharmaceut. KOTECHA
John M. SmithKline Beecham Pharmaceuticals BERGE
Robert W. SmithKline Beecham Pharmaceut. WARD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB9415304A external-priority patent/GB9415304D0/en
Priority claimed from GB9423179A external-priority patent/GB9423179D0/en
Priority claimed from GBGB9510485.7A external-priority patent/GB9510485D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0772585A1 publication Critical patent/EP0772585A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/08—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • 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
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/303—Cycloaliphatic acids
    • 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
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3223—Esters of cycloaliphatic acids
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.
  • European Patent Application, Publication Number 0328251 discloses certain 2-(2-hydroxy-3-phenoxypropylamino)ethylphenoxyacetamides which are stated to be useful in the treatment of obesity and related conditions. It has now surprisingly been discovered that a particular series of novel aryloxy and arylthio propanolamine derivatives have good ⁇ 3-adrenoreceptor agonist activity and in particular show good selectivity for ⁇ 3-adrenoreceptors over the ⁇ j- or ⁇ 2-adrenoreceptors, to the extent that these compounds are antagonists of the ⁇ j- and ⁇ 2-adrenoreceptors. These compounds are indicated to have 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 when induced by non-steroidal anti-inflammatory drugs or corticosteroids.
  • HDL high-density- lipoprotein
  • 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.
  • 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, arylsulphonamido, formamido, halogen, alkoxy and allyl;
  • X represents O or S;
  • Rl 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, arylalkyl, aryloxyalkyl, aralkyloxyalkyl or cycloalkyl and R ⁇ represent hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, aryloxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy or R ⁇ represents hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl or R ⁇ together with OR ⁇ represents O(CH2) n O 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):
  • Suitable aryl groups include phenyl or naphthyl groups, especially phenyl groups.
  • Suitable optional substitutents for R° include one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, alkylsulphonamido and halogen.
  • R° represents a phenyl group optionally substituted with hydroxy and/or hydroxymethyl and/or halogen, especially fluoro and/or alkylsulphonamido.
  • R° examples include 4-hydroxy-3-hydroxymethylphenyl, 3- and 4- hydroxyphenyl, 3-fluoro-4-hydroxyphenyl and 4-hydroxy-3-methylsulphonamido phenyl groups.
  • R* is an alkyl group and R* a represents hydrogen.
  • Rl and R ⁇ a each represents hydrogen.
  • Rl is alkyl, it is favourably a Cj.g alkyl group, especially a methyl group.
  • R a represents hydrogen.
  • R ⁇ represents OCH2CO2H, or an ester or amide thereof.
  • R ⁇ together with R ⁇ represents a moiety of formula (c) or R ⁇ represents a moiety of formula (b) and R ⁇ represents hydrogen, halogen, alkyl or alkoxy.
  • 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 ⁇ represents hydrogen, halogen, alkyl or alkoxy.
  • R ⁇ is hydrogen.
  • R ⁇ represent hydrogen, alkyl, hydroxyalkyl, phenylalkyl, benzyloxyalkyl or cycloalkyl.
  • R4 represents alkyl, especially Cj.g alkyl
  • examples include ethyl and butyl, especially n-butyl.
  • R ⁇ represents hydroxyalkyl, an example is hydroxypropyl.
  • R4 represents arylalkyl
  • an example is phenylpropyl.
  • R4 represents arylalkyloxyalkyl
  • an example is benzyloxyethyl.
  • R ⁇ represent hydrogen or alkyl, especially hydrogen.
  • R5 represents substituted alkyl
  • suitable substituents are selected from: hydroxy, alkoxy and arylalkoxy.
  • R ⁇ represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxy alky loxy, arylalkoxyalkyloxy or cycloalkyloxy, especially alkoxy, hydroxyalkyloxy or arylalkoxyalkyloxy.
  • R5 represents alkoxy, especially C ⁇ . alkoxy, examples include ethoxy and n-butoxy.
  • R5 represents arylalkyloxy
  • arylalkyloxy an example is phenylpropyloxy.
  • R5 represents arylalkoxyalkyloxy
  • an example is benzyloxypropyloxy.
  • the hydroxy group represented by R ⁇ is substituted on the terminal carbon atom of the alkyl group, for example as in a 2- hydroxyethyloxy group and a 3-hydroxypropyloxy group.
  • R ⁇ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl.
  • R5 represents cycloalkyl
  • an example is cyclohexyl
  • R ⁇ represents alkyl for example n-hexyl.
  • R ⁇ represents aryl for example phenyl.
  • R5 represents alkyl examples include n-hexyl.
  • R ⁇ represent alkyl, especially C ⁇ .(, alkyl, for example ethyl, and
  • R5 represent alkoxy, especially ⁇ . ⁇ alkoxy, for example ethoxy.
  • R ⁇ is alkyl, for example ethyl, and R ⁇ is hydrogen.
  • X represents O.
  • the invention provides a subgroup of the compounds of formula (I) wherein R°, Rl, Rl a , R ⁇ , R3 a nd x re as defined in relation to formula (I), providing that formula (I) does not include 4-[2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]propyl] phenoxyacetic acid and the salts and esters thereof or 4-[2-[2-hydroxy-3-phenoxypropylamino]ethyl] phenoxyacetic acid and an amide thereof.
  • the invention provides a subgroup of the compounds of formula (I) wherein R° and X are as defined in relation to formula (I), R ⁇ represents OCH2CO2H or an ester or amide thereof, R ⁇ represents hydrogen and R . R ⁇ are as defined in relation to formula (I) providing that at least one of R* or R a represents alkyl.
  • the invention provides a subgroup of the compounds of formula (I) wherein R°, Rl, R a and X are as defined in relation to formula (I) and R represents a moiety of formula (b) and R ⁇ represents hydrogen, halogen, alkyl or alkoxy or R ⁇ together with R ⁇ represents a moiety of formula (c), such compounds shall hereinafter be referred to as compounds of formula (IA).
  • 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 phosphorous atom of moiety (b) is different and other than OH the phosphorous atom is chiral:
  • the invention extends to mixed and separated isomers of such compounds in an analogous fashion to that discussed for chiral carbon atoms.
  • 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.
  • '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 C cycloalkyl groups.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.
  • sulphonamido refers to the moiety '-SO 2 -NH-', for example methylsulphonamido refers to the moiety 'CH 3 -SO 2 -NH-'.
  • 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 l wherein R s and R* 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. Salts of phosphinic acids are also suitable pharmaceutically acceptable salts of the invention.
  • 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.
  • Suitable pharmaceutically acceptable salts of carboxy groups, phosphonic acid or phosphinic acid groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium and lithium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C ⁇ .
  • alkylamines such as triethylamine, hydroxy-C g alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or t ⁇ i-(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.
  • 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):
  • R , R a , R ⁇ and R ⁇ are as defined in relation to formula (I) and T° represents a hydrogen or a protecting group; and thereafter, if required, carrying out one or more of the following optional steps:
  • the reaction between compounds of formulae (II) and (III) 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 ine ⁇ atmosphere such as nitrogen or argon, alternatively the reaction between compounds of formulae (II) and (III) may be carried out in a chlorinated solvent such as dichloromethane or in an aprotic solvent such as acetonitrile; suitably the reaction is carried out in the presence of a catalyst such as ytterbium triflate as described in Tetrahedron Letters, 1994, 35(3), 433 or a perchlorate such as lithium perchlorate.
  • R°' represents a protected form of R°, suitable protected forms being as defined herein.
  • Suitable protecting groups represented by T° are benzyl or p-methoxybenzyl groups.
  • 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.
  • a base such as an alkali carbonate, for example potassium carbonate.
  • L° represents a tosylate or a 3-nit ⁇ obenzenesulphonyloxy group.
  • the 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 of the required product, generally at an ambient to elevated temperature, suitably an elevated temperature, such as the reflux temperature of the solvent.
  • 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 R ⁇ is not hydrogen, is suitably prepared by the hydrogenolysis of a compound of formula (VI):
  • R l , R ⁇ and R ⁇ are as defined in relation to formula (I)
  • Y represents hydrogen or a moiety -B(OH)2 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 carried out in an inert atmosphere, generally under nitrogen .
  • a compound of formula (VI) wherein Y is a moiety B(OH)2 may be prepared from a corresponding compound of formula (VI) wherein Y is H, by treatment with boron tribromide in an inert solvent such as methylene chloride at ambient temperature, preferably in an inert atmosphere such as argon, followed by removal of Y using catalytic hydrogenolysis, using for example a palladium on carbon catalyst.
  • a compound of formula (VI) wherein Y is H may be prepared by stereoselective reduction of a compound of formula (VII):
  • Rl, R ⁇ and R ⁇ are as defined in relation to formula (I) and the ***C carbon is a chiral carbon.
  • 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.
  • an alkanol solvent such as methanol or ethanol
  • the compound of formula (VII) may be prepared by reacting a compound of formula (VIII):
  • Rl, R ⁇ and R ⁇ 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 (VIII) 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 ⁇ 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 ⁇ are as defined in relation to formula (I) and as stated R ⁇ is as defined in relation to the required compounds 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.
  • a compound of formula (IX) may be prepared by reacting a compound of formula (X):
  • R ⁇ and R ⁇ are as defined in relation to formula (IX), with a nitroalkane, such as nitromethane or nitroethane.
  • 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.
  • the 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 (XII):
  • 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
  • Rl and R ⁇ a are as defined in relation to formula (I) and T* represents a protecting group, such as a t-butoxycarbonyl group, by reaction with a compound of formula (XIV):
  • L* and L ⁇ each represents a leaving group or atom, suitably a halogen atom such as bromine atom, and T ⁇ and T ⁇ each represents a protecting group; and thereafter if required removing any protecting group.
  • T ⁇ and T ⁇ each represent a C ⁇ . ⁇ alkoxy group, for example an ethoxy group.
  • the compound of formula (XIII) is in an activated form.
  • a suitable activated form of a compound of formula (XIII) 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 (XIII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (XIII) with a base such as an alkali carbonate, for example potassium carbonate.
  • a base such as an alkali carbonate, for example potassium carbonate.
  • the compound of formula (XIII) is usually in an activated form, such as an anionic form.
  • the activated form is conveniently prepared in-situ prior to addition of the compound of formula (XIV).
  • the reaction between the compounds of formula (XIII) and (XIV) may be carried out in an aprotic solvent, such as acetone, at any temperature which provides a suitable rate of formation of the required product but usually at an elevated temperature, such as the reflux temperature of the solvent, preferably in the presence of a base such as potassium carbonate and preferably under an inert atmosphere such as argon.
  • an aprotic solvent such as acetone
  • the compounds of formula (XIII) are known compounds or they are prepared according to methods used to prepare known compounds, such as those disclosed in J. Med. Chem. 1973, 16(5), 480.
  • R l , R ⁇ a , R ⁇ and T are as defined in relation to formula (XIII): a) for compounds of formula (III) wherein R ⁇ is OCH2CO2H or an ester or amide thereof, by reaction with a compound of formula (XVI):
  • L ⁇ is a leaving group or atom, suitably a halogen atom such as a bromine atom, and T 4 is a protecting group; or b) for compounds of formula (III) wherein R ⁇ is a moiety of the above defined formula (b), by reaction with a compound of formula (XVII):
  • R 4 and R ⁇ are as defined in relation to formula (I) and L 4 is a leaving group or atom; and thereafter, as necessary removing any protecting group.
  • T* is a t-butoxycarbonyl group.
  • T 4 is a C g alkoxy group such as a methoxy group.
  • the compound of formula (XV) is usually in an activated form, such as an anionic form.
  • the activated form is conveniently prepared in-situ prior to addition of the compound of formula (XVI) or (XVII).
  • the activated form of the compound of formula (XV) is prepared by reaction of the compound of formula (XV) with a base such as sodium hydride.
  • a base such as sodium hydride.
  • the reaction between the compounds of formulae (XV) and (XVI) is suitably carried out in an aprotic solvent, such as acetone, at any temperature which provides a suitable rate of formulation of the required product usually an elevated temperature such as the reflux temperature of the solvent, preferably in the presence of a base such as potassium carbonate and preferably under an inert atmosphere such as argon.
  • the reaction between compounds of formulae (XV) and (XVII) 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.
  • the compounds of formula (XV) wherein Rl and R* a each represent hydrogen are known compounds of 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, 6.2, 153.
  • a compound of formula (XVII) may be prepared by hydroxymethylation of a compound of formula (XX):
  • R 4 and R ⁇ are as defined in relation to the compounds of formula (I), to provide a compound of the above defined formula (XII); and thereafter reacting the compound so formed with a source of leaving group T.
  • the hydroxymethylation is carried out using formaldehyde, generally in the form of paraldehyde, using conventional procedures depending upon the exact nature of the 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.
  • the conditions of reaction of the hydroxymethylated compound of formula (XII) with the source of the leaving group will depend upon the nature of the leaving group L 4 but the appropriate conventional conditions are employed.
  • L 4 represents a 4-chlorobenzenesulphonyloxy group
  • the literature method of J. Cornforth ⁇ t_ai J.C.S. Perkin I, 1994, 1897 may be employed.
  • 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 (XXI):
  • R°, R l , R3 and X are as defined in relation to formula (I) and R ⁇ ' represents R2 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:
  • 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.
  • R ⁇ represents a moiety of the above defined formula (b)
  • R ⁇ ' generally represents a protected form of R 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.
  • T e compound of formula (XXI) may be prepared by reacting a compound of formula (XXII):
  • reaction between compounds of formulae (VIII) and (XXII) may be carried out under conventional amination conditions, for example in a solvent such as toluene or, preferably, methanol.
  • the compound of formula (XXI) is prepared in-situ by reacting compounds of the above defined formulae (VIII) and (XXII) 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 (XXI).
  • R°- (XXIII) wherein Rl, R ⁇ a and X are as defined in relation to formula (I), R° is as defined in relation to formula (II), T ⁇ is a protecting group, R ⁇ a represent R ⁇ or a group or atom convertible into R ⁇ and R ⁇ a represents R ⁇ or a group or atom convertible into R ⁇ , wherein R ⁇ and R ⁇ are each as defined in relation to formula (I), with a reagent capable of converting R ⁇ into R ⁇ and/or a reagent capable of converting R ⁇ a into R » and thereafter, if required, carrying out one or more of the following optional steps:
  • R ⁇ in the required compound of formula (I) is hydrogen, halogen, alkyl or alkoxy R ⁇ a is R ⁇ .
  • R ⁇ together with R ⁇ in the required compound of formula (I) represents a moiety of the above defined formula (c), or an ester or amide thereof, then R ⁇ a and R ⁇ a each represent OH.
  • R ⁇ a and R ⁇ a each represent OH they may be converted into a moiety of formula (c) by treating the compound of formula (XXIII) with a compound of the above defined formula (XIV) and thereafter as required forming an ester or amide of the resulting compound of formula (I).
  • reaction conditions for the reaction between compounds of formulae (XXIII) and (XIV) are analogous to those for the reaction between compounds of formulae (XIII) and (XIV).
  • R2 in the required compound of formula (I) represents OCH2CO2H or an ester or amide thereof, then R ⁇ a is suitably an OH group.
  • a compound of formula (I) wherein R ⁇ represents OCH2CO2H or an ester or amide thereof may be prepared by reacting a compound of formula (XXIII) with a compound of the above defined formula (XVI).
  • reaction conditions for the reaction between the compounds of formulae (XXIII) and (XVI) are analogous to those for the reaction between the compounds of formulae (XV) and (XVI).
  • R ⁇ a is suitably an OH group.
  • a compound of formula (I) wherein R ⁇ represents a moiety of formula (b) may be prepared by reacting a compound of formula (XXIII) with a compound of the above defined formula (XVII).
  • reaction conditions for the reaction between the compounds of formulae (XXIII) and (XVII) are analogous to those for the reaction between the compounds of formulae (XV) and (XVII).
  • the compounds of formula (XXII) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those methods disclosed in Swiss Patent number 1549945 (1976).
  • the compounds of formula (XXIII) are prepared according to conventional procedures depending upon the value of R ⁇ a and R ⁇ a .
  • R ⁇ a and R3a eac h represents OH or when R ⁇ a is OH and R ⁇ a is hydrogen, halogen, alkyl or alkoxy then they may be prepared by reaction of a compound of above defined formula (II) with a compound of above defined formula (XIII) or (XV) as appropriate using conditions analogous to those used in the reaction between compounds of formulae (II) and (in).
  • the compounds of formula (V) 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 ⁇ ; or when R ⁇ is OCH2CO2H or an ester or amide thereof, converting one R ⁇ into another R ⁇ ; or when R together with R represents a moiety of the above defined formula (a) or an ester or amide thereof, by converting one (a) into another (a).
  • Suitable conversions of one group OR 4 into another group OR 4 include: (i) converting OR 4 as hydroxy into OR 4 as alkoxy; (ii) converting OR 4 as alkoxy into OR 4 as hydroxy; (iii) converting OR 4 as alkoxy into OR 4 as another alkoxy group.
  • the abovementioned conversion (i) may be carried out under conventional phosphonate alkylation methods, using for example the appropriate alcohol (R ⁇ OH) in the presence of hydrogen chloride, alternatively, the appropriate alcohol may be used with benzotriazole-l-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate in dimethylformamide in the presence of diisopropylethylamine.
  • 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.
  • the abovementioned conversion (iii) may be carried out by first convening OR 4 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 convening one group OR 4 into another group OR 4 .
  • suitable conversions of one R into another R ⁇ include converting OCH2CO2 e wherein CO2R e is an ester, into OCH2CO2H, usually by conventional carboxylic acid hydrolysis, using for example basic hydrolysis with sodium hydroxide in an aprotic solvent such as 1 ,4- dioxan, at room temperature and preferably in an inert atmosphere such as argon.
  • Other suitable conversions include interconverting the respective acids, esters and amides, such conversions being accomplished by the appropriate conventional procedure including those described herein.
  • suitable conversions of one (a) into another (a) include hydrolysing esters to acids using an appropriate conventional procedure, such as treating the ester with lithium hydroxide in dioxan or methanol at ambient temperature, preferably in an inert atmosphere such as argon.
  • Other suitable conversions include interconverting the respective acids, esters and amides using an appropriate conventional procedure including those described herein.
  • the protection of 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 such as di-ten- butylsilylbis(trifluoromethanesulfonate): 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 is ⁇ -butyl esters of carbamic acid may be formed by treating the amino group with di-tert-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 amino group also may be protected as an aminoboronic acid, prepared from the appropriate amine and boron tribromide followed by work up with iced water.
  • 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.
  • 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.
  • esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art:
  • acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.
  • Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid 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 1 ' wherein R s and R l are as defined above.
  • a Cj. ⁇ 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 and diastereoisomers 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 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.
  • 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.
  • compositions of the present invention may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • pharmaceutical 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.
  • 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, polyvinylpolypynolidone, magnesium stearate or sodium lauryl sulphate.
  • composition will be formulated in unit dose form.
  • unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.
  • the present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable 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 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.
  • Lithium aluminium hydride (0.235g, 6.2mMol) was suspended in tetrahydrofuran
  • Procedure 12 (S)-2,2-Di-ter.-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2- benzodioxasilinane.
  • Procedure 21 (R)-5-(2-Aminopropyl)-l,3-benzodioxoIe-2,2-dicarboxylic acid, diethyl ester, hydrochloride salt.
  • the title compound was prepared from (R)-5-(2-aminopropyl)-l,3-benzodioxole-2,2- dicarboxylic acid diethyl ester and (S)-2,2-di-r-butyl-6-(oxiran-2-ylmethoxy)-4H- 1,3,2-benzodioxasilinane by heating in ethanol as solvent according to the method described in Procedure 13.
  • Potassium carbonate (1.95g, 14.2 mMol) was added to a solution of (R)-2-(4- hydroxyphenyl)-l-methylethylcarbamic acid, r-butyl ester (2.96g, 1 1.8 mMol) in acetone (50ml) at room temperature under argon.
  • Methyl bromoacetate (1.81g, 11.8 mMol) was added dropwise and the reaction mixture was heated at reflux for 3 hours.
  • Procedure 31 Hydroxymethylphosphonic acid, bis-(3-benzyloxy-propyl)ester.
  • Phosphonic acid bis-(3-benzyloxypropyl) ester was prepared by the general method of Houben-Weyl, Phosphor Verbinungen, p28 and J. Amer. Chem. Soc, 1955, 77, 3522.
  • a mixture of this crude phosphite (5g, 0.012 Mol based on 85% purity), paraformaldehyde (0.365g, 1 equiv.) and triethylamine (0.17ml, 0.1 equiv.) was heated under argon in an oil bath to 90°C Further triethylamine (2ml in total) was added to promote reaction. After ca 0.5h. the mixture was allowed to cool and then chromatographed on silica gel with 0-5% methanol in dichloromethane to give the title compound as a colourless oil.
  • the title compound was prepared in a similar manner to the literature procedure ⁇ from hydroxymethylphosphonic acid, bis-(3-benzyloxy-propyl) ester as an oil.
  • the title compound was prepared as a viscous oil from 4-chlorobenzene sulfonoxymethylphosphonate, bis-(3-benzyloxypropyl) ester and (R)-2-(4- hydroxyphenyl)-l-methylethylcarbamic acid, r-butyl ester according to the method described in Procedure 24.
  • Procedure 36 (SR)-4- ⁇ 2-[3-(2,2-Di-f-butyl-4H-l,3,2-benzodioxasilinan-6-yl-oxy)- 2-hydroxypropylamino]propyl ⁇ phenoxyrnethylphosphonic acid, bis-(3- hydroxypropyl)ester.
  • the title compound was prepared by the general method of Procedure 31 by hydroxymethylation of phenylphosphinic acid ethyl ester* (10.136g, 0.059Mol). The product was obtained as a colourless viscous oil after chromatography.
  • the title compound was prepared as a white crystalline solid, m.p. 70-72°C, from hydroxymethylphenylphosphinic acid, ethyl ester (9.525g, 0.0476 Mol) by a method similar to that of Procedure 32.
  • the title compound was prepared as a colourless gum from 4-chlorobenzenesulfonoxymethylphenylphosphinic acid ethyl ester (3.9 lg, 10.4mMol) and (R)-2-(4-hydroxyphenyl)-l-methylethylcarbamic acid, f-butyl ester (2.5g, 9.96mMol) by the method described in Procedure 24 .
  • the title compound was prepared as a colourless gum by a method similar to that described in Procedure 13 from (R)-4-(2-aminopropyl)phenoxymethylphenyl phosphinic acid, ethyl ester (lg, 3mMol) and (S)-2,2-di-r-butyl-6-(oxiran-2- ylmethoxy)-4H-l,3,2-benzodioxasilinane (1.009g, 3mMol.)
  • the title compound was prepared from allylbenzyl ether and 50% aqueous phosphinic acid by an analogous procedure to that described in J. Inorg. Nucl. Chem., 1965, 27, 697.
  • the title compound was prepared from 3-benzyloxypropylphosphinic acid and n- butanol according the general procedure described in European Patent 0093010. The compound was used without further purification.
  • the title compound was prepared from 3-benzyloxypropylphosphinic acid n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
  • the title compound was prepared from 3-benzyloxypropylhydroxy-methylphosphinic acid, H-butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The crude compound was used without further purification.
  • the title compound was prepared from 3-benzyloxypropyl-(4-chloro- benzenesulfonyloxymethy phosphinic acid, n-butyl ester and 2-(4- hydroxyphenyl)ethylcarbamic acid, r-butyl ester according to the procedure described in Procedure 24.
  • the crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
  • the title compound was prepared from 4-(2-r-butoxycarbonylaminoethyl) phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • Procedure 48 (S) 4- ⁇ 2-[3-(2,2-Di-/-butyl-4H-1.3,2-benzodioxasilinan-6-yloxy)-2- hydroxypropylamino]ethyl ⁇ phenoxymethyI(3-benzyloxypropyl) phosphinic acid, n-butyl ester
  • the title compound was prepared from 4-(2-aminoethyl)phenoxymethyl(3- benzyloxypropyl)phosphinic acid, n-butyl ester and (S)-2,2-di-r-butyl-6-(oxiran-2- ylmethoxy)-4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica gel eluting with dichloromethane containing 3% methanol to give a viscous gum.
  • the title compound was prepared from 3-benzyloxypropyl-(4- chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and (R)-2-(4- hydroxyphenyl)-l-methylethylcarbamic acid, r-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
  • Procedure 51 (SR)-4- ⁇ 2-[3-(2,2-Di-f-butyl-4H-l,3,2-benzodioxasilinan-6-yloxy)- 2-hydroxypropylamino]propyl ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
  • the title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethyl -(3-benzyloxypropyl)phosphinic acid, n-butyl ester and (S)-2,2-di-r-butyl-6-(oxiran- 2-ylmethoxy)-4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica gel eluting with dichloromethane containing 3% methanol to give a viscous gum.
  • the title compound was prepared from cyclohexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
  • Procedure 54 (4-Chlorobenzenesulfonyloxy)cyclohexylphosphinic acid, n-butyl ester
  • the title compound was prepared from cyclohexylhydroxymethylphosphinic acid, n- butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The crude compound was used without further purification.
  • the title compound was prepared from (4-Chlorobenzenesulfonyloxy) cyclohexylphosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, r-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
  • the title compound was prepared from 4-(2-r-butoxycarbonylaminoethyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • the title compound was prepared from 4-(2-aminoethyl)phenoxypropyl methylcyclohexylphosphinic acid, n-butyl ester and (S)-2,2-di-r-butyl-6-(oxiran-2- ylmethoxy)-4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica gel eluting with dichloromethane containing 3% methanol to give a viscous gum.
  • the title compound was prepared from 4-(2-aminoethyl)phenoxypropylmethyl cyclohexylphosphinic acid, n-butyl ester and (S)-2-(3- benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
  • the title compound was prepared from (4-chlorophenylsulfonyloxy) cyclohexylphosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-l- methylethylcarbamic acid, r-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
  • the title compound was prepared from (R)-4-(2-r-butoxycarbonylaminopropyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • the title compound was prepared from (R)-4-(2-aminopropyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester and (S)-2,2-di-r-butyl-6- (oxiran-2-ylmethoxy)-4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica eluting with dichloromethane containing 3% methanol to give a viscous gum.
  • the title compound was prepared from n-hexylphosphinic acid and n-butanol according the method described in Procedure 43. The compound was used without further purification.
  • the title compound was prepared from n-hexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
  • the title compound was prepared from n-hexylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride and according to the procedure described in procedure 32. The crude compound was used without further purification.
  • the title compound was prepared from 4-chlorobenzenesulfonyloxymethyl-n- hexylphosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-l-methylethyl- carbamic acid, r-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography, eluting with dichloromethane containing 3% methanol, to give an oil.
  • the title compound was prepared from (R)-4-(2-r-butoxycarbonylaminopropyl) phenoxymethyl-n-hexylphosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • the title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethyl-n- hexylphosphinic acid n-butyl ester and (S)-2,2-di-r-butyl-6-(oxiran-2-ylmethoxy)- 4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica gel eluting with dichloromethane containing 3% methanol to give a viscous gum.
  • Procedure 70 (S)-l-(4-BenzyIoxyphenoxy)-3-[N-2-(4- hydroxyphenyl)ethylamino]propan-2-ol.
  • the title compound was prepared from (S)-N-benzyl-l-(4-benzyloxyphenoxy)-3-[N- 2-(4-hydroxyphenyl)ethylamino]propan-2-ol and 4-chlorobenzenesulfonyloxy methyl-n-hexylphosphinic acid, n-butyl ester according to the method described in Procedure 24.
  • the title compound was prepared from phosphonic acid, bis-(2-phenylethyl) ester and paraformaldehyde according to the method described in Procedure 31. Purification by column chromatography on silica-gel in 2-5% methanol in dichloromethane gave the title compound as an oil.
  • the title compound was prepared from hydroxymethylphosphonic acid, bis-(2- phenylethyl) ester and 4-chlorobenzenesulphonyl chloride according to the method described in Procedure 32. The crude product was used in the next stage without further purification.
  • the title compound was prepared from (4-chlorobenzenesulfonyloxymethyl) phosphonic acid, bis-(2-phenylethyl) ester and (R)-2-(4-hydroxyphenyl)-l- methylethylcarbamic acid, r-butyl ester according to the method described in Procedure 24. Purification by column chromatography on silica-gel in 1 -2% methanol in dichloromethane gave the title compound as a gum.
  • the title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethyl phosphonic acid, bis-(2-phenylethyl) ester and (S)-2,2-di-r-butyl-6-(oxiran-2- ylmethoxy)-4H-l,3,2-benzodioxasilinane according to the method described in Procedure 13.
  • the crude product was purified by chromatography on silica-gel in 1- 5% methanol in dichloromethane to give the title compound as a gum.
  • a mixture of ammonium phosphinate (9.18g) and hexamethyldisilazane (25mL) was heated at 1 10°C for 2 hours.
  • the mixture was cooled in ice, dissolved in dry dichloromethane (120mL), benzyl chloride (20g; 14mL) was added and the mixture allowed to warm to room temperature and stirred 18 hours.
  • the solution was filtered, the solvent evaporated, the residue azeotroped with methanol (2x70mL), dissolved in toluene (150mL) containing n-butanol (30mL) and the solution was boiled under reflux in a Dean and Stark water trap for 5 hours.
  • the title compound was prepared from benzylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31.
  • the title compound was prepared from benzylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32.
  • the resulting white solid ( p 87-88°C) was used in the next stage without further purification.
  • the title compound was prepared from benzyl(4-chlorobenzenesulfonyloxy methyl)phosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-l- methylethylcarbamic acid, r-butyl ester according to the procedure described in Procedure 24.
  • the crude product was chromatographed on silica-gel in 2% methanol in dichloromethane to give a gum.
  • the title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethyl benzylphosphinic acid n-butyl ester and (S)-2,2-di-r-butyl-6-(oxiran-2-ylmethoxy)- 4H-l,3,2-benzodioxasilinane according to the procedure described in Procedure 13.
  • the crude product was purified by chromatography on silica-gel in 2-5% methanol in dichloromethane to give a gum.
  • Procedure 85 4-(2-fer.-Butoxycarbonylaminoethyl)phenoxymethylphenyl- phosphinic acid, ethyl ester
  • the title compound was prepared from 4-chlorobenzenesulfonyloxymethylphenyl phosphinic acid, ethyl ester (4.97g, 13.3mMol) and 2-(4-hydroxyphenyl)ethyl- carbamic acid, rerr-butyl ester (3.0g, 12.7 mMol) by the method described in Procedure 24 as a colourless gum.
  • the title compound was prepared by a method similar to that described in Procedure 25 from 4-(2-rerr-butoxycarbonylaminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester (3.197g, 7.63mMol), giving a very pale yellow gum.
  • the title compound was prepared as a colourless gum by a method similar to that described in Procedure 13 from 4-(2-aminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester (2.32g, 8.06mMol) and (S)-2,2-Di-rerr-butyl-6-(oxiran-2- ylmethoxy)-4H-l,3,2-benzodioxasilinane (l g, 2.98mMol).
  • Acetic acid, (4-benzyloxy-3-nitrophenyl)ester (3g, 10.45mMol) was dissolved in methanol (30ml) and hydrogenated at atmospheric pressure and room temperature with platinum (IV) oxide for 30 hours. The mixture was filtered through filteraid and the solvent evaporated in vacuo to yield a dark oil.
  • Acetic acid, (3-amino-4-benzyloxyphenyl)ester (1.70g, 6.61 mMol) in dichloromethane (35ml) was treated with triethylamine (0.802g, 7.93mMol) and methanesulfonyl chloride (0.832g, 7.27mMol) and the mixture stined at room temperature under argon for 20 minutes. The mixture was washed with water
  • Methyl 5-acetylsalicylate (15g, 0.077Mol), benzyl bromide (9.2ml) and potassium carbonate (11.7g) were heated at reflux in acetone (100ml) for 2 hours. After cooling, the solids were filtered off and the filtrate concentrated on a rotary evaporator. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (3:7) to afford the product as a white solid.
  • Lithium aluminium hydride (5.7g) was added to a solution of methyl 5-acetoxy-2- benzyloxybenzoate (16g, 0.053Mol) in dry diethylether (270ml) under an argon atmosphere and at ice bath temperature. The reaction mixture was allowed to warm to ambient temperature and stirring continued for 3 hours. Saturated aqueous ammonium chloride (530ml) was cautiously added and the solids filtered off. The filtrate was extracted with ethyl acetate and the organic extracts dried over anhydrous magnesium sulfate. Filtration and removal of solvent gave a white solid.
  • Procedure 103 (S,R) 4- ⁇ 2-[3-(4-r-ButyldimethyIsilyloxyphenoxy)-2- hydroxypropylamino]propyI ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
  • Procedure 104 (S,R) 4- ⁇ 2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropyIamino]propyl ⁇ phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
  • the title compound was prepared from 4-benzyloxy-3-fluoroacetophenone 1 according to the method described in Procedure 100.
  • the title compound was prepared from phosphinic acid and O-allylphenol according to the method described in Procedure 42. The crude product was used without further purification.
  • the title compound was prepared from 3-phenoxypropylphosphinic acid, ethyl ester and paraformaldehyde according to the method described in Procedure 31. Chromatography over silica gel eluting with dichloromethane containing 5% methanol gave a colourless oil.
  • the title compound was prepared from hydroxymethyl(3-phenoxypropyl) phosphinic acid, ethyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The crude product was used without further purification.
  • the title compound was prepared from 4-chlorobenzensulfonyloxymethyl (3- phenoxypropyl)phosphinic acid, ethyl ester and 2-(4-hydroxyphenyl)ethyl carbamic acid, rerr-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography over silica eluting with dichloromethane containing 5% methanol.
  • the title compound was prepared from 4-(2-rerr-butoxycarbonylaminoethyl) phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • the title compound was prepared from 4-(2-aminoethyl)phenoxymethyl (3-phenoxypropyl)phosphinic acid, ethyl ester and (S)-2-(4-benzyloxy-3- hydroxymethylphenoxy)methyloxirane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica eluting with dichloromethane containing 5% methanol.
  • the title compound was prepared from phosphinic acid and allylbenzene according to the method described in Procedure 42. The crude product was used without further purification.
  • the title compound was prepared from 3-phenylpropylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Chromatography over silica gel eluting with dichloromethane containing 5% methanol gave a colourless oil.
  • Procedure 120 4-Chlorobenzenesulfonyloxymethyl(3-phenylpropyl) phosphinic acid, n-butyl ester
  • the title compound was prepared from hydroxymethyl(3-phenylpropyl) phosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32. The crude product was used without further purification.
  • the title compound was prepared from 4-chlorobenzensulfonyloxymethyl(3- phenylpropyl)phosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethyl carbamic acid, r-butyl ester according to the method described in Procedure 24.
  • the crude product was purified by chromatography over silica eluting with dichloromethane containing 5% methanol.
  • the title compound was prepared from 4-(2-rerr-butoxycarbonylaminoethyl) phenoxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification.
  • the title compound was prepared from 4-(2-aminoethyl)phenoxymethyl-(3- phenylpropyl)phosphinic acid, n-butyl ester and (S)-2-(4-benzyloxy-3- hydroxymethylphenoxy)methyloxirane according to the method described in Procedure 13.
  • the crude product was purified by chromatography over silica eluting with dichloromethane containing 5% methanol.
  • the title compound was prepared from cyclohexanol and phosphorus tribromide according to the method described in Procedure 31. Purification by chromatography on silica gel eluting with dichloromethane to 2% methanol in dichloromethane gave the title compound as an oil.
  • the title compound was prepared from phosphonic acid, bis-cyclohexyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography on silica-gel eluting with 2% methanol in dichloromethane gave the title compound as an oil.
  • the title compound was prepared from hydroxymethylphosphonic acid, bis- cyclohexyl ester and 4-chlorobenzenesulfonyl chloride according to the method described in Procedure 32 as a colourless oil following chromatography on silica gel eluting with 10-20% ethyl acetate in hexane. The oil thus obtained solidified to give a white solid, mp 55-57°C.
  • the title compound was prepared from (4-chlorobenzenesulphonyloxymethyl) phosphonic acid, bis-cyclohexyl ester and (R)-2-(4-hydroxyphenyl)-l- methylethylcarbamic acid, r ⁇ ?rr-butyl ester according to the method described in Procedure 24. Purification by column chromatography on silica gel eluting with 2% methanol in dichloromethane gave the title compound as a gum.
  • the title compound was prepared from (fl)-4-(2-aminopropyl)phenoxymethyl phosphonic acid, bis-cyclohexyl ester and (S)-glycidyl-4-benzyloxyphenol according to the method described in Procedure 13.
  • the crude product was purified by chromatography on silicagel eluting with 2% methanol in dichloromethane to give the title compound as a gum.
  • Procedure 130 Phosphonic acid, bis-(2,2-diphenylethyl) ester
  • the title compound was prepared from 2,2-diphenylethanol and phosphorus tribromide according to the method described in Procedure 31. Purification by chromatography on silica gel eluting with 2% methanol in dichloromethane gave the title compound as an oil.
  • the title compound was obtained from phosphonic acid, bis-(2,2-diphenylethyl) ester and paraformaldehyde according to the method described in Procedure 31 as a solid (mp 95-97°C) following chromatography on silica gel eluting with 2% methanol in dichloromethane.
  • the title compound was prepared from hydroxymethylphosphonic acid, bis-(2,2- diphenylethyl) ester and 4-chlorobenzenesulphonyl chloride according to the method described in Procedure 32. Purification by chromatography on silica gel eluting with 10% ethyl acetate in hexane followed by trituration of the residue with diethyl ether- hexane gave the title compound as a solid (mp 75-76°C).
  • the title compound was prepared from (4-chlorobenzenesulfonyloxymethyl) phosphonic acid, bis-(2,2-diphenylethyl) ester and 2-(4-hydroxyphenyl) ethyl carbamic acid, rerr-butyl ester according to the method described in Procedure 24. Purification by column chromatography on silica gel eluting with 1% methanol in dichloromethane gave the title compound as a gum.
  • the title compound was made from 4-(2-rerr-butoxycarbonylaminoethyl) phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester according to the method described in Procedure 25 and was used in the next stage without further purification.
  • Procedure 135 (S)-4- ⁇ 2[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino] ethyl ⁇ phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester
  • the title compound was prepared from 4-(2-aminoethyl)phenoxymethyl phosphonic acid, bis-(2,2-diphenylethyl) ester and (S)-glycidyl-4-benzyloxyphenol according to the method described in Procedure 13.
  • the crude product was purified by chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound.
  • the title compound was prepared from 2,2-di-rerr-butyl-4H-l,3,2-benzodioxasilin-6- ol (700mg, 2.50mMol) and (2R)-(-)-glycidyl-3-nitrobenzenesulfonate (780mg, 3.0mMol) employing a method similar to that described in Procedure 12.
  • the title compound was prepared from (R)-2,2-di-rerr-butyl-6-(oxiran-2-ylmethoxy)- 4H-l,3,2-benzodioxasilinane (240mg, 0.7 ImMol) and (R)-4-(2- aminopropyl)phenoxymethyl-phenylphosphinic acid, ethyl ester (238mg, 0.7 ImMol) following a method similar to that in Procedure 14.
  • the title compound is prepared from (S,R)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl Jphenoxymethylphosphonic acid, methyl ester according to a modification of the procedure described in Example 7. Acidification to pH 7 with IM hydrochloric acid followed by reverse phase chromatography and freeze drying provides the title compound.
  • the title compound is prepared from (S,R)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethylphosphonic acid diethyl ester according to a modification of the procedure described in Example 5. Acidification to pH 7 with IM dilute hydrochloric acid followed by reverse phase chromatography and freeze drying provides the title compound.
  • the title compound was prepared from (S)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]ethyl ⁇ phenoxymethyl phosphonic acid, diethyl ester using an experimental procedure similar to that described in Example 4.
  • the title compound was prepared and isolated as a white foam.
  • the title compound was prepared from (S)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]ethyl ⁇ phenoxymethyl phosphonic acid, diethyl ester using a procedure similar to that employed for Example 5 and isolated as a solid after freeze drying.
  • Example 17 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl ⁇ phenoxymethylphosphonic acid, (3- benzyloxypropyl) ester, lithium salt.
  • the title compound was prepared from (SR)-4- ⁇ 2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl ⁇ phenoxyrnethyl- phosphonic acid, bis-(3-hydroxypropyl) ester (0.248g, 0.36mMol) by a method similar to that of Example 4.
  • Example 19 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl ⁇ phenoxymethylphosphonic acid, mono-(3- hydroxypropyl) ester, lithium salt.
  • the title compound was prepared from (SR)- (2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl )phenoxy- methylphenylphosphinic acid, ethyl ester (0.906g, 1.35mMol) by a method similar to that of Example 4 and was obtained as a colourless gum.
  • Example 21 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propyl-amino]propyl ⁇ phenoxymethyl-phenylphosphinic acid, lithium salt.
  • the title compound was prepared as a white foam after freeze-drying, from (SR)-4- ⁇ 2-[4-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propyl amino]propyl ⁇ phenoxymethylphenylphosphinic acid, ethyl ester (0.715g, 1.35mMol) by a method similar to that of Example 5, except that methanol was used as co- solvent instead of 1,4-dioxan.
  • Example 22 (S)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]ethyl ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
  • the title compound was prepared from (S)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1.3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]ethyl ⁇ phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, n-butyl ester according to the procedure described in Example 4, the crude product was used without further purification.
  • the title compound was prepared from (S)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethyl-phenoxy)propylamino]ethyl ⁇ phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, n-butyl ester according to a modification of the procedure described in Example 5. Acidification to pH 3.5 with IM hydrochloric acid followed by C18 reverse phase chromatography, eluting with water-methanol (30%) and freeze drying of the resultant foam gave the title compound as a solid.
  • the title compound was prepared from (SR)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl ⁇ phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, n-butyl ester according to the procedure described in Example 4. The crude product was used without further purification.
  • the title compound was prepared from (SR)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethyl(3- benzyloxypropyl)phosphinic acid, n-butyl ester according to a modification of the procedure described in Example 5. Acidification to pH 3.5 with IM hydrochloric acid followed by C18 reverse phase chromatography, eluting with water-methanol (30%) and freeze drying of the resultant foam gave the title compound as a solid.
  • Example 26 (S)- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]ethyI ⁇ phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
  • Example 27 (S)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]ethyl ⁇ phenoxymethylcyclohexyl phosphinic acid, lithium salt.
  • the title compound was prepared from (S)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethyl-phenoxy)propylamino]ethyl ⁇ phenoxymethyl cyclohexylphosphinic acid, n-butyl ester according the procedure described in Example 5 as a solid after C18 reverse phase chromatography, eluting with water-methanol (30%), and freeze drying of the resultant foam.
  • Example 28 (S)-4- ⁇ 2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl ⁇ phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
  • the title compound was prepared from (SR)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl )phenoxymethyl cyclohexylphosphinic acid, n-butyl ester according to the procedure described in Example 4. The crude product was used without further purification.
  • Example 33 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl ⁇ phenoxymethylcyclohexylphosphinic acid, lithium salt.
  • the title compound was prepared from (SR)-4 ⁇ 2-[2-hydroxy-3-[(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethylcyclo hexylphosphinic acid, n-butyl ester according the procedure described in Example 5 as a solid after C18 reverse phase chromatography, eluting with water methanol (30%), and freeze drying of the resultant foam.
  • Example 34 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethyl-n-hexyl phosphinic acid, n-butyl ester.
  • the title compound was prepared from (SR)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl ⁇ phenoxy-methyl-n- hexylphosphinic acid, n-butyl ester according to the procedure described in Example 4. The crude product was used without further purification.
  • Example 35 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethyl-n-hexylphosphinic acid, lithium salt.
  • Example 36 (S)-4- ⁇ 2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl ⁇ phenoxymethyI-n-hexylphosphinic acid, n- butyl ester.
  • Example 37 (S) 4- ⁇ 2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl ⁇ phenoxymethyl-n-hexylphosphinic acid.
  • the title compound was prepared from (S)-4- ⁇ 2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl ⁇ phenoxymethyl-n-hexyl phosphinic acid, n- butyl ester according a modification of the procedure described in Example 25. Acidification to pH 6 with IM hydrochloric acid followed by C18 reverse phase chromatography and freeze drying gave the title compound as a solid.
  • the title compound was prepared from (R)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H- 1,2,3- benzodioxasilinan-6-yloxy)-2-(S)-hydroxypropylamino]propyl)phenoxy methylphosphonic acid, bis-(2-phenylethyl) ester according to the procedure described in Example 4. The crude product was used in the next stage without further purification.
  • the title compound was prepared from (SR)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl ⁇ phenoxymethylphosphonic acid, bis-(2- phenylethyl) ester according to the method described in Example 5 as a solid following chromatography on C18 reverse phase silica-gel, eluting with 40% methanol-water, and freeze drying of the resultant foam.
  • the title compound was prepared from (SR)-4- ⁇ 2-[3-(2,2-di-r-butyl-4H-l,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl) phenoxy methylbenzylphosphinic acid, n-butyl ester according to the procedure described in Example 5. The compound was used in the next stage without further purification.
  • Example 41 (SR)-4- ⁇ 2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)- propylamino]propyl ⁇ phenoxymethylbenzylph ⁇ sphinic acid.
  • the title compound was prepared from (SR)-4- ⁇ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethyl-phenoxy)propylamino]propyl ⁇ phenoxymethylbenzylphosphinic acid, n-butyl ester according to the method described in Example 5 followed by acidification to pH 3.5 with IM hydrochloric acid, as a solid (mp 180-183°C) following chromatography on Cl 8 reverse phase silica-gel, eluting with 40% methanol in water.
  • the title compound was prepared from (S)-4- ⁇ 2-[3-(2,2-di-rerr-butyl-4H- 1,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]ethyl)phenoxymethylphenyl phosphinic acid, ethyl ester (0.926g, 14. ImMol) by a method similar to that of Example 4 and was obtained as a colourless gum.
  • the title compound was prepared as a white foam (after freeze-drying) from (S)-4- ⁇ 2-[3-(4-hydroxy-3-hydroxymethylphenoxy)-2-hydroxypropylamino]ethyl ⁇ - phenoxymethylphenylphosphinic acid, ethyl ester (483mg, 0.94mMol) by a method similar to that of Example 21.
  • Example 48 (S,R)-4- ⁇ 2-[3-(4-Hydroxy-3-methanesulfonylaminophenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethylphenylphosphinic acid, ethyl ester
  • the title compound was prepared from (S,R)-4- ⁇ 2-[3-(4-hydroxy-3-methane sulfonylaminophenoxy)-2-hydroxypropylarnino]propyl Jphenoxymethylphenyl ⁇ phosphinic acid, ethyl ester and trimethylsilyl bromide using the procedure described by D.M. Walker et. al. J. Chem. Soc. Chem. Commun., (1987) 22, 1710.
  • Example 50 (S) 4- ⁇ 2-[3-(4-Hydroxyphenoxy)-2- hydroxypropylamino]ethyl ⁇ phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride salt.-
  • Example 51 (S) 4- ⁇ 2-[3-(4-Hydroxyphenoxy)-2- hydroxypropylamino]ethyl ⁇ phenoxymethyl(3-benzyloxypropyl)phosphinic acid, lithium salt.
  • the title compound was prepared from (S) 4- ⁇ 2-[3-(4-hydroxyphenoxy)-2- hydroxypropylamino]ethyl ⁇ phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n- butyl ester, hydrochloride according to the procedure described in Example 5.
  • Example 52 (S,R) 4- ⁇ 2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride.
  • Example 53 (S,R) 4- ⁇ 2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, lithium salt.
  • the title compound was prepared from (S,R) 4- ⁇ 2-[4-hydroxyphenoxy)-2- hydroxypropylaminojpropyl ⁇ phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n- butyl ester, hydrochloride according to procedure described in Example 5.
  • Example 54 (S,R) 4- ⁇ 2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
  • Example 55 (S,R) 4- ⁇ 2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethylcyclohexylphosphinic acid, lithium salt.
  • the title compound was prepared from (S,R) 4- ⁇ 2-[4-hydroxyphenoxy)-2- hydroxypropylaminojpropyljphenoxymethylcyclohexylphosphinic acid, n-butyl ester according to the procedure described in Example 5.
  • Example 56 (S,R) 4- ⁇ 2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl ⁇ phenoxymethylhexylphosphinic acid, n-butyl ester.
  • the title compound was prepared from (S,R) 4- ⁇ 2-[4-hydroxyphenoxy)-2- hydroxypropylaminojpropyljphenoxymethylhexylphosphinic acid, n-butyl ester according to the procedure described in Example 5.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Obesity (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP95929029A 1994-07-29 1995-07-27 Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof Withdrawn EP0772585A1 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB9415304A GB9415304D0 (en) 1994-07-29 1994-07-29 Novel compounds
GB9415304 1994-07-29
GB9423179A GB9423179D0 (en) 1994-11-17 1994-11-17 Novel compounds
GB9423179 1994-11-17
GBGB9510485.7A GB9510485D0 (en) 1995-05-24 1995-05-24 Novel compounds
GB9510485 1995-05-24
PCT/EP1995/003037 WO1996004233A1 (en) 1994-07-29 1995-07-27 Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof

Publications (1)

Publication Number Publication Date
EP0772585A1 true EP0772585A1 (en) 1997-05-14

Family

ID=27267307

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95929029A Withdrawn EP0772585A1 (en) 1994-07-29 1995-07-27 Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof

Country Status (12)

Country Link
EP (1) EP0772585A1 (cs)
JP (1) JPH10503507A (cs)
CN (1) CN1159797A (cs)
AU (1) AU3254695A (cs)
BR (1) BR9508991A (cs)
CA (1) CA2196193A1 (cs)
CZ (1) CZ25597A3 (cs)
HU (1) HUT76800A (cs)
MX (1) MX9700765A (cs)
NO (1) NO970372L (cs)
PL (1) PL318381A1 (cs)
WO (1) WO1996004233A1 (cs)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9605495D0 (en) * 1996-03-15 1996-05-15 Smithkline Beecham Plc Novel compounds
US5914339A (en) * 1996-05-14 1999-06-22 American Home Products Corporation Substituted 1,3-benzodioxoles
EP0827746B1 (en) 1996-09-05 2002-04-03 Eli Lilly And Company Carbazole analogues as selective beta3 adrenergic agonists
WO1998022480A1 (en) * 1996-11-18 1998-05-28 Smithkline Beecham Plc Phosphorus containing aryloxy or arylthio propanolamine derivatives
GB9703492D0 (en) * 1997-02-20 1997-04-09 Smithkline Beecham Plc Novel compounds
CO5011072A1 (es) * 1997-12-05 2001-02-28 Lilly Co Eli Etanolaminas pirazinil substituidas como agfonistas de los receptores
CA2285213C (en) * 1998-01-30 2013-07-30 Boulder Scientific Company Silylated and n-silylated compound synthesis
ATE423555T1 (de) * 1998-04-06 2009-03-15 Astellas Pharma Inc Verwendung von beta-3-adrenergen-rezeptoren agonisten in der behandlung von dysurie
AUPP549998A0 (en) * 1998-08-26 1998-09-17 Fujisawa Pharmaceutical Co., Ltd. New compound
US7098248B2 (en) 2001-07-09 2006-08-29 Research Development Foundation Beta-adrenergic blockade reversal of catabolism after severe burn
DE102008064003A1 (de) * 2008-12-19 2010-06-24 Clariant International Limited Verfahren zur Herstellung von mono-funktionalisierten Dialkylphosphinsäuren, -estern und -salzen und ihre Verwendung
CN107266341B (zh) * 2017-06-23 2020-01-07 华东师范大学 芳氧基取代丙-2-醇胺的衍生物作为β3肾上腺素能受体拮抗剂、制备方法和用途
CN112442167A (zh) * 2019-08-28 2021-03-05 广东广山新材料股份有限公司 一种反应型阻燃剂及其制备方法和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1262729A (en) * 1983-10-19 1989-11-07 Leo Alig Phenoxypropanolamines
EP0300290B1 (de) * 1987-07-21 1991-12-18 F. Hoffmann-La Roche Ag Phenoxypropanolamine
GB8801306D0 (en) * 1988-01-21 1988-02-17 Ici Plc Chemical compounds
GB9215844D0 (en) * 1992-07-25 1992-09-09 Smithkline Beecham Plc Novel compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9604233A1 *

Also Published As

Publication number Publication date
JPH10503507A (ja) 1998-03-31
MX9700765A (es) 1997-05-31
HUT76800A (en) 1997-11-28
WO1996004233A1 (en) 1996-02-15
CZ25597A3 (cs) 1998-02-18
NO970372D0 (no) 1997-01-28
AU3254695A (en) 1996-03-04
BR9508991A (pt) 1997-10-21
CN1159797A (zh) 1997-09-17
NO970372L (no) 1997-03-18
PL318381A1 (en) 1997-06-09
CA2196193A1 (en) 1996-02-15

Similar Documents

Publication Publication Date Title
KR101346527B1 (ko) 아민 화합물 및 그 의약 용도
WO1996004234A1 (en) Aryloxy andarycthio propanolamine derivatives useful as b3-adrenoreceptor agonists and antagons of the b1 and b2 adrenoreceptors and pharmaceutical composition thereof
WO1996004233A1 (en) Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof
US5273989A (en) 3,5-disubstituted 2-isoxazolines and isoxazoles, agents containing them and their use
JP2006306885A (ja) 新規なアミノプロピルホスフィン酸
FR2606018A1 (fr) Nouveaux a-aminoacides substitues, leur preparation et leur utilisation en therapeutique comme medicaments
JPH10501546A (ja) メタロペプチダーゼ阻害作用を有するホスフィン酸誘導体
JP2930366B2 (ja) 置換アミノアルキルホスフィン酸
RU2267495C2 (ru) Новые (аминопропил)метилфосфиновые кислоты
EP0652884B1 (en) Phosphonated arylethanolamine compounds with anti-hyperglycemic and/or anti-obesity activity
WO1998022480A1 (en) Phosphorus containing aryloxy or arylthio propanolamine derivatives
IE903614A1 (en) Phenethanolamine Compound
AU657554B2 (en) Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents
KR970011164B1 (ko) 불포화 아미노산 화합물의 제조방법
EP0170121A1 (en) 2-Hydroxy-3-aryloxypropyl or 2-hydroxy-2-benzofuranyl ethyl tertiary amine having an anti-hyperglycaemic and/or anti-obesity activity
IE61587B1 (en) Method for preparing phosphinic acids used in preparing ace inhibitors and intermediates produced thereby
EP1383779B1 (en) A process for manufacture of fosinopril sodium
EP0717746B1 (en) Phosphinic acid derivatives with anti-hyper glycemic and/or anti-obesity activity
CA2329637A1 (fr) Derives d'(alpha-aminophosphino) peptides et compositions les contenant
JP2008526908A (ja) 有用な二置換アミンの新規な一段合成法
IL93960A (en) Unsaturated History of Aminodicarboxylic Phosphoric Acid, Preparation and Pharmaceutical Preparations Containing Them
WO1995011223A1 (fr) Nouveau compose d'arylethanolamino(aryl)propanol
WO1997034905A1 (en) Phosphorus containing aryloxy and arylthiopropanol amine derivatives useful as beta adrenoreceptor agonists
DK175352B1 (da) Fremgangsmåde til fremstilling af 4-phenylpiperidinderivater
AU2001288037A1 (en) A Process for manufacture of fosinopril sodium

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970204

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: SI

RAX Requested extension states of the european patent have changed

Free format text: SI PAYMENT 970204

17Q First examination report despatched

Effective date: 19980723

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19990203

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1012331

Country of ref document: HK