WO1996004233A1 - 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 Download PDF

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Publication number
WO1996004233A1
WO1996004233A1 PCT/EP1995/003037 EP9503037W WO9604233A1 WO 1996004233 A1 WO1996004233 A1 WO 1996004233A1 EP 9503037 W EP9503037 W EP 9503037W WO 9604233 A1 WO9604233 A1 WO 9604233A1
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Prior art keywords
formula
acid
compound
procedure
hydroxy
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PCT/EP1995/003037
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French (fr)
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Lee James Beeley
Mervyn Thompson
David Kenneth Dean
Nikesh Rasiklal Kotecha
John Michael Berge
Robert William Ward
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Smithkline Beecham Plc
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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 Plc filed Critical Smithkline Beecham Plc
Priority to EP95929029A priority Critical patent/EP0772585A1/en
Priority to AU32546/95A priority patent/AU3254695A/en
Priority to BR9508991A priority patent/BR9508991A/en
Priority to MX9700765A priority patent/MX9700765A/en
Priority to JP8506193A priority patent/JPH10503507A/en
Publication of WO1996004233A1 publication Critical patent/WO1996004233A1/en
Priority to NO970372A priority patent/NO970372L/en

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    • C07F9/02—Phosphorus compounds
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    • 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
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    • 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
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    • 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
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    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
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    • 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
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    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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    • 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.

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Abstract

A compound formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein R0 represents an aryl group optionally substituted with one, two or three substituents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, formamido, halogen, alkoxy and allyl; X represents O or S; R?1 and R1a¿ each independently represents hydrogen or an alkyl group; R2 represents OCH¿2?CO2H, or an ester or amide thereof, or R?2¿ represents a moiety of formula (b), wherein R4 represents hydrogen, alkyl, hydroxyalkyl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl or cycloalkyl and R5 represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, aryloxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy or R5 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl or R5 together with OR4 represents O(CH¿2?)nO, wherein n is 2, 3 or 4; and R?3¿ represents hydrogen, halogen, alkyl or alkoxy or R3 together with R2 represents a moiety of formula (c) or an ester or amide thereof; providing that 4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetic acid and salts and esters thereof and the compounds of examples 1 to 36 disclosed in EP0328251 are excluded from the scope of formula (I); a pharmaceutical composition containing such a compound, a process of preparing such a compound and the use of such a compound in medicine.

Description

ARYLOXY AND ARYLTHIOPROPANOLAMINE DERIVATIVES USEFUL AS BETA 3-ADRENORECEPTOR AGONISTS AND ANTAGONISTS OF THE BETA 1 and BETA 2-ADRENORECEPTORS AND PHARMACEUTICAL COMPOS ITION THEREOF
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 β3-adrenoreceptor agonist activity and in particular show good selectivity for β3-adrenoreceptors over the βj- or β2-adrenoreceptors, to the extent that these compounds are antagonists of the βj- and β2-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.
These compounds may also be of use in increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.
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.
Accordingly the present invention provides a compound of formula (I):
Figure imgf000003_0001
(I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein,
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):
-O-CH2-P-OR4
Ra
(b)
wherein 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)nO wherein n is 2, 3 or 4; and
R3 represents hydrogen, halogen, alkyl or alkoxy or R^ together with R^ represents a moiety of formula (c):
Figure imgf000004_0001
(c) or an ester or amide thereof; providing that 4-[2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]propyl] phenoxyacetic acid and salts and esters thereof and the compounds of examples 1 to 36 disclosed in EP0328251 are excluded from the scope of formula (I).
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. Suitably, R° represents a phenyl group optionally substituted with hydroxy and/or hydroxymethyl and/or halogen, especially fluoro and/or alkylsulphonamido.
Examples of R° include 4-hydroxy-3-hydroxymethylphenyl, 3- and 4- hydroxyphenyl, 3-fluoro-4-hydroxyphenyl and 4-hydroxy-3-methylsulphonamido phenyl groups.
Suitably, R* is an alkyl group and R*a represents hydrogen.
Suitably, Rl and R^a each represents hydrogen.
When Rl is alkyl, it is favourably a Cj.g alkyl group, especially a methyl group. Suitably, R a represents hydrogen.
In one aspect, R^ represents OCH2CO2H, or an ester or amide thereof.
Suitably, 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. In one aspect, R^ represents a moiety of formula (b).
In one aspect of the invention, R^ together with R^ represents a moiety of formula (c).
Preferably, R^ is a moiety of formula (b).
Favorably, R^ represents hydrogen, halogen, alkyl or alkoxy. Preferably, R^ is hydrogen.
Suitably, R^ represent hydrogen, alkyl, hydroxyalkyl, phenylalkyl, benzyloxyalkyl or cycloalkyl.
When R4 represents alkyl, especially Cj.g alkyl, examples include ethyl and butyl, especially n-butyl. When R^ represents hydroxyalkyl, an example is hydroxypropyl.
When R4 represents arylalkyl, an example is phenylpropyl.
When R4 represents arylalkyloxyalkyl, an example is benzyloxyethyl.
Favourably, R^ represent hydrogen or alkyl, especially hydrogen.
When R5 represents substituted alkyl, suitable substituents are selected from: hydroxy, alkoxy and arylalkoxy.
Suitably, R^ represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxy alky loxy, arylalkoxyalkyloxy or cycloalkyloxy, especially alkoxy, hydroxyalkyloxy or arylalkoxyalkyloxy.
When R5 represents alkoxy, especially C\. alkoxy, examples include ethoxy and n-butoxy.
When R5 represents arylalkyloxy an example is phenylpropyloxy.
When R5 represents arylalkoxyalkyloxy an example is benzyloxypropyloxy. Suitably, in the hydroxyalkyloxy group represented by R^ the hydroxy group is substituted on the terminal carbon atom of the alkyl group, for example as in a 2- hydroxyethyloxy group and a 3-hydroxypropyloxy group.
Favourably, R^ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl.
When R5 represents cycloalkyl an example is cyclohexyl.
Preferably, R^ represents alkyl for example n-hexyl. Preferably, R^ represents aryl for example phenyl.
When R5 represents alkyl examples include n-hexyl. Preferably, R^ represent alkyl, especially C\.(, alkyl, for example ethyl, and
R5 represent alkoxy, especially \.^ alkoxy, for example ethoxy.
In another aspect, R^ is alkyl, for example ethyl, and R^ is hydrogen.
Preferably, X represents O.
In one aspect the invention provides a subgroup of the compounds of formula (I) wherein R°, Rl, Rla, R^, R3 and 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. In a further aspect 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. In one particular aspect 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.
In addition when the substituents on the phosphorous atom of moiety (b) are 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. Preferably, the asymmetric carbon atom indicated by a single asterisk (*) is in the S-configuration.
Preferably, 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.
One favoured form of a compound of formula (I) is the SR enantiomer.
The term '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.
The term 'cycloalkyl' includes C3_g cycloalkyl groups, especially C5 or C cycloalkyl groups.
When used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.
When used herein the term "sulphonamido" refers to the moiety '-SO2-NH-', for example methylsulphonamido refers to the moiety 'CH3-SO2-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 -CONRsRl wherein Rs 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 tτi-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, 1 ,4-dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.
In a further aspect 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°'-X-CH — CH— CH
/
\>
(II)
wherein X is as defined in relation to formula (I) and R° represents R° as defined in relation to formula (I) or a protected form thereof, with a compound of formula (III):
Figure imgf000008_0001
(HI)
wherein 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:
(i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
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 ineπ 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. Suitably 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):
RO'-XH (IV)
wherein R0' and X are as defined in relation to formula (II), with a compound of formula (V):
L— CH,— CH— CH,
/
\ (V)
wherein 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.
Suitably, L° represents a tosylate or a 3-nitτobenzenesulphonyloxy 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.
When L° 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):
Figure imgf000010_0001
wherein Rl, 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.
Suitably, 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):
Figure imgf000010_0002
(VII)
wherein 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.
The compound of formula (VII) may be prepared by reacting a compound of formula (VIII):
Figure imgf000011_0001
(VIII)
wherein Rl, R^ and R^ are as defined in relation to formula (I), with R-α-methylbenzylamine.
The reaction between compounds of formulae (VIII) and R-α-methylbenzylamine may be carried out under conventional amination conditions, for example in a solvent such as methanol or toluene.
Conveniently, the compound of formula (VII) is prepared in-situ by reacting a compound of the above defined formula (VIII) with R-α-methylbenzyl amine and thereafter reducing the compound of formula (VII) so formed using reaction conditions and catalysts as described above.
The compounds of formula (VIII) wherein R^ represents OCH2CO2H or an ester or amide thereof or wherein R2 represents a moiety of the above defined formula (b) wherein R^ represent hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R^ together with OR^ represents O(CH2)nO, are known compounds or they may be prepared by processes analogous to those used to prepare such compounds, for example they may be prepared according to methods disclosed in European Patent Application, Publication Number 0023385 or International Application number WO 94/02493.
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):
Figure imgf000011_0002
(IX)
wherein 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):
Figure imgf000012_0001
(X)
wherein, R^ and R^ are as defined in relation to formula (IX), with a nitroalkane, such as nitromethane or nitroethane.
Generally, 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
(XI):
Figure imgf000012_0002
(XI)
wherein 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):
HO-CH2-P-OR
R" (XII) wherein R^ and R are as defined in relation to formula (I).
A suitable activated form of a compound of formula (XII) is an ionic form, such as a salted form, for example an alkali metal salted form.
An activated form of a compound of formula (XII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (XII) with a base such as an alkali metal hydride, for example sodium hydride.
The 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.
Compounds of formula (III) wherein R^ together with R3 represent a moiety of above defined formula (c), or an ester or amide thereof, are prepared from a protected form of a sub-set of the compounds of formula (III) of formula (XIII):
Figure imgf000013_0001
wherein 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):
L1 CO 2
L2 X COT3 (XIV)
wherein 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.
Suitably T^ and T^ each represent a C\.^ alkoxy group, for example an ethoxy group.
Preferably, 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. In the above mentioned reactions 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. 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.
The compounds of formula (XIV) are known commercially available compounds. Compounds of formula (III), wherein R^ is OCH2CO2H or an ester or amide thereof or a moiety of the above defined formula (b) and R^ is hydrogen, halogen, alkyl or alkoxy are conveniently prepared from a protected form of a sub-set of the compounds of formula (III) of formula (XV):
Figure imgf000014_0001
wherein Rl, Rι 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):
L3-CH2-CO-T4 (XVI) wherein L^ is a leaving group or atom, suitably a halogen atom such as a bromine atom, and T4 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):
Figure imgf000014_0002
wherein R4 and R^ are as defined in relation to formula (I) and L4 is a leaving group or atom; and thereafter, as necessary removing any protecting group. Suitably, T* is a t-butoxycarbonyl group.
Suitably, T4 is a C g alkoxy group such as a methoxy group.
Suitably, represents a tosylate group, a 4-chlorobenzenesulphonyloxy group or a 3-nitrobenzenesulphonyloxy group. In the above mentioned reactions 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).
Preferably, 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. 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.
The compounds of formula (XV) wherein either Rl or R* is hydrogen are prepared by hydrogenolysis of a compound of formula (XIX):
Figure imgf000015_0001
wherein R , R^, Y and the **CH and ***CH carbon atoms are as defined in relation to formula (VI). The hydrogenolysis of compounds of formula (XIX) is carried out under analogous conditions to the hydrogenolysis of the compounds of formula (VI). The compounds of formula (XIX) wherein Y is a moiety -B(OH)2 are prepared from compounds of formula (XIX) wherein Y is the H, using analogous methods to those described above for compounds of formula (VI) wherein Y is a moiety -B(OH)2- The compounds of formula (XIX) wherein Y is H are known compounds or they are prepared using analogous methods to those used to prepare known compounds for example those disclosed in J. Med. Chem. 1973, 16(5), 480.
A compound of formula (XVII) may be prepared by hydroxymethylation of a compound of formula (XX):
O
11 4
H— P-OR
R R5 (XX)
wherein R4 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 L4 but the appropriate conventional conditions are employed. For example when L4 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):
Figure imgf000016_0001
wherein R°, Rl, 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:
(i) converting one compound of formula (I) to another compound of formula (I); (ii) removing any protecting group; and
(iii) preparing a pharmaceutically acceptable salt, ester or amide thereof of a compound of formula (I) or a pharmaceutically acceptable solvate thereof. The reduction of the compound of formula (XXI) may be carried out using any suitable reduction procedure, for example by using catalytic reduction.
Suitable catalysts include platinum oxide or 10% palladium on charcoal.
Suitable reduction conditions include using an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example when using the platinum catalyst the reaction may conveniently be carried out at ambient temperature or when using the palladium catalyst the reaction may be carried out at a medium temperature such as 50°C, under a pressure of 1-5 atmospheres of hydrogen. For compounds of formula (I) wherein 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):
OH
R °-X-CH2-CH-CH2-NH2
(XXII)
wherein R° and X are as defined in relation to formula (II) with a compound of the above defined formula (VIII).
The 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.
Conveniently, 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).
In a further aspect of the present invention there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (XXIII):
R°-
Figure imgf000017_0001
(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:
(i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
Suitably, when R^ in the required compound of formula (I) is hydrogen, halogen, alkyl or alkoxy R^a is R^.
Suitably, when 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.
Suitably, when 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).
The 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).
When R2 in the required compound of formula (I) represents OCH2CO2H or an ester or amide thereof, then R^a is suitably an OH group.
When R^a is OH, then 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).
The 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).
When R2 in the required compound of formula (I) represents a moiety of the above mentioned formula (b), then R^a is suitably an OH group.
When R2 is OH, then 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).
The 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. For example, when R^a and R3a each 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).
Compounds of formula (III) including those of formula (XIII) or (XV) wherein Rl and R^a each independently represent alkyl are known compounds or they may be prepared according to processes used to prepare known compounds, such as those disclosed by B. Renger in Arch. Pharm. (Weinheim)., 1983, 316(3), 193-201. The compounds of formula (IV) are either known commercially available compounds or they are prepared according to published methods or by use of analogous methods to the published methods, for example those disclosed J.C.S. Perkin I; 1974, 1353.
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 OR4 into another group OR4 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 OR4 into another group OR4 include: (i) converting OR4 as hydroxy into OR4 as alkoxy; (ii) converting OR4 as alkoxy into OR4 as hydroxy; (iii) converting OR4 as alkoxy into OR4 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 OR4 as alkoxy into OR4 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).
The abovementioned conversion (iii) is of particular use for preparing compounds of formula (I) wherein OR4 represents methoxy: such compounds are generally prepared from compounds of formula (I) wherein OR4 represents an alkyloxy group other than methoxy (suitably ethoxy) by first hydrolysing the relevant OR4 group (via conversion (ii)) to prepare a compound of formula (I) wherein OR4 represents hydroxy and thereafter methylating (via conversion (i)) to provide the required compound wherein OR4 represents methoxy.
Suitable conversions of one group R^ into another group R^, when R^ represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy, include analogous conversions to those mentioned above in regard to convening one group OR4 into another group OR4. When R^ is OCH2CO2H or an ester or amide thereof, suitable conversions of one R into another R^ include converting OCH2CO2 e wherein CO2Re 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.
When R3 together with R^ represents a moiety of the above defined formula (a) or an ester or amide thereof 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. Alternatively 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 isπ-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. In addition, 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.
The salts, esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art: For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid. Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions. Amides may be prepared using conventional amidation procedures, for example amides of formula CONRsRl may be prepared by treating the relevant carboxylic acid with an amine of formula HNRSR1' wherein Rs and Rl are as defined above. Alternatively, a Cj.β alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNRsRl to provide the required amide.
Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof; or a pharmaceutically acceptable solvate thereof, produced by the above processes, may be recovered by conventional methods.
If required 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. Suitable 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.
Alternatively, 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.
As previously indicated, the compounds of formula (I) have been discovered to possess valuable pharmacological properties.
The present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
In one aspect, 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.
In addition 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.
Finally, 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. Accordingly, the present invention also provides 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. As used herein the term "pharmaceutically acceptable" embraces compounds, compositions and ingredients for both human and veterinary use: for example the term "pharmaceutically acceptable salt" embraces a veterinarily acceptable salt.
The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. Usually the 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.
Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
In accordance with conventional pharmaceutical practice 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.
Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.
The present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof.
The present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
The present invention further provides a method for treating gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non- steroidal anti-inflammatory drugs or corticosteroids, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
In addition 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. 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.
Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
In treating hyperglycaemic or obese humans 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. In treating non-human mammals, especially dogs, 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.
In a further aspect 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. Whilst 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.
In the preceding method 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. Suitably the compounds are administered in the feed-stuff or drinking water provided for the livestock. Conveniently 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. For administration in feed-stuff the drugs are conveniently formulated as a premix in association with a suitable carrier.
Accordingly, 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.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. The following Examples and Procedures illustrate the invention but do not limit it in any way. Procedure 1: (S)-GlycidyI-2-benzyloxyphenoI
Figure imgf000026_0001
A mixture of 2-benzyloxyphenol (900mg, 4.5 mMol) and potassium carbonate (1.87g, 13.5 mMol) in acetone (45 ml) was heated under reflux for 15 mins. (S)- Glycidyl-3-nitτobenzenesulphonate (l.Og, 4.5 mMol) was added and the reaction mixture was heated under reflux for 23 hours. After cooling, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.
δ (270MHz , CDCI3): 7.36 (5H, m), 6.88 (4H, m), 5.10 (2H, s), 4.26 (IH, dd, J=11.4, 3.3Hz), 4.20 (IH, dd, J=l 1.4, 5.5Hz), 3.36 (IH, m), 2.85 (IH, dd, J=5.0, 4.1Hz), and 2.73 (IH, dd, J=5.0, 2.5Hz) ppm.
Procedure 2: (S,R)-Methyl-4-[2-[2-hydroxy-3-(2- benzyloxyphenoxy)propylamino]propyl] phenoxyacetate
Figure imgf000026_0002
A mixture of (S)-glycidyl-2-benzyloxyphenol (666mg, 2.59 mMol) and (R)-methyl- 4-(2-aminopropyl)phenoxyacetate (501mg, 2.25 mMol) in MeOH (15ml) was heated under reflux under argon for 24 hours. After cooling, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by column chromatography eluting with 0-10% methanol in dichloromethane giving the title compound as an oil. δlH (270MHz, CDC13): 7.5-7.25 (5H, m), 7.05 (2H, d, J=8.6Hz), 6.92 (4H, m), 6.79 (2H, d, J=8.6Hz), 5.08 (2H, s), 4.59 (2H, s), 4.2-4.0 (3H, m), 3.80 (3H, s), 3.0- 2.4 (5H, m) and 1.04 (3H, d, J=6.3Hz) ppm.
Procedure 3: (S,R)-Methyl-4-[2-[2-hydroxy-3-(2- hydroxyphenoxy)propylamino]propyl] phenoxyacetate
Me
Figure imgf000027_0001
(S,R)-Methyl-4-[2-[2-hydroxy-3-(2-benzyloxyphenoxy)propylamino]propyl] phenoxyacetate (270mg, 0.56mMol) was dissolved in methanol (40ml), palladium on charcoal (5%, 40mg) was added and the mixture was hydrogenated at room temperature and pressure for 18 hours. The suspension was filtered through a pad of filter aid, the filter pad was washed with methanol and the combined filtrates were evaporated giving a dark residue. Purification by column chromatography eluting with 0-10 % methanol in dichloromethane gave the title compound as an oil.
δxH (270MHz, CDCI3): 7.08 (2H, d, J=8.8Hz), 6.79 (6H, m), 4.61 (2H, s), 4.1- 3.9 (3H, m), 3.80 (3H, s), 3.0-2.7 (5H, m) and 1.12 (3H, d, Jό.lHz) ppm.
Procedure 4: (S)-GlycidyI-3-benzyloxyphenol
Figure imgf000027_0002
A mixture of 3-benzyloxyphenol (900mg, 4.5 mMol) and potassium carbonate (1.87g, 13.5 mMol) in acetone (45 ml) was heated under reflux for 15 mins. (S)- Glycidyl-3-nitrobenzenesulphonate (l.Og, 4.5 mMol) was added and the reaction mixture was heated under reflux for 23 hours. After cooling the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.
δlH (270MHz, CDCI3): 7.25 (5H, m), 7.15 (IH, m), 6.50 (3H, m), 5.14 (2H, s), 4.10 (IH, dd, J=l 1.0, 3.3Hz), 3.80 (IH, dd, J=11.0, 5.8Hz), 3.40 (IH, m), 2.80 (lH,dd, J=5.0, 4.1Hz) and 2.70 (IH, dd, J=5.0, 2.5Hz) ppm.
Procedure 5: (S,R)-MethyI-4-[2-[2-hydroxy-3-(3- benzyloxyphenoxy)propylamino]propyl] phenoxyacetate
Me
Figure imgf000028_0001
A mixture of (S)-glycidyl-3-benzyloxyphenol (580mg, 2.27 mMol) and (R)-methyl- 4-(2-aminopropyl)phenoxyacetate (640mg, 2.87 mMol) in MeOH (15ml) was heated under reflux under argon for 24 hours. After cooling, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by column chromatography eluting with 0-20% methanol in dichloromethane giving the title compound as an oil.
δ*H (270MHz, CDCI3): 7.5-7.08 (8H, m), 6.83 (2H, d, J=8.5Hz), 6.7-6.5 (3H, m), 5.03 (2H, s), 4.60 (2H, s), 3.90 (3H, m), 3.80 (3H, s), 2.9-2.5 (5H, m) and 1.06 (3H, d, J=6.3Hz) ppm.
Procedure 6: (S,R)-MethyI-4-[2-[2-hydroxy-3-(3- hydroxyphenoxy)propylamino]propyl] phenoxyacetate
Figure imgf000029_0001
(S,R)-Methyl-4-[2-[2-hydroxy-3-(3-benzyloxyphenoxy)propylamino]propyl] phenoxyacetate (540mg, 1.13 mMol) was dissolved in methanol (50ml), palladium on charcoal (5%, 75mg) was added and the mixture was hydrogenated at room temperature and pressure for 24 hours. The suspension was filtered through a pad of filter aid, the filter pad was washed with methanol and the combined filtrates were evaporated giving a dark residue. Purification by column chromatography eluting with 0-20 % methanol in dichloromethane gave the title compound as an oil.
δlH (270MHz, d6-DMSO/D20): 7.2-7.0 (3H, m), 6.79 (2H, d, J=8.8Hz), 6.4-6.3 (3H, m), 4.73 (2H, s), 3.95-3.75 (3H, m), 3.69 (3H, s), 2.9-2.6 (4H, m), 2.45-2.35 (IH, m) and 0.92 (3H, d, J=6.0Hz) ppm.
Procedure ?: (S)-Glycidyl-4-benzyloxyphenol
Figure imgf000029_0002
A mixture of 4-benzyloxyphenol (2.0g, 10 mMol) and potassium carbonate (4.14g, 30 mMol) in acetone (50 ml) was heated under reflux for 15 mins. (S)-Glycidyl-3- nitrobenzenesulphonate (2.23g, 10 mMol) was added and the reaction mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil. δ*H (270MHz , CDCI3): 7.35 (5H, m), 6.87 (4H, m), 5.01 (2H, s), 4.16 (IH, dd, J=11.0, 3.3Hz), 3.91 (IH, dd, J=l 1.0, 5.8Hz), 3.34 (IH, m), 2.89 (IH, dd, J=5.0, 4.1Hz) and 2.74 (IH, dd, J=5.0, 2.8Hz) ppm.
Procedure 8: (S,R)-Methyl-4-[2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino]propyl] phenoxyacetate
Me
Figure imgf000030_0001
A mixture of (S)-glycidyl-4-benzyloxyphenol (330mg, 1.29 mMol) and (R)-methyl- 4-(2-aminopropyl)phenoxyacetate (380mg, 1.47 mMol) in MeOH (15ml) was heated under reflux under argon for 24 hours. After cooling, the solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by column chromatography eluting with 0-15% methanol in dichloromethane giving the title compound as an oil.
δ*H (270MHz, CDCI3): 7.26(5H, m), 7.08 (2H, m), 6.80 (6H, m), 5.01 (2H, s), 4.61 (2H, s), 3.90 (3H, m), 3.80 (3H,s), 2.75 (5H, m) and 1.08 (3H, d, J=6.3Hz) ppm.
Procedure 9: (S,R)-Methyl-4-[2-[2-hydroxy-3-(4- hydroxyphenoxy)propyIarnino]propyl] phenoxyacetate
Figure imgf000030_0002
(S,R)-Methyl-4-[2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino]propyl] phenoxyacetate (200mg, 0.42mMol) was dissolved in methanol (25ml), palladium on charcoal (5%, 20mg) was added and the mixture was hydrogenated at room temperature and pressure for 18 hours. The suspension was filtered through a pad of filter aid, the filter pad was washed with methanol and the combined filtrates were evaporated giving a dark residue. Purification by column chromatography eluting with 0-10 % methanol in dichloromethane gave the title compound as an oil.
δxH (270MHz, d6-DMSO/D2O): 7.10 (2H, d, J=8.5Hz), 6.80 (2H, d, J=8.5Hz), 6.72 (2H, d, J=8.9Hz), 6.65 (2H, d, J=8.9Hz), 4.73 (2H, s), 3.8-3.75 (3H, m), 3.70 (3H, s), 2.9-2.4 (5H, m) and 0.90 (3H, d, J=6.1Hz) ppm.
Procedure 10: 2,2-Di-tert-butyl-4H-l,3,2-benzodioxasilin-6-oI
Figure imgf000031_0001
A mixture of 2,2-di-tert-butyl-6-(benzyloxy)-4H-l,3,2-benzodioxasilinane (2g, 5.41mMol) and 10% palladium on charcoal (50mg) in dichloromethane (20ml) was hydrogenated at atmospheric pressure. After 6 hours the reaction mixture was filtered through a short pad of celite and the solvent evaporated to yield a clear oil.
δxH (250MHz, CDC13): 6.80 (IH, d, J=8); 6.67 (IH, dd, J=8.1Hz and 2.4Hz); 6.45 (IH, d, J=2.4Hz); 4.90 (2H, s); 1.14 (18H, s).
Procedure 11: 2,2-Di-tert-butyl-6-(benzyloxy)-4H-l,3,2- benzodioxasilinane
Figure imgf000032_0001
Lithium aluminium hydride (0.235g, 6.2mMol) was suspended in tetrahydrofuran
(25ml) and cooled to 0°C. 5-Benzyloxy-2-hydroxy benzoic acid methyl ester (2g,
7.75mMol) in tetrahydrofuran (10ml) was added dropwise, via cannula. The mixture was warmed to room temperature and stirred for 20 minutes. The reaction was then cooled to 0°C and cautiously quenched by the addition of water (0.5ml), 2M sodium hydroxide solution (0.5ml), and water (1ml). The resulting mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was evaporated in vacua to yield 4-benzyloxy-2-hydroxymethyl phenol as a clear oil which was used in the next step without further purification.
To a solution of 4-benzyloxy-2-hydroxymethyl phenol in chloroform (10ml) was added 2,6-lutidine (2.49g, 23.25mMol) at room temperature under argon. Di-tert- butylsily bis(trifluoromethanesulfonate) (4.1g, 9.3mMol) was added and the mixture stirred at room temperature for 18 hours. The solvent was evaporated in vacua and the residue purified by normal phase column chromatography, eluting with 50% hexane in ether to give the title product as pale yellow oil.
δ*H (250MHz, CDC13): 7.34-7.48 (5H, m); 6.85 (2H, ); 6.61 (IH, m), 5.0
(2H, s); 4.78 (2H, s); 1.14 (18H, s).
Procedure 12: (S)-2,2-Di-ter.-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2- benzodioxasilinane.
Figure imgf000033_0001
To a solution of 2,2-di-tert-butyl-4H-l,3,2-benzodioxasilin-6-ol (1.4g, 5mMol) in acetone (40ml) at room temperature under argon was added potassium carbonate (2.07g, 15mMol). (25)-(+)-glycidyl-3-nitrobenzenesulfonate (1.43g 5.5mMol) was added portionwise and the reaction mixture was heated at reflux for 48 hours. The solvent was removed under reduced pressure. The residue was taken into ethyl acetate and washed with water (2x15ml). The organic extracts were dried (Na2SU4) and the solvent evaporated in vacuo. The crude product was purified by chromatography over normal phase silica eluting with 50% hexane in ether to give (S)-2,2-Di-tert-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2-benzodioxasilinane.
δ*Η (250MΗz, CDCI3): 6.75-6.90 (2H, m), 6.7 (IH, d, J=2.5Hz); 4.97 (2H, s); 4.16 (IH, dd, J=l l, 3Hz); 3.88 (IH, dd, J=l 1, 5.7Hz); 3.35 (IH, m); 2.89 (IH, dd, J=5.0, 4.1 Hz); 2.73 (IH, dd, J=5, 2.4Hz); 1.14 (18H, s).
Procedure 13: (SR)-4-{2-[3-(2,2-Di-terf-butyl-4H-l,3,2-benzodioxasilinan-
6-yl-oxy)-2-hydroxy propylamine]propyl}phenoxymethyl phosphonic acid diethyl ester
Figure imgf000033_0002
A mixture of (S)-2,2-di-tert-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2-benzodio- xasilinane (0.622g, 1.85mMol) and (fl)-diethyl 4-(2-aminopropyl)phenoxymethyl phosphonate (0.55g, 1.83mMol) was dissolved in methanol (10ml) and refluxed under a argon atmosphere for 20 hours. The methanol was evaporated and the residue taken up into dichloromethane (75ml), washed with water (3x50ml) and dried with anhydrous sodium sulfate. After evaporation of the solvent in vacuo, the crude product was purified by column chromatography over normal phase silica, eluting with 10% methanol in ethyl acetate to give the title compound as a dark oil.
δ*H (250MHZ, CDCI ): 7.15 (2H, d, J=9.3Hz); 6.09 (2H, d, J=9.0Hz); 6.85 (IH, d, J=7.9Hz); 6.72 (IH, dd, J=7.9Hz and 2.7Hz); 6.50 (IH, dd, J=2.6Hz); 4.93 (2H, s); 4.25 (6H, m); 3.9 (3H, m); 2.5-2.9 (5H, m); 1.36 (6H, t, J=6.6Hz); 1.07 (3H, d, J=6.8Hz); 1.04 (18H, s)
Procedure 14: (SR)-4-{2-[3-(2,2-Di-tør/-butyl-.</H-l,3,2-Benzodioxasilinan-
6-yI-oxy)-2-hydroxypropylamine]propyl}phenoxymethyl carboxylic acid methyl ester
Figure imgf000034_0001
A solution of (S)-2,2-Di-tert--butyl-6-(oxiran-2-ylmethoxy)-4H-l ,32,-benzodio- xasilinane (0.65g, 1.93mMol) in acetonitrile (25ml) was treated with lithium perchlorate (0.205g, 1.93mMol), then stirred until complete solution of the salt. To the resulting stirred solution was added (Λ)-methyl 4-(2-aminopropyl) phenoxymethyl carboxylic acid methyl ester (0.43g, 1.93mMol). The mixture was heated at 80°C for 20 hours, then cooled, diluted with ethyl acetate and washed with water (2x50ml). The dried (Na2SO_ι) extracts were concentrated in vacuo, and the crude product purified by column chromatography over normal phase silica, eluting with 5% methanol in ethyl acetate to give the title compound as an oil.
δ*Η (250MHz, CDCI3): 7.12 (2H, d, J=8.7Hz); 6.87 (3H, m); 6.75 (IH, dd, J=8.8Hz and 2.7Hz); 6.53 (IH, d, J=2.6Hz); 4.93 (2H, s); 4.60 (2H, s); 3.87 (3H, m); 3.81 (3H, s); 2.95-2.50 (5H, m); 1.07 (3H, d, J=6.7Hz); 1.03 (18H, s)
Procedure 15: 3,4-DibenzyIoxyphenol
Figure imgf000035_0001
A solution of 3,4-dibenzyloxyacetophenone (5.18g, 20mMol) in acetic acid (25ml), chloroform (8ml), water (4ml) and peracetic acid (36-40 wt% in acetic acid, 18ml) was stirred at 40°C for 4 hours. After cooling to room temperature, saturated sodium thiosulfate solution was added and the product was extracted into ethyl acetate. The organic extracts were separated, washed with saturated sodium bicarbonate solution, water and brine. The organic solution was dried and evaporated. A solution of the residue in methanol (25ml) was treated with sodium hydroxide solution (2M, 8ml) and the reaction was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was dissolved in water (10ml) and the pH of the solution was adjusted to 9 with IM hydrochloric acid. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extracts were separated, dried and evaporated giving the title compound as a colourless solid.
δ(CDCl3): 7.25 (10H, m), 6.77 (IH, d, J = 8.5Hz), 6.48 (IH, d, J = 2.8Hz), 6.27 (IH, dd, J = 8.5, 2.8Hz), 5.10 (2H, s), 5.06 (2H, s), 4.65 (IH, br, exchanges with D2O).
Procedure 16: (S)-3-(3,4-Dibenzyloxyphenoxy)-l,2-epoxypropane
Figure imgf000035_0002
The title compound was prepared from 3,4-dibenzyloxphenol and (S)-glycidyl 3- nitrobenzene sulfonate according to the method described in Procedure 12.
δ(CDCl ): 7.36 (10H, m), 6.85 (IH, d, J = 8.8Hz), 6.60 (IH, d, J = 2.9Hz), 6.38 (IH, dd, J = 8.8, 2.9Hz), 5.13 (2H, s), 5.08 (2H, s), 4.14 (IH, dd, J = 11, 3.3Hz), 3.85 (IH, dd, J = 11, 5.8Hz), 3.31 (IH, m), 2.88 (IH, dd, J = 4.9, 4.1Hz), 2.71 (IH, dd, J = 4.9, 2.6Hz). Procedure 17: (SR)-4-{2-[3-(3,4-Dibenzyloxyphenoxy)-2- hydroxypropylamino]propyl}phenoxy acetic acid, methyl ester
Me
Figure imgf000036_0001
The title compound was prepared from (S)-3-(3,4-dibenzyloxyphenoxy)-l,2- epoxypropane and (R)-4-(2-aminopropyl)phenoxyacetic acid methyl ester according to the method described in Procedure 13.
δ(CDCl3): 7.5-7.3 (10H, m), 7.09 (2H, d, J = 8.8Hz), 6.85-6.80 (3H, m), 6.58 (IH, d, J = 3.0Hz), 6.35 (IH, dd, J = 8.8, 3.0Hz), 5.12 (2H, s), 5.07 (2H, s), 4.60 (2H, s), 3.9- 3.83 (3H, m), 3.80 (3H, s), 3.0-2.5 (5H, m), 1.06 (3H, d, J = 6.3Hz).
Procedure 18: (R)-3-(3,4-Dihydroxyphenyl)-2-propylamine hydrobromide
Figure imgf000036_0002
A solution of (R)-3-(3,4-dimethoxyphenyl)-2-propylamine hydrochloride 1 (500 mg, 2.15 mMol) in hydrogen bromide (48%, 5 ml) was stirred at 100°C under an argon atmosphere for 20 hours. After cooling, the solvent was evaporated and the residue was dried giving the title compound.
δ(D<>DMSO + D2O): 6.9 - 6.4 (3H, m), 3.5 - 2.4 (3H, m), 1.3 (3H, d, J = 7 Hz) ppm.
1 D.E. Nichols, CF. Barfknecht and D.B. Rusterholz. J.Med.Chem., 1973, 16(5), 480.
Procedure 19: (R)-2-(3,4-DihydroxyphenyI)propylcarbamic acid, f-butyl ester. BOCNH
Figure imgf000037_0001
A solution of (R)-3-(3,4-dihydroxyphenyl)-2-propylamine hydrobromide (480 mg, 1.9 mMol) in dimethylformamide (5 ml) containing triethylamine (3 equiv, 586 mg, 5.7 mMol) was stirred at 5°C under an argon atmosphere for 15 minutes.
Di-r-butyl dicarbonate (414 mg, 1.9 mMol) was added and the reaction mixture was stirred at 5°C for 1 hour and then at ambient temperature for 1 hour. The solvent was evaporated. Ethyl acetate (100 ml) and water (50 ml) were added and the organic layer was separated, washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. Purification of the residue by chromatography on silica gel eluting with 25% ethyl acetate in n-hexane gave the title compound, m.p. 116-118°C;
δ(CDCl3): 6.76 (IH, d, J = 7.9 Hz), 6.70 (IH, d, J = 2 Hz), 6.55 (IH, dd, J = 7.9, 2 Hz), 6.25-5.90 (2H, br, exchanges with D2O), 4.45 (IH, br, exchanges with D2O), 3.8 (IH, b), 2.75 - 2.5 (2H, ), 1.43 (9H, s), 1.07 (3H, d, J = 6.6 Hz) ppm.
Procedure 20: (R)-5-[N-(/-Butyloxycarbonyl)-2-aminopropyl]-l,3-benzodioxole- 2,2-dicarboxylic acid, diethyl ester
BOCNH
Figure imgf000037_0002
A solution of (R)-2-(3,4-dihydroxyphenyl)propylcarbamic acid, r-butyl ester. (1.07g, 4 mMol) in acetone (25 ml) containing potassium carbonate (3 equiv, 1.66 g, 12 mMol) was stirred at 60°C under an argon atmosphere for 1 hour. After cooling to ambient temperature, a solution of diethyl dibromomalonate (1.27 g, 4 mMol) in acetone (7 ml) was added and the reaction was stined at ambient temperature for 18 hours. The suspension was filtered and the residue was washed with ethyl acetate. The filtrates were combined, evaporated and the residue was partitioned between ethyl acetate (200 ml) and dilute hydrochloric acid (100 ml, pH5). The organic layer was separated, washed with water (2 x 100 ml) and brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in n-hexane giving the title compound as an oil; δ(CDCl3): 6.86 (IH, d, J = 8 Hz), 6.78 (IH, d, J = 1.3 Hz), 6.71 (IH, dd, J = 8, 1.3 Hz), 4.41-4.32 (5H, ), 3.8 (IH, br, exchanges with D O),2.76 (IH, dd, J = 13.5, 5.6 Hz), 2.60 (IH, dd, J = 13.5, 7.2 Hz),1.43 (9H, s), 1.36 - 1.31 (6H, m), 1.07 (3H, d, J = 6.6 Hz) ppm.
Procedure 21: (R)-5-(2-Aminopropyl)-l,3-benzodioxoIe-2,2-dicarboxylic acid, diethyl ester, hydrochloride salt.
Me HCl
Figure imgf000038_0001
A solution of (R)-5-[N-(r-butyloxycarbonyl)-2-aminopropyl]-l,3-benzodioxole-2,2- dicarboxylic acid diethyl ester (3.0 g, 7 mMol) in ethyl acetate (40 ml) and hydrogen chloride solution in diethyl ether (IM, 56 ml, 56 mMol) was stirred at ambient temperature under an argon atmosphere for 48 hours. The solvent was evaporated and the residue was dried giving the title compound as a glass.
δ(d6-DMSO): 8.07 (3H, br, exchanges with D2O), 7.10 - 7.06 (2H, m), 6.85 (IH, dd, J = 8, 1.4 Hz), 4.33 (4H, q, J = 7.1 Hz), 3.5 - 3.4 (IH, m), 2.93 (IH, dd, J = 13.4, 5.8 Hz), 2.66 (IH, d, J = 13.5, 8.2 Hz), 1.24 (6H, t, J = 7.1 Hz), 1.12 (3H, d, J = 6.3 Hz) ppm.
Procedure 22: (R)-5-(2-Aminopropyl)-l,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester
Figure imgf000038_0002
A solution of (R)-5-(2-aminopropyl)-l,3-benzodioxole-2,2-dicarboxylic acid diethyl ester hydrochloride (646 mg, 2 mMol) in dichloromethane (80ml) was shaken with a saturated solution of sodium hydrogen carbonate (20 ml) for 30 seconds. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 50 ml). The combined organic extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4). The solvent was evaporated giving the title compound which was used immediately.
Procedure 23: (SR)-5-{2-[3-(2,2-Di-t-butyl-4H-l,3,2-benzodioxasiIinan-6-yloxy)- 2-hydroxypropylamino]propyI}-l,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester
Me
Figure imgf000039_0001
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.
δ(CDCI3): 6.86-6.49 (6H, m), 4.94 (2H, s), 4.36 (4H, q, J = 7.2Hz), 4.1-3.8 (3H, m), 3.0-2.5 (5H, m), 1.34 (6H, t, J = 7.2Hz), 1.08 (3H, d, J = 6.3Hz), 1.03 (18H, s).
Procedure 24: 4-(2-/-ButoxycarbonyIaminoethyl)phenoxymethyl phosphonic acid, diethyl ester
Figure imgf000039_0002
A solution of 2-(4-hydroxyphenyl)ethylcarbamic acid, r-butyl ester * (4.0g, 16.9 mMol) in dry DMSO (37.5 ml) was cooled in an ice-bath and treated with sodium hydride (80% in mineral oil 0.557g, 1.1 equiv) with stirring under argon according to the method described by Cornforth^. When effervescence ceased a solution of 4-chlorobenzenesulfonyloxymethylphosphonate diethyl ester (6.07g, 1.05 equiv) in dry DMSO (110ml) was added and the resulting pale yellow solution stirred at room temperature overnight. The mixture was then poured into water (550ml) and extracted with diethyl ether/ethyl acetate (1: 1, 3x 150ml) and finally ethyl acetate (3x 100ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil was purified by chromatography on silica gel with a gradient of 3:2 pentane: ethyl acetate rising to 100% ethyl acetate to give the title compound as a colourless viscous oil.
δ*H (250MHz, CDC13): 7.12 (2H, d), 6.90 (2H, d), 4.51 (IH, br s), 4.30-4.15 (6H, m), 3.33 (2H, br. q), 2.74 (2H, t), 1.43 (9H, s), 1.37 (6H, t).
l F. Houlihan et. al. Can. J. Chem., 1985, 63, 153.
2 J. Cornfoπh and J.R.H Wilson. J.C.S. Perkin I., 1994, 1897.
Procedure 25: 4-(2-Aminoethyl)phenoxyrnethylphosphonic acid, diethyl ester
Figure imgf000040_0001
4-(2-f-Butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, diethyl ester (2.856g, 9.95 mMol) in methylene chloride (300ml) and trifluoracetic acid (16ml) was stined at room temperature for 5h. The solution was concentrated under reduced pressure and product dried under in vacuo. The trifluoacetic acid salt was neutralized with aqueous sodium carbonate and extracted with dichloromethane containing a small proportion of methanol (5x100ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give the title compound as a pale yellow gum.
δ*H (250MHz, CDCI3): 7.12 (2H, d), 6.9 (2H, d), 4.30-4.15 (6H, m), 3.00-2.55 (4H, m) and 1.37 (6H, t).
Procedure 26: (S)-4-{2-[3-(2,2-Di-.-butyl-4H-l,3,2-benzodioxasilinan-6-yl-oxy)-2- hydroxypropylamino]ethyl}phenoxymethyl phosphonic acid, diethyl ester
Figure imgf000041_0001
Using similar a experimental method to that of Procedure 13, the title compound was obtained from 4-(2-aminoethyl)phenoxymethylphosphonic acid diethyl ester and (S)-2,2-di-/-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2-benzodioxasilinane as an oil.
δ*H (250MHz, CDC13): 7.1 (2H, d, J=8.7Hz), 6.87 (2H, d, J=8.9Hz), 6.84 (IH, m); 6.75 (IH, dd, J=8.3Hz and 3.1Hz), 6.52 (IH, d, J=3.0Hz), 4.94 (2H, s), 4.25 (6H, m), 3.88 (3H, m), 2.5-2.85 (7H, m), 1.37 (6H, t, J=6.7Hz), 0.99 (18H, s); [α]D 22 - 18.5° (c = 0.2, CHCI3).
Procedure 27: (RR)-2-(4-Hydroxyphenyl)-l-methylethyl-(l-phenyl- ethyl)aminoboronic acid
Figure imgf000041_0002
(RR)-[2-(4-Methoxyphenyl)-l-methylethyl]-(l-phenylethyl)amine hydrochloride saltl (lOg, 0.0327 Mol) in dichloromethane (50ml) was treated with boron tribromide (IN in CH2CI2, 72 ml) under argon and stining continued overnight at room temperature. The mixture was then evaporated to dryness and ice added to hydrolyse the complex. The resulting white solid was collected and dried to give the title compound.
δxH (250MHz, CDCI3 + CD3OD): 7.50 (5H, m), 6.83 (2H, d), 6.72 (2H, d), 4.38 (IH, q), 3.23 (IH, dd), 3.00 (IH, m), 2.67 (IH, dd), 1.78 (3H, d), 1.24 (3H, d)
m/z: FAB MH+: 300 (5%), 256 (100) 1 D.E. Nichols, CF. Barfknecht and D.B. Rusterholz. J.Med.Chem., 1973, 16(5), 480.
Procedure 28: (R)-4-(2-Aminopropyl)phenol
Me
Figure imgf000042_0001
(RR)-2-(4-Hydroxyphenyl)-l-methylethyl-(l-phenylethyl)aminoboronic acid
(9.73g, 0.0325 Mol) was dissolved in methanol (120ml) and hydrogenated at 50 psi and 50°C with 10% palladium on charcoal (lg) for 2 days. The mixture was allowed to cool, then filtered through Kieselguhr and evaporated to dryness to give the title compound as a pale yellow solid.
δxH (250MHz, CDCI3): 7.06 (2H, d), 6.80 (2H, d), 4.12 (3H, br s), 3.12 (IH, m), 2.96 (IH, dd), 2.73 (IH, dd), 1.30 (3H, d).
Procedure 29: (R)-2-(4-HydroxyphenyI)-l-methylethylcarbamic acid, /-butyl ester
Me
Figure imgf000042_0002
(R)-4-(2-Aminopropyl)phenol (4.9 lg, 0.0325 mol) in dichloromethane (240 ml) and dry dimethylformamide (50ml) was treated with triethylamine (7.59 ml) and di-r- butyldicarbonate (11.77g, 1.2 equiv.) and the mixture stined at room temperature for 1 day. After evaporation of volatile material in vacuo, the residue was washed with diethyl ether. The combined portions of diethyl ether (500ml) were washed with water (3 x 100ml) and dried over anhydrous sodium sulfate. After evaporation to dryness the residue was chromatographed on silica gel with 0-3% methanol in dichloromethane to give the title compound as a gum that slowly solidified.
δ*H (250MHz, CDCI3): 7.00 (2H, d), 6.76 (2H, d), 6.25 (IH, br s), 4.44 (IH, br s), 3.83 (IH, m), 2.73 (IH, m), 2.57 (IH, dd), 1.43 (9H, s), 1.07 (3H, d).
Procedure 30: (R)-4-(2-/-ButoxycarbonylaminopropyI)phenoxyacetic acid, methyl ester
Me
Figure imgf000043_0001
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.
The solvent was removed under reduced pressure and the residue was taken into ethyl acetate and washed with water (2x30ml). The organic extracts were dried with sodium sulfate and the solvent evaporated in vacuo. The crude product was purified by chromatography on Kieselgel 60 (eluting with 20% ethyl acetate in pentane) to give the title compound as an oil.
δ*H (250MHz, CDCI3): 7.1 (2H, d, J=7.3Hz), 6.85 (2H, d, J=7.3Hz), 4.53 (2H, s), 4.35 (IH, br s), 3.85 (IH, ), 3.8 (3H, s), 2.5-2.8 (2H, m), 1.42 (9H, s), 1.07 (3H, d, J=6.6Hz); [α]D 22 -7.9° (c=0.49, MeOH)
Procedure 31: Hydroxymethylphosphonic acid, bis-(3-benzyloxy-propyl)ester.
Figure imgf000043_0002
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.
δ*H (250MHz, CDC13): 7.32 (10H, m), 4.49 (4H, s), 4.22 (4H, m), 3.85 (2H, t), 3.58 (4H, t), 3.08 (IH, m), and 1.97 (4H, m).
Procedure 32: 4-Chlorobenzenesulfonyloxymethylphosphonate, bis-(3- benzyloxypropyl) ester
Figure imgf000044_0001
The title compound was prepared in a similar manner to the literature procedure ^ from hydroxymethylphosphonic acid, bis-(3-benzyloxy-propyl) ester as an oil.
δ*H (250MHz, CDCI3): 7.82 (2H, d), 7.50 (10H, m), 4.48 (4H, s), 4.30-4.10 (6H, m), 3.53 (4H, t), 1.93 (4H, m).
]J. Cornforth and J.R.H. Wilson, JC.S Perkin I, 1994, 1897.
Procedure 33: (R)-4-(2-f-Butoxycarbonylarninopropyl)phenoxymethyl- phosphonic acid, bis-(3-benzyloxypropyl) ester
Me
Figure imgf000044_0002
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.
δlU (200MHz, CDCI3): 7.30 (10H, m), 7.09 (2H, d), 6.83 (2H, d), 4.48 (4H, s), 4.40-4.15 (7H, m), 3.83 (IH, br m), 3.57 (4H, t), 2.78 (IH, dd), 2.59 (IH, dd), 1.98 (4H, m), 1.52 (9H, s) and 1.05 (3H, d).
Procedure 34: (R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-(3- benzyloxypropyl) ester
Me
Figure imgf000045_0001
(R)-4-(2-r-Butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis-(3- benzyloxypropyl) ester (3.2g, 4.99 mMol) was converted into the title compound using the method described in Procedure 25.
δ (200MHz, CDCI3): 7.30 (10H, m), 7.10 (2H, d), 6.85 (2H, d), 4.47 (4H, s), 4.35-4.15 (6H, m), 3.56 (4H, t), 3.22 (IH, m), 2.70 (2H, d), 2.60 (2H, br s), 1.98 (4H, ), 1.18 (3H, d).
Procedure 35: (SR)-4-{2-[3-(2,2-Di-/-butyl-4H-l,3,2-benzodioxasilinan-6-yl-oxy)- 2-hydroxy-propyIamino]propyl}phenoxyrnethylphosphonic acid, bis-(3- benzyloxypropyl)ester
Me
Figure imgf000045_0002
(R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl) ester (2.507g, 4.6 mMol) was reacted with (S)-2,2-di-r-butyl-6-(oxiran-2-ylmethoxy)- 4H-l,3,2-benzodioxasilinane (1.557g, 1 equiv.) using the method described in Procedure 14 to yield the title compound as a colourless gum.
δ*H (200MHz, CDCI3): 7.30 (10H, m), 7.09 (2H, d), 6.83 (3H, m), 6.70 (IH, dd), 6.49 (IH, d), 4.93 (2H, s), 4.47 (4H, s), 4.35 - 4.20 (6H, m), 3.99 (IH, m), 3.87 (2H, d), 3.55 (4H, t), 3.1 - 2.5 (5H, m), 2.32 (2H, br s), 1.98 (4H, m), 1.11 (3H, d), 1.03 (18H, s).
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.
Me
Figure imgf000046_0001
(SR)-4- { 2-[3-(2,2-Di-t-butyl- 4H- 1 ,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxy- propylamino]propyl}phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl) ester (lg, 1.14mmol) was hydrogenated at 50°C and 50psi for 2 days in methanol (120ml) in the presence of 10% palladium on charcoal (l.Og). After allowing the mixture to cool, it was filtered through Kieselguhr, evaporated to dryness and purified by column chromatography on silica gel eluting with 0-15% methanol dichloromethane. The title compound was obtained as a clear gum.
δ*H (250MHz, CDCI3): 7.13 (2H, d), 6.90 (2H, d), 6.82 (IH, d), 6.70 (IH, dd), 6.49 (IH, d), 4.93 (2H, s), 4.40 - 4.25 (6H, m), 4.07 (IH, m), 3.88 (2H, m), 3.73 (4H, t), 3.40 - 2.60 (9H, overlapping m + br. s), 1.90 (4H, m), 1.18 (3H, d), 1.02 (18H, s).
Procedure 37: Hydroxymethylphenylphosphinic acid, ethyl ester 0 ii ^
Ph — P "OH I OEt
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.
δxH (250MHz, CDC13): 7.83 (2H, ), 7.65 - 7.42 (3H, m), 4.26 - 3.90 (5H, m), 1.32 (3H, t).
!D.G. Hewitt. Aust. J. Chem., 1979, 32, 463.
Procedure 38: 4-Chlorobenzenesulfonyloxymethylphenylphosphinic acid ethyl ester
Figure imgf000047_0001
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.
δ U (250MHz, CDCI3): 7.83 - 7.58 (5H, m), 7.58 - 7.40 (4H, m), 4.40 (IH, dd), 4.28 - 4.00 (3H, ), 1.35 (3H, t).
Procedure 39: (R)-4-(2-/-Butoxycarbonylaminopropyl)phenoxymethyl- phenylphosphinic acid, ethyl ester.
Figure imgf000047_0002
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 .
δ*H (200MHz, CDCI3): 7.93 (2H, ), 7.52 (3H, m), 7.07 (2H, d), 6.82 (2H, d), 4.52-4.0 (5H, m), 3.81 (IH, br), 2.76 (IH, dd), 2.57 (IH, dd), 1.42 (9H, s), 1.38 (3H, t), 1.03 (3H, d).
Procedure 40: (R)-4-(2-AminopropyI)phenoxymethylphenylphosphinic acid, ethyl ester
Me
Figure imgf000048_0001
The title compound was prepared by a method similar to that described in Procedure 25 from (R)-4-(2-r-butoxycarbonylaminopropyl)phenoxymethyl-phenylphosphinic acid, ethyl ester (2.647g, 6.1mMol).
δ!H (250MHz, CDCI3): 7.93 (2H, m), 7.65 - 7.44 (8H, m), 7.07 (2H, d), 6.83 (2H, d), 4.44 (IH, dd), 4.36 - 4.02 (3H, m), 3.09 (IH, m), 2.63 (IH, dd), 2.43 (IH, dd), 1.38 (3H, t), 1.08 (3H, d).
Procedure 41: (SR)-4-{2-[3-(2,2-Di-/-butyl-4H-l,3,2-benzodioxasilinan-6-yl-oxy)- 2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester Me
Figure imgf000049_0001
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.)
δ*H (400MHz, CDC13): 7.92 (2H, m), 7.59 (IH, m), 7.51 (2H, ), 7.07 (2H, d), 6.82 (3H, m), 6.69 (IH, dd), 6.48 (IH, d), 4.93 (2H, s), 4.43 (IH, dd), 4.30 (IH, m), 4.25 - 4.05 (2H, m), 3.98 (IH, m), 3.88 (2H, ), 3.03 - 2.35 (7H, m), 1.38 (3H, t), 1.10 (3H, d), 1.03 (18H, s).
Procedure 42: 3-Benzyloxypropylphosphinic acid
H
Figure imgf000049_0002
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.
δ(CDCl3): 10.83(1H, s, exchanges with D2O); 7.36-7.18(5H, m.); 7.10(1H, d, J = 546.57Hz.); 4.49(2H, s.); 3.52(2H, t, J = 5.77Hz.); 1.94- 1.80(4H, m.).
Procedure 43: 3-Benzyloxypropylphosphinic acid, n-butyl ester
Figure imgf000049_0003
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.
δ(CDCI3): 7.39-7.15(5H, .); 7.09(1H, ddd, J = 532.27, 1.92, 1.65Hz.); 4.51(2H, s.); 4.17-3.91(2H, m.); 3.53(2H, t, J = 5.77Hz.); 1.99-1.72(4H, m.); 1.69-1.58(2H, .); 1.47-1.33(2H, m.); 0.94(3H, t, J = 7.15Hz.).
Procedure 44: 3-Benzyloxypropylhydroxymethylphosphinic acid, π-butyl ester
Figure imgf000050_0001
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.
δ(CDCI3): 7.38-7.25(5H, m.); 4.50(2H, s.); 4.09-3.97(2H, m.); 3.83(2H, t, J = 4.95Hz.); 3.77-3.71(1H, m. exchanges with D2O); 3.54-3.51(2H, m.); 1.99-1.86(4H, m.); 1.68-1.60(2H, m.); 1.48-1.34(2H,m.); 0.92(3H, t, J = 7.42Hz.).
Procedure 45: 3-Benzyloxypropyl-(4- chlorophenylsulfonyloxymethy phosphinic acid, n-butyl ester
Figure imgf000050_0002
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. δ(CDCI3): 7.84(2H, d, J = 8.80Hz.); 7.52(2H, d, J = 8.79Hz.); 7.36-7.26(5H, m.); 4.50(2H, s.); 4.27-3.78(4H, m.); 3.51(2H, t, J = 6.05Hz.); 1.97- 1.83(4H, m.); 1.67- 1.55(2H, m.); 1.42-1.26(2H, .); 0.91(3H, t, J = 7.15Hz.).
Procedure 46: 4-(2-f-Butoxycarbonylaminoethyl)phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, t-butyl ester
Figure imgf000051_0001
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.
δ(CDCl3): 7.37-7.24(5H, m.); 7.1 1(2H, d, J = 8.80Hz.); 6.87(2H, d, J = 8.80Hz.); 4.49(2H, s.); 4.27-3.95(4H, m.); 3.55(2H, t, J = 6.05Hz.); 3.36-3.32(2H, m.); 2.74(2H, t, J = 6.88Hz.); 2.06-1.79(5H, m.); 1.71-1.60(2H, .); 1.47-1.31(2H, m.); 1.25(9H, s.); 0.91(3H, t, J = 7.15Hz.).
Procedure 47: 4-(2-Aminoethyl)phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester
Figure imgf000051_0002
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.
δ(CDCl3): 7.36-7.26(5H, m.); 7.12(2H, d, J = 8.80Hz.); 6.87(2H, d, J = 8.53Hz.); 4.49(2H, s.); 4.23-4.19(2H, m.); 4.15-3.97(2H, m.); 3.54(2H, t, J = 5.78Hz.); 2.94(2H, t, J = 6.60Hz.); 2.70(2H, t, J = 6.60Hz.); 2.05-1.95(4H, m.) 1.67-1.59(4H, m. 2H exchange with D2O); 1.43-1.35(2H, m.); 0.91(3H, t, J = 7.42Hz.).
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
Figure imgf000052_0001
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.
δ(CDCl3 + D2O): 7.36-7.26(5H, m.); 7.13(2H, d, J = 8.80Hz.); 6.86(2H, d, J = 8.80Hz.); 6.83(1H, d, J = 8.80Hz.); 6.72(1H, dxd, J = 8.80 & 3.03Hz.); 6.50(1H, d, J = 3.02Hz.); 4.94(2H, s.); 4.49(2H, s.); 4.22-3.88(7H, .); 3.54(2H, t, J = 6.05Hz.); 2.92-2.70(6H, m.); 2.06-1.93(4H, m.); 1.46-1.30(2H, m.); 1.02(18H, s.); 0.91(3H, t, J = 7.14Hz.).
Procedure 49: (R)-4-(2-/-Butoxycarbonylaminopropyl)phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, n-butyl ester
Figure imgf000053_0001
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.
δ(CDCl3 + D2O): 7.34-7.26(5H, m.); 7.1 1 (2H, d, J = 8.53Hz.); 6.86(2H, d, J = 8.52Hz.); 4.50(2H, s.); 4.36-3.85(5H, m.); 3.56(2H, t, J = 5.91Hz.); 2.80(1H, dd, J = 13.48, 3.49Hz.); 2.60(1H, dd, J = 13.48, 7.43Hz); 2.17-2.00(4H, m.); 1.69-1.62(4H, m.); 1.43(9H, s.); 1.06(3H, d, J = 6.60Hz.); 0.91(3H, t, J = 6.60Hz.).
Procedure 50: (R)-4-(2-Aminopropyl)phenoxymethyl-(3- benzyloxypropy phosphinic acid, n-butyl ester
Me
Figure imgf000053_0002
The title compound was prepared from (R)-4-(2-r-butoxycarbonylaminopropyl) phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used without further purification
δ(CDCI3 + D2O): 7.36-7.26(5H, m.); 7.12(2H, d, J = 8.80Hz.); 6.87(2H, d, J = 8.80Hz.); 4.50(2H, s.); 4.21(2H, d, J = 6.88Hz.); 4.17-3.97(2H, m.); 3.54(2H, t, J 3.55Hz.); 3.25-3.10(1H, m.); 2.74-2.53(2H, m.); 2.11-1.93(4H, m.); 1.67-1.59(2H, m.); 1.43-1.35(2H, m.); 1.13(3H, d, J = 6.32Hz.); 0.91(3H, t, J = 7.42Hz.).
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.
Me
Figure imgf000054_0001
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.
δ(CDCl3): 7.37-7.31(5H, m.); 7.1 1 (2H, d, J = 8.52Hz.); 6.86(2H, d, J = 8.60Hz.); 6.83(1H, J = 8.80Hz.); 6.72(1H, dd, J = 8.80, 3.30Hz.); 6.50(1H, d, J = 2.75Hz.); 4.94(2H, s.); 4.50(2H, s.); 4.21 -3.88(8H, m.); 3.54(2H, m.); 2.92-2.66(5H, m.); 2.57(1H, dd, J = 13.47, 6.50Hz.); 2.09- 1.90(4H, .); 1.77- 1.60(2H, m.); 1.57- 1.38(2H, m.); 1.02(18H, s.); 1.06(3H, d, J = 6.25Hz.); 0.92(3H, t, J = 7.14Hz.).
Procedure 52: Cyclohexylphosphinic acid, n-butyl ester
H
Figure imgf000054_0002
The title compound was prepared from cyclohexylphosphinic acid and n-butanol according the the method described in Procedure 43. The compound was used without further purification. δ(CDCI3): 6.82(1H, d, J = 517.97Hz.); 4.17-3.92(2H, m.); 1.92- 1.22(15H, m,); 0.94(3H, t, J = 7.43Hz.).
Procedure 53: Cyclohexylhydroxymethylphosphinic acid, n-butyl ester
Figure imgf000055_0001
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.
δ(CDCI3 + D2O): 4.13-4.93(2H, m.); 3.88-3.65(2H, m.); 1.97-1.22(15H, m.); 0.93(3H, t, J = 7.15Hz.).
Procedure 54: (4-Chlorobenzenesulfonyloxy)cyclohexylphosphinic acid, n-butyl ester
Figure imgf000055_0002
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.
δ(CDCI3): 7.87(2H, d, J = 8.80Hz.); 7.57(2H, d, J = 8.80Hz.); 4.19(2H, d, J = 7.70Hz.); 4.12-3.81 (2H, m.); 2.05-1.20(15H, m.); 0.91(3H, t, J = 7.15Hz.).
Procedure 55: 4-(2-f-Butoxycarbonylaminoethyl)phenoxymethyl cyclohexylphosphinic acid, n-butyl ester
Figure imgf000056_0001
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.
δ(CDCI3): 7.13(2H, d, J = 8.80Hz.); 6.88(2H, d, J = 8.80Hz.); 4.50(1H, s. exchanges with D2O); 4.32-3.95(4H, m.); 3.34(2H, q, J = 7.15Hz.); 2.74(2H, t, J = 7.15Hz.); 2.07-1.47(15H, m.); 1.44(9H, s.); 0.92(3H, t, J = 7.43Hz.);
Procedure 56: 4-(2-Aminoethyl)phenoxyrnethylcyclohexylphosphinic acid, n- butyl ester
Figure imgf000056_0002
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.
δ(CDCl3 + D2O): 7.14(2H, d, J = 8.80Hz.); 6.68(2H, d, J = 8.80Hz.); 4.26-3.98(4H, m.); 2.96-2.90(2H, m.); 2.75-2.70(2H, m.); 2.12-1.26(15H, m.): 0.92(3H, t, J = 7.15Hz.); Procedure 57: (S)- 4-{2-[3-(2,2-Di-r-butyl-4H-l,3,2-benzodioxasilinan-6-yloxy)-2- hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester
Figure imgf000057_0001
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.
δ(CDCl3 + D2O): 7.14(2H, d, J = 8.56Hz.); 6.88(2H, d, J = 8.65Hz.); 6.82(1H, d, J = 8.79Hz.); 6.72(1H, dd, J = 8.78, 3.00Hz.); 6.50(1H, d, J = 2.95Hz.); 4.95(2H, s.); 4.26-4.11(4H, m.); 4.09-3.95(3H, m.); 3.89(2H, d, J = 5.1 1Hz.); 2.92-2.83(2H, m.); 2.77-2.72(2H, m.); 2.03-1.93(3H, m.); 1.93-1.83(2H, m.); 1.72- 1.61(4H, m.); 1.51- 1.40(4H, m.); 1.39-1.21(2H, m.); 1.03(18H, s.); 0.91 (3H, t, J =7.39Hz.).
Procedure 58: (S)-4-{2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester
Figure imgf000057_0002
The title compound was prepared from 4-(2-aminoethyl)phenoxy methylcyclohexylphosphinic acid, n-butyl ester and (S)-2-(4- benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
δ(CDCl3): 7.44-7.26 (5H, m), 7.14 (2H, d, J = 8.8Hz), 6.91-6.80 (6H, m), 5.01 (2H, s), 4.25-4.0 (5H, m), 3.91 (2H, d, J = 5Hz), 3.0-2.75 (6H, m), 2.1-1.25 (15H, m), 0.92 (3H, t, J =7.4Hz).
Procedure 59: (S)-4-{2-[3-(3-Benzyloxyphenoxy)-2-hydroxypropylamino] ethyl}phenoxymethylcyclohexy!phosphinic acid, n-butyl ester
Figure imgf000058_0001
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.
δ(CDCl3): 7.5-7.3 (5H, m), 7.2-7.1 (3H, m), 6.88 (2H, d, J = 8.5Hz), 6.65-6.45 (3H, m), 5.04 (2H, s), 4.25-3.9 (7H, m), 2.95-2.75 (6H, m), 2.1 -1.25 (15H, m), 0.92 (3H, t, J = 7.2Hz).
Procedure 60: (R)-4-(2-r-Butoxycarbonylaminopropyl)phenoxymethyl- cyclohexylphosphinic acid, n-butyl ester BOCNH
Figure imgf000059_0001
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.
δ(CDCI3): 7.10(2H, d, J = 8.53Hz.); 6.87(2H, d, J = 8.60Hz.); 4.34-3.85(6H, m. IH exchanges with D20); 2.78(1H, dd, J = 13.74, 5.49Hz.); 2.60(1H, dd, J = 13.48, 7.43Hz.); 2.04-1.13(15H, m.); 1.42(9H, s.); 1.07(3H, d, J = 6.87Hz.); 0.92(3H, t, J = 7.42Hz.).
Procedure 61: (R)-4-(2-Aminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester
Me
Figure imgf000059_0002
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.
δ(CDCl3): 7.13(2H, d, J = 8.80Hz.); 6.88(2H, d, J = 8.80Hz.); 4.23-4.02(4H, m.); 3.20-3.12(lH, m.); 2.68(1H, dd, J = 13.48, 5.50Hz.); 2.54(1H, dd, J = 13.47, 7.70Hz.); 2.06- 1.21 (17H, m. 2H exchanged with D20); 1.14(3H, d, J = 6.32Hz.); 0.92(3H, t, J = 7.15Hz.).
Procedure 62: (SR)-4-{2-[3-(2,2-di-f-Butyl-4H-l,3,2-benzodioxasilinan-6-yloxy)- 2-hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n- butyl ester
Figure imgf000060_0001
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.
δ(CDCl3 + D2O): 7.10(2H, d, J = 8.53Hz.); 6.87(2H, d, J = 8.80Hz.); 6.83(1H, d, J = 8.80Hz.); 6.70(1H, dxd, J = 8.80 & 3.02Hz.); 6.50(1 H, d, J = 3.02Hz.); 4.94(2H, s.); 4.26-3.88(7H, m.); 2.91-2.53(5H, m.); 2.05-1.26(15H, m.); 1.06(3H, d, J = 6.32Hz.); 1.02(18H, s.); 0.92(3H, t, J = 7.43Hz.).
Procedure 63: n-Hexylphosphinic acid
O
H- -C6H13
OH
The title compound was prepared from n-hexene and 50% aqueous phosphinic acid by an analogous procedure to that described in J. Inorg. Nucl. Chem., 1965, 27, 697. δ(CDCI3): 12.10(1H, s, exchanges with D2O); 7.08(1H, dd, J = 540.10, 1.93Hz.); 1.82-1.51(4H, m.); 1.42-1.23(6H, m.); 0.87(3H, t, J = 6.87Hz.).
Procedure 64: n-Hexylphosphinic acid, n-butyl ester
O II H- P C6H13
OC4H9
The title compound was prepared from n-hexylphosphinic acid and n-butanol according the the method described in Procedure 43. The compound was used without further purification.
δ(CDCl3): 7.08(1H, d, J = 525.92Hz.); 4.12-3.98(2H, m.); 1.80-1.26(14H, m.); 0.97- 0.86(6H, m.).
Procedure 65: n-Hexylhydroxymethylphosphinic acid, n-butyl ester
O HO. / P C6H13
OC4Hs
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.
δ(CDCl3): 4.09-3.99(3H, m.); 3.89-3.79(2H, m.); 1.83-1.75(2H, m.); 1.69- 1.46(4H, m.); 1.43-1.29(8H, .); 0.96-0.86(6H, m.).
Procedure 66: 4-Chlorobenzenesulfonyloxymethyl-n-hexylphosphinic acid, n-butyl ester
Figure imgf000061_0001
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.
δ(CDCI3): 7.89(2H, d, J = 8.88Hz.); 7.57(2H, d, J = 8.80Hz.); 4.25-3.84(4H, m.); 2.04-1.23(14H, m.); 0.97-0.86(6H, m.).
Procedure 67: (R)-4-(2-r-Butoxycarbonylaminopropyl)phenoxymethyl-n- hexylphosphinic acid, n-butyl ester
Me
Figure imgf000062_0001
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.
δ(CDCl3): 7.1 1(2H, d, J = 8.80Hz.); 6.87(2H, d, J = 8.52Hz.); 4.21-4.00(4H, m.); 3.83(1H, s.); 3.41(1H, m.); 2.77(1H, dd, J = 13.83, 5.58Hz.); 2.58(1H, dd, J = 13.76, 7.12Hz.); 1.89-1.84(2H, m.); 1.68-1.60(6H, m.); 1.44-1.39(2H, m.); 1.43(9H, s.); 1.38-1.25(4H, m.); 1.07(3H, d, J = 6.95Hz.); 0.94-0.85(6H, m.).
Procedure 68: (R)-4-(2-AminopropyI)phenoxymethyl-«-hexylphosphinic acid, n-butyl ester
Figure imgf000063_0001
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.
δ(CDCl3): 7.12(2H, d, J = 8.53Hz.); 6.89(2H, d, J = 8.80 Hz.); 4.22-3.86(6H, m. 2H exchanges with D2O); 3.24(1H, q, J = 6.59Hz.); 2.70(2H, d, J = 6.88Hz.); 1.95- 1.84(2H, m.); 1.71-1.58(4H, m.); 1.47-1.25(8H, m.); 1.18(3H, d, J = 6.32Hz.); 0.95- 0.84(6H, m.).
Procedure 69: (SR)-4-{2-[3-(2,2-Di-f-butyI-4H-l,3,2-benzodioxasilinan-6-yloxy)- 2-hydroxypropylamino]propyl}phenoxymethyl-n-hexylphosphinic acid, n-butyl ester
Figure imgf000063_0002
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. δ(CDCl3): 7.12(2H, d, J = 8.53Hz.); 6.87(2H, d, J = 8.80Hz.); 6.72( 1H, d, J = 8.80Hz.); 6.72(1H, dd, J = 8.80, 3.03Hz.); 6.50(1H, d, J = 3.03Hz.); 4.92(2H, s.); 4.27-3.86(8H, m. 2H exchange with D20); 2.93-2.86(lH, .); 2.84-2.63(2H, m.); 2.57(1H, dd, J = 13.47, 6.59Hz.); 1.96-1.84(4H, m.); 1.71- 1.58(4H, m.); 1.47- 1.15(8H, m.); 1.06(3H, d, J = 6.32Hz.); 1.03(18H, s.); 0.97-0.85(6H, m.).
Procedure 70: (S)-l-(4-BenzyIoxyphenoxy)-3-[N-2-(4- hydroxyphenyl)ethylamino]propan-2-ol.
Figure imgf000064_0001
The title compound was prepared from tyramine and (S)-2-(4- benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
δ(d6-DMSO): 9.3-8.9 (IH, b, exchanged with D2O), 7.5-7.25 (5H, m), 6.98 (2H, d, J = 8.6Hz), 6.92 (2H, d, J = 9Hz), 6.83 (2H, d, J = 9Hz), 6.65 (2H, d, J = 8.6Hz), 5.02 (2H, s), 4.9 (IH, b, exchanged with D20), 3.9-3.75 (3H, m), 2.75-2.55 (6H, ).
Procedure 71: (S)-N-Benzyl-l-(4-benzyloxyphenoxy)-3-[N-2-(4- hydroxyphenyl)ethylamino]propan-2-ol.
Figure imgf000064_0002
A solution of (S)-l-(4-benzyloxyphenoxy)-3-[N-2-(4-hydroxyphenyl) ethylamino]propan-2-ol (1.9g, 4.8mMol) and benzyl bromide (0.57ml, 4.8mMol) in dimethylformamide (10ml) containing sodium carbonate (770mg, 7.2mMol) was stined at room temperature for 18 hours. The mixture was filtered and the residue was washed with ethyl acetate. The filtrates were combined, washed with water and brine, dried and evaporated. Purification of the residue by flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the title compound.
δ(CDCl3 + D2O): 7.5-7.25 (10H, m), 6.96 (2H, d, J = 8.5Hz), 6.88 (2H, d, J = 9.1Hz), 6.79 (2H, d, J = 9.1Hz), 6.71 (2H, d, J = 8.5Hz), 5.01 (2H, s), 4-3.78 (4H, m), 3.59 (IH, d, J = 13.5Hz), 2.9-2.6 (6H, m).
Procedure 72: (S)-N-Benzyl-4-{2-[-3-(4-benzyloxyphenoxy)-2- hydroxypropylamino]ethyI}phenoxymethyI-n-hexylphosphinic acid, n-butyl ester
Figure imgf000065_0001
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.
δ(CDCl3 + D2O): 7.45-7.25 (10H, ), 7.04 (2H, d, J = 8.5Hz), 6.9-6.78 (6H, m), 5.01 (2H, s), 4.2-3.83 (8H, m), 3.54 (IH, d, J = 12.3Hz), 2.9-2.6 (6H, m), 1.9 (2H, m), 1.65 (4H, ), 1.5-1.25 (8H, ), 0.95-0.85 (6H, m).
Procedure 73: Phosphonic acid, bis-(2-phenylethyl) ester
Figure imgf000065_0002
The title compound was prepared from 2-phenylethanol and phosphorus tribromide according to the method described in Procedure 31. Purification by chromatography on silica-gel eluting with 5% methanol in dichloromethane gave the title compound as an oil. δ(CDCI3): 7.92-5.32 (lH, d.); 7.16-7.33 (10H, m.); 4.10-4.28 (4H, m.); 2.92-3.04 (4H, t.)
Procedure 74: Hydroxymethylphosphonic acid, bis-(2-phenylethyI) ester
Figure imgf000066_0001
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.
δ(CDCI3): 7.17-7.33 (10H, m.); 4.15-4.30 (4H, m.); 3.70-3.74 (2H, t.); 2.86-2.96 (4H, m.)
Procedure 75: (4-Chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-(2- phenylethyl) ester
Figure imgf000066_0002
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.
δ(CDCI3): 7.75-7.90 (2H, d.); 7.49-7.52 (2H, d.); 7.13-7.33 (10H, m.); 4.15-4.23 (4H, m.); 4.02-4.05 (2H, d.); 2.88-2.95 (4H, m.)
Procedure 76: (S)-4-(2-t-Butoxycarbonylaminopropyl)phenoxyrnethyl phosphonic acid, bis-(2-phenylethyl) ester Me
Figure imgf000067_0001
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.
δ(CDCl3): 7.19-7.27 (10H, m.); 7.07-7.17 (2H, d.); 6.78-6.81 (2H, d.); 4.26-4.30 (4H, m.); 4.03-4.06 (2H, d); 3.75-3.90 (IH, s. exchanges with D20); 2.93-2.98 (4H, t.); 2.52-2.81 (3H, complex m.); 1.43 (9H,s.); 1.05- 1.07 (2H, d.).
Procedure 77: (R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-(2- phenylethyl) ester
Figure imgf000067_0002
The title compound was prepared from (R)-4-(2-t-butoxycarbonyl aminopropy phenoxymethyl phosphonic acid, bis-(2-phenylethyl) ester according to the method described in Procedure 25. The crude product was used in the next stage without further purification.
δ(CDCl ): 7.07-7.30 (12H, complex m.); 6.78-6.83 (2H, d); 4.22-4.32 (4H, m); 4.03- 4.07 (2H, d.); 2.65-3.25 (9H, complex m, 2H exchange with D2O); 1.17-1.20 (3H, d). Procedure 78: (SR)-4-{2-[3-(2,2-di-f-Butyl-4H-l,2,3-benzodioxasilinan-6-yloxy)- 2-hydroxypropylarnino]propyl}phenoxymethylphosphonic acid, bis-(2- phenylethyl) ester
Figure imgf000068_0001
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.
δ(CDCl3): 7.20-7.30 (10H, complex m.); 7.07-7.18 (2H, d.); 6.68-6.84 (4H, complex m.); 6.49-6.50 (IH, d.); 4.94 (2H, s.); 4.22-4.33 (4H, m.); 4.04-4.08 (2H, d.); 3.97- 4.04 (IH, m.); 3.86-3.89 (2H, m.); 2.93-2.98 (4H, m.); 2.56-2.89 (3H, complex m.); 1.07-1.10 (3H, d.); 1.03 (18H, s.)
Procedure 79: Benzylphosphinic acid, n-butyl ester
Figure imgf000068_0002
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 solvent was evaporated, the residue slurried with dichloromethane (120mL), filtered and evaporated and the residue chromatographed on silica-gel in 1-2% methanol in dichloromethane to give the title compound as an oil.
δ(CDCl3): 8.05-6.03 (IH, d.); 7.24-7.36 (5H, complex m.); 3.88-4.15 (2H, dd.); 3.16-3.24 (2H,d.); 1.57-1.67 (2H, m.); 1.27-1.41 (2H, m.); 0.87-0.93 (3H, t.)
Procedure 80: Benzylhydroxymethylphosphinic acid, n-butyl ester
Figure imgf000069_0001
The title compound was prepared from benzylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31.
δ(CDC-3): 7.21-7.35 (5H, s.); 3.5-4.5 (IH, s, exchanges with D20); 3.93-3.98 (2H, q.); 3.77-3.78 (2H, d.); 3.22-3.28 (2H, d.); 1.52-1.63 (2H, m.); 1.25-1.39 (2H, m.); 0.86-0.91 (3H, t.)
Procedure 81: BenzyI(4-chIorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester
Figure imgf000069_0002
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.
δ(CDCl3): 7.81-7.85 (2H, d.); 7.59-7.62 (2H, d.); 7.19-7.28 (5H, m.); 3.85-4.18 (4H, complex m.); 3.19-3.26 (2H, d.); 1.52-1.63 (2H, complex m.); 1.25-1.39 (2H, complex m.); 0.87-0.92 (3H, t.) Procedure 82: 4-[2-(S)-(2-t-Butoxycarbonylamino)propyl]- phenoxymethylbenzylphosphinic acid, n-butyl ester
Figure imgf000070_0001
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.
δ(CDCI3): 7.21-7.29 (5H, s.); 7.09-7.13 (2H, d.); 6.83-6.87 (2H, d.); 4.01-4.11 (3H, m.); 3.30-3.38 (2H, dd.); 2.88-2.96 (2H, d.); 2.61-2.96 (2H, complex m.); 1.59-1.65 (2H, m.); 1.34-1.43 (11H, complex .); 1.05-1.09 (3H, d.); 0.87-0.92 (3H, t.)
Procedure 83: (R)-4-(2-Aminopropyl)phenoxymethylbenzylphosphinic acid, n-butyl ester
Me
Figure imgf000070_0002
The title compound was prepared from (R)-4-[2-(2-r-butoxycarbonylamino) propyl]phenoxymethylbenzylphosphinic acid, n-butyl ester according to the method described in Procedure 25. The crude product was used in the next stage without further purification. δ(CDCl3): 7.22-7.29 (5H, s.); 7.1 1 -7.19 (2H, d.); 6.84-6.88 (2H, d.); 3.99-4.12 (3H, complex m.); 3.30-3.38 (2H, complex m.); 3.10-3.17 (2H, complex m.); 2.44-2.70 (2H, complex m.); 1.57-1.65 (2H, complex .); 1.23-1.44 (2H, complex m.); 1.10- 1.13 (3H, d.); 0.87-0.94 (3H, t.)
Procedure 84: (SR)-4-[2-[3-(2,2-di-/-Butyl-4H-l,3,2-benzodioxasilinan-6-yloxy)- 2-hydroxypropylamino]propyl]phenoxymethylbenzylphosphinic acid, n-butyl ester
Me
Figure imgf000071_0001
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.
δ(CDCl3): 7.26-7.28 (5H, s.); 7.10-7.13 (2H, d.); 6.65-6.86 (4H, complex m.); 6.50 (IH, d.); 4.94 (2H, s.); 4.07-4.19 (4H, complex m.); 3.89 (2H, s.); 3.27-3.35 (2H, dd.); 2.55-3.08 (4H, complex m.); 1.60-1.72 (2H, m.); 1.28-1.45 (2H, m.); 1.03-1.08 (23H, complex m.); 0.86-0.91 (3H, t.).
Procedure 85: 4-(2-fer.-Butoxycarbonylaminoethyl)phenoxymethylphenyl- phosphinic acid, ethyl ester
Figure imgf000072_0001
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.
δ'H (200MHz, CDC1,): 7.92 (2H, m), 7.66-7.42 (3H, m), 7.08 (2H, d), 6.83 (2H, d), 4.6-4.0 (5H, m), 3.31 (2H, ), 2.71 (2H, t), 1.42 (9H, s), 1.38 (3H, t, partially overlapping the signal at 1.42).
Procedure 86: 4-(2-Aminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester
Figure imgf000072_0002
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.
δ'H (250MHz, CDCI3): 7.93 (2H, m), 7.65-7.42 (3H, m), 7.09 (2H, d), 6.83 (2H, d), 4.5-4.0 (4H, m), 2.90 (2H, t), 2.67 (2H, t), 1.38 (3H, t with overlapping 2H).
Procedure 87: (S)-4-{2-[3-(2,2-Di-f<?rr-butyl-4H-l,3,2-benzodioxasilinan-6-yloxy)- 2-hydroxypropylarnino]ethyl}phenoxymethylphenylphosphinic acid, ethyl ester
Figure imgf000073_0001
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).
δ'H (250MHz, CDCI3): 7.93 (2H, m), 7.65-7.44 (3H, m), 7.10 (2H, d), 6.88-6.77 (3H, m), 6.71 (IH, dd), 6.50 (IH, d), 4.93 (2H, s), 4.49-3.92 (5H, m), 3.88 (2H, d), 2.94-2.68 (6H, m), 2.04 (2H, br s), 1.38 (3H, t), 1.02 (18H, s).
Procedure 88: (S)-4-{2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropylarnino]ethyl}phenoxymethylphenylphosphinic acid, ethyl ester
Figure imgf000073_0002
The title compound was prepared from 4-(2-aminoethyl)phenoxymethyl- phenylphosphinic acid, ethyl ester and (S)-2-(4-benzyloxyphenoxy)methyloxirane according to the method described in Procedure 13.
δ'H (250MHz, CDC13): 7.9-7.8 (2H, m); 7.55 (3H, ); 7.5-7.25 (5H, ); 7.10 (2H, d, J=8.0Hz); 6.90-6.70 (6H, m); 4.98 (2H, s); 4.5-4.0 (5H, m); 3.89 (2H, d, J=6Hz); 3.0-2.75 (6H, m); 1.45 (3H, t, J=7.3Hz).
Procedure 89: (S,R)-4-{2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropylarnino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester Me
Figure imgf000074_0001
The title compound was prepared from (R)-4-(2-aminopropyl)phenoxy-methylphenyl phosphinic acid, ethyl ester and (S)-2-(4-benzyloxyphenoxy)-methyloxirane according to the method described in Procedure 14. δ'H (250MHz, CDCI3): 7.92 (2H, m); 7.55 (3H, m); 7.4 (3H, m); 7.35 (5H, m); 7.07 (2H, d, J=8.2Hz); 6.82 (3H, m); 5.02 (2H, s); 4.5-4.07 (4H, m); 3.91 (3H, m); 2.95- 2.49 (5H, m); 1.37 (3H, t, J=7.1Hz); 1.07 (3H, d, J=7.4 Hz).
Procedure 90: l-(4-Benzyloxy-3-nitrophenyl)ethanone
Figure imgf000074_0002
A mixture of l-(4-hydroxy-3-nitrophenyl)ethanone (l()g, 55.2mMol) and potassium carbonate (1 1.5g, 82.8 mMol) in acetone (150 ml) was heated at reflux for 10 mins. Benzylbromide (6.6 ml, 55.2 mMol) was added and the mixture heated at reflux for 48 hours. After cooling, the reaction mixture was filtered and the solvent evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried and the solvent evaporated to give the title compound as an oil.
δ'H (250MHz, CDCI3): 8.42 (IH, d, J=1.4Hz); 8.1 1 (IH, dd, J=8.2Hz and 1.4Hz); 7.4 (5H, m); 7.18 (IH, d, J=8.3Hz); 5.32 (2H, s); 2.60 (3H, s).
Procedure 91: Acetic acid, (4-benzyloxy-3-nitrophenyl)ester
Figure imgf000075_0001
A mixture of l-(4-benzyloxy-3-nitrophenyl)ethanone (6g, 22.1 mMol) and 3- chloroperoxybenzoic acid (19.1g, 110.7mMol) in dichloromethane (150ml) was heated at reflux for 72 hours. After cooling, the reaction mixture was filtered and the organic phase washed with saturated sodium carbonate (2x25ml), water (30ml) and brine (30ml). The solution was dried and the solvent evaporated in vacuo. The residue was purified by normal phase column chromatography eluting with 40% diethyl ether in hexane to give the title compound as a clear oil.
δ'H (250MHz, CDCI3): 7.68 (IH, d, J=1.6Hz); 7.4 (5H, m); 7.26 (IH, dd, J=8.2Hz and 1.4Hz); 7.10 (IH, d, J=8.2Hz); 5.24 (2H, s); 2.31 (3H, s).
Procedure 92: Acetic acid, (3-amino-4-benzyloxyphenyl)ester
Figure imgf000075_0002
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.
δ'H (200MHz, CDCI3): 7.35 (7H, m); 6.82 (IH, d, J=8.8Hz); 6.48 (IH, d, J=1.5Hz); 6.40 (IH, dd, J=6.6Hz and 1.3Hz); 5.05 (2H, s); 2.23 (3H, s).
Procedure 93: Acetic acid (4-benzyloxy-3-rnethanesulfonylaminophenyl)ester
Figure imgf000076_0001
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
(3x10ml), dried and the solvent evaporated in vacuo. Trituration with diethyl ether gave the title compound as an off-white solid.
δ'H (250MHz, CDC13): 7.40 (5H, m); 7.33 (IH, d, J=2.2Hz); 6.96 (IH, d, J=8.5Hz); 6.88 (IH, br s); 6.84 (IH, dd, J=8.2Hz and 2.1Hz); 5.08 (2H, s); 2.94 (3H, s); 2.31 (3H, s).
Procedure 94: Acetic acid, 4-benzyloxy-3-(N-r<2rr-butoxycarbonyl)methane- sulfonylaminophenyl ester
Figure imgf000076_0002
To a solution of acetic acid, (4-benzyloxy-3-methanesulfonylaminophenyl) ester (0.9g, 2.69mMol) in dichloromethane (10ml) was added di-rerr-butyldicarbonate (0.704g, 3.23mMol) and 4-dimethylaminopyridine (0.065g, 0.54mMol) at room temperature under argon. The mixture was stined at room temperature for 1 hour after which the solvent was evaporated in vacuo. Purification by normal phase column chromatography eluting with diethyl ether gave the title compound as a white foam.
δ'H (250MHz, CDCI3): 7.38 (5H, m); 7.15 (2H, m); 6.96 ( 1 H, d, J=8.6Hz); 5.08 (2H, s); 3.24 (3H, s); 2.27 (3H, s); 1.4 (9H, s). Procedure 95: 4-Benzyloxy-3-(N-tørr-butoxycarbonyl)methanesulfonyI- aminophenol
Figure imgf000077_0001
To a solution of acetic acid, 4-benzyloxy-3-(N-r^rr-butoxycarbonyl)- methanesulfonylaminophenyl ester (1.16g, 2.67mMol) in a mixture of methanol (10ml) and water (5ml) was added IM sodium hydroxide solution (3.20mMol) at room temperature. The mixture was stined for 10 minutes and citric acid added to adjust to pH 6-7. The solvent was evaporated in vacuo and the residue taken up into dichloromethane (30ml), washed with water (3x15ml) and dried. Evaporation of the solvent gave the title compound as a white foam.
δ'H (250MHz, CDCI3): 7.37 (5H, m); 6.82 (3H, m); 5.09 (IH, br s); 5.20 (2H, s); 3.24 (3H, s); 1.42 (9H, s).
Procedure 96: (S)-2-[4-Benzyloxy-3-(N-rι*r/-butoxycarbonyl)- methanesulfonylamino]phenoxymethyloxirane
Figure imgf000077_0002
The title compound was prepared from [4-benzyloxy-3-(N-rerr-butoxycarbonyl)- methanesulfonylamino]phenol and (2S)-(+)-glycidyl-3-nitrobenzene sulfonate according to the method described in Procedure 12.
δ'H (250MHz, CDCI3): 7.35 (5H, m); 6.94 (3H, m); 5.05 (2H, s); 4.20 (IH, dd, J=l lHz and 2.7Hz); 3.90 (IH, m); 3.35 (I H, m); 3.25 (3H, s), 2.92 (IH, m); 2.77 (lH. ); 1.42 (9H, s).
Procedure 97: (S,R)-4-{2-[3-(4-Benzyloxy-3-methanesulfonylaminophenoxy)-2- hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester Me
Figure imgf000078_0001
A solution of (S)-2-[4-benzyloxy-3-(N-rerr-butoxycarbonyl)- methanesulfonylamino]phenoxymethyloxirane (0.45g, ImMol) in acetonitrile (25ml) was treated with lithium perchlorate (0.107g, ImMol), then stined until complete dissolution of the salt. To the resulting stined solution was added (R)-4-(2- aminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester (0.40g, 1.2mMol). The mixture was stined at room temperature for 1 10 hours, and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (25ml) and IM hydrochloric acid (2ml) added. The mixture was stined for 30 minutes at room temperature then washed with saturated sodium bicarbonate (3x 10ml), water (15ml) and brine (15ml). The dried extracts were concentrated in vacuo, and the crude product purified by normal phase column chromatography, eluting with 10% methanol in dichloromethane to give the title compound as a white foam.
δ'H (200MHz, CDC13 + D2O): 7.85 (2H, m); 7.57 (3H, m); 7.38 (5H, m); 7.12 (3H, m); 6.85 (3H, m); 6.62 (IH, m); 5.07 (2H, s); 4.5-4.35 (2H, ); 4.2 (3H, m); 3.92 (2H, m), 3.4-2.9 (3H, m); 2.85 (3H, s); 2.78 (2H, m); 1.37 (3H, t, J=7.2Hz); 1.30 (3H, d, J=7.8Hz).
Procedure 98: (S)-4-{2-[3-(4-r<?rf-Butyldimethylsilyloxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
Figure imgf000078_0002
The title compound was prepared from 4-(2-aminoethyl)phenoxymethyl(3- benzyloxypropyl)phosphinic acid, n-butyl ester and (S)-2-(4-r<?rr- butyldimethylsilyloxyphenoxy)methyloxirane' according to the method described in Procedure 13.
δ'H (CDCI3 + D2O): 7.35-7.25 (5H, m), 7.1 (2H, d, J = 8.5Hz), 6.78-6.7 (4H, m), 6.55 (2H, d, J = 8.5Hz), 4.70 (2H, s), 4.25-3.75 (7H, m), 3.5-2.75 (8H, m), 2.05-1.9 (4H, m), 1.7-1.6 (2H, m), 1.45-1.35 (2H, m), 0.96 (9H, s), 0.93 (3H, t, J = 7.1Hz), 0.15 (6H, s).
1 European patent EP 0611003.
Procedure 99: Methyl 5-acetyl-2-benzyloxybenzoate.
Figure imgf000079_0001
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.
δ1H (CDC13): 8.44-7.05 (8H, m), 5.27 (2H, s), 3.94 (3H, s), 2.58 (3H s).
Procedure 100: Methyl 5-acetoxy-2-bcnzyloxybenzoate.
Figure imgf000079_0002
A solution of methyl 5-acetyl-2-benzyloxybenzoate (15.6g, 0.055Mol) and 3- chloroperoxybenzoic acid (42g) in dichloromethane (250ml) was stined overnight at ambient temperature. The reaction mixture was washed with saturated aqueous sodium metabisulfite solution (2x250ml), saturated sodium hydrogen carbonate (3x250)and dried over anhydrous magnesium sulfate. Filtration and removal of solvent under reduced pressure gave a white solid. δ'H (CDCI3): 7.59-6.99 (8H, m), 5.18 (2H, s), 3.89 (3H, s), 2.27 (3H, s).
Procedure 101: 3-Hydroxymethyl-4-benzyloxyphenol.
Figure imgf000080_0001
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.
δ'H (d'-DMSO): 8.85 (IH, br, exchanges with D2O), 7.44-6.51 (8H, m), 4.96 (3H, m collapses to 2H after addition of D2O), 4.48 (2H, d, collapses to singlet after addition of D.O).
Procedure 102: (S)-2-(4-Benzyloxy-3-hydroxymethylphenoxy)-methyloxirane.
Figure imgf000080_0002
To a solution of 3-hydroxymethyl-4-benzyloxyphenol (10.4g) in dimethylformamide (55ml) at ice-bath temperature was added sodium hydride (60% dispersion in mineral oil, 1.8g). The reaction was stirred for 5 minutes and (2S)-glycidyl-3- nitrobenzenesulfonate (1 1.7g) was added in a single portion. The temperature was allowed to warm to ambient and stirring continued overnight. Ethyl acetate (370ml) was added and the organic phase washed with water (2x560ml), saturated brine solution (370ml) and dried over anhydrous magnesium sulfate. Filtration followed by removal of solvent gave the crude product as an oil. Purification by flash chromatography (silica gel, 20%acetone/hexane) gave an oil, which slowly solidified on standing. δ'H (CDCI3): 7.40-6.78 (8H, m), 5.07 (2H, s), 4.69 (2H, d), 4.18 (IH, dd), 3.91 (IH, dd), 3.33 (IH, m), 2.90 (IH, m), 2.75 (IH, m), 2.28 (IH, t).
Procedure 103: (S,R) 4-{2-[3-(4-r-ButyldimethyIsilyloxyphenoxy)-2- hydroxypropylamino]propyI}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
CH,
Figure imgf000081_0001
The title compound was prepared from (R) 4-(2-aminopropyl)phenoxymethyl-(3- benzyloxypropyl)phosphinic acid, n-butyl ester and (S)-2-[(4-r<?rr- butyldimethylsilyloxyphenoxy)methylloxirane according to the method described in Procedure 13.
δ'H (CDCI3+ D2O): 7.40-6.75 (13H, ), 4.50 (2H, s), 4.25-3.80 (7H, m), 3.55 (2H, m), 2.95-2.50 (3H, m), 2.00 (6H, m), 1.60, (2H, m), 1.40 (2H, m), 1.06 (3H, d), 0.97 (9H, s), 0.95 (3H, t), 0.01 (6H, s).
Procedure 104: (S,R) 4-{2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropyIamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000081_0002
The title compound was prepared from (R)-4-(2- aminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester and (S)-2-[(4- benzyloxyphenoxy)methyl]oxirane according to the method described in Procedure 13. δ'H (CDCI3 + D2O): 7.50-6.75 (13H, m), 5.00 (2H, s), 4.27-3.85 (7H, ), 3.10-2.60 (5H, m), 2.20-1.10 (18H, m), 0.94 (3H, t).
Procedure 105: (S,R) 4-{2-[3-(4-Benzyloxyphenoxy)-2- hydroxypropylamino]propyI}phenoxymethylhexylphosphinic acid, n-butyl ester.
CH,
Figure imgf000082_0001
The title compound was prepared from (R)-4-(2- aminopropyl)phenoxymethylhexylphosphinic acid, n-butyl ester and (S)-2-[(4- benzyloxyphenoxy)methyl]oxirane according to the method described in Procedure 13.
δ'H (CDC13 + D.O): 7.40-6.75 (13H, m), 5.00 (2H, s), 4.25-3.90 (7H, m), 3.20-2.68 (5H, ), 1.97-1.30 (14H, m), 1.15 (3H, d), 0.95 (6H, ).
Procedure 106: Acetic acid, (4-benzyloxy-3-fluorophenyl)ester.
Figure imgf000082_0002
The title compound was prepared from 4-benzyloxy-3-fluoroacetophenone1 according to the method described in Procedure 100.
δ'H (CDCI3): 7.45-7.32 (5H, ), 7.00-6.75 (3H, m), 5.12 (2H, s), 2.27 (3H, s).
1 J. Med. Chem., 1983, 26 (11), 1570-6.
Procedure 107: 4-Benzyloxy-3-fluorophenol.
Figure imgf000083_0001
A solution of acetic acid, (4-benzyloxy-3-fluorophenyl)ester (5.96g, 23mMol) in methanol (80ml) and sodium hydroxide (l.Og, 25mMol) in water (20ml) was heated under reflux for 90 minutes. After cooling, the solution was concentrated and the residue was partitioned between ethyl acetate and IM hydrochloric acid. The organic extracts were separated, washed with water and brine, dried and concentrated giving the title compound.
δ'H (CDCI3): 7.43-7.25 (5H, m), 6.85 (IH, t, J = 9.1Hz), 6.63 (IH, dd, J = 12.1, 3Hz), 6.46 (IH, m), 5.06 (2H, s), 4.65 (IH, br, exchanges with D2O).
Procedure 108: (S)-2-(4-Benzyloxy-3-fluorophenoxy)methyloxirane.
Figure imgf000083_0002
The title compound was prepared from 4-benzyloxy-3-fluorophenol and (S)-glycidyl- 3-nitrobenzene sulfonate according to the method described in Procedure 102.
δ'H (CDCI3): 7.44-7.25 (5H, m), 6.90 (IH, t, J = 9.2Hz), 6.72 (IH, dd, J = 12.5,
3Hz), 6.58 (IH, ddd, J = 9.2, 3, 1.6Hz), 5.07 (2H, s), 4.17 (IH, dd, J = 11, 3Hz), 3.86 (IH, dd, J = 11, 5.8Hz), 3.35-3.29 (IH, m), 2.90 (IH, dd, J = 5, 4.1Hz), 2.73 (IH, dd, J = 4.1, 2.5Hz).
Procedure 109: (S)-4-{2-[3-(4-Benzyloxy-3-fluorophenoxy)-2- hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000084_0001
The title compound was prepared from 4-(2-aminoethyl)phenoxy methylcyclohexylphosphinic acid, n-butyl ester and (S)-2-(4-benzyloxy-3- fluorophenoxy)methyloxirane according to the method described in Procedure 13.
δ'H (CDCI3): 7.44-7.31 (5H, m), 7.14 (2H, d, J = 8.5Hz), 6.9-6.86 (3H, m), 6.69 (IH, dd, J = 12.5, 2.8Hz), 6.55 (IH, ddd, J = 8.9, 3, 1.5Hz), 5.06 (2H, s), 4.25-3.93 (5H, m), 3.88 (2H, d, J = 4.9Hz), 2.93-2.71 (6H, m), 2.2-1.2 (17H, m), 0.91 (3H, t, J = 7.3Hz).
Procedure 110: 3-Phenoxypropylphosphinic acid
Figure imgf000084_0002
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.
δ'H (CDCI3): 9.06(1H, s.); 7.31-7.15(2H, m.); 7.19(1H, d, J = 548.72Hz.); 6.94(1H, t, J = 7.4Hz.); 6.89-6.81(2H, m.); 4.01 (2H, t, J = 6.04Hz.); 2.14-1.84(4H, m).
Procedure 111: 3-Phenoxypropylphosphinic acid, ethyl ester
Figure imgf000084_0003
The title compound was prepared from 3-phenoxypropylphosphinic acid and ethanol according to the method described in Procedure 43. The crude product was used without further purification. δ'H (CDCI3): 7.32-7.20(2H, ); 7.18(1H, dt, J = 533.65, 1.65Hz); 6.95(1H, t, J = 7.43Hz); 6.88(2H, t, J = 7.78Hz); 4.28-4.06(2H, m); 4.03(2H, t, J = 5.49Hz); 2.15- 1.93(4H, m); 1.37(3H, t, J = 7.87Hz).
Procedure 112: Hydroxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester
Figure imgf000085_0001
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.
δ'H (CDCI3): 7.30-7.24(2H, ); 6.94(1H, t, J = 7.43Hz); 6.88(2H, d, J = 8.25Hz); 4.30(1H, s, exchanges with D20); 4.20-4.07(2H, m); 4.02(2H, t, J = 5.33Hz); 3.88(2H, d, J = 5.50Hz); 2.15-1.95(4H, m); 1.32(3H, t, J = 7.15Hz).
Procedure 113: 4-Chlorobenzenesulfonyloxymethyl(3-phenoxypropyl) phosphinic acid, ethyl ester
Figure imgf000085_0002
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.
δ'H (CDCI3): 7.87 (2H, d, J = 8.00Hz); 7.54 (2H, d, J = 8.45Hz); 7.29-7.26 (2H, m); 6.96 (IH, t, J = 7.42Hz); 6.87 (2H, d, J = 7.70Hz); 4.26-3.98 (6H, m); 2.08-2.00 (4H, m); 1.31 (3H, t, J = 7.15Hz).
Procedure 114: 4-(2-terf-Butoxycarbonylaminoethyl)phenoxymethyl (3-phenoxypropyl)phosphinate, ethyl ester
Figure imgf000086_0001
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.
δ'H (CDC13): 7.29-7.23 (3H, m); 7.13 (2H, d, J = 8.52Hz); 6.97-6.85 (4H, m); 4.50 (IH, s); 4.25-4.10 (4H, m); 4.05 (2H, t, J = 5.50Hz); 3.37-3.32 (2H, m); 2.74 (2H, t, J = 7.15Hz); 2.16-2.06 (4H, ); 1.43 (9H, s); 1.34 (3H, t, J = 7.15Hz).
Procedure 115: 4-(2-Aminoethyl)phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester
Figure imgf000086_0002
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.
δ'H (CDCI3): 7.31-7.23 (3H, m); 7.15 (2H, d, J = 8.80Hz); 6.97-6.85 (4H, m); 4.31- 4.00 (6H, m); 2.95 (2H, t, J = 6.88Hz); 2.71 (2H, d, J = 6.87Hz); 2.22-2.06 (4H, m); 1.79 (2H, s, exchanges with D20); 1.34 (3H, t, J = 7.14Hz).
Procedure 116: (S)-4-{2-[3-(4-Benzyloxy-3-hydroxymethyl)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester
Figure imgf000087_0001
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.
δ'H (CDCl3+D2O ): 7.39-7.26 (5H, m); 7.15 (2H, d, J = 8.79Hz); 6.91-6.75 (10H, m); 5.06 (2H, s); 4.69 (2H, s); 4.22-3.90 (7H, m); 2.90-2.77 (6H, m); 2.12-2.05 (2H, m); 1.82-1.54 (4H, m); 1.34 (3H, t, J = 6.88Hz)m); 1.61 -1.53 (2H, m).
Procedure 117: 3-Phenylpropylphosphinic acid
Figure imgf000087_0002
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.
δ'H (CDCI3): 11.28 (IH, s, exchanges with D2O); 7.31-7.14 (5H, m); 7.05 (IH, dt, J = 542.72, 1.92Hz); 2.71 (2H, t, J = 7.15Hz); 1.99-1.84 (2H, m); 1.79-1.68 (2H, m).
Procedure 118: 3-Phenylpropylphosphinic acid, n-butyl ester
Figure imgf000087_0003
The title compound was prepared from 3-phenylpropylphosphinic acid and n-butanol according to the method described in Procedure 43. The crude product was used without further purification. δ'H (CDCI3): 7.32-7.15 (5H, ); 7.06 (IH, dt, J = 548.72, 1.92Hz); 4.01-3.97 (2H, m); 2.73 (2H, t, 7.15Hz); 1.95- 1.62 (6H, m); 1.44-1.35 (2H, m); 0.94 (3H, t, J = 7.15Hz).
Procedure 119: Hydroxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester
Figure imgf000088_0001
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.
δ'H (CDCI3): 7.32-7.16 (5H, m.); 4.13-3.95 (3H, m, IH exchanges with D2O); 3.90- 3.77 (2H, m); 2.70 (2H, t, J = 6.87Hz); 2.02-1.74 (4H, m); 1.67-1.56 (2H, m); 1.43- 1.25 (2H, m); 0.92 (3H, t, 7.43Hz).
Procedure 120: 4-Chlorobenzenesulfonyloxymethyl(3-phenylpropyl) phosphinic acid, n-butyl ester
Figure imgf000088_0002
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.
δ'H (CDCI3): 7.82 (2H, d, J = 9.07Hz); 7.54 (2H, d, J = 8.79Hz); 7.33-7.13 (5H, m); 4.25-3.82 (4H, m);2.70 (2H, t, J = 6.05Hz); 1.99-1.73(4H, m); 1.66-1.54 (2H, ); 1.43-1.23 (2H, m);0.91 (3H, t, J = 7.42Hz).
Procedure 121: 4-(2-/er/-Butoxycarbonylaminoethyl)phenoxyrnethyl (3-phenylpropyl)phosphinic acid, n-butyl ester
Figure imgf000089_0001
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.
δ'H (CDCI3): 7.28-7.11 (7H, m); 6.85 (2H, d, J = 8.80Hz); 4.50 (IH, s); 4.21-3.99 (4H, m); 3.45-3.30 (2H, m); 2.77-2.72 (4H, m); 1.95-1.80 (3H, m); 1.75-1.62 (3H, m); 1.51-1.30 (2H, m);1.43 (9H, s); 0.91 (3H, t, J = 7.42Hz).
Procedure 122: 4-(2-Aminoethyl)phenoxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester
Figure imgf000089_0002
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.
δ'H (CDCI3): 7.28-7.12 (7H, m); 6.86 (2H, d, J = 8.79Hz); 4.21-3.90 (4H, m); 3.00- 2.87 (2H, m); 2.74-2.71 (4H, m); 1.95-1.80 (4H, m); 1.76-1.51 (4H, m, 2H exchanges with D20); 1.48-1.34 (2H, m); 0.91 (3H, t, J = 7.42Hz).
Procedure 123: (S)- 4-{2-[3-(4-Benzyloxy-3-hydroxymethyl)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenylpropyl)phosphinic acid, n- butyl ester
Figure imgf000090_0001
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.
δ'H (CDCl3+D2O ): 7.43-7.1 1 (13H, ); 6.92-6.74 (4H, m); 5.30 (2H, s); 5.06 (2H, s); 4.69-3.91 (7H, m); 2.94-2.70 (8H, m); 2.03-1.77 (6H, m); 1.67-1.46 (2H, m); 0.91 (3H, t, J = 7.42Hz).
Procedure 124: Phosphonic acid, bis-cyclohexyl ester
Figure imgf000090_0002
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.
δΗ^DC^): 8.16-5.61 (IH, d), 4.38-4.51 (2H, m), 1.19-1.96 (20H, m).
Procedure 125: Hydroxymethylphosphonic acid, bis-cyclohexyl ester
Figure imgf000090_0003
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.
δ'H(CDCl3 + D2O): 4.81-4.42 (2H, m), 3.86-3.84 (2H, d), 1.21 - 1.96 (20H, m). Procedure 126: (4-Chlorobenzenesulfonyloxymethyl)phosphonic acid, bis- cyclohexyl ester
Figure imgf000091_0001
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.
δ'H(CDCI3): 7.85-7.88 (2H, d), 7.53-7.57 (2H, d), 4.40-4.49 (2H, m), 4.08-4.18 (2H, m), 1.20-1.86 (20H, m).
Procedure 127: (/x 4-(2-tørf-Butoxycarbonylaminopropyl)phenoxyιnethyl phosphonic acid, bis-cyclohexyl ester
Me
Figure imgf000091_0002
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.
δ'H(CDCl3): 7.12-7.14 (2H, d), 6.88-6.92 (2H, d), 4.49-4.60 (2H, m), 4.21-4.24 (2H, d), 3.75-3.90 (IH, broad s), 2.52-2.81 (3H, m), 1.22-2.05 (20H, m), 1.42 (9H, s), 1.05-1.07 (3H, d).
Procedure 128: (/?)-4-(2-Arninopropyl)phenoxyrnethylphosphonic acid, bis- cyclohexyl ester Me
Figure imgf000092_0001
The title compound was prepared from (R)-4-(2-rerr-butoxycarbonylamino propyl)phenoxymethylphosphonic acid, bis-cyclohexyl ester according to the method described in Procedure 25. Purification by column chromatography on silica gel eluting with 10% methanol in dichloromethane gave the title compound as a gum.
δ'H(CDCl3): 7.07-7.09 (2H, d), 6.88-6.90 (2H, d), 4.48-4.58 (2H, m), 4.22-4.25 (2H, d), 2.45-3.20 (3H, m), 1.22-2.05 (22H, m), 1.11-1.13 (3H, d).
Procedure 129: (S,/?)-4-{2-[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino] propyljphenoxymethylphosphonic acid, bis-cyclohexyl ester
Me
Figure imgf000092_0002
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.
δ'H(CDCl3): 7.25-7.48 (5H, m), 7.13-7.16 (2H, d), 6.76-6.90 (6H, ), 5.00 (2H, s), 4.48-4.62 (2H, m), 4.18-4.22 (2H, d), 3.85-4.00 (2H, m), 2.62-3.22 (6H, m), 1.20- 2.02 (20H, m), 1.18-1.20 (3H, d).
Procedure 130: Phosphonic acid, bis-(2,2-diphenylethyl) ester
Figure imgf000093_0001
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.
δ'H(CDCl3): 7.78-5.18 (IH, d), 7.08-7.35 (20H, m), 4.18-4.49 (6H, m).
Procedure 131: Hydroxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester
Figure imgf000093_0002
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.
δ'H(CDCl3): 7.15-7.31 (20H, m), 4.25-4.51 (6H, m), 3.52-3.57 (2H, t), 2.07-2.14 (IH, t).
Procedure 132: (4-ChlorobenzenesuIfonyloxymethyl)phosphonic acid, bis-(2,2- diphenylethyl) ester
Figure imgf000093_0003
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).
δ'H(CDCI3): 7.62-7.67 (2H, d), 7.41-7.45 (2H, d), 7.12-7.31 (20H, m), 4.31-4.45 (4H, m), 4.20-4.25 (2H, t), 3.83-3.87 (2H, d).
Procedure 133: 4-(2-terr-ButoxycarbonyIaminoethyl)phenoxyιrιethyl phosphonic acid, bis-(2,2-diphenylethyl) ester
Figure imgf000094_0001
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.
δ'(CDCl3 + D20): 7.04-7.29 (22H, m), 6.70-6.73 (2H, d), 4.41-4.55 (4H, m), 4.26- 4.31 (2H, t), 3.87-3.90 (2H, d), 3.31-3.45 (2H, t), 2.70-2.75 (2H, t), 1.43 (9H, s).
Procedure 134: 4-(2-Aιτιinoethyl)phenoxymethylphosphonic acid, bis-(2,2- diphenylethyl) ester
Figure imgf000095_0001
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.
δ'H(CDCl3): 7.05-7.29 (22H, m), 6.70-6.74 (2H, d), 4.41-4.51 (4H, m), 4.26-4.31 (2H, t), 3.87-3.91 (2H, dd), 3.31-3.44 (IH, m), 2.90-2.96 (IH, t), 2.67-2.75 (2H, q), 1.56-1.70 (2H, broad s, exchanges with D2O).
Procedure 135: (S)-4-{2[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino] ethyl}phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester
Figure imgf000095_0002
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.
δ'H(d'-DMSO + D2O): 6.69-7.40 (33H, m), 5.01 (2H, m), 4.28-4.47 (7H, m), 3.86- 4.18 (4H, m), 2.74-2.95 (6H, m). Procedure 136: (R)-2,2-Di-ter/-butyl-6-(oxiran-2-ylmethoxy)-4H-l,3,2- benzodioxasilinane
Figure imgf000096_0001
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.
δ'H (250MHz, CDCI3): 6.72-6.88 (2H, m); 6.52 (IH, d); 4.95 (2H, s); 4.16 (IH, dd); 3.89 (IH, dd); 3.34 (IH, m); 2.90 (IH, t); 2.73 (IH, dd) and 1.04 (18H, s).
Procedure 137: (RR)-4-{2-[3-(2,2-Di-terf-butyl-4H-l,3,2-benzodioxasilinan-6-yl- oxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester.
Figure imgf000096_0002
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.
δ'H (250MHz, CDCI3): 7.93 (2H, m); 7.46-7.62 (3H, m); 7.08 (2H, d); 6.83 (3H, m); 6.69 (IH, dd); 6.48 (IH, d); 4.93 (2H, s); 4.48-3.99 (4H, m); 3.88 (2H, d); 3.04-2.46 (8H, m); 1.38 (3H, t); 1.11 (3H, d) and 1.03 (18H, s).
Example 1: (S,R)- Sodium-4-[2-[2-hydroxy-3-(2- hydroxyphenoxy)propylamino]propyl] phenoxyacetate
Me
Figure imgf000097_0001
A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(2-hydroxyphenoxy)propylamino] propyljphenoxyacetate (120mg, 0.3 ImMol) in dioxan (8ml) and sodium hydroxide solution (2M, 5ml) was stined at room temperature under an argon atmosphere for 18 hours. The pH of the solution adjusted to pH9 with 2M hydrochloric acid and the solvent was evaporated.The residue was purified by reverse phase chromatography eluting with 0-5% isopropanol in water giving the title compound as a colourless solid; m.p. 130°C; [α]D 25 -13° (c = 0.35, water).
δ1H(270MHz, d6-DMSO/D2O): 7.0-6.7 (8H, m), 4.18 (2H, s), 4.2-3.9 (3H, m), 3.1-2.8 (4H, m), 2.40 (IH, m) and 0.90 (3H, d, J=6.3Hz) ppm.
Example 2: (S,R)- Sodium-4-[2-[2-hydroxy-3-(3- hydroxyphenoxy)propylamino]propyl] phenoxyacetate
Me
Figure imgf000097_0002
A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(3-hydroxyphenoxy)propylamino] propyljphenoxyacetate (140mg, 0.36mMol) in dioxan (8ml) and sodium hydroxide solution (2M, 5ml) was stined at room temperature under an argon atmosphere for 5 hours. The pH of the solution adjusted to pH9 with 2M hydrochloric acid and the solvent was evaporated.The residue was purified by reverse phase chromatography eluting with 0-5% isopropanol in water giving the title compound as a colourless solid; m.p. 136°C; [α]rj>25 -11° (c = 0.16, 50% isopropanol / 50% water). δ!H(270MHz, d6-DMSO/D2O): 7.1-6.9 (3H, m), 6.70 (2H, d, J=8.5Hz), 6.35- 6.25 (3H, m), 4.19 (2H, s), 4.0-3.7 (3H, m), 2.9-2.3 (5H, m) and 0.91 (3H, d, J=6.3Hz) ppm.
Example 3: (S,R)- Sodium-4-[2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]propyl] phenoxyacetate
Figure imgf000098_0001
A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino] propyljphenoxyacetate (140mg, 0.36mMol) in dioxan (8ml) and sodium hydroxide solution (2M, 5ml) was stined at room temperature under an argon atmosphere for 18 hours. The pH of the solution adjusted to pH9 with 2M hydrochloric acid and the solvent was evaporated.The residue was purified by reverse phase chromatography eluting with 0-20% isopropanol in water giving the title compound as a colourless solid; m.p. 119°C; [CCJD25 -15° (c = 0.34, 70% isopropanol / 30% water).
δ!H(270MHz, d6-DMSO/D2O): 6.93 (2H, d, J=8.0Hz), 6.8-6.6 (6H, m), 4.22 (2H, s), 4.1-3.8 (3H, m), 2.95-2.75 (4H, m), 2.5-2.4 (IH, m) and 0.90 (3H, d, J=6.3Hz) ppm.
Example 4: (S-R)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy) propyIamino]propyl}phenoxymethyl phosphonic acid diethyl ester.
Figure imgf000098_0002
To a solution of (S,/?)-4-{2-[3-(2,2-Di-tert-butyl-4H-l,3,2-benzodioxasilinan-6- yloxy)-2-hydroxypropylamine]propyl } phenoxymethyl phosphonic acid diethyl ester
(270mg, 0.424mMol) in tetrahydrofuran (10ml) in a plastic container at room temperature under argon was added hydrogen fluoride pyridine complex (5 drops). After 15 minutes, alumina (220mg) was added and the stirring was continued for a further 30 minutes. The reaction mixture was filtered through a short pad of celite and the solvent evaporated in vacuo. The crude product was purified by reverse phase chromatography over C18 silica, eluting with 20% ethanol in water to give the title compound as a beige coloured foam.
δ!Η (400MHz, dό-DMSO): 8.81 (s, br, exchanges with D20; 7.18 (2H, d,
J=10.7Hz); 6.95 (2H, d, J=10.7Hz); 6.92 (IH, d, J=2.4Hz); 6.70 (IH, d, J=9.6Hz);
6.65 (IH, d, J=9.6Hz and 2.4Hz); 4.47 (2H, s); 4.40 (2H, d, J=10.7Hz); 4.15 (4H, q,
J=6.4Hz); 4.0 (IH, m); 3.85 (2H, d, J=3.2Hz); 2.8-3.1 (5H, m); 1.27 (6H, t, J=6.4Hz); 1.04 (3H, d, J=7.5Hz)
Example 5: (S,R)-Lithium(4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxyrnethyI- phenoxy)propylamino]propyI}phenoxymethyl) ethyl phosphonate
Figure imgf000099_0001
(S, ?)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl phenoxy) propylamino}- propyl) phenoxymethyl phosphonic acid diethyl ester (220mg, 0.443mMol) and IM lithium hydroxide (5ml) in 1 ,4-dioxan (5ml) was stined at room temperature for 24 hours under argon. The solution was adjusted to pH 9 by addition of solid carbon dioxide, and the solvents evaporated. The residue was purified by reverse phase chromatography over C18 silica eluting with 0-10% ethanol in water to give a white powder, mpt. 120-21°C.
δ*H (400MHz, d6-DMSO): 9.25 (s, br, exchanges with D2O); 7.07 (2H, d,
J=10.7Hz); 6.9 (IH, d, J=2.0Hz); 6.78 (2H, d, J=10.7Hz); 6.71 (IH, d, J=10Hz,); 6.5 (IH, d, J=10.5Hz and 2.1Hz); 5.2 (s, br, exchanges with D2O); 4.45 (2H, s); 4.07 (IH, m); 3.8 (6H, m); 2.8-3.2 (5H, m); 1.14 (3H, t, J=6.5Hz); 0.94 (3H, d, J=7.5Hz) Example 6: (S,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy) propylamino]propyl}phenoxymethyl carboxylic acid methyl ester
Figure imgf000100_0001
To a solution of (S,R)-4-{ 2-[3-2,2-di-tert-butyl-4H-l,3,2-benzodioxasilian-6-yl-oxy)- 2-hydroxypropylamine]propyl} phenoxymethyl carboxylic acid methyl ester (0.262g, 0.469mMol) in tetrahydrofuran (10ml) in a plastic container at room temperature under argon was added hydrogen fluoride pyridine complex (5 drops). After 10 minutes, aluminia (250mg) was added and the stining was continued for a further 30 minutes. The reaction mixture was filtered through a short pad of celite and the solvent evaporated in vacuo. The crude product was used in the next step.
δ*Η (400MHz, d6-DMSO): 8.83 (s, br, exchanges with D2O); 7.15 (2H, d, J=9.8Hz); 6.89 (IH, d, J=2.6Hz); 6.83 (2H, d, J=9.6Hz); 6.66 (2H, m); 4.95 (s, br, exchanges with D2O); 4.73 (2H, s); 4.46 (2H, s); 3.96 (IH, m); 3.82 (2H, m); 3.68 (3H, s); 3.30-2.75 (5H, m); 1.07 (3H, d, J=7.8Hz)
Example 7: (SR) Sodium-(4-{2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy) propylamino]propyl}phenoxymethylcarboxylate
Figure imgf000100_0002
(SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]prop- yl} phenoxymethyl carboxylic acid methyl ester (0.16g, 0.382mMol) and 2M sodium hydroxide (5ml) in 1,4-dioxane (5ml) was stined at room temperature for 20 hours under argon. The solution was adjusted to pH 9 by addition of solid carbon dioxide, and the solvents evaporated. The residue was purified by reverse phase chromatography over Ci g silica eluting with 0-20% ethanol in water to give white crystals, mpt. 140-2°C.
δ!H(400MHz, d6-DMSO): 9.0 (s, br, exchanges with D20); 6.94 (3H, m); 6.81- 6.62 (4H, m); 4.48 (2H, s); 4.41 (2H, s); 4.18 (IH, m); 3.87 (2H, m); 3.25 (2H, m); 2.94 (IH, m); 2.82 (IH, m); 2.34 (IH, m); 0.94 (3H, d, J=7.5Hz).
Example 8: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)- propylamino]propyl}phenoxyacetic acid
Me
Figure imgf000101_0001
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.
Example 9: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)- propylamino]propyI}phenoxymethylphosphonic acid, ethyl ester
Figure imgf000101_0002
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.
Example 10: (SR)-4-{2-[3-(3,4-Dihydroxyphenoxy)-2-hydroxy- propylamino]propyl}phenoxyacetic acid, methyl ester, hydrochloride
Me
Figure imgf000102_0001
A solution of (SR)-4-{2-[3-(3,4-dibenzyloxyphenoxy)-2- hydroxypropylaminojpropyl) phenoxyacetic acid, methyl ester (230mg, 0.4mMol) in methanol (30ml) containing palladium(II)chloride (71mg, 0.4mMol) was hydrogenated at room temperature and pressure for 18 hours. The mixture was filtered through a pad of filter aid, the filter pad was washed with methanol and the combined filtrates were evaporated. The residue was dissolved in water and the solution was freeze dried giving the title compound as a colourless solid.
δ(D2O): 7.28 (2H, d, J = 8.6Hz), 6.94 (2H, d, J = 8.6Hz), 6.85 (IH, d, J = 8.7Hz), 6.51 (IH, d, J = 3Hz), 6.40 (IH, dd, J = 8.7, 3Hz), 4.72 (2H, s), 4.3-4.25 (IH, m), 4.05-3.97 (2H, m), 3.82 (3H, s), 3.68 (IH, dd, J = 13.8, 6.9Hz), 3.4-3.36 (2H, m), 3.05 (IH, dd, J = 13.1, 7Hz), 2.94 (IH, dd, J = 13.8, 7.6Hz), 1.34 (3H, d, J = 6.6Hz).
Example 11: (SR)-4-{2-[3-(3,4-Dihydroxyphenoxy)-2- hydroxypropylaminojpropyl} phenoxyacetic acid, hydrochloride
Me
Figure imgf000102_0002
A solution of (SR)-4-{2-[2-hydroxy-3-(3,4- dihydroxyphenoxy)propylamino]propyl) phenoxyacetic acid, methyl ester, hydrochloride (78mg, 0.17mMol) in water (2ml) containing hydrochloric acid (IM, 0.5ml, 0.5 ImMol) was heated at 100°C under argon for 3 hours. After cooling to room temperature the solution was freeze dried giving the title compound as a colourless solid.
δ(d6-DMSO + D2O): 7.16 (2H, d, J = 8.6Hz), 6.86 (2H, d, J = 8.6Hz), 6.64 (IH, d, J = 8.5Hz), 6.42 (IH, d, J = 3Hz), 6.21 (IH, dd, J = 8.5, 3Hz), 4.65 (2H, s), 4.25 (IH, m), 3.9-3.8 (2H, m), 3.5 (IH, m), 3.3-3.2 (2H, m), 3.05 (IH, dd, J = 12.5, 9.7Hz), 2.60 (IH, dd, J = 12.5, 11Hz), 1.10 (3H, d, J = 6.3Hz).
Example 12: (SR)-5-{2-[3-(4-Hydroxy-3-hydroxymethylphenoxy)-2- hydroxypropylamino]propyl}-l,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester
Me
Figure imgf000103_0001
The title compound was prepared from (SR)-5-{2-[3-(2,2-di-r-butyl-4H- 1,3,2- benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl ) - 1 ,3-benzodioxole-2,2- dicarboxylic acid, diethyl ester according to the procedure described in Example 4.
δ(d6-DMSO + D20): 7.1-6.6 (6H, m), 4.44 (2H, s), 4.32 (4H, q, J = 7Hz), 4.1-3.8 (3H, m), 3.2-2.6 (5H, m), 1.24 (6H, t, J = 7Hz), 1.02 (3H, d, J = 6.5Hz).
Example 13: (SR)-5-{2-[3-(4-Hydroxy-3-hydroxymethylphenoxy)-2- hydroxypropylamino]propyI}-l,3-benzodioxole-2,2-dicarboxylic acid, dilithium salt
Figure imgf000104_0001
A solution of (SR)-5-{2-[3-(4-Hydroxy-3-hydroxymethylphenoxy)-2- hydroxypropylamino]propyl}-l,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester (520mg, mMol) in dioxan (10ml), water (3ml) and lithium hydroxide solution (IM, 6ml, 6mMol) was stined at room temperature under argon for 24 hours. The pH of the solution was adjusted to 9 with dilute hydrochloric acid and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with water-methanol mixtures to give the title compound as a colourless solid.
δ(d6-DMSO + D2O): 6.90 (IH, d, J = 2.2Hz), 6.76-6.58 (4H, m), 6.49 (IH, d, J = 7.7Hz), 4.42 (2H, s), 4.1-4.0 (IH, m), 3.84-3.81 (2H, m), 3.2-2.8 (4H, m), 2.45-2.38 (IH, m), 0.98 (3H, d, J = 6.3Hz).
Example 14: (S)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]ethyl}phenoxymethylphosphonic acid, diethyl ester
Figure imgf000104_0002
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. δxH (200MHz, d6-DMSO): 7.20 (2H, br d), 6.95 (3H, m), 6.67 (2H, ), 5.10 (IH, br t), 4.45 (4H, m), 4.15 (7H, m), 3.88 (2H, m), 2.8 - 3.2 (4H, ), 1.25 (6H, t, J=6.5Hz)
Example 15: (S)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]ethyl}phenoxymethylphosphonate, ethyl ester, mono lithium salt
Figure imgf000105_0001
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.
δ!H (250MHz, d6-DMSO): 7.0 (2H, d, J=8Hz), 6.70 (4H, m), 6.25 (IH, dd, J=8Hz and 2.3Hz), 4.42 (2H, s), 4.20 (IH, br s), 3.75 (5H, m); 3.55 (IH, m), 2.4-2.8 (5H, m), 0.95 (3H, t, J=6.7Hz)
Example 16: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, bis-(3- benzyloxypropyl) ester
Me
Figure imgf000105_0002
(SR)-4-{2-[3-(2,2-Di-r-butyl-4H-l,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxy- propylamino]propyl}phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester (0.49g, 0.56 mMol) was converted into the title compound by a method similar to Example 4.
δxH (250MHz, CDC13): 7.25 (10H, m), 7.05 (2H, d), 6.73 (2H, d), 6.62 (IH, d), 6.55 - 6.35 (2H,m), 4.50 (2H, br), 4.42 (4H, s), 4.30 - 4.00 (8H, m, ), 3.70 (2H, br), 3.58 - 3.30 (5H, m), 3.30 - 2.85 (3H, overlapping br.), 2.71 (IH, br), 1.92 (4H, m), 1.18 (3H, d).
Example 17: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, (3- benzyloxypropyl) ester, lithium salt.
Me
Figure imgf000106_0001
The title compound was prepared by a similar method to that of Example 5 from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]-2- propyljphenoxymethylphosphonic acid, bis-(3-benzyloxypropyl) ester (0.314g, 0.43mMol).
δxH (400MHz, CD3OD): 7.15 (5H, m), 6.97 (2H, d), 6.74 (3H, m), 6.55 (IH, d), 6.48 (IH, dd), 4.49 (2H, s), 4.29 (2H, s), 4.00 - 3.80 (5H, m), 3.71 (2H, m), 3.47 (2H, t), 2.82 - 2.54 (4H, m), 2.42 (IH, dd), 1.78 (2H, ), 0.92 (3H, d).
Example 18: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, bis-(3- hydroxypropyl) ester. Me
Figure imgf000107_0001
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.
δ*H (200MHz, CD3OD): 7.25 (2H, d), 7.10 -6.90 (3H, m), 6.71 (2H, m), 4.64 (2H, s), 4.42 (2H, d), 4.30 (5H, m), 3.97 (2H, m), 3.68 (4H, t), 3.54 (IH, ), 3.25 (3H, m), 2.74 (IH, ), 1.91 (4H, m), 1.24 (3H, d).
Example 19: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, mono-(3- hydroxypropyl) ester, lithium salt.
Me
Figure imgf000107_0002
The title compound was obtained by hydrolysis of (SR)-4-{2-[2-hydroxy-3-(4- hydroxy-3-hydroxymethylphenoxy)propylamino]propyl } phenoxy-methyl)phosphonic acid, bis-(3-hydroxypropyl) ester (0.198g, 0.356mMol) using a method similar to that of Example 5.
δ*H (250MHz, CD3OD): 7.11 (2H, d), 6.90 (3H, m), 6.70 (IH, d), 6.60 (IH, dd), 4.62 (2H, s), 4.15 - 3.92 (5H, m) 3.85 (2H, d), 3.69 (2H, t), 3.05 - 2.68 (4H, m), 2.57 (IH, dd), 1.83 (2H, ), 1.08 (3H, d). Example 20: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propyl amino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester.
Me
Figure imgf000108_0001
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.
m/z: FAB MH+ 530 (14%)
Example 21: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propyl-amino]propyl}phenoxymethyl-phenylphosphinic acid, lithium salt.
Me
Figure imgf000108_0002
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. δ*H (250MHz, CD3OD): 7.89 (2H, ), 7.40 (3H, m), 7.08 (2H, d), 6.91 (IH, d), 6.84 (2H, d), 6.70 (lH,d), 6.64 (IH, dd), 4.62 (2H, s), 4.20 - 4.00 (3H, m), 3.91 (2H, m), 3.37 - 2.85 (4H, m), 2.62 (IH, dd), 1.15 (3H, d).
Example 22: (S)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]ethyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester.
Figure imgf000109_0001
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.
δ(d6-DMSO + D2O): 7.43-7.28(5H, m.); 7.27(2H, d, J = 8.86Hz); 7.04(2H, d, J = 8.80Hz.); 6.99(1H, d, J = 2.20Hz.); 6.74-6.71(2H, m.); 4.53(2H, s.); 4.44-4.42(2H, m.); 4.40-3.91(7H, m.); 3.56(2H, t, J = 6.05Hz.); 3.25-2.90(6H, m.); 1.93-1.79(4H, m.); 1.66-1.6K2H, m.); 1.44-1.39(2H, .); 0.94(3H, t, J = 7.41Hz.).
Example 23: (S)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethyIphenoxy)propylamino]ethyl}phenoxymethyl-(3- benzyIoxypropyl)phosphinic acid.
Figure imgf000109_0002
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.
δ(d6-DMSO + D2O)
7.31-7.21(5H, m.); 7.06(2H, d, J = 8.40Hz.); 6.88(1H, d, J = 2.97Hz.); 6.81(2H, d, J = 8.40Hz.); 6.66(1H, d, J = 8.65Hz.); 6.59(1H, dd, J = 8.68, 2.99Hz.); 4.42( 2H, s.); 4.38(2H, s.); 4.12-4.09(1H, m.); 3.87-3.70(2H, m.); 3.72(2H, d, J = 8.00Hz.) 3.38(2H, t, J = 6.57Hz.); 3.40-2.95(4H, .); 2.84-2.82(2H, m.); 1.73-1.67(2H, m.); 1.46-1.38(2H, m.).
Example 24: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyI}phenoxymethyl(3- benzyloxypropyl)phosphinic acid, n-butyl ester
Figure imgf000110_0001
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.
δ(CDCI3 + CD3OD): 7.44-7.30(5H, m.); 7.17(2H, d, J = 8.53Hz.); 6.82(2H, d, J = 8.57Hz.); 6.76-6.68(2H, m.); 6.65-6.59(lH, m.); 4.75(2H, s.); 4.51(2H, s.); 4.20- 3.86(7H, m.); 3.55(2H, t, J = 5.77Hz.); 3.28-3.09(4H, m.); 2.81-2.73(1H, m); 2.12- 1.91(4H, m.); 1.75-1.55(2H, m.); 1.48-1.37(2H, .); 1.24(3H, d, J = 5.50Hz.); 0.91(3H, t, J = 7.15Hz.); Example 25: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy) propylamino]propyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, hydrochloride salt.
Figure imgf000111_0001
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.
δ(d6-DMSO + D2O): 7.33-7.23(5H, .); 7.00(2H, d, J = 8.31Hz.); 6.81(1H, d, J = 2.94Hz.); 6.75(2H, d, J = 8.32Hz.); 6.70(1H, d, J = 8.62Hz.); 6.28(1H, dd, J = 8.52, 2.69Hz.); 4.46(2H, s.); 4.41 (2H, s.); 3.73-3.66(5H, m.); 3.42(2H, t, J = 6.58Hz.); 2.88-2.72(2H, m.); 2.67-2.52 (3H ,m), 1.79-1.69(2H, m.); 1.45-1.37(2H, m); 0.97(3H, d, J = 6.12Hz.).
Example 26: (S)-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]ethyI}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000111_0002
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 cyclohexylphosphinic acid, n-butyl ester according to the procedure described in Example 4. The crude product was used without further purification
δ(d6-DMSO + D2O): 7.18(2H, d, J = 8.25Hz.); 6.96(2H, d, J = 8.52Hz.); 6.89(1H, s.); 6.70-6.66(2H, m.); 4.45(2H, s.); 4.31 (2H, d, J = 6.87Hz); 4.05-3.88(2H, m.); 3.78(D2O obscuring IH signal), 2.87-2.77(3H, m.); 2.54-2.52(3H, m.); 2.00- 1.04(15H, m.); 0.86(3H, t, J = 7.43Hz.).
Example 27: (S)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]ethyl}phenoxymethylcyclohexyl phosphinic acid, lithium salt.
Figure imgf000112_0001
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.
δ(CD3OD): 7.24(2H, d, J = 8.56Hz.); 7.01 (2H, d, J = 8.56Hz.); 6.90(1H, d, J = 3.09Hz.); 6.78(1H, dd, J = 8.76, 3.16Hz.); 6.70(1 H, d, J = 8.75Hz.); 4.62(2H, s.); 4.04(2H, s.); 4.09-4.00(lH, m); 3.97(1H, dd, J = 10.45, 6.70Hz.); 3.90(1H, dd, J = 10.46, 6.24Hz.); 2.91-2.71(6H, m.); 1.92-1.65(6H, m.); 1.33-1.15(5H, m.).
Example 28: (S)-4-{2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000113_0001
A solution of (S)-4-{2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino] ethyljphenoxymethylcyclohexylphosphinic acid, n-butyl ester (l .OOg, 1.64mMol) in methanol (100ml) containing 10% palladium on charcoal (50mg) was hydrogenated at 40°C and 40 p.s.i. for 24 hours. After cooling to room temperature the suspension was filtered through a pad of filter aid and the filtrate was evaporated giving the title compound.
δ(d6-DMSO + D20): 7.14 (2H, d, J = 8.8Hz), 6.93 (2H, d, J = 8.8Hz), 6.73 (2H, d, J = 9Hz), 6.66 (2H, d, J = 9Hz), 4.31 (2H, d, J = 7.2Hz), 4.1-3.7 (5H, m), 2.8-2.55 (6H, m), 2.0-1.2 (15H, m), 0.86 (3H, t, J = 7.2Hz).
Example 29: (S)-4-{2-[2-Hydroxy-3-(4-hydroxyphenoxy)propylamino]ethyl} phenoxymethylcyclohexylphosphinic acid, lithium salt
Figure imgf000113_0002
The title compound was prepared from (S)-4- { 2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl } phenoxymethylcyclohexylphosphinic acid, n- butyl ester according to the procedure described in Example 5.
δ(d6-DMSO + D2O): 7.07 (2H, d, J = 8.5Hz), 6.81 (2H, d, J = 8.5Hz), 6.67 (2H, d, J = 9.1Hz), 6.60 (2H, d, J = 9.1Hz), 3.85-3.6 (5H, ), 2.8-2.5 (6H, ), 1.95-1.0 (1 IH, m).
-I l l- Example 30: (S)-4-[2-[2-Hydroxy-3-(3- hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000114_0001
The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(3- benzyloxyphenoxy)propylamino]ethyl Jphenoxymethylcyclohexylphosphinic acid, n- butyl ester according to the procedure described in Example 28.
δ(d6-DMSO + D2O): 7.19 (2H, d, J = 8.5Hz), 7.05-6.98 (3H, m), 6.4-6.35 (3H, m), 4.33 (2H, d, J = 6.9Hz), 4.0-3.88 (5H, m), 3.25-2.8 (6H, m), 2.0-1.2 (15H, m), 0.87 (3H, t, J = 6.4Hz).
Example 31: (S) 4-{2-[2-Hydroxy-3-(3-hydroxyphenoxy)propylamino]ethyl} phenoxymethylcyclohexylphosphinic acid, lithium salt
Figure imgf000114_0002
The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(3- hydroxyphenoxy)propylamino]ethyl jphenoxymethylcyclohexylphosphinic acid, n- butyl ester according to the procedure described in Example 5.
δ(d6-DMSO + D20): 7.01 (2H, d, J = 8.5Hz), 6.98 (IH, t, J = 8Hz), 6.78 (2H, d, J = 8.5Hz), 6.48 (IH, d, J = 2.2Hz), 6.3-6.25 (2H, m), 4.0-3.75 (5H, m), 2.85-2.55 (6H, m), 1.9-1.0 (l lH, m). Example 32: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Me
Figure imgf000115_0001
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.
δ(CDCl + D2O): 7.19(2H, d, J = 8.80Hz.); 6.90(2H, d, J = 8.52Hz.); 6.78(1H, d, J = 2,74Hz.); 6.72(1H, d, J = 8.80Hz.); 6.65(1H, dd, J = 8.80, 2.75Hz.); 4.68(2H, s.); 4.17(2H, d, J = 11.82Hz.); 4.13-3.91 (3H, m.): 3.48-3.42(lH, m.); 3.24(2H, d, J = 14.03Hz.); 3.10(1H, t, J = 9.90Hz.); 2.72(1H, t, J = 10.17Hz.); 2.01-1.06(15H, m.); 1.25(3H, d, J = 6.33Hz.); 0.93(3H, t, J = 7.15Hz.).
Example 33: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylcyclohexylphosphinic acid, lithium salt.
Me
Figure imgf000115_0002
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.
δ(D2O): 7.20(2H, d, J = 8.56Hz.); 6.96(2H, d, J = 8.64Hz.); 6.91(1H, d, J = 5.37Hz.); 6.80(1H, d, J = 8.76Hz.); 6.75(1H, dd, J = 8.75, 5.15Hz.); 4.63(2H, s.); 4.08-3.86(3H, m.); 4.01(2H, d, J = 7.55Hz.); 3.04-2.98(5H, m.); 1.87-1.67(7H, m.); 1.29-1.14(4H, m.); 1.09(3H, t, J = 6.17Hz.).
Example 34: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl}phenoxymethyl-n-hexyl phosphinic acid, n-butyl ester.
Me
Figure imgf000116_0001
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.
δ(d6-DMSO+D2O): 7.15(2H, d, J = 8.50Hz.); 6.94(2H, d, J = 8.63Hz.); 6.90(1H, d, J = 2.84Hz.); 6.68(1H, d, J = 8.61Hz.); 6.63(1H, dd, J = 8.68, 2.97Hz.); 4.45(2H, s.); 4.35-4.28(2H, m.); 4.05-3.90(4H, m.); 3.86-3.81(1H, m.); 2.97-2.90(lH, m.); 2.89(3H, m.); 2.50-2.45(lH, m.); 1.86-1.79(2H, m.); 1.59- 1.48(4H, m.); 1.38- 1.21(8H, m.); 0.97(3H, d, J = 6.25Hz.); 0.86(3H, t, J = 7.28Hz.); 0.84(3H, t, J = 6.87Hz.).
Example 35: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl}phenoxymethyl-n-hexylphosphinic acid, lithium salt.
Figure imgf000117_0001
The title compound was prepared from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl}phenoxymethyl-n-hexyl phosphinic 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
δ(d6-DMSO+D2O): 7.09(2H, d, J = 8.48Hz.); 6.85(2H, d, J = 8.45Hz.); 6.89(1H, d, J = 3.00Hz.); 6.68(1H, d, J = 8.62Hz.); 6.52(1H, dd, J = 8.62, 3.00Hz.); 4.47(2H, s.); 3.84(1H, t, J = 5.32Hz.); 3.82-3.73(4H, m.); 2.81-2.73(2H, m.) 2.71-2.61(2H, m.); 2.52-2.43(lH, m.); 1.44-1.41(4H, m.); 1.28-1.15(6H, m.); 0.95(3H, d, J = 6.24Hz.); 0.81(3H, t, J = 6.70Hz.).
Example 36: (S)-4-{2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl}phenoxymethyI-n-hexylphosphinic acid, n- butyl ester.
Figure imgf000117_0002
The title compound was prepared from (S)-N-benzyl-4-{ 2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino]ethyl}phenoxymethyl-n-hexylphosphinic acid, n- butyl ester according to the procedure described in Example 28. δ(d6-DMSO + D2O): 7.14 (2H, d, J = 8.5Hz), 6.92 (2H, d, J = 8.5Hz), 6.74 (2H, d, J = 8.6Hz), 6.66 (2H, d, J = 8.6Hz), 4.35-3.75 (7H, m), 2.75-2.6 (6H, m), 1.85-1.75 (2H, m), 1.6-1.45 (4H, m), 1.4-1.25 (8H, m), 0.9-0.8 (6H, ).
Example 37: (S) 4-{2-[2-Hydroxy-3-(4- hydroxyphenoxy)propylamino]ethyl}phenoxymethyl-n-hexylphosphinic acid.
Figure imgf000118_0001
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.
δ(d6-DMSO + D2O): 7.05 (2H, d, J = 8.5Hz), 6.79 (2H, d, J = 8.5Hz), 6.65 (4H, b), 3.9-3.7 (5H, ), 2.85-2.65 (6H, m), 1.4 (4H, m), 1.2 (6H, m), 0.80 (3H, t, J = 7.0Hz).
Example 38: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, bis-(2- phenylethyl) ester
Me
Figure imgf000118_0002
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.
Example 39: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyl- phenoxy)propylamino]propyl}phenoxymethylphosphonic acid, 2-phenylethyl ester, lithium salt
Me
Figure imgf000119_0001
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.
δ(d6-DMSO + D2O): 9.44 (IH, s, exchanges with D2O); 7.15-7.26 (5H, complex m.); 7.03-7.05 (2H, d.), 6.81-6.82 (IH, d.); 6.67-6.78 (2H, d.); 6.67-6.69 (2H, d.); 6.35-6.38 (IH, dd.); 5.08 (IH, t.); 4.43-4.44 (2H, d.); 3.94-3.99 (2H, q.); 3.65-3.76 (5H, complex m.); 2.78-2.83 (2H, t.); 2.45-2.76 (3H, complex m.); 0.95-0.96 (3H, d.).
Example 40: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethyI- phenoxy)propylamino]propyl}phenoxymethylbenzylphosphinic acid, n-butyl ester
Figure imgf000120_0001
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.
δ(CDCl3+D2O): 7.24-7.26 (5H, s.); 7.05-7.09 (2H, d.); 6.65-6.72 (3H, complex m.); 6.40-6.62 (3H, complex .); 4.58 (2H, s.); 3.82-4.08 (4H, complex m.); 3.68-3.72 (2H, d.); 3.25-3.30 (2H, d.); 2.52-3.00 (5H, complex m.); 1.50-1.63 (2H, m.); 1.27- 1.39 (2H, m.); 1.03-1.15 (3H, d.), 0.86-0.93 (3H,t.)
Example 41: (SR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)- propylamino]propyl}phenoxymethylbenzylphυsphinic acid.
Me
Figure imgf000120_0002
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.
δ(d6-DMSO + D2O): 7.00-7.24 (7H, complex m.); 6.94-6.95 ( 1 H, d.); 6.79-6.81 (2H, d.); 6.70-6.72 (IH, d.); 6.61-6.69 (IH, m.); 4.46 (2H, s.); 4.14-4.17 (IH, m.); 3.83-3.91 (IH, m.); 3.64-3.69 (2H, d.); 3.25-3.30 (IH, m).; 2.98-3.29 (5H, complex m.); 2.92-3.00 (2H, d.); 1.03-1.23 (3H, d.)
Example 42: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethyIphenoxy)propylamino] ethyl}phenoxymethylphenylphosphinic acid, ethyl ester
Figure imgf000121_0001
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.
m/z: MH+ 516 (60%).
Example 43: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethylphenoxy)-2- hydroxypropylarnino]ethyl}phenoxymethylphenylphυsphinic acid, lithium salt
Figure imgf000121_0002
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.
δΗ (250MHz, CD3OD): 7.89 (2H, m), 7.41 (3H, ), 7.09 (2H, d), 6.90 (IH, d), 6.82 (2H, d), 6.69 (IH, d), 6.63 (IH, dd), 4.62 (2H, s), 4.05 (3H, m), 3.87 (2H, m), 3.05- 2.63 (6H, ).
Example 44: (S)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl}- phenoxymethylphenylphosphinic acid, ethyl ester
Figure imgf000122_0001
The title compound was prepared from (S)-4-{2-[3-(4-benzyloxyphenoxy)-2- hydroxypropylamino] ethyl Jphenoxymethylphenylphosphinic acid ethyl ester according to the procedure described in Example 28.
δlH (250MHz, CD3OD): 7.92 (2H, ); 7.65 (3H, m); 7.14 (2H, d, J=8.6Hz); 6.87 (2H, d, J=8.6Hz); 6.74 (4H, m); 4.51 (2H, m); 4.20 (2H, m); 4.05 (IH, m); 3.93 (2H, d, J=6.5Hz); 2.9-2.7 (6H, m); 1.38 (3H, t, J=7.1Hz).
Example 45: (S)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl} phenoxymethylphenylphosphinic acid, lithium salt
Figure imgf000122_0002
The title compound was prepared from (S)-4- {2-[3-(4-hydroxyphenoxy)-2- hydroxypropylaminojethyl Jphenoxymethylphenylphosphinic acid, ethyl ester according to the procedure described in Example 5.
δΗ (250MHz, CD3OD): 7.94 (2H, m); 7.41 (3H, m); 7.08 (2H, d, J=8.4Hz); 6.82 (2H, d, J=8.3Hz); 6.75 (4H, m); 4.07 (3H, m); 3.85 (2H, d, J=6Hz); 2.9-2.7 (6H, m).
Example 46:(S,R)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropyIamino]propyl}- phenoxymethyiphenylphosphinic acid, ethyl ester
Me
Figure imgf000122_0003
The title compound was prepared from (S,R)-4- {2-[3-(4-benzyloxyphenoxy)-2- hydroxypropylaminojpropyl Jphenoxymethylphenylphosphinic acid, ethyl ester according to the procedure described in Example 28.
δ'H (250MHz, CD3OD): 7.89 (2H, m); 7.64 (3H, m); 7.18 (2H, d, J=8.8Hz); 6.92 (2H, d, J=8.0Hz); 6.75 (4H, m); 4.52 (2H, m); 4.18 (3H, m); 3.92 (2H, m); 3.45 (IH, m); 3.35-3.08 (3H, m); 2.7 (IH, m); 1.4 (3H, t, J=7.4Hz); 1.22 (3H, d, J=7.7 Hz).
Example 47: (S,R)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]propyl} phenoxymethylphenylphosphinic acid, lithium salt
Me
Figure imgf000123_0001
The title compound was prepared from (S,R)-4- {2-[3-(4-hydroxyphenoxy)-2- hydroxypropylaminojpropyl Jphenoxymethylphenylphosphinic acid, ethyl ester according to the procedure described in Example 5.
δ'H (250MHz, CD,OD): 7.9 (2H, m); 7.42 (3H, ); 7.08 (2H, d, J=8.4Hz); 6.84 (2H, d, J=8.3Hz); 6.75 (4H, s); 4.08 (3H, m); 3.82 (2H, ); 3.1-2.55 (5H, m); 1.08 (3H, d, J=7.7Hz).
Example 48: (S,R)-4-{2-[3-(4-Hydroxy-3-methanesulfonylaminophenoxy)-2- hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester
Me
Figure imgf000123_0002
The title compound was prepared from (S,R)-4-{2-[3-(4-benzyloxy-3- methanesulfonylaminophenoxy)-2-hydroxypropylaminolpropyl }phenylphosphinic acid, ethyl ester according to the procedure described in Example 28. δΗ (250MHz, d'-DMSO): 7.8 (2H, m); 7.68 (IH, m); 7.61 (2H, m); 7.16 (2H, d, J=8.2Hz); 7.01 (IH, d, J=1.40Hz); 6.94 (2H, d, J=7.9); 6.84 (IH, d, J=8.4Hz); 6.71 (IH, m); 4.52 (2H, m); 4.17 (3H, m); 3.96 (2H, m); 3.3-3.14 (4H, ); 2.94 (3H, s); 2.71 (IH, m); 1.38 (3H, t, J=7.4Hz); 1.21 (3H, d, J=7.1Hz)
Example 49: (S,R)-4-{2-[3-(4-Hydroxy-3-methanesulfonylaminophenoxy)-2- hydroxypropylamino]propyl}phenoxymethyIphenylphosphinic acid, hydrobromide salt
Figure imgf000124_0001
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.
δ'H (250MHz, CD3OD): 7.9 (2H, m); 7.48 (3H, m); 7.13 (2H, d); 7.0 (IH, d); 6.89 (2H, d); 6.83 (IH, d); 6.68 (IH, dd); 4.20 (3H, m); 3.95 (2H, m); 3.5-2.9 (4H, m); 2.93 (3H, s); 2.72 (IH, ); 1.23 (3H, d); m/z: [M-H | 563 (28%).
Example 50: (S) 4-{2-[3-(4-Hydroxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride salt.-
Figure imgf000124_0002
A solution of (S) 4-{2-[3-(4-r-butyldimethylsilyloxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n- butyl ester (199mg, 0.28mMol) in dichloromethane (10ml) and IM hydrogen chloride in diethylether (1ml) was stined at room temperature for 2 hours. The solution was concentrated giving the title compound as a solid.
δ'H (d6-DMSO + D2O): 7.4-7.25 (5H, m), 7.19 (2H, d, J = 8.8Hz), 6.98 (2H, d, J = 8.6Hz), 6.77 (2H, m), 6.68 (2H, m), 4.45 (2H, s), 4.35-3.8 (7H, m), 3.5-2.8 (8H, m), 1.95-1.75 (4H, ), 1.6-1.5 (2H, m), 1.4-1.25 (2H, m), 0.86 (3H, t, J = 7.4Hz).
Example 51: (S) 4-{2-[3-(4-Hydroxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, lithium salt.
Figure imgf000125_0001
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.
δ'H (d6-DMSO + D2O): 7.36-7.26 (5H, m), 7.09 (2H, d, J = 8.5Hz), 6.82 (2H, d, J = 8.5Hz), 6.7-6.6 (4H, br), 4.42 (2H, s), 3.8-3.6 (5H, m), 3.41 (2H, t, J = 6.7Hz), 2.7- 2.55 (6H, m), 1.75-1.65 (2H, ), 1.45-1.30 (2H, m).
Example 52: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride.
Figure imgf000125_0002
A solution of (S,R) 4-{2-[4-t-Butyldimethylsilyloxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n- butyl ester (525mg, 0.74mMol) in methanol (50ml) was treated with acetyl chloride (2.70ml). The reaction was stined for 8 hours at ambient temperature and solvent removed to give the title compound.
δ'H (d'-DMSO): 7.37-6.67 (13H, m), 4.45 (2H, s), 4.33 (2H,m), 4.18 (IH brs), 4.04- 3.83 (4H, m), 3.48 (2H, t), 3.35 (lH,m), 3.18 (2H, m), 3.06 (IH, m), 2.60 (IH, t),1.95-1.81 (4H, m),1.53 (2H, m), 1.32 (2H, m), 1.08 (3H, d), 0.86 (3H, t).
Example 53: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, lithium salt.
CH,
Figure imgf000126_0001
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.
δ'H (d'-DMSO): 7.32-6.50 (13H, m), 4.41 (2H, s), 3.80-3.69 (5H, m), 3.45 (2H, t), 2.95-2.50 (5H, m), 1.75 (2H, ), 1.44 (2H, m), 0.95 (3H, d).
Example 54: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
CH,
Figure imgf000126_0002
The title compound was prepared from (S,R) 4-{2-[4-benzyloxyphenoxy)-2- hydroxypropylaminojpropyljphenoxymethylcyclohexylphosphinic acid, n-butyl ester according to the procedure described in Example 28. δ'H (CDC1,): 7.10-6.45 (8H, m), 4.25-3.80 (7H, m), 3.20-2.75 (5H, m), 2.15-1.15 (18H, m), 0.93 (3H, d).
Example 55: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, lithium salt.
CH,
Figure imgf000127_0001
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.
δ'H (d'-DMSO + D.O): 7.20 (2H, d), 6.80 (2H, d), 6.71 (4H, m), 4.1 1 (IH, m), 3.84-3.77 (4H, m), 3.08-2.82 (5H, m), 1.88-1.23 (1 IH, m), 0.98 (3H, d).
Example 56: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethylhexylphosphinic acid, n-butyl ester.
Figure imgf000127_0002
The title compound was prepared from (S,R) 4- {2-[4-benzyloxyphenoxy)-2- hydroxypropylaminojpropyljphenoxymethylhexylphosphinic acid, n-butyl ester according to the method described in Example 28.
δ'H (d'-DMSO + D2O): 7.15-6.64 (8H, m), 5.25 (2H, s), 4.30 (2H, m), 4.02-3.80 (5H, m), 3.10-2.75 (4H, m), 2.45 (I H, m), 2.40-1.70 (13H, m) 0.96 (3H, d), 0.86 (6H, m). Example 57: (S,R) 4-{2-[4-Hydroxyphenoxy)-2- hydroxypropylamino]propyl}phenoxymethylhexylphosphinic acid lithium salt.
Figure imgf000128_0001
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.
δ'H (d'-DMSO): 7.04-6.41 (8H, m), 3.80-3.63 (5H, ), 2.90-2.50 (5H, m), 1.50- 1.20 (10H, m), 0.97 (3H, d), 0.83 (3H, t).
Example 58: (S)-4-{2-[3-(3-Fluoro-4-hydroxyphenoxy)-2- hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester.
Figure imgf000128_0002
A solution of (S)-4-{2-[3-(4-benzyloxy-3-fluorophenoxy)-2- hydroxypropylaminojethyljphenoxymethylcyclohexyl phosphinic acid, n-butyl ester (0.88g, 1.36mMol) in methanol (50ml) containing palladium (II) chloride (20mg) was hydrogenated at room temperature and atmospheric pressure for 4 hours. The suspension was filtered through a pad of filter aid and the filtrate was evaporated giving the title compound.
δ'H (CDCI3 + D2O): 7.10 (2H, d, J = 8.5Hz), 6.88-6.78 (3H, m), 6.54 (IH, dd, J = 12.2, 2.8Hz), 6.36-6.32 (IH, m), 4.16-3.98 (5H, ), 3.84 (2H, d, J = 5.0Hz), 3.06- 2.77 (6H, m), 2.02-1.23 (15H, ), 0.92 (3H, t, J = 7.3Hz). Example 59: (S)-4-{2-[3-(3-Fluoro-4-hydroxyphenoxy)-2- hydroxypropylamino]ethyI}phenoxymethylcyclohexyIphosphinic acid, lithium salt
Figure imgf000129_0001
The title compound was prepared from (S)-4-{2-[3-(3-fluoro-4-hydroxyphenoxy)-2- hydroxypropylaminojethyl Jphenoxymethylcyclohexylphosphinic acid, n-butyl ester according to the procedure described in Example 5.
δ'H (d6-DMSO + D2O): 7.04 (2H, d, J = 8.6Hz), 6.89 (IH, dd, J = 10.2, 8.9Hz), 6.75 (2H, d, J = 8.6Hz), 6.60 (IH, dd, J = 12.9, 2.9Hz), 6.08 (IH, ddd, J = 8.9, 2.8, 1.3Hz), 3.91-3.63 (3H, m), 3.67 (2H, d, J = 7.7Hz), 2.78-2.58 (6H, m), 1.85-1.11 (HH, m).
Example 60: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethyI)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenylpropyl)phosphinic cid, n- butyl ester
Figure imgf000129_0002
The title compound was prepared from (S)-4- {2-[3-(4-benzyloxy-3- hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl }phenoxymethyl(3- phenylpropyl)phosphinic acid, n-butyl ester according to the method described in Example 28. The crude product was used without further purification.
Mass Spectrum m/z 586(92%)MH* Example 61: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethyl)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenylpropyl)phosphinic acid, lithium salt
Figure imgf000130_0001
The title compound was prepared from (S)-4-{2-[3-(4-hydroxy-3- hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl }phenoxymethyl(3- phenylpropyl)phosphinic acid, n-butyl ester according to the method described in Example 5. The crude product was purified by chromatography over C-18 reverse phase silica eluting with water/methanol mixtures.
δ'H (d6-DMSO + D2O): 7.26-7.22 (2H, m); 7.16-7.12 (3H, m);7.06 (2H, d, J = 8.63Hz); 6.89 (IH, d, J = 2.95Hz); 6.79 (2H, d, 8.63Hz); 6.69 (IH, d, J = 8.67Hz.); 6.55 (IH, dd, J = 8.67, 3.07Hz); 4.45 (2H, s); 4.10-4.00 (IH, m); 3.82 (2H, t, J =
5.35Hz); 3.71 (2H, d, J = 8.00Hz); 2.96-2.90 (3H, m); 2.85-2.74 (3H, m); 2.58 (2H, t, J = 7.48Hz); 1.79-1.73 (2H, ); 1.45-1.23 (2H, m)
Example 62: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethyl)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester
Figure imgf000130_0002
The title compound was prepared from (S)-4-{ 2-l3-(4-benzyloxy-3- hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3- phenoxypropyl)phosphinic acid, ethyl ester according to the method described in Example 28. The crude product was used without further purification. δ'H (CDCl3+D2O): 7.30-7.24 (3H, m.); 7.12 (2H, d, J = 8.52Hz); 6.97-6.74 (6H, m); 6.53 (IH, d, J = 8.52Hz); 4.73 (2H, s); 4.21-3.98 (7H, m); 3.79-3.73 (2H, m); 2.96-2.77 (6H, m); 2.35-2.10 (4H, m); 1.34 (3H, t, J = 7.15Hz)
Example 63: (S)-4-{2-[3-(4-Hydroxy-3-hydroxymethyl)phenoxy-2- hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, hydrochloride salt
Figure imgf000131_0001
The title compound was prepared from (S)-4-{2-f3-(4-hydroxy-3- hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3- phenoxypropyl)phosphinic acid, ethyl ester according to the method described in Example 25. The crude product was purified by chromatography over C- 18 reverse phase silica eluting with water/methanol mixture.
δ'H (d6-DMSO + D2O): 7.23 (2H, t, J = 7.7Hz); 6.94 (2H, d, J = 8.8Hz); 6.93 (IH, s); 6.89-6.86 (3H, m); 6.72 (2H, d, J = 8.6Hz); 6.67 (IH, d, J = 8.64Hz); 6.56 (IH, dd, J = 2.9, 8.6Hz); 4.44 (2H, s); 4.18-4.16 (IH, m); 3.97 (2H, t, J = 6.5Hz); 3.87- 3.79 (4H, m); 3.08 (IH, d, J = 10.3Hz); 2.97-2.90 (3H, ); 2.83-2.81 (2H, m); 1.97- 1.87 (2H, m), 1.61-1.53 (2H,m).
Example 64: (S,/?)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]propyI} phenoxymethylphosphonic acid, bis-cyclohexyl ester, hydrochloride salt
Me
Figure imgf000131_0002
HCl
The title compound was prepared from (S,/?)-4-{ 2-[3-(4-benzyloxyphenoxy)-2- hydroxypropylaminojpropyl } phenoxymethylphosphonic acid, bis-cyclohexyl ester according to the method described in Procedure 9. The crude product was purified by crystallisation of the hydrochloride salt from dichloromethane to give a solid (mp 187-189°C).
δ'H(CDCl3 + D2O): 7.18-7.21 (2H, d), 6.87-6.90 (2H, d), 6.25-6.28 (2H, d), 6.20- 6.22 (2H, d), 4.68-4.72 (IH, m), 4.45-4.58 (2H, m), 4.18-4.22 (2H, d) 4.00-4.06 (IH, m), 3.88-3.93 (IH, m), 3.11-3.48 (4H, m), 3.28-3.33 (IH, dd), 1.27-2.00 (20H, m), 1.35-1.37 (3H, d).
Example 65: (5)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyI} phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester
Figure imgf000132_0001
The title compound was prepared from (5)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxy propylaminojethyl } phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester according to the method described in Procedure 9. The title compound was obtained as an off-white solid.
δ1H(d6-DMSO + D2O): 6.72-7.41 (28H, complex); 4.32-4.66 (7H, m); 3.81-4.20 (4H, m); 2,72-2.99 (6H, ).
Example 66: (S)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl} phenoxymethylphosphonic acid, bis-(2-phenylethyl) ester
Figure imgf000132_0002
The title compound was prepared from (S)-4-{2-[3-(4-benzyloxyphenoxy)-2- hydroxypropylaminojethylj phenoxymethylphosphonic acid, bis-(2-phenylethyl) ester according to the method described in Procedure 9. The solid thus obtained was crystallised from methanol/dichloromethane (1 : 1) to give the title compound ( p 75- 76°C).
δ1H(d6-DMSO+D2O): 6.83-7.40 (18H, m); 3.80-4.72 (9H, ); 2.66-3.05 (10H, m).
Example 67: (RR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy) propylaminojpropyljphenoxymeth vlphenylphosphinic acid, ethyl ester.
Figure imgf000133_0001
The title compound was prepared from (RR)-4- {2-[3-(2,2-di-rerr-butyl-4H-l,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl Jphenoxymethylphenyl¬ phosphinic acid, ethyl ester (140mg, 0.21mMol) by a method similar to that in Example 4. The crude product, obtained as a grey gum, was used without further purification.
m/z: MH* 530 (18%).
Example 68: (RR)-4-{2-[2-Hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy) propylamino]propyl}phenoxymethylphenylphosphinic acid, lithium salt.
Figure imgf000133_0002
The title compound was prepared from (RR)-4-{ 2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylaminolpropyl Jphenoxymethylphenylphosphinic acid, ethyl ester (l lOmg, 0.21mMol) by a method similar to that used in Example 21; the product was isolated as a white powder after freeze-drying. δ'H (250MHz, CD3OD): 7.90 (2H, m); 7.42 (3H, m); 7.1 1 (2H, d); 6.95 (IH, d); 6.87 (2H, d); 6.69 (2H, d); 4.64 (2H, s); 4.19 (IH, m); 4.08 (2H, d); 3.97 (2H, m); 3.48 (IH, m); 3.36 (IH, m, partially obscured by MeOH signal); 3.20-3.02 (2H, m); 2.69 (lH, m) and 1.23 (3H, d).
Example 69: (5)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl} phenoxymethylphosphonic acid, 2-phenylethyl ester, hydrochloride salt dihydrate
Figure imgf000134_0001
HCl. H20
The title compound was prepared from (5)-4-{2-[3-(4-hydroxyphenoxy)-2- hydroxypropylaminojethylj phenoxymethylphosphonic acid, bis-(2-phenylethyl ester according to the method described in Example 25, as a white solid.
δ1H(d6-DMSO+D2O): 7.15-7.26 (5H, m); 7.04-7.08 (2H, d); 6.75-6.82 (4H, m); 6.69-6.72 (2H, d); 4.11-4.16 (IH, m), 3.95-3.99 (2H, q); 3.77-3.95 (4H, ); 2.79-2.87 (4H, m), 2.99-3.18 (4H, m).
Example 70: (5)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl} phenoxymethylphosphonic acid, (2,2-diphenylethyl) ester, hydrochloride salt
Figure imgf000134_0002
The title compound was prepared from (S)-4- { 2-l3-(4-hydroxyphenoxy)-2- hydroxypropylaminojethyljphenoxymethylphsphonic acid, bis- (2,2-diphenyl ethyl) ester according to the method described in Example 25, as a white solid. m/z: MH+ 578.
Pharmacological Data: The activity of the present compounds is tested by use of the following procedures:
Antagonist and Agonist Activity at Human βj, β 2, and β 3-Adrenoceptors.
Subclones of CHO cells are stably transfected with each of the human βj, β 2 and β 3-adrenoceptors^. Cells are then disrupted by immersion in ice-cold lysis buffer (10 mM TRIS, 2mM EDTA , pH 7.4) containing protease inhibitors leupeptin and benzamidine (5 μg / ml) and soyabean trypsin inhibitor (10 μg / ml). Membranes are prepared by the method of Bouvier et. al.^ and stored in 1 ml aliquots in liquid N2 for future use.
β 3-Adrenoceptor- Mediated Adenylyl Cyclase Activity Adenylyl cyclase activity is assayed by the method of Kirkham et. al.3 by the addition of 40 μl (70 -80 μg protein) to the incubation medium of the above CHO cell plasma membranes transfected with the human β3-adrenoceptor . cAMP produced over 20 minutes is separated from ATP by the method of Salomon et al A Agonist EC50 values and intrinsic activities are expressed as the concentration of agonist producing 50 % activation of adenylyl cyclase and the maximum response produced by each agonist relative to that produced by (-) isoprenaline respectively.
Antagonist Binding at βj, and β 2-Adrenoceptors
Displacement of [^^I]-iodocyanopindolol from CHO cell plasma membranes transfected with either the human β], or β 2-adrenoceptors is carried out by the method of Blin et. al A Ki values (nM) are calculated from the binding IC50 values for each agonist, using the Cheng -Prusoff equation.
Results
ample Beta- 3 Beta-1 Beta-2
EC50 (IA) uM Ki uM Ki uM
17 1.1 (0.7) 21 10
21 1.26 (> 1.0) 155 15
29 1.7 (0.72) 288 269 References
1. T. Frielle et. al., Proc. Natl. Acad. Sci., 1987, 84, 7920; B. Kobilka, Proc. Natl. Acad. Sci., 1987, 84, 46; S. Liggett and D. Schwinn, DNA Sequence, 1991, 2, 61.
2. M. Bouvier et. al., Mol. Pharmacol., 1987, 33, 133.
3. D. Kirkham et. al., Biochem. J., 1992, 284, 301.
4. Y. Salomon et al., Anal. Biochem., 1974, 58, 541.
5. N. Blin, et. al., Br. J. Pharmacol., 1994, 112, 911.

Claims

CLAIMS:
1. A compound of formula (I):
Figure imgf000137_0001
(I)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein,
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;
R represents OCH2CO2H, or an ester or amide thereof, or R^ represents a moiety of formula (b):
-0-CH,-P-OR
R"
(b)
wherein 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)nO wherein n is 2, 3 or 4; and R3 represents hydrogen, halogen, alkyl or alkoxy or R^ together with R^ represents a moiety of formula (c):
Figure imgf000137_0002
(c) or an ester or amide thereof; providing that 4-[2-[2-hydroxy-3-(4- hydroxyphenoxy)propylamino]propyl] phenoxyacetic acid and salts and esters thereof and the compounds of examples 1 to 36 disclosed in EP0328251 are excluded from the scope of formula (I).
2. A compound according to claim 1 , wherein, R° represents a phenyl group optionally substituted with hydroxy and/or hydroxymethyl.
3. A compound according to claim 1 or claim 2, wherein R° is 4-hydroxy-3- hydroxymethylphenyl, 3- and 4-hydroxyphenyl groups, 3-hydroxyphenyl or 4- hydroxyphenyl.
4. A compound according to any one of claims 1 to 3, wherein R* is an alkyl group and R^a represents hydrogen.
5. A compound according to any one of claims 1 to 3, wherein R^ and R*a each represents hydrogen.
6. A compound according to any one of claims 1 to 5, wherein R^ together with
R2 represents a moiety of formula (c) or R^ represents a moiety of formula (b) and R3 represents hydrogen, halogen, alkyl or alkoxy.
7. A compound according to any one of claims 1 to 6, wherein R^ represents a moiety of formula (b).
8. A compound according to any one of claims 1 to 7, wherein R^ is a moiety of formula (b).
9. A compound according to any one of claims 1 to 8, wherein R^ represents hydrogen, alkyl, hydroxyalkyl, phenylalkyl, benzyloxyalkyl or cycloalkyl.
10. A compound according to any one of claims 1 to 9, wherein R^ represents hydrogen, ethyl, n-butyl, hydroxypropyl, phenylpropyl or benzyloxyethyl.
11. A compound according to any one of claims 1 to 10, wherein R^ represents hydrogen or alkyl.
12. A compound according to any one of claims 1 to 1 1 , wherein R^ represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy, especially alkoxy, hydroxyalkyloxy or arylalkoxyalkyloxy.
13. A compound according to any one of claims 1 to 12, wherein R^ is hydrogen, phenyl, n-hexyl, cyclohexy, ethoxy, n-butoxy, phenylpropyloxy, benzyloxypropyloxy, 2-hydroxyethyloxy group or 3-hydroxypropyloxy.
14. A compound according to any one of claims 1 to 13, wherein R^ n-hexyl or phenyl.
15. A compound according to claim 1 selected from a title compound of examples 1 to 70 disclosed herein; or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable solvate thereof.
16. A compound according to any one of claims 1 to 15, wherein with reference to formula (I), the asymmetric carbon atom conesponding to that indicated by a single asterisk (*) is in the S-configuration and the asymmetric carbon atom conesponding to that indicated by two asterisks (**) is in the R-configuration
17. 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:
(a) reacting a compound of formula (II):
R°-X-CH2— CH -CH. / 2
\>
(ID
wherein X is as defined in relation to formula (I) and R° represents R° as defined in relation to formula (I) or a protected form thereof, with a compound of formula (III):
Figure imgf000139_0001
(III) wherein Rl, R^a, R2 and R^ are as defined in relation to formula (I) and T° represents a hydrogen or a protecting group; or
(b) for preparing a compound of formula (I), wherein R*a represents hydrogen, by reducing a compound of formula (XXI):
Figure imgf000140_0001
wherein R°, Rl, R 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; or (c) reacting a compound of formula (XXIII):
Figure imgf000140_0002
(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^a into R^ and/or a reagent capable of converting R^ into R ; and thereafter, if required, canying out one or more of the following optional steps:
(i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group;
(iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
18. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable canier therefor.
19. A method for treating hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; o.- a pharmaceutically acceptable f lvate thereof, to the human or non-human mammal in need thereof.
20. A method for increasing weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable salt thereof; or a veterinarily acceptable solvate thereof.
21. A veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable salt thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.
22. A compound of formula (XXI):
Figure imgf000141_0001
wherein R°, Rl, R^ and X are as defined in relation to formula (I) of claim 1 and R^' represents R^ as defined in relation to formula (I) or a protected form thereof.
23. A compound of formula (XXIII):
Figure imgf000141_0002
wherein Rl, R^a and X are as defined in relation to formula (I) in claim 1, R°' represents R° as defined in relation to formula (I) of claim 1 or is a protected form thereof, 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 R3 are each as defined in relation to formula (I) in claim 1.
-139-
SUBST1TUTE SHEET (RULE 26)
PCT/EP1995/003037 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 WO1996004233A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP95929029A 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
AU32546/95A AU3254695A (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
BR9508991A BR9508991A (en) 1994-07-29 1995-07-27 Compound process for the preparation of a compound pharmaceutical composition process for the treatment of hyperglycemia obesity arteriosclerosis hyperinsulinemia gastrointestinal disorders or the treatment of gastrointestinal ulcerations in a human or non-human mammal process to increase weight gain and / or improve the efficiency of the use of feeding and / or increasing the body mass curve and / or decreasing the birth mortality rate and increasing the postnatal survival rate of farm animals and veterinarily acceptable pre-mix formulation
MX9700765A MX9700765A (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.
JP8506193A JPH10503507A (en) 1994-07-29 1995-07-27 Aryloxy and arylthiopropanolamine derivatives useful as beta3-adrenergic receptor agonists and beta1- and beta2-adrenergic receptor antagonists, and pharmaceutical compositions thereof
NO970372A NO970372L (en) 1994-07-29 1997-01-28 Aroyloxy and aroylthiopropanolamine derivatives useful as <beta> -3-adrenoreceptor agonists and antagonists for <beta> -1 and <beta> -2-adrenoreceptors and pharmaceutical mixtures thereof

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9415304A GB9415304D0 (en) 1994-07-29 1994-07-29 Novel compounds
GB9423179A GB9423179D0 (en) 1994-11-17 1994-11-17 Novel compounds
GB9423179.2 1995-05-24
GB9510485.7 1995-05-24
GBGB9510485.7A GB9510485D0 (en) 1995-05-24 1995-05-24 Novel compounds
GB9415304.6 1995-05-24

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CA (1) CA2196193A1 (en)
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WO1997034905A1 (en) * 1996-03-15 1997-09-25 Smithkline Beecham Plc Phosphorus containing aryloxy and arylthiopropanol amine derivatives useful as beta adrenoreceptor agonists
WO1998022480A1 (en) * 1996-11-18 1998-05-28 Smithkline Beecham Plc Phosphorus containing aryloxy or arylthio propanolamine derivatives
WO1998037056A1 (en) * 1997-02-20 1998-08-27 Smithkline Beecham Plc Phenoxypropanolamine derivatives and pharmaceutical compositions containing them
US5914339A (en) * 1996-05-14 1999-06-22 American Home Products Corporation Substituted 1,3-benzodioxoles
WO1999051564A1 (en) * 1998-04-06 1999-10-14 Fujisawa Pharmaceutical Co., Ltd. Propanolamine derivatives
EP0980375A1 (en) * 1998-01-30 2000-02-23 Boulder Scientific Company N-silylated compound synthesis
WO2000012462A1 (en) * 1998-08-26 2000-03-09 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives and their use as beta 3 adrenergic agonists
US6046227A (en) * 1997-12-05 2000-04-04 Eli Lilly And Company Selective β3 adrenergic agonists
US6140352A (en) * 1996-09-05 2000-10-31 Eli Lilly And Company Carbazolyl-substituted ethanolamines as selective β-3 agonists
EP1411911A1 (en) * 2001-07-09 2004-04-28 Research Development Foundation Beta-adrenergic blockade reversal of catabolism after severe burn

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DE102008064003A1 (en) * 2008-12-19 2010-06-24 Clariant International Limited Process for the preparation of monofunctionalized dialkylphosphinic acids, esters and salts and their use
CN107266341B (en) * 2017-06-23 2020-01-07 华东师范大学 Aryloxy substituted propan-2-ol amine derivative as beta3 adrenergic receptor antagonist, preparation method and application
CN112442167A (en) * 2019-08-28 2021-03-05 广东广山新材料股份有限公司 Reactive flame retardant and preparation method and application thereof

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034905A1 (en) * 1996-03-15 1997-09-25 Smithkline Beecham Plc Phosphorus containing aryloxy and arylthiopropanol amine derivatives useful as beta adrenoreceptor agonists
US5914339A (en) * 1996-05-14 1999-06-22 American Home Products Corporation Substituted 1,3-benzodioxoles
US6140352A (en) * 1996-09-05 2000-10-31 Eli Lilly And Company Carbazolyl-substituted ethanolamines as selective β-3 agonists
US6686372B2 (en) 1996-09-05 2004-02-03 Eli Lilly And Company Selective β3 adrenergic agonists
US6413991B1 (en) 1996-09-05 2002-07-02 Eli Lilly And Company Selective β3 adrenergic agonists
WO1998022480A1 (en) * 1996-11-18 1998-05-28 Smithkline Beecham Plc Phosphorus containing aryloxy or arylthio propanolamine derivatives
WO1998037056A1 (en) * 1997-02-20 1998-08-27 Smithkline Beecham Plc Phenoxypropanolamine derivatives and pharmaceutical compositions containing them
US6617347B1 (en) 1997-12-05 2003-09-09 Eli Lilly And Company Selective β3 adrenergic agonists
US6046227A (en) * 1997-12-05 2000-04-04 Eli Lilly And Company Selective β3 adrenergic agonists
EP0980375A4 (en) * 1998-01-30 2003-01-22 Boulder Scient Co Silylated and n-silylated compound synthesis
EP0980375A1 (en) * 1998-01-30 2000-02-23 Boulder Scientific Company N-silylated compound synthesis
US6495546B1 (en) 1998-04-06 2002-12-17 Fujisawa Pharmaceutical Co., Ltd. Propanolamine derivatives
WO1999051564A1 (en) * 1998-04-06 1999-10-14 Fujisawa Pharmaceutical Co., Ltd. Propanolamine derivatives
US7217706B2 (en) 1998-04-06 2007-05-15 Astellas Pharma Inc. Propanolamine derivatives
WO2000012462A1 (en) * 1998-08-26 2000-03-09 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives and their use as beta 3 adrenergic agonists
EP1411911A1 (en) * 2001-07-09 2004-04-28 Research Development Foundation Beta-adrenergic blockade reversal of catabolism after severe burn
EP1411911A4 (en) * 2001-07-09 2005-06-15 Res Dev Foundation Beta-adrenergic blockade reversal of catabolism after severe burn
US7098248B2 (en) 2001-07-09 2006-08-29 Research Development Foundation Beta-adrenergic blockade reversal of catabolism after severe burn

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PL318381A1 (en) 1997-06-09
CN1159797A (en) 1997-09-17
AU3254695A (en) 1996-03-04
NO970372D0 (en) 1997-01-28
HUT76800A (en) 1997-11-28
BR9508991A (en) 1997-10-21
EP0772585A1 (en) 1997-05-14
JPH10503507A (en) 1998-03-31

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