NO970372L - Aroyloxy and aroylthiopropanolamine derivatives useful as <beta> -3-adrenoreceptor agonists and antagonists for <beta> -1 and <beta> -2-adrenoreceptors and pharmaceutical mixtures thereof - Google Patents

Description

AROYLOXY AND AROYLTHIOPANOLAMINE DERIVATIVES USABLE AS BETA 3-ADRENORECEPTOR AGONISTS AND ANTAGONISTS FOR BETA-1 AND BETA-2 ADRENORECEPTORS, AND PHARMACEUTICAL MIXTURES OR PREPARATIONS CONTAINING THESE.

The present invention relates to new compounds, methods for producing these pharmaceutical preparations containing such compounds and the use of the compounds and preparations in medicine and agriculture.

European patent application publication no. 0328251 describes certain 2-(2-hydroxy-3-phenoxypropylamino)ethylphenoxyacetamides which can be used in the treatment of obesity and related conditions.

It has now surprisingly been found that certain special series of new aryloxy and arylthiopropanolamine derivatives have good p3-adrenoceptor agonist activity, and show particularly good selectivity for p3-adrenoreceptors in relation to pr or p2-adrenoreceptors, i.e. to a high degree that these compounds are antagonists for the Pr and p2-adrenoceptors. It is also indicated that these compounds have good antihyperglycaemic activity and activity against obesity coupled with particularly good selectivity with regard to cardiac and tremorgenic side effects.

It is also stated that these compounds have a healing effect in the treatment of intestinal disorders such as peptic ulcer, oseophagitis, gastritis and duodenitis, ulcers in the duodenum, this includes inflammatory diseases of the stomach and in the so-called irritable bowel syndrome, in addition to the treatment of chronic ulcers in the intestinal tract, especially those induced by non-steroidal anti-inflammatory drugs and corticosteroids.

Said compounds can also be used to increase the concentration of high-density lipoprotein (HDL) cholesterol while reducing the triglyceride concentration in human blood serum, and will therefore be able to be used in the treatment and/or prophylaxis with respect to atherosclerosis. It is also stated that the compounds can be used in the treatment of hyperinsulinemia, besides that they can be used in the treatment of depression.

These compounds also have potential application as growth promoters for livestock and for lowering perinatal mortality and increasing postnatal survival rates in livestock.

The present invention therefore provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound,

where

R° is an aryl group, optionally substituted with one, two or three substituents selected from the list consisting of hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulfonamido, arylsulfonamido, formamido, halogen, alkoxy and allyl;

X is O or S;

R1 and R<1a> are independently hydrogen or an alkyl group;

R2 is OCH2CO2H or an ester or an amide of this group, or R<2>represents a group of formula (b):

where R<4>hydrogen, alkyl, hydroxyalkyl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl or cycloalkyl, and R<5>is hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, aryloxyalkyloxy, arylalkyloxy or cycloalkyloxy, or R<5>is hydrogen, alkyl , substituted alkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl or R5 together with OR4 is 0(CH2)nO where n is 2, 3 or 4; and

R<3> is hydrogen, halogen, alkyl or alkoxy, or R<3> is together with R<2> a group of formula (c):

or an ester or amide of such a group; provided that 4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetic acid and its salts and esters and the compounds mentioned in examples 1 to 36 of EP0328251 are not included in the compounds indicated by formula (I).

Suitable aryl groups include phenyl and naphthyl groups, especially phenyl groups.

Suitable optional substituents for R° include one, two or substituents selected from the group consisting of hydroxy, hydroxy methyl, alkylsulfonamido and halogen.

R° is suitable a phenyl group optionally substituted with hydroxy and/or

hydroxymethyl and/or halogen, then especially fluorine and/or alkylsulfonamido.

Examples of R° include 4-hydroxy-3-hydroxymethylphenyl, 3- and 4-hydroxyphenyl, 3-fluoro-4hydroxyphenyl and 4-hydroxymethylsulfonamido phenyl groups.

R<1> is suitably an alkyl group and R<1a> is hydrogen.

R<1> and R<1a> are preferably both hydrogen.

When R<1> is alkyl, it is preferably an alkyl group, then especially a methyl group.

R<1a> is preferably hydrogen.

In another aspect, R<2>OCH2CO2H, or an ester or an amide of this group. R<3> is suitable together with R<2> a group of formula (c) or R<2> is a group of formula (b) and R<3> is hydrogen, halogen, alkyl or alkoxy.

In one aspect, R 2 is a group of formula (b).

In another aspect of the invention, R<3> together with R2 is a group of formula (c).

R<2> is preferably a group of formula (b).

R<3> is most advantageously hydrogen, halogen, alkyl or alkoxy.

R 3 is preferably hydrogen.

R 4 can suitably be hydrogen, alkyl, hydroxyalkyl, phenylalkyl, benzyloxyalkyl or cycloalkyl.

When R4 is alkyl, especially alkyl, examples include ethyl and butyl, especially n-butyl.

When R4 is hydroxyalkyl, an example is hydroxypropyl.

When R4 is aralkyl then phenylpropyl is an example.

When R4 is arylalkyloxyalkyl then benzyloxyethyl is an example.

R 4 can advantageously be hydrogen or alkyl, then especially hydrogen.

When R 5 is substituted alkyl, then suitable substituents can be chosen from hydroxy, alkoxy and aryl alkoxy.

R 5 can suitably be hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkyloxy or cycloalkyloxy, especially hydroxy, hydroxyalkyloxy or arylalkyloxy.

When R<5> is alkoxy, then especially alkoxy, then ethoxy and n-butoxy are examples.

When R<5> is arylalkyloxy, phenylpropyloxy is an example.

When R<5> is arylalkyloxyalkyloxy then benzyloxypropyloxy is an example.

In the hydroxyalkyloxy group represented by R<5>, a suitable hydroxy group can be substituted on the terminal carbon atom in the alkyl group, for example as in a 2-hydroxyethyloxy group and a 3-hydroxypropyloxy group.

R<5> is preferably hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl.

When R<5> is cycloalkyl, cyclohexyl is an example.

R<5> is preferably alkyl, for example n-hexyl. R<5> is further preferably aryl, for example phenyl.

When R<5> is alkyl, n-hexyl is an example.

R 4 is preferably alkyl, then especially C 14 , for example ethyl, and R<5> is alkoxy, then especially alkoxy, for example ethoxy.

In another aspect, R4 is alkyl, for example ethyl, while R<5> is hydrogen.

X is preferably 0.

One aspect of the present invention provides a subset of the compounds of formula (I) wherein R°, R<1>, R<1a>, R2, R<3> and X are as defined in relation to formula (I), provided that formula (I) does not include 4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetic acid and its salts and esters, or 4-[2-[2-hydroxy-3-phenoxypropylamino]ethyl ]phenoxyacetic acid and an amide of this compound.

In another aspect of the invention there is provided a subgroup of compounds of formula (I) where R° and X are as defined in relation to formula (I), R<2> is OCH 2 CO 2 H or an ester or an amide of this group, R<3> is hydrogen while R1, R1<a> are as defined in relation to formula (I), provided that at least one of R<1> and R<1a> is alkyl.

One particular aspect of the invention provides a subgroup of compounds of formula (I) wherein R°, R<1>, R<1a> and X are as defined in relation to formula (I), while R<2> is a group of formula (b) and R<3> is hydrogen, halogen, alkyl or alkoxy, or R<3> together with R<2> is a group with formula (c), and such compounds will be referred to subsequently as compounds with formula (IA).

The compounds with formula (I) have one or two asymmetric carbon atoms marked with an asterisk (<*>) or two stars (<**>) in the formula. These compounds can therefore exist in up to four stereoisomeric forms. The present invention includes all stereoisomeric forms of compounds of formula (I) whether they are free from other isomers or mixed with other isomers in any proportion, for example mixtures of diastereoisomeric forms and racemic mixtures of enantiomers.

In addition to this, there is the fact that when the substituents on the phosphorus atom in group (b) are different and different from OH, then the phosphorus atom will also be chiral. The invention also relates to mixed and separated isomers of such compounds in the same manner as mentioned above with respect to the chiral carbon atoms.

The asymmetric carbon atom indicated by a single asterisk (<*>) is preferably in the S configuration.

The asymmetric carbon atom indicated by two asterisks (<**>) is preferably in the R configuration.

A suitable form of a compound of formula (I) is a mixture of the SR and RS enantiomers.

A favorable form of a compound of formula (I) is the SR enantiomer.

By the term "alkyl" when used alone or when it is part of other groups (for example, as in an "alkoxy group"), this includes straight or branched alkyl groups of from one to 12 carbon atoms, preferably one to six carbon atoms, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or a tert-butyl group.

The term "cycloalkyl" includes C3.8 cycloalkyl groups, especially C5 or C6 cycloalkyl groups.

The term "halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

The term "sulfonamido" means the group "-SOyNH-," so for example the methylsulfonamido group denotes "CH3-S02-NH-".

Suitable pharmaceutically acceptable esters of the carboxyl group include alkyl esters, especially C 1-6 alkyl esters such as methyl.

Suitable pharmaceutically acceptable amides are those of the formula -CONRsR1 where Rs and R<1> independently of each other are 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 according to the present invention.

Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, or sulfuric acid, or with organic acids such as methanesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, malic acid or acetylsalicylic acid.

Suitable pharmaceutically acceptable salts of carboxy groups, phosphonic acid or phosphinic acid groups include metal salts such as aluminum, 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 alkylamines such as triethylamine, hydroxy-C₁ alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloamines such as bicyclohexylamine, or with procaine, 1,4-dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabiethylamine , N,N'-bisdehydroabiethylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.

Suitable pharmaceutically acceptable solvates are commonly known solvates, preferably hydrates.

In another aspect, the invention also relates to a method for producing a compound of formula (I) or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable solvate of such a compound, which includes reacting a compound of formula (II):

where X is as defined in relation to formula (I), and R<0>' is R° as defined in relation to formula (I) or a protected form thereof, with a compound of formula (III): where R< 1>, R<1a>, R2 and R<3> are as defined in relation to formula (I) and T° is a hydrogen atom or a protecting group; after which, as required, one or more of the following optional steps are carried out: (i) converting a compound of formula (I) into another compound of formula (i); (ii) removes any protecting groups; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate.

The reaction between the compounds (II) and (III) can be carried out in any suitable solvent such as methanol, at any temperature which gives a suitable production rate with regard to the desired product, generally an elevated temperature such as the boiling point of the solvent is used ; preferably under an inert atmosphere such as nitrogen or argon, or alternatively the reaction between the compounds of formula (II) and (III) can be carried out in a chlorinated solvent such as dichloromethane, or in an aprotic solvent such as acetonitrile; and 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<0>' is a protected form of R°, and where suitable protected forms are as defined herein.

Suitable protecting groups represented by T° are benzyl or p-methoxybenzyl groups.

A compound of formula (II) can be prepared by reacting an activated form of a compound of formula (IV): where R<0>' and X are as defined in relation to formula (II), with a compound of formula ( V):

where L° represents a leaving group.

A specifically activated form of a compound of formula (IV) is an ionic form, for example an alkali metal salt form, for example a potassium salt form.

An activated form of a compound of formula (IV) can be prepared using commonly known methods, for example the salt form can be prepared by treating the compound of formula (IV) with a base such as an alkali carbonate, for example potassium carbonate.

L° preferably represents a tosylate or a 3-nitrobenzenesulfonyloxy group.

The reaction between the compounds of formula (IV) and (V) can be carried out in an aproic solvent such as acetone or dimethylformamide at any temperature which gives a suitable rate of production of the desired product, usually at room temperature to an elevated temperature, preferably an elevated temperature such as for example the boiling point of the solvent.

L° can also stand for OH.

When L° is OH, then the compound of formula (V) is oxyranyl methanol, and the reaction between this and the compound of formula (IV) can conveniently be carried out using a Mitsunobu reaction by means of the methods described in Tetrahedron Letters, 1994 35, 5997-6000 and Organic Reactions 1992, 42, 335-656.

A compound of formula (III) where R<1> is different from hydrogen can suitably be prepared by a hydrogenolysis of a compound of formula (VI):

where R<1>, R<2>, and R<3> are as defined in relation to formula (I), Y is hydrogen or a group -B(OH)2 and **CH carbon and<***> The CH carbon atoms are chiral carbon atoms.

Suitably, one can use catalytic hydrogenolysis, for example by using 10% palladium on charcoal in the presence of ammonium formate, preferably in an alkanol solvent such as methanol, at any temperature which gives an appropriate production rate of the desired product, for example room temperature; and preferably the reaction is carried out in an inert atmosphere, usually under nitrogen.

A compound of formula (VI) where Y is the group B(OH)2 can be prepared from a corresponding compound of formula (VI) where Y is H; by treating this with boron tribromide in an inert solvent such as methylene chloride at room temperature, preferably in an inert atmosphere, for example argon, after which Y is removed by using catalytic hydrogenolysis, for example by using palladium on carbon.

A compound of formula (VI) where Y is H can be prepared by a stereoselective reduction of a compound of formula (VII):

where R<1>, R2 and R3 are as defined in relation to formula (I), and the<***>C carbon atom is a chiral carbon atom.

The reduction of the compound of formula (VII) can be carried out using catalytic reduction in the presence of hydrogen.

A preferred catalyst is platinum oxide.

Suitable reducing conditions include the use of an alkanol solvent such as methanol or ethanol, at any temperature which provides a suitable rate of production of the desired product, preferably at room temperature using a hydrogen pressure of from 1 to 5 atmospheres.

The compound of formula (VII) can be prepared by reacting a compound of formula (VIII):

where R<1>, R2 and R<3> are as defined in relation to formula (I), with R-α-methylbenzylamine.

The reaction between the compounds of formula (VIII) and R-α-methylbenzylamine can be carried out under commonly known amination conditions, for example in a solvent such as methanol or toluene.

Conveniently, the compound of formula (VII) can be prepared in situ by reacting a compound of the above formula (VIII) with R-α-methylbenzylamine and then reducing the compound of formula (VII) using reaction conditions and catalysts as described above.

The compounds of formula (VIII) wherein R<2> is OCH2CO2H or an amide or a

ester of such a group, or where R<2> is a group as defined above in formula (b) where R<5> is hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy, or where R<5> together with OR4 is 0(CH2 )nO, are known compounds, or they can be prepared by methods which are analogous to those used for the preparation of such compounds, and they can, for example, be prepared using the methods described in European patent application publication no. 0023385 or International Application No. WO 94/02493.

A compound of formula (VIII) where R<2>is a group as defined by formula (b) where R<5>is hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl, can be prepared by reducing a compound of formula ( IX):

where R<1> and R<3> are as defined in relation to formula (I), and where R<2> is as defined in relation to the desired compounds of formula (VIII).

The reduction of the compound of formula (IX) can conveniently be carried out using iron powder in the presence of acetic acid in an aqueous solvent such as aqueous methanol and the reaction can take place at any temperature which gives a suitable production rate of the desired product, usually at an elevated temperature, and most appropriate at the boiling point of the solvent.

A compound of formula (IX) can be prepared by reacting a compound of formula (X):

where R<2> and R<3> are as defined in relation to formula (IX), with a nitroalkane, for example nitromethane or nitroethane.

In general, the carbon atom in the -CHO group in the compound of formula (X) will be in an activated form, and a suitable active form can be provided by forming an imine of said carbonyl group. The imine can be prepared by reacting the compound of formula (X) with an amine, preferably a primary alkylamine such as n-butylamine. The reaction between the compound of formula (X) and the amine can be carried out in a separate solvent, for example toluene, at a temperature which gives a suitable production rate of the desired product, usually at a temperature elevated as the boiling point of the solvent; and preferably in the presence of a catalytic amount of toluenesulfonic acid.

The reaction between the compound of formula (X) and when this is in the form of an imine, and the nitroalkane can be carried out in glacial acetic acid, preferably in the presence of an ammonium acetate catalyst, usually at an elevated temperature, for example between 60°C and 120°C, most suitable at about 100°C.

A compound of formula (X) can be prepared from a compound of formula

(XI):

where R<3> is as defined in relation to formula (IX) and L° is a leaving group or atom, usually a fluorine atom, with an activated form of a compound of formula (XII):

where R<4> and R<5> are as defined in relation to formula (I).

A suitable activated form of a compound of formula (XII) is an ionic form, for example a salt form, for example an alkali metal salt form.

An activated form of a compound of formula (XII) can be prepared using suitable methods known in the art, for example a salt form can 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 formula (XI) and (XII) can be carried out in any suitable solvent, usually an aprotic solvent such as dimethylformamide or N-methylpyrrolidinone at a low to room temperature, for example in the range from -15°C to 20°C, for example at 5°C.

Compounds of formula (III) where R<2> and R<3> form a group as defined by formula (c) or an ester or an amide of such a group can be prepared from a protected form of a subgroup of compounds of formula (III) with formula

(XIII):

where R<1> and R<1a> are as defined in relation to formula (I), and T<1> is a protecting group, for example a t-butoxycarbonyl group, by reaction with a compound of formula (XIV):

wherein L<1> and L<2> are each a leaving group or atom, suitably a halogen atom such as bromine, and T2 and T<3> are each a protecting group; after which any protective groups are removed as required.

Suitable are T2 and T<3> each an alkoxy group, for example an ethoxy group. The compound of formula (XIII) is preferably in an activated form.

A suitable activated form of a compound of formula (XIII) is an ionic form, for example an alkali metal salt form, for example a potassium salt form.

An activated form of a compound of formula (XIII) can be prepared using conventional methods known in the art, and for example a salt form can 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, for example an anionic form. The activated form can conveniently be prepared in situ before adding the compound of formula (XIV).

The reaction between the compounds of formula (XIII) and (XIV) can be carried out in an aprotic solvent, for example acetone, at any temperature which gives a reasonable rate of production of the desired product, but usually takes place at an elevated temperature, for example the boiling point of the solvent , and preferably in . 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 can be prepared by methods used for the preparation of known compounds, for example those described in J. Med. Chem. 1973,16(5), 480.

The compounds of formula (XIV) are known commercially available compounds.

Compounds of formula (III) where R<2> is OCH2C02H or an ester or an amide of this group or a group of the above-mentioned defined formula (b), and R<3> is hydrogen, halogen, alkyl or alkoxy, can conveniently be prepared from a protected form of a subgroup of compound of formula (III) having formula

(XV):

where R1, R1a, R<3> and V are as defined in relation to formula (XIII):

a) for compounds of formula (III) where R<2> is OCH2C02H or an ester or an amide of such a group, by reacting a compound of formula (XVI):

where l_<3> is a leaving group, suitably a halogen atom such as a bromine atom, and T4 is a protecting group; or b) for compounds of formula (III) where R<3>is a group of the above-mentioned formula (b), by a reaction with a compound of formula (XVII):

wherein R<4> and R<5> are as defined in relation to formula (I), and L<4> is a leaving group or an atom; and then, if necessary, removing any protecting groups.

T<1> is suitably a t-butoxycarbonyl group.

T4 is suitable an alkoxy group, for example a methoxy group.

L4 is suitably a tosylate group, a 4-chlorobenzenesulfonyloxy group or a 3-nitrobenzenesulfonyloxy group.

In the above reactions, the compound of formula (XV) is usually in an activated form, for example an anionic form. The activated form can conveniently be prepared in situ before adding the compounds of formula (XVI) or (XVII).

It is preferred that the activated form of the compound of formula (XV) is prepared by reacting the compound of formula (XV) with a base such as sodium hydride.

Reaction between the compounds of formula (XV) and (XVI) can suitably be carried out in an aprotic solvent such as acetone, at any temperature which gives a reasonable production rate of the desired product, usually at an elevated temperature, for example the boiling point of the solvent, preferably in presence of a base such as potassium carbonate and preferably under an inert atmosphere of argon.

The reaction between the compounds of formula (XV) and (XVII) is carried out in an aprotic solvent, for example dimethylformamide or dimethylsulfoxide at a temperature which gives a satisfactory reaction rate, suitably at room temperature.

The compounds of formula (XV) where R<1> and R<1a> are each hydrogen are known compounds which can be prepared by methods used for the preparation of such compounds, for example as described for such compounds when T<1> is t -butoxycarbonyl in Can. J. Chem. 1985, 63, 153.

The compounds of formula (XV) where neither R1 nor R<1a> is hydrogen can be prepared by a hydrogenolysis of a compound of formula (XIX):

where R<1>, R<3>, Y and<**>CH and<***>CH the carbon atoms are as defined 1 relation to formula (VI).

The hydrogenolysis of the compounds of formula (XIX) is carried out under analogous conditions as indicated for the hydrogenolysis of compounds of formula (VI).

The compounds of formula (XIX) wherein Y is a group -B(OH) 2 can be prepared from compounds of formula (XIX) wherein Y is H using analogous procedures to those described above for compounds of formula (VI) wherein Y is the group -B(OH)2.

The compounds of formula (XIX) where Y is H are known compounds, or can be prepared using methods analogous to those used to prepare known compounds, for example as described in J. Med. Chem. 1973, 16(5), 480.

A compound of formula (XVII) can be prepared by a hydroxymethylation of a compound of formula (XX):

where R<4> and R<5> are as defined in relation to compounds of formula (I), giving a compound of the above defined formula (XII); after which the prepared compound is reacted with a source for the leaving group L<4>.

The hydroxymethylation is carried out using formaldehyde, usually in the form of paraldehyde, using commonly known methods depending on the exact nature of the substrate, for example as described in Houben-Weyl in Phosphor Verbindungen p. 28, J. Amer. Chem.-Soc. 1955, 77, 3522, Phosphorus and Sulfur 1978, 5, 455 or in Aust. J. Chem. 1979, 32, 463.

The conditions used in the reaction between the hydroxymethylated compound of formula (XII) and the source for the deplating group will depend on the group L<4>, but common known conditions can be used. When, for example, L<4> is a 4-chlorobenzenesulfonyloxy group, the method described by J. Cornforth et al (J.C.S. Perkin I, 1994, 1897) can be used.

A compound of formula (I) where R<1a> is hydrogen or a pharmaceutically acceptable salt or an ester or an amide thereof, or a pharmaceutically acceptable solvate of this compound, can also be prepared by reducing a compound of formula (XXI ):

where R°, R<1>, R<3> and X are as defined in relation to formula (I), and R<2>' is as R<2> in relation to formula (I) or a protected form of this, after which, if necessary, one or more of the following possible steps are carried out: (i) converting a compound of formula (I) into another compound of formula (I);

(ii) removes any protecting groups; and

(iii) prepares a pharmaceutically acceptable salt, ester or amide of such a compound of formula (I) or one of its pharmaceutically acceptable solvates.

The reduction of the compound of formula (XXI) can be carried out using suitable reduction methods, for example using catalytic reduction.

Suitable catalysts include platinum oxide or 10% palladium on charcoal.

Suitable reduction conditions include using an alkanol solvent such as ethanol at any temperature which gives a suitable reaction rate with respect to the desired product. When, for example, a platinum catalyst is used, the reaction can conveniently be carried out at room temperature, or when the palladium catalyst is used, the reaction can be carried out at temperatures around 50°C at a hydrogen pressure of between 1 and 5 atmospheres.

For compound of formula (I) where R<2> is a group of the above defined formula (b) and R<2>' is a protected form of R<2>, for example a benzylated form, then this benzylated form can be removed using hydrogenolysis with ammonium formate in the presence of a 10% palladium on carbon catalyst.

The compounds of formula (XXI) can be prepared by reacting a compound of formula (XXII):

where R<0>' and X are as defined in relation to formula (II), with a compound of formula (VIII).

The reaction between these compounds can be carried out in a commonly known manner for amination, for example in a solvent such as toluene or preferably methanol.

Conveniently, the compound of formula (XXI) can be prepared in situ by

one reacts compounds of the above formulas (VIII) and (XXII) under reductive amination conditions, which includes a reaction in an alkanol solvent such as methanol, in the presence of a suitable reducing catalyst, for example of the type described above for the reduction of the compound with formula (XXI).

The present invention further provides a method for

preparation of a compound of formula (I) or a pharmaceutical thereof

acceptable salts or acceptable solvates, characterized by reacting a compound of formula (XXIII):

where R<1>, R<1a> and X are as defined in relation to formula (I), R<0>'s as defined in relation to formula (II), T<5>is a protecting group, R< 2a>is R2 or a group or atom that can be converted to R<2>, and R<3a>is R<3>or a group that can be converted to R<3>, where R<2>and R3 both are as defined in relation to formula (I), with a reagent capable of converting R<2a> to R2 and/or a reagent capable of converting R33 to R<3>; then, if desired, performing one or more of the optionally following steps: (i) converting a compound of formula (I) into another compound of formula (I); (ii) removes any protecting groups; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or one of its pharmaceutically acceptable solvates.

When R<3> in the desired compound of formula (I) is hydrogen, halogen, alkyl or alkoxy, then R<3a> is suitable as R<3>.

Similarly, when R3 together with R<2> in the desired compound of formula (I) is a group of the above formula (c) or an amide or an ester thereof, then R<2a> and R3a are both OH.

When R2a and R<3a> are both OH, then these can suitably be converted into a group of formula (c) by treating the compound of formula (XXIII) with a compound of formula (XIV), after which, if desired, an ester or an amide of the resulting compound of formula (I).

The reaction conditions for the reaction between the compounds of formula (XXIII) and (XIV) are analogous to those described for the reaction between the compounds of formula (XIII) and (XIV).

When R<2> in the desired compound of formula (I) is OCH2CO2H or an ester or an amide thereof, then R<2a> is preferably an OH group.

When R<2a> is OH, the compound of formula (I) where R2 is OCH2CO2H or an ester or an amide thereof can be prepared by reacting a compound of formula (XXIII) with a compound of formula (XVI).

The reaction conditions in this reaction are analogous to those described for the reaction between the compounds of formula (XV) and (XVI).

When R<2> in the desired compound of formula (I) is a group as mentioned above with formula (b), then R<2a> is suitably an OH group.

When R<2> is OH, a compound of formula (I) where R<2> is a group of formula (b) can be prepared by reacting a compound of formula (XXIII) with a compound of formula (XVII) .

The reaction conditions for the reaction between the compounds of formula (XXIII) and (XVII) are analogous to those described for the reaction between the compounds of formula (XV) and (XVII).

The compounds of formula (XXII) are known compounds or can be prepared by methods used for the preparation of known compounds, for example of the type described in Swiss patent no. 1549945 (1976).

The compounds of formula (XXIII) can be prepared by commonly known methods depending on R2a and R3a. When, for example, R2a and R3 are both

OH, or when R<2a> is OH and R<3a> is hydrogen, halogen, alkyl or alkoxy, they can be prepared by reacting a compound of formula (II) with a compound of formula (XIII) or (XV ) as desired, using conditions analogous to those used for a reaction between the compounds of formula (II) and (III).

Compounds of formula (III) include those of formula (XIII) and (XV) where R<1> and R<1a> independently of each other are alkyl, are known compounds or can be prepared by methods used for the preparation of known compounds , for example as described 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 can be prepared by means of published and known methods, or by using methods analogous to these, for example of the type described in 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 can be prepared by methods analogous to those used to prepare known compounds, for example, compounds of formula (XII) can be prepared using methods described in Phosphorus and Sulphur, 1978 , 5, 455.

Suitable conversions of a compound of formula (I) into another compound of formula (I) include converting the group OR4 into another group OR<4> and/or converting a group R<5> into another group R< 5>, or when R<2> is OCH2CO2H or an ester or an amide thereof, one R2 converts to another R<2>; or when R3 together with R2 is the group as defined by formula (a) or an ester or an amide thereof, converts one (a) into another (a).

Suitable conversions of one group OR<4> to another group OR<4> include: (i) converting OR4 as hydroxy to OR<4> as alkoxy; (ii) converts OR 4 as alkoxy to OR 4 as hydroxy;

(iii) converts OR 4 as alkoxy to OR 4 as another alkoxy group.

The above-mentioned conversions (i) can be carried out using commonly known phosphonate alkylation methods, for example using a suitable alcohol (R<4>OH) in the presence of hydrogen chloride, alternatively a suitable alcohol can be used together with benzotriazol-1-yloxy-tris -(dimethylamino)phosphonium hexafluorophosphate in dimethylformamide in the presence of diisopropylethylamine.

The above-mentioned conversions (ii) can be carried out using the commonly known phosphonate hydrolysis method, for example by treating the compound of formula (I) with an alkali metal hydroxide, for example sodium hydroxide.

The above-mentioned conversion (iii) can be carried out by first converting OR<4> as alkoxy to OR4 as hydroxy using the conditions indicated for the above-mentioned conversion (ii), after which converting the produced hydroxy group into another alkoxy group using the conditions specified for the conversion (i).

The above-mentioned transformation (iii) can in particular be used for the preparation of compounds of formula (I) where OR4 is methoxy, and such compounds will usually be prepared from compounds of formula (I) where OR<4>is an alkyloxy group different from methoxy (for example ethoxy), by first hydrolysing the relevant OR<4> group (via conversion to (ii)), which gives a compound of formula (I) where OR<4> is hydroxy, after which a methylation is carried out (via conversion (i)), giving the desired compound wherein OR<4> is methoxy.

Suitable conversions of a group R<5> to another group R<5>, when R<5> is hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkyloxy or cycloalkyloxy, include conversions analogous to those mentioned above with respect to to convert a group OR4 into another group OR<4>.

When R<2> is OCH2C02H or an ester or an amide thereof, then suitable conversions of one R<2> to another R2 will include converting OCH2C02R<e>where CO2Re is an ester, to OCH2C02H, by conventional means carboxylic acid hydrolysis, for example using basic hydrolyses with sodium hydroxide in an aprotic solvent such as 1,4-dioxane at room temperature, preferably in an inert atmosphere such as argon. Other suitable conversions include carrying out an internal conversion of the respective acids, esters and amides, and such conversions can be carried out by suitable commonly known methods of the type described here.

When R<3> together with R<2> represents a group of formula (a) or an ester or an amide thereof, then suitable conversions of one (a) into another (a) include a hydrolysis of esters to acids by to use commonly known methods, for example by treating the ester with lithium hydroxide in dioxane or methanol at room temperature, preferably under argon. Other suitable conversions include carrying out an internal conversion of the respective acids, esters and amides using commonly known methods of the type described here.

The protection of any reactive groups or atoms can be carried out at any suitable time in the aforementioned methods. Suitable protecting groups include those commonly used in organic chemistry with respect to the particular group or atom to be protected. Protecting groups can be produced and removed using commonly known methods, thus for example OH groups, and this includes diols, can be protected as silylated derivatives by treatment with a suitable silylating agent, for example di-tert-butylsilylbis(trifluoromethanesulfonate): the silyl group can then removed by

use a commonly known method, for example by treatment with hydrogen fluoride, preferably in the form of a pyridine complex. Alternatively, benzyloxy groups can be used to protect phenoxy groups, after which the benzyloxy group can be removed using catalytic hydrogenolysis, for example using catalysts such as palladium (II) chloride or 10%

palladium on carbon.

Amino groups can be protected by using any commonly known protective agent

group, for example tert-butyl esters of carbamic acid can be prepared by treating the amino group with di-tert-butyl dicarbonate, after which the amino group can be regenerated by hydrolysing esters under acidic conditions, for example using hydrogen chloride in ethyl acetate or trifluoroacetic acid in methylene chloride.

The amino group can also be protected as an aminoboric acid prepared from the relevant amine and boron tribromide followed by a work-up with ice water. The aminoboric acid can be removed using catalytic hydrogenolysis, for example

by using a palladium on carbon catalyst. In addition, the amino group can be protected as a benzyl derivative prepared from the relevant amine and a benzyl halide under basic conditions, after which the benzyl group can be removed by catalytic hydrogenolysis by using, for example, a palladium on carbon catalyst.

A leaving group or atom is any group or atom that wants to sub

the relevant reaction conditions are cleaved from the starting compound, and will thus promote a reaction in a specified position. Suitable examples of such groups if nothing else is indicated are halogen atoms, mesyloxy groups and tosyloxy groups.

The salts, esters, amides and solvates of the compounds mentioned here,

can be produced by methods which are known per se. For example, acid addition salts can be prepared by treating a compound of formula (I) with a suitable acid.

Esters of the carboxylic acids can be prepared by usual esterification methods, for example alkyl esters can be prepared by treating the relevant carboxylic acid with a suitable alkanol usually under acidic conditions.

The amides can be prepared using common known amidation methods, for example amides of the formula CONR<s>R' can be prepared by treating the relevant carboxylic acid with an amine of the formula HNR<s>R<l>, where Rs and R1 are as defined above. Alternatively, an alkyl ester, for example a methyl ester of the acid, can be treated with an amine of the above defined formula HNR<S>R', giving the desired amide.

Compounds of formula (I) and their pharmaceutically acceptable acid addition salts or their pharmaceutically acceptable solvates prepared by the above-mentioned methods can be recovered in a commonly known manner.

If necessary or desirable, mixtures of the isomers of the compounds according to the present invention can be separated into their individual stereoisomers and diastereoisomers by commonly known methods, for example by using an optically active acid as a solvent. Suitable optically active acids which can be used as solvents are described in "Topics in Stereochemistry", vol.6, Wiley Interscience, 1971, Allinger, N.L and Eliel, W.L. ed.

Alternatively, each enantiomer of a compound according to the invention can be prepared by a stereospecific synthesis using optically pure starting compounds of known configuration.

The absolute configuration of the compounds can be determined by conventional X-ray crystallography techniques.

As mentioned earlier, it has been discovered that compounds of formula (I) have valuable pharmacological properties.

The present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt or solvate of such a compound, which can be used as an active therapeutic substance.

In one aspect, the invention provides a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates for use in the treatment of hyperglycemia in humans and animals.

Furthermore, the invention provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt or solvate of such a compound, for use in the treatment of obesity in both animals and humans.

In addition, the invention provides a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates which can be used for the treatment of intestinal diseases such as peptic ulcer, oseophagitis, gastritis and duodenitis, peptic ulcer, and this includes inflammatory disorders and diseases and the so-called irritable bowel syndrome, and further for the treatment of bleeding peptic ulcers, especially when these are induced by non-steroidal anti-inflammatory drugs or corticosteroids.

Furthermore, the invention provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt or solvate of such a compound, which can be used to increase the high-density lipoprotein (HDL) cholesterol concentration and decrease the triglyceride concentration in human blood serum, especially when treating and /or prophylaxis with respect to atherosclerosis and in the treatment of hyperinsulinemia or depression.

A compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates can be used as such, or preferably as a pharmaceutical preparation which also contains a pharmaceutically acceptable carrier.

The present invention accordingly provides a pharmaceutical preparation or a mixture containing a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable" means compounds, mixtures and components both for humans and animals, and thus a term such as "pharmaceutically acceptable salt" will also include a veterinary acceptable salt.

The preparation can, if desired, be in the form of a package followed by written or printed instructions for use.

Generally, pharmaceutical preparations according to the present invention will be adapted for oral use, although the preparations can also be administered in another way, for example by injection.

Particularly suitable preparations for oral use are unit dose forms such as tablets and capsules. You can also use other fixed unit dose forms, for example powder in small bags.

In accordance with common pharmaceutical practice, the carrier may include a diluent, filler, disintegrant, wetting agent, lubricant, coloring agent, flavoring agent or other commonly known additives.

Typical carriers will include, for example, microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate and sodium lauryl sulfate.

Most suitable, the preparation will be prepared in a unit dose form. Such unit doses will normally contain an amount of the active ingredient from 0.1 to 1000 mg, more commonly from 2 to 100 mg or from 0.1 to 500 mg, more particularly from 0.1 to 250 mg.

The present invention further provides a method for the treatment of hyperglycemia in both animals and humans which comprises administering an effective, non-toxic amount of a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates, to a human or a animals suffering from hyperglycaemia and in need of said treatment.

The present invention further provides a method for the treatment of obesity or for the treatment and/or prophylaxis of atherosclerosis in humans and animals, which comprises administering an effective non-toxic amount of a compound of formula (I) or one of its pharmaceutically acceptable acid addition alters or solvates to a human or an animal in need of this.

Furthermore, the invention provides a method for the treatment of intestinal disorders and diseases such as peptic ulcers, oseophagitis, gastritis and duodenitis, peptic ulcers and this includes inflammatory disorders and the so-called irritable bowel syndrome, and further for the treatment of bleeding peptic ulcers, especially when this is induced by non-steroidal anti-inflammatory medicinally active compounds or corticosteroids, both in animals and humans, comprising administering to an animal or human an effective, non-toxic amount of a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates need for this.

Furthermore, the present invention provides a method for increasing the concentration of high-density lipoprotein (HDL) cholesterol concentration and for decreasing the triglyceride concentration in human blood serum, especially in the treatment and/or prophylaxis of atherosclerosis, and for the treatment of hyperinsulinemia or depression both in animals and humans, which involves administering an effective, non-toxic amount of a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates to a human or animal in need thereof.

The present invention also provides the use of a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates for the preparation of a drug or preparation for the treatment of: hyperglycemia, obesity, gastrointestinal diseases such as peptic ulcers, oseophagitis, gastritis and duodenitis, bleeding stomach ulcers and this includes inflammatory stomach diseases and the so-called irritable stomach syndrome and for the treatment of bleeding stomach ulcers, especially when this is induced by non-steroidal anti-inflammatory drugs or corticosteroids, to increase the high-density lipoprotein (HDL) cholesterol concentration and decrease the triglyceride concentration in human blood serum, then especially in the treatment and/or prophylaxis of atherosclerosis and for the treatment of hyperinsulinemia or depression.

Appropriately, the active ingredient can be supplied as a pharmaceutical preparation as defined above, and this constitutes a special aspect of the invention.

When treating hyperglycaemic or obese patients can

the compound of formula (I) or one of its pharmaceutically acceptable salts, esters or amides or solvates, is taken in doses, for example of the type described above, from one to six times per day in such a way that the total daily dose for a 70 kg patient will generally range from 0.1 to 6000 mg, more commonly from 1 to 1500 mg.

The treatment regime for the treatment of the above-mentioned diseases of the digestive system, atherosclerosis, hyperinsulinaemia and depression is essentially as described for hyperglycaemia.

When treating animals, especially dogs, the active ingredient can be administered orally, usually once or twice a day in an amount of between 0.025 mg per kg to 25 mg per kg, for example from 0.1 mg per kg to 20 mg per kg.

In another aspect, the invention also provides a method for improving the weight gain and/or improving the utilization effect and/or increasing the body mass of emaciated individuals and/or reducing the birth mortality and increasing the survivability after birth in domestic animals, and where said method includes that the domestic animals are supplied with an effective non - toxic amount of a compound of formula (I) or a veterinary acid addition salt of such a compound or a veterinary acceptable solvate.

Although the compound of formula (I) and their veterinary acceptable acid addition salts and solvates can be used in connection with any type of livestock in the above method, they are particularly well suited to improve weight gain and/or utilization and body mass in emaciated individuals and/or improve mortality at birth and increase survival after birth, in poultry, particularly turkey and chicken, cattle, pigs and sheep.

In the preceding method, the compounds of formula (I) or their veterinary acceptable acid addition alters will normally be administered orally, although said compounds can also be administered via injection or implantation. Suitably, the compounds can be supplied via the feed or in the drinking water supplied to the livestock. Appropriately, these can be added to the feed in amounts of from 10-<3>ppm to 500 ppm per daily feed intake, usually between 0.01 ppm to 250 ppm, suitably less than 100 ppm.

The special preparations used will of course depend on which route of administration is used, but will be those that are usually used for the specified routes of administration. For use in for, the aforementioned active ingredients will usually be prepared as a premix together with a suitable carrier or diluent.

The present invention therefore also provides a livestock-acceptable premix containing a compound of formula (I) or one of its veterinary-acceptable acid addition salts or solvates, together with a veterinary-acceptable carrier or diluent.

Suitable carriers are inert common agents such as powdered starch. You can also use other carriers of the type used in various premixes.

No unacceptable toxicological effects are expected when compounds according to the present invention are used as described here.

The following examples and methods illustrate the invention without it being limited to these.

Method 1: (S)-Glycidyl-2-benzyloxyphenol

A mixture of 2-benzyloxyphenol (900 mg, 4.5 mmol) and potassium carbonate (1.87 g, 13.5 mmol) in 45 mL of acetone was refluxed for 15 minutes. (S)-glycidyl-3-nitrobenzenesulfonate (1.0 g, 4.5 mmol) was added to the reaction mixture which was then refluxed for 23 hours. After cooling, the mixture was filtered and the solvent 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.

8<1>H (270MHz, CDCl3): 7.36 (5H, m), 6.88 (4H, m), 5.10 (2H, s), 4.26 (1H, dd, J=11, 4, 3.3Hz), 4.20 (1H, dd, J=11.4, 5.5Hz), 3.36 (1H, m), 2.85 (1H, dd, J=5.0, 4 .1 Hz), and 2.73 (1H, dd, J=5.0, 2.5Hz) ppm.

Method 2: (S,R)-methyl-4-[2-[2-hydroxy-3-(2-benzyloxyphenoxy)propylamino]propyl]phenoxyacetate

A mixture of (S)-glycidyl-2-benzyloxyphenol (666 mg, 2.59 mmol) and (R)-methyl-4-(2-aminopropyl)phenoxyacetate (501 mg, 2.25 mmol) in methanol (15 mL ) was refluxed under argon for 24 h. 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 from 0 to 10% methanol in dichloromethane to give the title compound as an oil.

8<1>H (270MHz, CDCI3): 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.

Method 3: (S,R)-methyl-4-[2-[2-hydroxy-3-(2-hydroxyphenoxy)-propylamino]propyl]phenoxyacetate

(S,R)-methyl-4-[2-[2-hydroxy-3-(2-benzyloxyphenoxy)

propylamino]propyl]phenoxyacetate (270 mg, 0.56 mmol) was dissolved in 40 ml of methanol and then palladium on charcoal (5%, 40 mg) was added, after which the mixture was hydrogenated at room temperature and pressure for 18 hours. The suspension was filtered through a cake of a filter aid, after which the filter cake was washed with methanol and the combined filtrates were then evaporated, giving a dark residue. Purification of this by column chromatography and elution with from 0 to 10% methanol in dichloromethane gave the title compound as an oil.

6<1>H (270MHz, CDCl3): 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, J6.1Hz) ppm.

Method 4: (S)-glycidyl-3-benzyloxyphenol

A mixture of 3-benzyloxyphenol (900 mg, 4.5 mmol) and potassium carbonate (1.87 g, 13.5 mmol) in 45 mL of acetone was refluxed for 15 minutes.

(S)-glycidyl-3-nitrobenzenesulfonate (1.0 g, 4.5 mmol) was added and the reaction mixture was refluxed for 23 h. After cooling, the mixture was filtered and the solvent 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.

5<1>H (270MHz, CDCI3): 7.25 (5H, m), 7.15 (1H, m), 6.50 (3H, m), 5.14 (2H, s), 4.10 (1H, dd, J=11.0, 3.3Hz), 3.80 (1H, dd, J=11.0, 5.8Hz), 3.40 (1H, m), 2.80 (1H, dd, J=5.0, 4.1 Hz) and 2.70 (1H, dd, J=5.0, 2.5Hz) ppm.

Method 5: (S,R)-methyl-4-[2-[2-hydroxy-3-(3-benzyloxyphenoxy)propylamino]propyl]phenoxyacetate

A mixture of (S)-glycidyl-3-benzyloxyphenol (580 mg, 2.27 mmol) and (R)-methyl-4-(2-aminopropyl)phenoxyacetate (640 mg, 2.87 mmol) in 15 mL of methanol was refluxed 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, then dried and evaporated. The residue was purified by column chromatography eluting with 0 to 20% methanol in dichloromethane to give the title compound as an oil.

6<1>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.

Method 6: (S,R)-methyl-4-[2-[2-hydroxy-3-(3-hydroxyphenoxy)propylamino]propyl]phenoxyacetate

(S,R)-methyl-4-[2-[2-hydroxy-3-(3-benzyloxyphenoxy)

propylamino]propyl]phenoxyacetate (540 mg, 1.13 mmol) was dissolved in 50 mL of methanol and palladium on charcoal (5%, 75 mg) was added, and the mixture was hydrogenated at room temperature and pressure for 24 h. The suspension was filtered through a cake of a filter medium, after which the filter cake was washed with methanol, and the combined filtrates were then evaporated, giving a dark residue. Purification by column chromatography and elution with from 0 to 20% methanol in dichloromethane gave the title compound as an oil.

6<1>H (270MHz, d<6->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 (1H, m) and 0.92 (3H, d, J=6.0Hz) ppm.

Method 7: (S)-glycidyl-4-benzyloxyphenol

A mixture of 4-benzyloxyphenol (2.0 g, 10 mmol) and potassium carbonate (4.14 g, 30 mmol) in 50 mL of acetone was refluxed for 15 minutes. (S)-Glycidyl-3-nitrobenzenesulfonate (2.23 g, 10 mmol) was added and the reaction mixture was refluxed for 18 h. After cooling, the mixture was filtered and the solvent 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.

5<1>H (270MHz, CDCl3): 7.35 (5H, m), 6.87 (4H, m), 5.01 (2H, s), 4.16 (1H, dd, J=11, 0, 3.3Hz), 3.91 (1H, dd, J=11.0, 5.8Hz), 3.34 (1H, m), 2.89 (1H, dd, J=5.0, 4 ,1 HZ) and 2.74 (1H, dd, J=5.0, 2.8Hz) ppm.

Method 8: (S,R)-methyl-4-[2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino]propyl]phenoxyacetate

A mixture of (S)-glycidyl-4-benzyloxyphenol (330 mg, 1.29 mmol) and (R)-methyl-4-(2-aminopropyl)phenoxyacetate (380 mg, 1.47 mmol) in 15 mL of methanol was boiled under reflux and 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 using from 0 to 15% methanol in dichloromethane, which gave the title compound as an oil.

5<1>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.

Method 9: (S,R)-methyl-4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetate

(S,R)-methyl-4-[2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino]propyl]phenoxyacetate (200 mg, 0.42 mmol) was dissolved in 25 mL of methanol and the mixture was then added 20 mg (5%) palladium on charcoal, after which the mixture was hydrogenated at room temperature and pressure for 18 hours. The suspension was filtered through a cake of a filter medium, after which the cake was washed with methanol, and the combined filtrates were then evaporated, giving a dark residue. Purification of this by column chromatography and elution with 0 to 10% methanol in dichloromethane gave the title compound as an oil.

5<1>H (270MHz, d<6->DMSO/D20): 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.

Method 10: 2,2-di-tert-butyl-4H-1,3,2-benzodioxasilin-6-ol

A mixture of 2,2-di-tert-butyl-6-(benzyloxy)-4H-1,3,2-benzodioxasilylane (2 g, 5.41 mmol) and 50 mg of 10% palladium on charcoal in 20 mL of dichloromethane was hydrogens! at atmospheric pressure. After six hours, the reaction mixture was filtered through a pad of celite, after which the solvent was evaporated to give a clear oil.

8<1>H (250MHz, CDCL3): 6.80 (1H, d, J=8); 6.67 (1H, dd, J=8.1Hz and 2.4Hz); 6.45 (1H, d, J=2.4Hz); 4.90 (2H, s); 1.14 (18H, p).

Method 11: 2,2-di-tert-butyl-6-(benzyloxy)-4H-1,3,2-benzodioxasilynan

Lithium aluminum hydride (0.235 g, 6.2 mmol) was suspended in 25 mL of tetrahydrofuran and cooled to 0°C. 5-Benzyloxy-2-hydroxybenzoic acid methyl ester (2 g, 7.75 mmol) in 10 ml of tetrahydrofuran was then added dropwise via a syringe. The mixture was warmed to room temperature and stirred for 20 minutes. The temperature was then lowered to 0°C, and 0.5 ml of water, 0.5 ml of a 2 M sodium hydroxide solution and 1 ml of water were added gradually and carefully. The resulting mixture was stirred at room temperature for 30 minutes and then filtered. The filtrate was evaporated in vacuo to give 4-benzyloxy-2-hydroxymethylphenol as a clear oil which was used in the next step without further purification.

To a solution of 4-benzyloxy-2-hydroxymethylphenol in 10 mL of chloroform was added 2,6-lutidine (2.49 g, 23.25 mmol) at room temperature under argon. Di-tert-butylsilyl bis(trifluoromethanesulfonate) (4.1 g, 9.3 mmol) was added and the mixture was stirred at room temperature for 18 h. The solvent was evaporated in vacuo and the residue was purified by normal phase column chromatography, and an elution with 50% hexane in ether gave the title product as a pale yellow oil.

8<1>H (250MHz, CDCl 3 ): 7.34-7.48 (5H, m); 6.85 (2H, m); 6.61 (1H, m); 5.0 (2H, s); 4.78 (2H, s); 1.14 (18H, p).

Method 12: (S)-2,2-di-tert-butyl-6-(oxiran-2-ylmethoxy)-4H-1,3,2-benzodioxasilynan

At room temperature and under argon, potassium carbonate (2, 07 g, 15 mmol). (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (1.43 g, 5.5 mmol) was added portionwise and the reaction mixture was refluxed for 48 h. The solvent was then removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 x 15 ml of water. The organic extracts were then dried over sodium sulfate, after which the solvent was evaporated in vacuo. The crude product was purified by chromatography over plain silica eluting with 50% hexane in ether to give (S)-2,2-di-tert-butyl-6-(oxyran-2-ylmethoxy)-4/-/-1 ,3,2-benzodioxasilylane.

8<1>H (250MHz, CDCl3): 6.75-6.90 (2H, m), 6.7 (1H, d, J=2.5Hz); 4.97 (2H, s); 4.16 (1H, dd, J=11, 3Hz); 3.88 (1H, dd, J=11, 5.7Hz); 3.35 (1H, m); 2.89 (1H, dd, J=5.0, 4.1 Hz); 2.73 (1H, dd, J=5, 2.4Hz); 1.14 (18H, p).

Method 13: (Sfi)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamine]

propyl}phenoxymethylphosphonic acid diethyl ester

A mixture of (S)-2,2-di-tert-butyl-6-(oxyran-2-ylmethoxy)-4/-/-1,3,2-benzodioxasilynan (0.622 g, 1.85 mmol) and ( R)-diethyl 4-(2-aminopropyl)phenoxymethylphosphonate (0.55 g, 1.83 mmol) was dissolved in 10 mL of methanol and refluxed under argon for 20 h. The methanol was evaporated, and the residue was dissolved in 75 ml of dichloromethane and washed with 3 x 50 ml of water, and then dried over anhydrous sodium sulfate. After evaporation of the solvent in vacuo, the crude product was purified by column chromatography and over normal phase silica, and the product was eluted with 10% methanol in ethyl acetate, giving the title compound as a dark oil.

5<1>H (CDCl3): 7.15 (2H, d, J=9.3Hz); 6.09 (2H, d, J=9.0Hz); 6.85 (1H, d, J=7.9Hz); 6.72 (1H, dd, J=7.9Hz and 2.7Hz); 6.50 (1H, 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).

Method 14: (S/?)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamine]

propyl}phenoxymethylcarboxylic acid methyl ester

A solution of (S)-2,2-di-tert-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3,2-benzodioxasilylane (0.65 g, 1.93 mmol) in 25 mL acetonitrile was treated with lithium perchlorate (0.205 g, 1.93 mmol), after which the mixture was stirred until the salt was completely dissolved. To the resulting solution was then added (f?)-methyl 4-(2-aminopropyl)phenoxymethylcarboxylic acid methyl ester (0.43 g, 1.93 mmol). The mixture was kept at 80°C for 20 hours, then cooled, diluted with ethyl acetate and washed with 2 x 50 ml of water. The dried extracts (Na 2 SO 4 ) were concentrated in vacuo and the crude product was purified by column chromatography over normal phase silica eluting with 5% methanol in ethyl acetate to give the title compound as an oil.

5<1>H (250MHz, CDCl3): 7.12 (2H, d, J=8.7Hz); 6.87 (3H, m), 6.75 (1H, dd, J=8.8Hz and 2.7Hz); 6.53 (1H, 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, p).

Method 15: 3,4-dibenzyloxyphenol

A solution of 3,4-dibenzyloxyacetophenone (5.18 g, 20 mmol) in 25 mL acetic acid, 8 mL chloroform, 4 mL water, and 18 mL peracetic acid (36-40 wt% in acetic acid) was stirred at 40°C for four hours. After cooling to room temperature, a 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, then with water and then with brine. The organic solution was then dried and evaporated. A solution of the residue in 25 ml of methanol was treated with 8 ml of 2 M sodium hydroxide solution, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was dissolved in 10 ml of water, after which the pH was adjusted to 9 with 1 M hydrochloric acid. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic extracts were then separated, dried and evaporated to give the title compound as a colorless solid.

8(CDCl3): 7.25 (10H, m), 6.77 (1H, d, J=8.5Hz), 6.48 (1H, d, J=2.8Hz), 6.27 (1H, dd, J=8.5, 2.8Hz), 5.10 (2H, s), 5.06 (2H, s), 4.65 (1H, br, exchanged with D 2 O).

Method 16: (S)-3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane

The title compound was prepared from 3,4-dibenzyloxyphenol and (S)-glycidyl 3-nitrobenzenesulfonate by the method described in method 12.

6(CDCl3): 7.36 (10H, m), 6.85 (1H, d, J=8.8Hz), 6.60 (1H, d, J02.9Hz), 6.38 (1H, dd, J=8.8, 2.9Hz), 5.13 (2H, s), 5.08 (2H, s), 4.14 (1H, dd, J=11, 3.3Hz), 3.85 ( 1H, dd, J=11, 5.8Hz), 3.31 (1H, m), 2.88 (1H, dd, J=4.9, 4.1Hz), 2.71 (1H, dd, J =4.9, 2.6Hz).

Method 17: (SR)-4-{2-[3-(3,4-dibenzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxyacetic acid, methyl ester

The title compound was prepared from (S)-3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane and (R)-4-(2-aminopropyl)phenoxyacetic acid methyl ester by the method described in method 13.

6(CDCl3): 7.5-7.3 (10H, m), 7.09 (2H, d, J=8.8Hz), 6.85-6.80 (3H, m), 6.58 ( 1H, d, J=3.0Hz), 6.35 (1H, dd, J=8.8, 3.0Hz), 5.12 (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).

Method 18: (R)-3-(3,4-dihydroxyphenyl)-2-propylamine hydrobromide

A solution of (R)-3-(3,4-dimethoxyphenyl)-2-propylamine hydrochloride<1> (500 mg, 2.15 mmol) in 5 mL of 48% hydrogen bromide was stirred at 100°C under argon for 20 hours. After cooling, the solvent was evaporated and the residue was dried to give the title compound.

8(D<6>DMSO+D2O): 6.9-6.4 (3H, m), 3.5-2.4 (3H, m), 1.3 (3H, d, J=7Hz) ppm .

<1>D.E. Nichols, CF. Barfknecht and D.B. Rusterholz. J. Med. Chem., 1973, 16(5), 480. Method 19: (R)-2-(3,4-dihydroxyphenyl)propylcarbamic acid, f-butyl ester

A solution of (R)-3-(3,4-dihydroxyphenyl)-2-propylamine hydrobromide (480 mg, 1.9 mmol) in 5 mL of dimethylformamide containing triethylamine (3 equivalents, 586 mg, 5.7 mmol) was stirred at 5°C under an argon atmosphere for 15 minutes. Di-/-butyl dicarbonate (414 mg, 1.9 mmol) was added and the reaction mixture was stirred at 5°C for one hour and then at room temperature for one hour. The solvent was then evaporated. 100 ml of ethyl acetate and 50 ml of water were added, after which the organic layer was separated, washed with 50 ml of water and 50 ml of brine, dried over magnesium sulfate and evaporated. Purification of the residue by chromatography on silica gel and elution with 25% ethyl acetate in n-hexane gave the title compound, melting point 116<0>C-118°C.

5(CDCl3): 6.76 (1H, d, J=7.9Hz), 6.70 (1H, d, J=2Hz), 6.55 (1H, dd, J=7.9, 2Hz), 6.25-5.90 (2H, br. is exchanged with D2O), 4.45 (1H, br. is exchanged with D2O), 3.8 (1H, b), 2.75-2.5 (2H, m ), 1.43 (9H, s), 1.07 (3H, d, J=6.6Hz) ppm.

Method 20: (R)-5-[N-(f-butyloxycarbonyl)-2-aminopropyl]-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester

A solution of (R)-2-(3,4-dihydroxyphenyl)propylcarbamic acid, f-butyl ester (1.07 g, 4 mmol) in 25 mL of acetone containing potassium carbonate (3 equivalents, 1.66 g, 12 mmol) was stirred at 60°C under argon for one hour. After cooling to room temperature, a solution of diethyl dibromomalonate (1.27 g, 4 mmol) in 7 ml of acetone was added, and the reaction mixture was stirred at room temperature for 18 hours. The suspension was filtered and the residue was washed with ethyl acetate. The filtrates were combined, evaporated, after which the residue was partitioned between 200 ml ethyl acetate and 100 ml dilute hydrochloric acid at pH 5. The organic layer was separated, washed with 2 x 100 ml water and 100 ml brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in n-hexane to give the title compound as an oil.

6(CDCl3): 6.86 (1H, d, J= 8Hz), 6.78 (1H, d, J=1.3Hz), 6.71 (1H, dd, J=8, 1.3Hz), 4.41-4.32 (5H, m), 3.8 (1H, br. exchanged with D20), 2.76 (1H, dd, J=13.5, 5.6Hz), 2.60 (1H , dd, J=13.5, 7.2Hz), 1.43 (9H, s), 1.36-1.31 (6H, m), 1.07 (3H, d, J=6.6Hz) ppm.

Method 21: (R)-5-(2-aminopropyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester, hydrochloride salt

A solution of (R)-5-[N-(f-butoxycarbonyl)-2-aminopropyl]-1,3-benzodioxole-2,2-dicarboxylic acid diethyl ester (3.0 g, 7 mmol) in 40 mL of ethyl acetate and a hydrogen chloride solution in diethyl ether (1 M, 56 mL, 56 mmol) was stirred at room temperature under argon for 48 h. The solvent was evaporated and the residue was dried to give the title compound as a glass.

5(d<6->DMSO): 8.07 (3H, br. exchanged with D2O), 7.10-7.06 (2H, m), 6.85 (1H, dd, J=8.1, 4Hz), 4.33 (4H, q, J=7.1Hz), 3.5-3.4 (1H, m), 2.93 (1H, dd, J=13.4, 5.8Hz), 2.66 (1H, d, J=13.5, 8.2 Hz), 1.24 (6H, t, J=7.1Hz), 1.12 (3H, d, J=6.3Hz) ppm .

Method 22: (R)-5-(2-aminopropyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester

A solution of (R)-5-(2-aminopropyl)-1,3-benzodioxole-2,2-dicarboxylic acid diethyl ester hydrochloride (646 mg, 2 mmol) in 80 mL of dichloromethane was shaken with a saturated solution of 20 mL of sodium bicarbonate for 30 seconds. The organic layer was separated and the aqueous layer was extracted with 2 x 50 mL of dichloromethane. The combined organic extracts were then washed with 50 ml of water and 50 ml of saline, and then dried over magnesium sulfate. The solvent was evaporated to give the title compound which was used immediately.

Method 23: (SR)-5-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl}-1, 3-Benzodioxole-2,2-dicarboxylic acid, diethyl ester

The title compound was prepared from (R)-5-(2-aminopropyl)-1,3-benzodioxole-2,2-dicarboxylic acid diethyl ester and (S)-2,2-di-f-butyl-6-(oxyran-2-ylmethoxy )-4H-1,3,2-benzodioxasilylane by heating in ethanol as solvent using the method described in method 13.

8(CDCl3): 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, p).

Method 24: 4-(2-f-butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, diethyl ester

A solution of 2-(4-hydroxyphenyl)ethylcarbamic acid, f-butyl ester<1> (4.0 g, 16.9 mmol) in 37.5 mL of dry DMSO was cooled in an ice bath and treated with sodium hydride (80% in mineral oil 0.557 g, 1.1 equivalents) and stirred under argon using the method described by Cornforth<2>. After gas evolution had stopped, a solution of 4-chlorobenzenesulfonyloxymethylphosphonate diethyl ester (6.07 g, 1.05 equivalents) in 110 mL of dry DMSO was added, and the resulting pale yellow solution was stirred at room temperature overnight. It was then poured into 550 ml of water and extracted with 3 x 150 ml of a 1:1 mixture of diethyl ether and ethyl acetate and finally with 3 x 100 ml of ethyl acetate. The combined extracts were washed with saline, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil was purified by chromatography on silica gel with a gradient from 3:2 pentane:ethyl acetate to 100% ethyl acetate to give the title compound as a colorless viscous oil.

5<1>H (250MHz, CDCl3): 7.12 (2H, d), 6.90 (2H, d), 4.51 (1H, 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).

<1>F. Houlihan et al. eel. Can. J. Chem., 1985, 63, 153.

<2>J. Cornforth and J.R.H.Wilson. J.C.S. Perkin I., 1994, 1897.

Method 25: 4-(2-Aminoethyl)phenoxymethylphosphonic acid, diethyl ester

4-(2-f-butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, diethyl ester (2.856 g, 9.95 mmol) in 300 mL of methylene chloride and 16 mL of trifluoroacetic acid was stirred at room temperature for five hours. The solution was then concentrated under reduced pressure and the product dried under vacuum. The trifluoroacetic acid salt was neutralized with aqueous sodium carbonate and extracted with dichloromethane containing a small amount of methanol (5 x 100 ml). The combined organic layers were dried over sodium sulfate and evaporated to dryness to give the title compound as a pale yellow gum.

5<1>H (250MHz, CDcl3): 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).

Method 26: (S)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid , diethyl ester

Using an experimental procedure as set forth in Method 13, the title compound was prepared from 4-(2-aminoethyl)phenoxymethylphosphonic acid diethyl ester and (S)-2,2-di-tert-f-butyl-6-(oxyran-2-ylmethoxy) -4H-1,3,2-benzodioxasilylane as an oil.

6<1>H (250MHz, CDcl3): 7.1 (2H, d, J=8.7Hz), 6.87 (2H, d, J=8.9Hz), 6.84 (1H, m), 6.75 (1H, dd, J=8.3Hz and 3.1 Hz), 6.52 (1H, 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); [a]d<22->18.5° (c=0.2, CHCl 3 ).

Method 27: (RR)-2-(4-hydroxyphenyl)-1-methylethyl)-1-phenylethyl) aminoboronic acid

(RR)-[2-(4-Methoxyphenyl)-1-methylethyl]-(1-phenylethyl)amine hydrochloride salt 1 (10 g, 0.0327 mmol) in 50 mL dichloromethane was treated with boron tribromide (1 N in CH 2 Cl 2 , 72 mL) under argon, and stirring was continued overnight at room temperature. The mixture was then evaporated to dryness and ice was added to hydrolyze the complex. The resulting white solid was collected and dried to give the title compound. 8<1>H (250MHz, CDCl3+CD3OD): 7.50 (5H, m), 6.83 (2H, d), 6.72 (2H, d), 4.38 (1H, q), 3 .23 (1H, dd), 3.00 (1H, m), 2.67 (1H, 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. Method 28: (R)-4-(2-Amonipropyl)phenol (RR)-2-(4-hydroxyphenyl)-1-methylethyl-(1-phenylethyl)aminoboric acid ( 9.73 g, 0.0325 Mol) was dissolved in 120 ml of methanol and hydrogenated at a pressure of 3.5 kg per cm<2>, and 50°C with 1 g of 10% palladium on charcoal for two days. The mixture was cooled, filtered through diatomaceous earth and evaporated to dryness to give the title compound as a pale yellow solid. 6<1>H (250MHz, CDCI3): 7.06 (2H, d), 6.80 (2H, d), 4.12 (3H, br s), 3.f2 (1H, m), 2, 96 (1H, dd), 2.73 (1H, dd), 1.30 (3H, d). Method 29: (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester (R)-4-(2-aminopropyl)phenol (4.91 g, 0.0325 mol) in 240 mL of dichloromethane and 50 ml of dry dimethylformamide was treated with 7.59 ml of triethylamine and 11.77 g (1.2 equivalents) of di-f-butyl dicarbonate, after which the mixture was stirred at room temperature for one day. After evaporation of volatile compounds in vacuo, the residue was washed with diethyl ether. The combined extracts in 500 ml of diethyl ether were washed with 3 x 100 ml of water, and then dried over anhydrous sodium sulfate. After evaporation to dryness, the residue was chromatographed on silica gel with 0 to 3% methanol in dichloromethane to give the title compound as a slowly solidifying gum. 5<1>H (250MHz, CDCI3): 7.00 (2H, d), 6.76 (2H, d), 6.25 (1H, br s), 4.44 (1H, br s), 3 .83 (1H, m), 2.73 (1H, m), 2.57 (1H, dd), 1.43 (9H, s), 1.07 (3H, d). Method 30: (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxyacetic acid, methyl ester

Potassium carbonate (1.95 g, 14.2 mmol) was added to a solution of (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester (2.96 g, 11.8 mmol) in 50 mL acetone at room temperature under argon. Methyl bromoacetate (1.81 g, 11.8 mmol) was added dropwise and the mixture was refluxed for three hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed with 2 x 30 ml of water. The organic extracts were dried with sodium sulfate, after which the solvent was evaporated in vacuo. The crude product was purified by chromatography on diatomaceous earth 60 eluting with 20% ethyl acetate in pentane to give the title compound as an oil.

8<1>H (250MHz, CDCI3): 7.1 (2H, d, J=7.3Hz9, 6.85 (2H, d, J=7.3Hz), 4.53 (2H, s), 4 .35 (1H, brs), 3.85 (1H, m), 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).

Method 31: Hydroxymethylphosphonic acid, bis-(3-benzyloxypropyl) ester

Phosphonic acid bis-(3-benzyloxypropyl) ester was prepared by the general procedure described by Houben-Weyl, PhosphorVerbindungen, p28 and J. Amer. Chem. Soc, 1955, 77, 3522. A mixture of this impure phosphite (5 g, 0.012 mol based on 85% purity), paraformaldehyde (0.365 g, 1 equiv) and triethylamine (0.17 ml, 0.1 equiv) was kept at 90°C in an oil bath under an argon atmosphere. Furthermore, a total of 2 ml of triethylamine was added to promote the reaction. After half an hour the mixture was cooled and chromatographed on silica gel with 0 to 5% methanol in dichloromethane to give the title compound as a colorless oil.

8<1>H (250MHz, CDCI3): 7.32 (10H, m), 4.49 (4H, s), 4.22 (4H, m), 3.85 (2H, t), 3.58 (4H, t), 3.08 (1H, m), and 1.97 (4H, m).

Method 32: 4-Chlorobenzenesulfonyloxymethylphosphonate, bis-(3-benzyloxypropyl) ester

The title compound was prepared in the same manner as described in the literature<1> from hydroxymethylphosphonic acid, bis-(3-benzyloxy-propyl) ester, as an oil.

8<1>H (250MHz, CDCl3): 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).

<1>J. Cornforth and J.R.H. Wilson, JC.S. Perkin I, 1994, 1897.

Method 33: (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester

The title compound was prepared as a viscous oil from 4-chlorobenzenesulfonoxymethylphosphonate, bis-(3-benzyloxypropyl)ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester by the procedure outlined in Method 24.

6<1>H (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 (1H, br m), 3.57 (4H, t), 2.78 (1H, dd), 2.59 (1H, dd), 1.98 (4H, m), 1.52 (9H, s), and 1.05 (3H, d).

Method 34: (R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester

(R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis(3-benzyloxypropyl)ester (3.2 g, 4.99 mmol) was converted to the title compound using the procedure described in Method 25. 5< 1>H (200MHz, CDCl3): 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 (1H, m), 2.70 (2H, d), 2.60 (2H, br s), 1.98 (4H , m), 1.18 (3H,d). Method 35: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxy-propylamino]propyl }phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester (R)-4-(2-aminopropyl)phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester (2.507 g, 4.6 mmol) was reacted with (S)-2, 2-di-f-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3,2-benzodioxasilylane (1.557 g, 1 equiv) by the procedure outlined in Method 14, affording the title compound as a colorless rubber. 5<1>H (200MHz, CDCl3): 7.30 (10H, m), 7.09 (2H, d), 6.83 (3H, m), 6.70 (1H, dd), 6.49 (1H, d), 4.93 (2H, s), 4.47 (4H, s), 4.35-4.20 (6H, m), 3.99 (1H, 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). Method 36: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylmino]propyl}phenoxymethylphosphonic acid , bis-(3-hydroxypropyl) ester

(SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxy-propylamino]propyl}phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester (1 g, 1.14 mmol) was hydrogenated at 50°C and a pressure of about 3.5 kg per cm<2> for two days in 120 ml of methanol, in the presence of 1, 0 g 10% palladium on charcoal. After cooling, the mixture was filtered through diatomaceous earth, evaporated to dryness and purified by column chromatography on silica gel and eluted with 0 to 15% methanol in dichloromethane. The title compound was prepared as a clear gum.

6<1>H (250MHz, CDCl3): 7.13 (2H, d), 6.90 (2H, d), 6.82 (1H, d9, 6.70 (1H, dd), 6.49 ( 1H, d), 4.93 (2H, s), 4.40-4.25 (6H, m), 4.07 (1H, 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).

Method 37: Hydroxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared by the general method indicated in method 31 by a hydroxymethylation of phenylphosphinic acid ethyl ester <1> (10.136 g, 0.059 Mol). The product was obtained as a colorless viscous oil after chromatography.

6<1>H (250MHz, CDcl3): 7.83 (2H, m), 7.65-7.42 (3H, m), 4.26-3.90 (5H, m), 1.32 ( 3H, h).

<1>D.G. Hewitt. Aust. J. Chem., 1970, 32, 463.

Method 38: 4-Chlorobenzenesulfonyloxymethylphenylphosphinic acid ethyl ester

The title compound was prepared as a white crystalline solid, mp 70°C to 72°C, from hydroxymethylphenylphosphinic acid ethyl ester (9.525 g, 0.0476 mol) by a method similar to that described in Method 32.

5<1>H (250MHz, CDCl3): 7.83-7.58 (5H, m), 7.58-7.40 (4H, m), 4.40 (1H, dd), 4.28- 4.00 (3H, m), 1.35 (3H, h).

Method 39: (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared as a colorless gum from 4-chlorobenzenesulfonoxymethylphenylphosphinic acid ethyl ester (3.91 g, 10.4 mmol) and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester (2.5 g, 9, 96 mmol) using the method described in method 24.

5<1>H (200MHz, CDCl3): 7.93 (2H, m), 7.52 (3H, m), 7.07 (2H, d), 6.82 (2H, d), 4.52 -4.0 (5H, m), 3.81 (1H, br), 2.76 (1H, dd), 2.57 (1H, dd), 1.43 (9H, s), 1.38 ( 3H, t), 1.03 (3H, d).

Method 40: (R)-4-(2-aminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared by a method similar to that given in Method 25, from (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester (2.647g, 6.1mmol).

6<1>H (250MHz, CDCI39: 7.93 (2H, m), 7.65-7.44 (8H,m), 7.07 (2H, d), 6.83 (2H, d), 4.44 (1H, dd), 4.36-4.02 (3H, m), 3.09 (1H, m), 2.63 (1H, dd), 2.43 (1H, dd), 1 .38 (3H,t), 1.08 (3H,d).

Method 41: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid , ethyl ester

The title compound was prepared as a colorless gum by a method analogous to that described in Method 13, from (R)-4-(2-aminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester (1 g, 3 mmol) and (S)-2 ,2-di-f-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3,2-benzodioxasilynan (1.009 g, 3 mmol).

5<1>H (400MHz, CDCl3): 7.92 (2H, m), 7.59 (1H, m), 7.51 (2H, m), 7.07 (2H, d), 6.82 (3H, m), 6.69 (1H, dd), 6.48 (1H, d), 4.93 (2H, s), 4.43 (1H, dd), 4.30 (1H, m) , 4.25-4.05 (2H, m), 3.98 (1H, m), 3.88 (2H, m), 3.03-2.35 (7H, m), 1.38 (3H , t), 1.10 (3H, d), 1.03 (18H, s).

Method 42: 3-Benzyloxypropylphosphinic acid

The title compound was prepared from allyl benzyl ether and 50% aqueous phosphinic acid by a method analogous to that described in J. Inorg. Nucl. Chem., 1965, 27, 697. 8 (CDCl 3 ): 10.83 (1H, s, exchanged with D 2 O); 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). Method 43: 3-Benzyloxypropylphosphinic acid, n-butyl ester

The title compound was prepared from 3-benzyloxypropylphosphinic acid and n-butanol using the general method described in European Patent 0093010. The compound was used without further purification: 8(CDCl 3 ): 7.39-7.15 (5H, m); 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, m); 1.47-1.33 (2H, m); 0.94 (3H, t, J=7.15Hz).

Method 44: 3-Benzyloxypropyl hydroxymethylphosphinic acid, n-butyl ester

The title compound was prepared from 3-benzyloxypropylphosphinic acid n-butyl ester and paraformaldehyde using the method described in method 31. Purification by chromatography and elution with dichloromethane containing 5% methanol gave an oil.

δ(CDCl 3 ): 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, exchange with D 2 O); 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).

Method 45: 3-Benzyloxypropyl-(4-chlorophenylsulfonyloxymethyl)phosphinic acid, n-butyl ester

The title compound was prepared from 3-benzyloxypropylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride by the method described in method 32. The crude product was used without further purification.

δ(CDCl 3 ): 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=6.05Hz9); 1.97-1.83 (4H, m); 1.67-1.55 (2H, m); 1.42-1.26 (2H, m); 0.91 (3H, t, J=7.15Hz).

Method 46: 4-(2-f-butoxycarbonylaminoethyl)phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 3-benzyloxypropyl-(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, r-butyl ester by the method described in method 24. The crude product was purified by chromatography and eluted with 3% methanol in dichloromethane to give an oil.

δ(CDCl 3 ): 7.37-7.24 (5H, m); 7.11 (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, m); 1.47-1.31 (2H, m); 1.25 (9H, s); 0.91^3H, t, J=7.15Hz).

Method 47: 4-(2-Aminoethyl)phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-f-butoxycarbonylaminoethyl)phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester by the procedure outlined in Method 25. The crude product was used without further purification.

6(CDCl 3 ): 7.36-7.26 (5H, m); 7.12 (2H, d, J=8.80Hz); 6.86 (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=6.6jDHz); 2.70 (2H, t, J=6.60Hz); 2.05-1.95 (4H, m); 1.67-1.59 (4H, m, 2H is exchanged with D 2 O); 1.43-1.35 (2H, m); 0.91 (3H, t, J=7.42Hz).

Method 48: (S) 4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]ethyl}phenoxymethyl(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-f-butyl-6-(oxyran-2-ylmethoxy)-4H-1 ,3,2-benzodioxasilylane using the method described in method 13. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 3% methanol, which gave the title compound as a viscous gum.

δ(CDCl 3 +D 2 O): 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, m), 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.f4Hz).

Method 49: (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 3-benzyloxypropyl-(4-chlorocenesulfonyloxymethyl)phosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester by the method described in method 24 The crude product was purified by chromatography eluting with dichloromethane containing 3% methanol to give an oil.

δ(CDCl 3 +D 2 O): 7.34-7.26 (5H, m); 7.11 (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).

Method 50: (R)-4-(2-aminopropyl)phenoxymethyl-(3-beryloxypropyl)phosphonic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-f-butoxycarbonylaminopropyl))phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester by the method described in Method 25. The crude product was used without further purification.

δ(CDCl 3 +D 2 O): 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); 1.43-1.35J2H, m); 1.13 (3H, d, J=6.32Hz); 0.91 (3H, t, J=7.42Hz).

Method 51: (SR)-4-{2-[3-(2,2-di-f-butyl-4H,1,3,2-benzodioxasilynan-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-f-butyl-6-(oxyran-2-ylmethoxy )-4H-1,3,2-benzodioxasilylane using the method described in method 13. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 3% methanol, which gave a viscous gum.

δ(CDCl 3 ): 7.37-7.31 (5H, m); 7.11 (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, m); 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).

Method 52: Cyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from cyclohexylphosphinic acid and n-butanol by the method described in method 43. The compound was used without further purification.

δ(CDCl 3 ): 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).

Method 53: Cyclohexylhydroxymethylphosphinic acid, n-butyl ester

The title compound was prepared from cyclohexylphosphinic acid, n-butyl ester and paraformaldehyde using the method described in method 31. Purification by chromatography and elution with dichloromethane containing 5% methanol gave an oil.

δ(CDCl 3 +D 2 O): 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).

Method 54: (4-Chlorobenzenesulfonyloxy)cyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from cyclohexylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride by the method described in method 32. The crude product was used without further purification.

δ(CDCl 3 ): 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).

Method 55: 4-(2-f-butoxycarbonylaminoethyl)phenoxymethyl cyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (4-chlorobenzenesulfonyloxy)cyclohexylphosphinic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, f-butyl ester by the method described in method 24. The crude product was purified by chromatography and elution with dichloromethane containing 3% methanol, which gave an oil.

δ(CDCl 3 ): 7.13 (2H, d, J=8.80Hz); 6.88 (2H, d, J=8.80Hz); 4.50 (1H, s, exchanged with D 2 O); 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).

Method 56: 4-(2-Aminoethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-f-butoxycarbonylaminoethyl)phenoxymethyl cyclohexylphosphinic acid, n-butyl ester by the method described in Method 25. The crude product was used without further purification.

δ(CDCl 3 +D 2 O): 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).

Method 57: (S)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilynan-6-yloxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n -butyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxypropylmethylcyclohexylphosphinic acid, n-butyl ester and (S)-2,2-di-f-butyph-6-oxyran-2-ylmethoxy)-4H-1,3,2-benzodioxasilynan by using the method described in method 13. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 3% methanol, which gave a viscous gum.

δ(CDCl 3 +D 2 O): 7.14 (2H, d, J=8.56 Hz); 6.88 (2H, d, J=8.65Hz); 6.82 (H, d, J=8.Z9Hz); 6.72 (1H, d, 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=5.11Hz); 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); 1.51-1.40J4H, m); 1.39-1.21 (2H, m); 1.03 (18H, s); 0.91 (3H, t, J=7.39Hz).

Method 58: (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethylcyclohexyl phosphinic acid, n-butyl ester and (S)-2-(4-benzyloxyphenoxymethyl)oxirane using the method described in method 13.

8(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=5, Hz), 3.0-2.75 (6H, m), 2.1- 1.25 (15H, m), 0.92 (3H, t, J=7.4Hz).

Method 59: (S)-4-{2-[3-(3-Benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxypropylmethylcyclohexylphosphinic acid, n-butyl ester and (S)-2-(3-benzyloxyphenoxymethyl)oxirane using the method described in method 13.

8(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).

Method 60: (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (4-chlorophenylsulfonyloxy)cyclohexylphosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester by the method described in method 24. The crude product was purified by flow chromatography and eluted with dichloromethane containing 3% methanol, which gave an efi oil.

6(CDCl 3 ): 7.10 (2H, d, J=8.53Hz); 6.87 (2H, d, J=8.60Hz); 4.34-3.85 (6H, m, 1H is exchanged with D 2 O); 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=6.78Hz); 0.92 (3H, t, J=7.42Hz).

Method 61: (R)-4-(2-Aminopropyl)

phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-r-butoxycarbonylaminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Method 25. The crude product was used without further purification.

8(CDCl 3 ): 7.13 (2H, d, J=8.80Hz); 6.88 (2H, d, J=8.80Hz); 4.23-4.02 (4H, m); 3.20-3.12 (1H, 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 replaced by D 2 O); 1.414 (3H, d, J=6.32Hz); 0.92 (3H, t, J=7.15Hz).

Method 62: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl}

phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester and (S)-2,2-di-f-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3 ,2-benzodioxasanilane using the method described in method 13. The crude product was purified by chromatography over silica and eluted with dichloromethane containing 3% methanol, which gave a viscous gum.

6(CPCl 3 +D 2 O): 7.10 (2H, d, J=8.53Hz); 6.87 (2H, d, J=8.80Hz); 6.83 (1H, d, J=8T80Hz); 6.70 (1H, dxd, J=8.80&3.02Hz); 6.50 (1H, d, J=3.02Hz); 4.94 (2H, s); 4.26-3.88 (7H, m); 2.91-3.53 (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).

Method 63: n-hexylphosphinic acid

The title compound was prepared from n-hexene and 50% aqueous phosphinic acid by a method analogous to that described in J. Inorg. Nucl. Chem., 1965, 27, 697.

8(CDCl 3 ): 12.10 (1H, s, exchanged for D 2 O); 7.08 (1H, dd, J=540.10, 1.93Hz); 1.82-1.54^4H, m); 1.42-1.23 (6H, m); 0.87 (3H, t, J=6.87Hz).

Method 64: n-hexylphosphinic acid, n-butyl ester

The title compound was prepared from n-hexylphosphinic acid and n-butanol by the method described in Method 43. The compound was used without further purification.

δ(CDCl 3 ): 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).

Method 65: n-hexylhydroxymethylphosphinic acid, n-butyl ester

The title compound was prepared from n-hexylphosphinic acid, n-butyl ester and paraformaldehyde using the method described in method 31. Purification by chromatography and elution with dichloromethane containing 5% methanol gave an oil.

δ(CDCl 3 ): 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, m); 0.96-0.86 (6H, m).

Method 66: 4-Chlorobenzenesulfonyloxymethyl-n-hexylphosphinic acid, n-butyl ester

The title compound was prepared from n-hexylhydroxymethylphosphinic acid, n-butyl ester and 4-chlorobenzenesulfonyl chloride by the method described in Method 32. The crude product was used without further purification.

δ(CDCl 3 ): 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).

Method 67: (R)-4-(2-Butoxycarbonylaminopropyl)phenoxymethyl-n-hexylphosphinic acid, n-butyl ester

The Tiffel compound was prepared from 4-chlorobenzenesulfonyloxymethyl-n-hex^tylphosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester using the method described in method 24. The crude product was purified by chromatography and eluted with dichloromethane containing 3% methanol to give an oil.

δ(CDCl 3 ): 7.11 (2H, d, J=8.80 Hz); 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).

Method 68: (R)-4-(2-Aminopropyl)phenoxymethyl-n-hexylphosphinic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-f-butoxycarbonylaminopropyl)phenoxymethyl-n-hexylphosphinic acid, n-butyl ester by the method described in Method 25. The crude product was used without further purification.

6(CDCl 3 ): 7.12 (2H, d, J=8.53 Hz); 6.89 (2H, d, J=8.80Hz); 4.22-3.86 (6H, m, 2H is exchanged with D 2 O); 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).

Method 69: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl6Rsy)-2-hydroxypropylamino]propyl}phenoxymethyl-n -hexylphosphinic acid, n-bujyl ester

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-(oxyran-2-ylmethoxy)-4H- 1,3,2-benzodioxasilylane using the method described in method 13. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 3% methanol, which gave a viscous gum.

δ(CDCl 3 ): 7.12 (2H, d, J=8.53 Hz); 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,jn, 2H is exchanged with D 2 O); 2.93-2.86 (1H, m); 2.84-2.63 (2H, m); 2.57 (1H, dd, J=1?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).

Method 70: (S)-1-(4-Benzyloxyphenoxy)-3-[N-2-(4-Hydroxyphenyl)ethylamino]propan-2-ol

The title compound was prepared from tyramine and (S)-2-(4-benzyloxyphenoxymethyl)oxirane using the method described in method 13.

5(d<6->DMSO): 9.3-8.9 (1H, 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 (1H, b, yielded with D 2 O), 3.9-3.75 (3H, m), 2.75-2.55 (6H, m).

Method 71: (S)-N-benzyl-1-(4-benzyloxyphenoxy)-3-[N-2-(4-hydroxyphenyl)ethylamino]propan-2-ol

Eh solution of (S)-1-(4-benzyloxyphenoxy)-3-[N-2-(4-hydroxyphenyl)ethylamino]propan-2-ol (1.9 g, 4.8 mmol) and benzyl bromide (0, 57 mL, 4.8 mmol) in 10 mL of dimethylformamide containing sodium carbonate (770 mg, 7.2 mmol) was stirred 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 chromatography (silica gel, 50% ethyl acetate in hexane) afforded the title compound.

5(CDCl 3 +D 2 O): 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 (1H,.d, J=13.5Hz), 2.9-2.6 (6H, m).

Method 72: (S)-N-benzyl-4-{2-[-3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethyl-n-hexylphosphinic acid, n-butyl ester

The title compound was prepared from (S)-N-benzyl-1-(4-benzyloxyphenoxy)-3-[N-2-(4-hydroxyphenyl)ethylamino]propan-2-ol and 4-chlorobenzenesulfonyloxymethyl-n-hexylphosphinic acid, n- butyl ester using the method described in method 24.

5(CDCl3+d20): 7.45-7.25 (10H, m), 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 (1H, d, J=12.3Hz), 2.9-2.6 (6H, m), 1, 9 (2H, m), 1.65 (4H, m), 1.5-1.25 (8H, m), 0.95-0.85 (6H, m).

Method 73: Phosphonic acid, bis-(2-phenylethyl) ester

The title compound was prepared from 2-phenylethanol and phosphorus tribromide using the method described in method 31. Purification by chromatography on silica gel and elution with 5% methanol in dichloromethane gave the title compound as an oil.

6(CDCl 3 ): 7.92-5.32 (1H, d); 7.16-7.33 (19H, m); 4.10-4.28 (4H, m); 2.92-3.04 (4H,tT.

Method 74: Hydroxymethylphosphonic acid, bis-(2-phenylethyl) ester

The title compound was prepared from phosphonic acid, bis-(2-phenylethyl)ester and paraformaldehyde using the method described in method 31. Purification by column chromatography on silica gel in 2 to 5% methanol in dichloromethane gave the title compound as an oil.

δ(CDCl 3 ): 7.17-7.33 (10H, m); 4.15-4.30 (4H, m); 3.70-3.74 (2H, t); 2.86-2.96 (4H, m).

Method 75: (4-Chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-(2-phenylethyl ester)

The title compound was prepared from hydroxymethylphosphonic acid, bis-(2-phenylethyl) ester and 4-chlorobenzenesulfonyl chloride by the method described in method 32. The crude product was used in the next step without further purification.

δ(CDCl 3 ): 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).

Method 76: (S)-4-(2-t-butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis-(2-phenylethyl)ester

The title compound was prepared from (4-chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-(2-phenylethyl)ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, f-butyl ester by the method described in method 24. Purification by column chromatography on silica gel with from 1 to 2% methanol in dichloromethane gave the title compound as a gum.

δ(CDCl 3 ): 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 (1H, s, exchanged with D 2 O); 2.93-2.98 (4H, t); 2.52-2.8T73H, complex m); 1.43 (9H, s); 1.05-1.07 (2H, d).

Method 77: (R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-(2-phenylethyl)ester

/the title compound was prepared from (R)-4-(2-t-butoxycarbonylaminopropyl)

y

Phenoxymethylphosphonic acid, bis-(2-phenylethyl) ester by the method described in Method 25. The crude product was used in the next step without further purification.

δ(CDCl 3 ): 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 is exchanged with D 2 O); 1.17-1.20 (3H, d).

Method 78: (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,2,3-benzodioxasilynan-6-yloxy)-2-hydroxypropylamino]propyl}phenoxymethylphosphonic acid, bis -(2-phenylethyl) ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylphosphonic acid, bis-T2-phenylethyl)ester and (S)-2,2-di-f-butyl-6-(oxyran-2-ylmethoxy)-4H -1,3,2-benzodioxasilylane using the method described in method 13. The crude product was purified by chromatography on silica gel with from 1 to 5% methanol in dichloromethane as eluent, which gave the title compound as a gum.

8(CDCl 3 ): 7.20-7.30 (10H, complex m); 7.07-7.18 (2H, d); 6.68-6.84 (4H, complex m); 6.49-6.50 (1H, d); 4.94 (2H, s); 4.22-4.33 (4H, m); 4.04-4.08 (2H, d); 3.97^.04 81H, m); 3.86-3.89 (2H, m); 2.93-2.98 (4H, m); 2.56-2.89 (3H, complex m) Jk07-1.10 (3H, d); 1.03 (18H, p).

Method 79: Benzylphosphinic acid, n-butyl ester

A mixture of 9.18 g of ammonium phosphinate and 25 ml of hexamethyldisilazane was held at 110°C for two hours. The mixture was cooled in ice, dissolved in 120 ml of dry dichloromethane, after which benzyl chloride (20 g, 14 ml) was added, and the mixture was warmed to room temperature and stirred for 18 hours. It was then filtered, the solvent evaporated, the residue azeotropically distilled with 2 x 70 ml of methanol, dissolved in 150 ml of toluene containing 30 ml of n-butanol, after which the solution was refluxed in a Dean and Stark water trap for five hours. The solvent was evaporated, the residue was stirred in 120 ml of dichloromethane, filtered and evaporated, after which the residue was chromatographed on silica gel with from 1 to 2% methanol in dichloromethane, giving the title compound as an oil.

δ(CDCl 3 ): 8.05-6.03 (1H, 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 8(2H, m); 0.87-0.93 (3H, t).

Method 80: Benzyl hydroxymethylphosphinic acid, n-butyl ester

The title compound was prepared from benzylphosphinic acid, n-butyl ester and paraformaldehyde using the method described in method 31.

δ(CDCl 3 ): 7.12-7.35 (5H, s); 3.5-4.5 (1H, s, exchanged with D 2 O); 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).

Method 81: Benzyl(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester

The title compound was prepared from benzylhydroxymethylphosphinic acid, n-butyl ester and 4=chlorobenzenesulfonyl chloride by the method described in Method 32. The resulting white solid (mp 87°C to 88°C) was used in the next step without further purification.

δ(CDCl 2 ): 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).

Method 82: 4-[2-(S)-(2-t-butoxycarbonylamino)propyl]-phenoxymethylbenzylphosphinic acid, n-butyl ester

The title compound was prepared from benzyl(4-chlorobenzenesulfonyloxymethyl)phosphinic acid, n-butyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester by the method described in method 24. The crude product was chromatographed on silica gel in 2% methanol in dichloromethane to give a gum. δ(CDCl 3 ): 7.21-7.29 (5H, s); 7.09-7.13 (2H, d); 6.83-6.87 (2H, d); 4.01-4.11 (3H, m); 3.30-3.28 (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 m); 1.05-1.09 (3H, d); 0.87-0.92 (3H, t). Method 83: (R)-4-(2-Aminopropyl)phenoxymethylbenzylphosphinic acid, n-butyl ester The title compound was prepared from (R)-4-[2-(2-f-butoxycarbonylamino)propylphenoxymethylbenzylphosphinic acid, n-butyl ester by the method of is described in method 25. The crude product was used in the next step without further purification. δ(CDCl 3 ): 7.22-7.29 (5H, s); 7.11-7.19 (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 m); 1.23-1.44 (2H, complex m); 1.10-1.13 (3H, d); 0.87-0.94 (3H, t). Method 84: (SR)-4-[2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilynan-6-yloxy)-2-hydroxypropylamino]propyl]phenoxymethylbenzylphosphinic acid, n -butyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylbenzyl phosphinic acid n-butyl ester and (S)-22-di-f-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3,2 -benzodioxasilinan using the method described in method 13. The crude product was purified by chromatography on silica gel with from 2 to 5% methanol in dichloromethane as eluent, which gave a gum.

δ(CDCX): 7.26-7.28 (5H, s); 7.10-7.13 (2H, d); 6.65-6.86 (4H, complex m); 6.50 (1H,#); 4.94 (2H, s); 4.07-4.19 (4H, complex m); 3.89 (2H, s); 3.27-3.35 (2H, dd); 2.55^.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).

Method 85: 4-(2-tert-butoxycarbonylaminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from 4-chlorobenzenesulfonyloxymethylphenylphosphinic acid, ethyl ester (4.97 g, 13.3 mmol) and 2-(4-hydroxyphenyl)ethylcarbamic acid, tert -butyl ester (3.0 g, 12.7 mmol) using the the method described in method 24, as a colorless gum.

6<1>H (200MHz, CDCl3): 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, m), 2.71 (2H, t), 1.42 (9H, s), 1.38 (3H, partially overlapping signal at 1.42).

Method 86: 4-(2-Aminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared by a method corresponding to that described in method 25, from 4-(2-tert-butoxycarbonylaminoethyl)phenoxymethylphenylphosphinic acid, ethyl ester (3.197 g, 7.63 mmol), and a very pale yellow gum was obtained.

8(250mHz, CDCl3): 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).

Method 87: (S)-4-{2-[3-(2,2-di-tert-butyl-4H-1H312-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]

ethyljphenoxymethylphenylphosphine, ethyl ester

The title compound was prepared as a colorless gum by a method similar to that described in Method 13 from 4-(2-amino6ethyl)phenoxymethylphenylphosphinic acid, ethyl ester (2.32 g, 8.06 mmol) and (S)-2 ,2-di-( ε )-butyl-6-(oxyran-2-ylmethoxy)-4H-1,3,2-benzodioxasilynan (1 g, 2.98 mmol).

8<1>H (CDCl 3 ): 7.93 (2H, m), 7.65-7.44 (3H, m), 7.10 (2H, d), 6.88-6.77 (3H, m), 6.71 (1H, dd), 6.50 (1H, 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).

Method 88: (S)-4-{2-[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethylphosphinic acid, ethyl ester and (S)-2-(4-benzyloxyphenoxy)methyloxirane using the method described in method 13.

8<1>H~(250MHz, CDCl 3 ): 7.9-7.8 (2H, m); 7.55 (3H, m); 7.5-7.25 (5H, m); 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).

Method 89: (S,R)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylphenylphosphinic acid, diethyl ester and (S)-2-(4-benzyloxyphenoxy)methyloxirane using the method described in method 14.

6<1>H (250MHz, CDCl 3 ): 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=7.4Hz).

Method 90: 1-(4-benzyloxy-3-nitrophenyl)ethanone

A mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (10 g, 55.2 mmol) and potassium carbonate (11.5 g, 82.8 mmol) in 150 mL of acetone was refluxed for 10 minutes. Benzyl bromide (6.6 mL, 55.2 mmol) was added and the mixture was refluxed for 48 h. After cooling, the mixture was filtered and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried, after which the solvent was evaporated to give the title compound as an oil.

5<1>Hj[250MHz, CDCl3): 8.42 (1H, d, J=1.4Hz); 8.11 (1H, dd, J=8.2Hz and 1.4Hz); 7.4 (5H, m); 7J8 (1H, d, J=8.3Hz); 5.32 (2H, s); 2.60 (3H, p).

Method 91: Acetic acid, (4-benzyloxy-3-nitrophenyl) ester

A mixture of 1-(4-benzyloxy-3-nitrophenyl)ethanone (6 g, 22.1 mmol) and 3-chloroperoxybenzoic acid (19.1 g, 110.7 mmol) in 150 mL of dichloromethane was refluxed for 72 hours. . After cooling, the mixture was filtered and the organic phase was washed with 2 x 25 ml saturated sodium carbonate solution, 30 ml water and 30 ml brine. The solution was then 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.

8<1>H~(250MHz, CDCl3): 7.68 (1H, d, J=1.6Hz); 7.4 (5H, m); 7.26 (1H, dd, J=8.2Hz and 1.4Hz); 7.10 (1H, d, J=8.2Hz); 5.24 (2H, s); 2.31 (3H, p).

Method 92: Acetic acid, (3-amino-4-benzyloxyphenyl) ester

Acetic acid, (4-benzyloxy-3-nitrophenyl)ester (3 g, 10.45 mmol) was dissolved in 30 mL of methanol and hydrogenated at atmospheric pressure and room temperature using platinum (IV) oxide for 30 h. The mixture was filtered through a filter medium and the solvent was evaporated in vacuo to give a dark oil.

6<1>H (200MHz, CDcl3): 7.35 (7H, m); 6.82 (1H, d, J=8.8Hz); 6.48 (1H, d, J=1.5Hz); 6.40 (1H, dd, J=6.6Hzand 1.3Hz); 5.05 (2H, s); 2.23 (3H, p).

Method 93: Acetic acid (4-benzyloxy-3-methanesulfonylaminophenyl) ester

Acetic acid, (3-amino-4-benzyloxyphenyl)ester (1.70 g, 6.61 mmol) in 35 mL of dichloromethane was treated with triethylamine (0.802 g, 7.93 mmol) and metarisulfonyl chloride (0.832 g, 7.27 mmol ), and the mixture was stirred at room temperature under argon for 20 min. It was then washed with 3 x 10 ml water, dried and the solvent evaporated in vacuo. Treatment with diethyl ether gave the title compound as a white solid.

6<1>H (250MHz, CDCl 3 ): 7.40 (5H, m); 7.33 (1H, d, J=2.2Hz); 6.96 (1H, d, J=8.5Hz); 6.88 (1H, br, s); 6.84 (1H, dd, J=8.2Hz and 2.1Hz); 5.08 (2H, s); 2.94 (3H, s); 2.31 (3H.S).

Method 94: Acetic acid, 4-benzyloxy-3-(N-terf-butoRsylcarbonyl)methanesulfonylaminophenyl ester

To a solution of acetic acid, (4-benzyloxy-3-methanesulfonylaminophenyl)ester (0.9 g, 2.69 mmol) in 10 mL of dichloromethane was added di-tert-butyl dicarbonate (0.704 g, 3.23 mmol) and 4-dimethylaminopyridine (0.065 g, 0.54 mmol) at room temperature under argon. The mixture was stirred at room temperature for one hour, after which the solvent was removed in vacuo. Purification by normal phase column chromatography and elution with diethyl ether gave the title compound as a white foam.

5<1>H (250MHz, CDCl 3 ): 7.38 (5H, m); 7.15 (2H, m); 6.96 (1H, d, J=8.6Hz); 5.08 (2H, s); 3.24 (3H, s); 2.27 (3H, s); 2.27 (3H, s); 1.4 (9H, p).

Method 95: 4-Benzyloxy-3-(N-tert-butoxycarbonyl)methanesulfonyl-aminophenol

To a solution of acetic acid, 4-benzyloxy-3-(N-tetrabutoxycarbonyl)-methanesulfonylaminophenyl ester (1.16 g, 2.67 mmol) in a mixture of methanol (10 mL) and water (5 mL) was added 1 M sodium hydroxide solution (3.20mMol) at room temperature. The mixture was stirred for 10 minutes and citric acid added to adjust to pH6-7. The solution was evaporated in vacuo and the residue was added with 30 ml of dichloromethane, washed with water (3x15 ml) and dried. Evaporation of the solvent gave the title compound as a white foam.

5<1>H (250MHz, CDCl 3 ): 7.37 (5H, m); 6.82 (3H, m); 5.09 (1H, br s); 5.20 (2H, s); 3.24 (3H, s); 1.42 (9H,s).

Method 96: (S)-2-[4-Benzyloxy-3-(N-tert-butoxycarbonyl)-methanesulfonylaminophenoxymethyloxirane

The title compound was prepared from [4-benzyloxy-3-(N-et-butoxycarbonyl)-methanesulfonylamino]phenol and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate by the method described in Method 12.

8<1>H (250MHz, CDCl 3 ): 7.35 (5H, m); 6.94 (3H, m); 5.05 (2H, s); 4.20 (1H, dd, J=11Hz and 2.7Hz); 3.90 (1H, m), 3.35 (1H, m); 3.25 (3H, s); 2.92 (1H, m); 2.77 (1H7 m); 1.42 (9H, p).

Method 97: (S,R)-4~{2-[3-(4-Benzyloxy-3-methanesulfonylaminophenoxy)-2-hydroxypropylamino]propytyphenoxymethylphenylphosphinic acid, ethyl ester

A solution of (S)-2-[4-benzyloxy-3-(N-/e/f-butoxycarbonyl)-methanesulfonylamino]phenoxymethyloxirane (0.45 g, 1 mmol) in 25 mL of acetonitrile was treated with lithium perchlorate (0.107 g , 1 mmol), and then stirred until a complete solution of the salt was obtained. To the resulting stirred solution was added (R)-4-(2-aminopropyl)phenoxymethylphenylphosphinic acid, ethyl ester (0.40 g, 1.2 mmol). The mixture was stirred at room temperature for 110 hours, after which the solvent was removed in vacuo. The residue was dissolved in 25 ml of dichloromethane and 2 ml of 1 M hydrochloric acid was added. The mixture was stirred for 30 minutes at room temperature, then washed with 3 x 10 ml saturated sodium bicarbonate solution, 15 ml water and 15 ml saline. The dried extracts were concentrated in vacuo and the crude product was purified by normal phase column chromatography eluting with 10% methanol in dichloromethane to give the title compound as a white foam.

6<1>H (200MHz, CDCl 3 +D 2 O): 7.85 (2H, m); 7.57 (3H, m); 7.38 (5H, m); 7.12 (3H, m); 6.85 (3H, m); 6.62 (1H, m); 5.07 (2H, s); 4.5-4.35 (2H, m); 4.2 (3H, m); 3.92 (2H7m); 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).

Method 98: (S)-4-{2-[3-(4-fe/*-butyldimethylsilyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethyl(3-benzylpropyl)phosphinic acid, n-butyl ester and (S)-2-(4-etr-butyldimethylsilylphenoxy)methyloxyran<1>by the method described in method 13 .

8<1>H (CDCl3+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 (6HJ5).

<1>Eurdpeic patent EP 0611003

Method 99: Methyl 5-acetyl-2-benzyloxybenzoate

Methyl 5-acetylsalicylate (15 g, 0.077 mol), 9.2 ml of benzyl bromide and 11.7 g of potassium carbonate were refluxed in 100 ml of acetone for two hours. After cooling, solids were filtered off, and the filtrate was concentrated in a rotary evaporator. The crude product was chromatographed on silica gel eluting with a 3% mixture of ethyl acetate and hexane to give the product as a white solid.

5<1>H (CDCl 3 ): 8.44-7.05 (8H, m), 5.27 (2H, s), 3.94 (3H, s), 2.58 (3H, s).

Method 100: Methyl 5-acetoxy-2-benzyloxybenzoate

A solution of methyl 5-acetyl-2-benzyloxybenzoate (15.6 g, 0.055 mol) and 42 g of 3-chloroperoxybenzoic acid in 250 ml of dichloromethane was stirred overnight at room temperature. The reaction mixture was then washed with 2 x 50 ml of a saturated aqueous sodium metabisulfite solution, 3 x 250 ml of saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent under reduced pressure gave a white solid.

6<1>H (CDCl 3 ): 7.59-6.99 (8H, m), 5.18 (2H, s), 3.89 (3H, s), 2.27 (3H, s).

Method 101: 3-hydroxymethyl-4-benzyloxyphenol

5.7 g of lithium aluminum hydride was added to a solution of methyl 5-acetoxy-2-benzyloxybenzoate (16 g, 0.053 mol) in 270 ml of dry diethyl ether under an argon atmosphere and at an ice bath temperature. The reaction mixture was allowed to warm to room temperature and stirred for three hours. 530 ml of saturated aqueous ammonium chloride solution was carefully 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 the solvent gave a white solid. 5'H (d<8->DMSO): 8.85 (1H, br, exchanged 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 a singlet after addition of D2O). Method 102: (S)-2-(4-Benzyloxy-3-hydroxymethylphenoxy)methyloxyrane

To a solution of 10.4 g of 3-hydroxymethyl-4-benzyloxyphenol in 55 ml of dimethylformamide at ice bath temperature was added 1.8 g of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for five minutes and then 11.7 g of (2S)-glycidyl-3-nitrobenzenesulfonate was added in a single portion. The temperature was raised to room temperature and stirring continued overnight. 370 ml of ethyl acetate was added, and the organic phase was washed with 2 x 560 ml of water, 370 ml of saturated saline and then dried over anhydrous magnesium sulfate. Filtration followed by removal of the solvent gave the crude product as an oil. Purification by chromatography (silica gel, 20% acetone in hexane) gave an oil which slowly solidified on standing.

5<1>H4eDCI3): 7.40-6.78 (8H,m), 5.07 (2H,s), 4.69 (2H,d), 4.18 (1H,dd), 3.91 (1H, dd), 33.3 (1H, m), 2.90 (1H, m), 2.75 (1H, m), 2.28 (1H, t).

Method 103: (S,R)-4-{2-[3-(4-f-butyldimethylIsilyloxyphenoxy)-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-[(4-tert-butyldimethylsilyloxyphenoxy)methyl]oxyrane by the method of described in procedure 13.

5<1>H (CDC 3 +D 2 O): 7.40-6.75 (13H, m), 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) r_0.95 (3H, t), 0.01 (6H, s).

Method 104: (S, R) 4-{2-[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester and (S)-2-[(4-benzyloxyphenoxy)methyl]oxirane using the method described in method 13.

5<1>H (CDCl2+D2O): 7.50-6.75 (13H, m), 5.00 (2H, s), 4.27-3.85 (7H, m), 3.10- 2.60 (5H, m), 2.20-1.10 (18H, m), 0.94 (3H, t).

Method 105: (S,R) 4-{2-[3-(4-Benzyloxyphenoxy)-2-hydroxypropylamino}propyl}phenoxymethylhexylphosphinic acid, n-butyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylhexylphosphinic acid, n-butyl ester and (S)-2-[(4-benzyloxyphenoxy)methyl]oxirane using the method described in method 13.

8<1>H (CDCl3+D2O): 7.40-6.75 (13H, m), 5.00 (2H, s), 4.25-3.90 (7H, m), 3.20- 2.68 (5H, m), 1.97-1.30 (14H, m), 1.15 (3H, d), 0.95 (6H, m).

Method 106: Acetic acid, (4-benzyloxy-3-fluorophenyl)ester

The title compound was prepared from 4-benzyloxy-3-fluoroacetophenone<1>by the method described in method 100.

5<1>H (CDCl 3 ): 7.45-7.32 (5H, m), 7.00-6.75 (3H, m), 5.12 (2H, s), 2.27 (3H, p).<1>J. With. Chem., 1983, 26 (11), 1570-6.

Method 107: 4-benzyloxy-3-fluorophenol

A solution of acetic acid, (4-benzyloxy-3-fluorophenyl)ester (5.96 g, 23 mmol) in 80 mL of methanol and sodium hydroxide (1.0 g, 25 mmol) in 20 mL of water was refluxed for 90 min. . After cooling, the solution was concentrated, and the residue was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic extracts were separated, washed with water and brine, dried and concentrated to give the title compound.

5<1>H (CDCl3): 7.43-7.25 (5H, m), 6.85 (1H, t, J=9.1Hz), 6.63 (1H, dd, J=12.1 , 3Hz), 6.46 (1H, m), 5.06 (2H, s), 6.65 (1H, br, exchanged with D2O).

Method 108: (S)-2-(4-Benzyloxy-3-fluorophenoxy)methyloxirane

The title compound was prepared from 4-benzyloxy-3-fluorophenol and (S)-glycidyl-3-nitrobenzenesulfonate by the method described in method 102.

6<1>H (CDCl3): 7.44-7.25 (5H, m), 6.90 (1H, t, J=9.2Hz), 6.72 (1H, dd, J=12.5 , 3Hz), 6.58 (1H, ddd, J=9.2, 3, 1.6Hz), 5.07 (2H, s), 4.17 (1H, dd, J=11, 3Hz), 3 .86 (1H, dd, J=11, 5.8Hz), 3.35-3.29 (1H, m), 2.90 (1H, dd, J=5, 4.1Hz), 2.73 ( 1H, dd, J=4,1,2,5Hz).

Method 109: (S)-4-{2-[3-(4-benzyloxy-3-fluorophenoxy)-2-hydipoxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester and (S)-2-(4-benzyloxy-3-fluorophenoxy)methyloxirane using the method described in method 13.

6<1>H (CDCl3): 7.44-7.31 (5H, m), 7.14 (2H, d, J=8.5Hz), 6.9-6.86 (3H, m), 6.96 (1H, dd, J=12.5, 2.8Hz), 6.55 (1H, 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).

Method 110: 3-phenoxypropylphosphinic acid

The title compound was prepared from phosphinic acid and O-allylphenol by the method described in method 42. The crude product was used without further purification.

8<1>H (CDCl 3 ): 9.06 (1H, s); 7.31-7.15 (2H, m); 7.19 (1H, d, J=548.72Hz); 6.94 (1H, t, J=f, 4Hz); 6.89-6.81 (2H, m); 4.01 (2H, t, J=6.04Hz); 2.14-1.84 (4H, m).

Method 111: 3-phenoxypropylphosphinic acid, ethyl ester

The title compound was prepared from 3-phenoxypropylphosphinic acid and ethanol using the method described in Method 43. The crude product was used without further purification.

8<1>H (CDCl 3 ): 7.32-7.20 (2H, m); 7.18 (1H, dt, J=5.33.65, 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).

Method 112: Hydroxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester

The title compound was prepared from 3-phenoxypropylphosphinic acid, ethyl ester and paraformaldehyde using the method described in method 31. Chromatography over silica gel and elution with dichloromethane containing 5% methanol gave a colorless oil.

5'H (CDCl 3 ): 7.30-7.24 (2H, m); 6.94 (1H, t, J=7.43Hz); 6.88 (2H, d, J=8.25Hz); 4.30 (1H is replaced by D2O); 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).

Method 113: 4-Chlorobenzenesulfonyloxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester

The title compound was prepared from hydroxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester and 4-chlorobenzenesulfonyl chloride by the method described in method 32. The crude product was used without further purification.

5<1>H (CDCl 3 ): 7.87 (2H, d, J=8.00Hz); 7.54 (2H, d, J08.45Hz); 7.29-7.26 (2H, m); 6.96 (1H, 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).

Method 114: (2-tert-butoxycarbonylaminoethyl)phenoxymethyl (3-phenoxypropyl)phosphinate, ethyl ester

The title compound was prepared from 4-chlorobenzenesulfonyloxymethyl (3-phenoXypropyl)phosphinic acid, ethyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, tert-butyl ester using the method described in method 24. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 5% methanol.

8<1>H (CDCl 3 ): 7.29-7.23 (3H, m); 7.13 (2H, d, J=8.52Hz); 6.97-6.85 (4H, m); 4.50 (1H, s); 4.25-4.10 (4H, m); 4.05 (2H, t, J=5.50Hz); 3.37-3.32 (2H, m); 2.72 (2H, t, J=7.15Hz); 2.16-2.06 (4H, m); 1.43 (9H, s); 1.34 (3H, t, J=7.15Hz).

Method 115: 4-(2-Aminoethyl)phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester

The title compound was prepared from 4-(2-tetrabutoxycarbonylaminoethyl)phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester by the method described in Method 25. The crude product was used without further purification.

5<1>H (CDCl 3 ): 7.31-7.32 (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, exchanged for D 2 O); 1.34 (3H, t, J=7.14Hz).

Method 116: (S)-4-{2-[3-(4-Benzyloxy-3-hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester and (S)-2-(4-benzyloxy-3-hydroxymethylphenoxy)methyloxirane by the method described in method 13. The crude product was purified by chromatography over silica gel and eluted with 5% methanol in dichloromethane.

5<1>H (CDCl 2 +D 2 O): 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).

Method 117: 3-phenylpropylphosphinic acid

The title compound was prepared from phosphinic acid and allylbenzene by the method described in method 42. The crude product was used without further purification.

5<1>H (CDCl 3 ): 11.28 (1H, s, exchanged with D 2 O); 7.31-7.14 (5H, m); 7.05 (1H, 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).

Method 118: 3-phenylpropylphosphinic acid, n-butyl ester

The title compound was prepared from 3-phenylpropylphosphinic acid and n-butanol using the method described in method 43. The crude product was used without further purification.

5<1>H (CDCl 3 ): 7.32-7.15 (5H, m); 7.06 (1H, 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).

Method 119: Hydroxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester

the title compound was prepared from 3-phenylpropylphosphinic acid, n-butyl ester and paraformaldehyde using the method described in method 31. Chromatography over silica gel and elution with dichloromethane containing 5% methanol gave a colorless oil.

5<1>H (CDCl 3 ): 7.32-7.16 (5H, m); 4.13-3.95 (3H, m, 1H is exchanged with D 2 O); 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).

Method 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 by the method described in method 32. The crude product was used without further purification.

8<1>H (CDCl 3 ): 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, m), 1.43-1.23 (2H, m); 0.91 (3H, t, J=7.42).

Method 121: 4-(2-tert-butoxycarbonylaminoethyl)phenoxymethyl (3-phenylpropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 4-chlorobenzenesulfonyloxymethyl(3-phenylpropyl) phosphoic acid, n-butyl ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, f-butyl ester by the method described in method 24. The crude product was purified by chromatography over silica gel and eluted with dichloromethane containing 5% methanol.

5<1>H (CDCl 3 ): 7.28-7.11 (7H, m); 6.85 (2H, d, J=8.80Hz); 4.50 (1H, s); 4.21-3.99 (4H, m); 3.45-3.30 (2H, m); 2.27-2.72 (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).

Method 122: 4-(2-Aminoethyl)phenoxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester

The title compound was prepared from 4-(2-fe/f-butoxycarbonylaminoethyl)phenoxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester by the method described in Method 25. The crude product was used without further purification.

5<1>H (CDCl 3 ): 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, exchanged with p20); 1.48-1.34 (2H, m); 0.91 (3H, t, J=7.42Hz).

Method 123: (S)-4-{2-[3-(4-Benzyloxy-3-hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3-phenylpropyl)phosphinic acid, n-byjyl ester

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 by the method described in method 13 The crude product was purified by chromatography over silica and eluted with dichloromethane containing 5% methanol.

5<1>H (CDCl 3 +D 2 O): 7.43-7.11 (13 H, m); 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); 0.91J3H, t, J=7.42Hz).

Method 124: Phosphonic acid, bis-cyclohexyl ester

The title compound was prepared from cyclohexanol and phosphorus tribromide using the method described in method 31. Purification by chromatography on silica gel and elution with dichloromethane to 2% methanol in dichloromethane gave the title compound as an oil.

5<1>H (CDCl 3 ): 8.16-5.61 (1H, d), 4.38-4.51 (2H, m), 1.19-1.96 (20H, m).

Method 125: Hydroxymethylphosphonic acid, bis-cyclohexyl ester

The title compound was prepared from phosphonic acid, bis-cyclohexyl ester and paraformaldehyde using the method from procedure 31. Purification by chromatography on silica gel and elution with 2% methanol in dichloromethane gave the title compound as an oil.

8<1>H (CDCl 3 +D 2 O): 4.81-4.42 (2H, m), 3.86-3.84 (2H, d), 1.21-1.96 (20H, m).

Method 126: (4-Chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-cyclohexyl ester

The title compound was prepared from hydroxymethylphosphonic acid, bis-cyclohexyl ester and 4-chlorobenzenesulfonyl chloride by the method described in Method 32 as a colorless oil, followed by chromatography on silica gel and eluted with from 10 to 20% ethyl acetate in hexane. The produced oil solidified to a white solid with a melting point of 55°C to 57°C.

8<1>H JCDCl3 ): 7.85-7.88 (2H, d), 7.53-7.57 (2H, d), 4.40-4.29 (2H, m), 4.08 -4.18 (2rtjn), 1.20-1.86 (20H, m).

Method 127: (R)-4-(2- tert -butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis-cyclohexyl ester

The title compound was prepared from (4-chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-cyclohexyl ester and (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, tert-butyl ester using the method from procedure 24. Purification by column chromatography on silica gel and elution with 2% methanol in dichloromethane gave the title compound as a gum.

8<1>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 (1H, wide s), 2.52-2.81 (3H, m), 1.22-2.05 (20H, m) , 1.42 (9H, s), 1.05-1.07 (3H, d).

Method 128: (R)-4-(2-Aminopropyl)phenoxymethylphosphonic acid, bis-cyclohexyl ester

The title compound was prepared from (R)-4-(2-et/f-butoxycarbonylaminopropyl)phenoxymethylphosphonic acid, bis-cyclohexyl ester using the method described in method 25. Purification by column chromatography on silica gel and elution with 10% methanol in dichloromethane gave the title compound as a gum.

5<1>H (CDCy: 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).

Method 129: (S,R)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphosphonic acid, bis-cyclohexyl ester

The title compound was prepared from (R)-4-(2-aminopropyl)phenoxymethylphosphonic acid, bis-cyclohexyl ester and (S)-glycidyl-4-benzyloxyphenol using the method described in method 13. The crude product was purified by chromatography on silica gel and eluted with 2% methanol in dichloromethane to give the title compound as a gum.

5<1>H (CDCl3): 7.25-7.48 (5H, m), 7.13-7.16 (2H, d), 6.76-6.90 (6H, m), 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).

Method 130: Phosphonic acid, bis-(2,2-diphenylethyl) ester

The title compound was prepared from 2,2-diphenylethanol and phosphorus tribromide using the method described in method 31. Purification by chromatography on silica gel and elution with 2% methanol in dichloromethane gave the title compound as an oil.

5<1>H (CDCl 3 ): 7.78-5.18 (1H, d), 7.08-7.35 (20H, m), 4.18-4.49 (6H, m).

Method 131: Hydroxymethylphosphonic acid, bis-(2,2-diphenylethyl) ester

The title compound was prepared from phosphonic acid, bis-(2,2-diphenylethyl)ester and paraformaldehyde by the method described in Method 31 as a solid (m.p. 95°C to 97°C) followed by chromatography on silica gel and elution with 2% methanol in dichloromethane.

6<1>H (CDCl3): 7.15-7.31 (20H, m), 4.25-4.51 (6H, m), 3.52-3.57 (2H, t), 2, 07-2.14 (1H,h).

Method 132: (4-Chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-(2,2-diphenylethyl)ester

The title compound was prepared from hydroxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester and 4-chlorobenzenesulfonyl chloride by the method described in method 32. Purification by chromatography on silica gel and elution with j10% ethyl acetate in hexane followed by a treatment of the residue with diethyl ether and hexane gave the title compound as a solid (mp 75°C to 76°C).

5<1>H (CDCl3): 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).

Method 133. 4-(2-tert-butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester

The title compound was prepared from (4-chlorobenzenesulfonyloxymethyl)phosphonic acid, bis-(2,2-diphenylethyl)ester and 2-(4-hydroxyphenyl)ethylcarbamic acid, tert-butyl ester using the method described in method 24. Purification by column chromatography on silica gel and eluting with 1% methanol in dichloromethane gave the title compound as a gum.

81(CDCl 3 +D 2 O): 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), 2, 70-2.75 (2H, t), 1.43 (9H, s).

Method 134: 4-(2-Aminoethyl)phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester

The title compound was prepared from 4-(2-te/f-butoxycarbonylaminoethyl)phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester by the method described in Method 25, and the product was used in the next step without further purification.

8<1>H (CDCl3): 7.05-7.29 (22H, m), 6.70-6.64 (2H, d), 4.41-4.51 (4H, m), 4, 26-4.31 (2H, t), 3.87-3.91 (2H, dd), 3.31-3.44 (1H, m), 2.90-2.96 (1H, t), 2.67-2.75 (2H, q), 1.56-1.17 (2H, broad s, exchanged with D 2 O).

Method 135: (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino] ethylphenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester

The title compound was prepared from 4-(2-aminoethyl)phenoxymethylphosphonic acid, bis-(2,2~-diphenylethyl)ester and (S)-glycidyl-4-benzyloxyphenol using the method described in method 13. The crude product was purified by chromatography on silica gel and eluted with 5% methanol in dichloromethane to give the title compound.

5<1>H Cd6-DMSO+D2O): 6.69-7.40 (33H, m), 5.01 (2H, m), 4.28-4.47 (7H, m), 3.86 -4.18(41-1, m), 2.74-2.95 (6H, m).

Method 136: (R)-2,2-di-tert-butyl-6-(oxyran-2-ylmethoxy)-4H, 1,3,2-beraodioxasilynan

The title compound was prepared from 2,2-di-ten>butyl-4H-1,3,2-benzodioxasilin-6-ol (700 mg, 2.50 mmol) and (2R)-(-)-glycidyl-3-nitrobenzenesulfonate (780 mg, 3.0 mmol) using a procedure similar to that described in procedure 12.

5<1>H (250MHz, CDCl 3 ): 6.72-6.88 (2H, m); 6.52 (1H, d); 4.95 (2H, s); 4.16 (1H, dd); 3.89 (1H, dd); 3.34 (1H, m); 2.90 (1H, t); 2.73 (1H, dd) and 1.04 (18H, s).

Method 137: (RR)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benrdioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid , ethyl ester

The title compound was prepared from (R)-2,2-di-tert-butyl-6-(oxyran-2-ylmethoxy)-4H-17372-benzodioxasilylane (240 mg, 0.71 mmol) and (R)-4-( 2-Aminopropyl)phenoxymethyl-phenylphosphinic acid, ethyl ester (238 mg, 0.71 mmol) using a procedure similar to that described in Method 14. 5<1>H (250MHz, CDCl3): 7.93 (2H , m); 7.46-7.62 (3H, m); 7.08 (2H, d); 6.83 (3H, m); 6.69 (1H, dd); 6.48 (1H, 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

A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(2-hydroxyphenoxy)propylamino] propyl]phenoxyacetate (120 mg, 0.31 mmol) in 8 mL of dioxane and 5 mL of a 2 M solution of sodium hydroxide was stirred at room temperature under argon for 18 h. The pH of the solution was adjusted to 9 with 2 M hydrochloric acid, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with from 0 to 5% isopropanol in water to give the title compound as a colorless solid, mp 130°C; [a]D<25>-13° (c=0.35, water).

5<1>H (270MHz, d<6->DMSO/D20): 7.0-6.7 (8H, s), 4.2-3.9 (3H, m), 3.1-2, 8 (4H, m), 2.40_{1H, m) and 0.90 (3H, d, J=6.3Hz).

Example 2: (S,R)-sodium 4-[2-[2-hydroxy-3-(3-hydroxyphenoxy)propylamino]propyl]phenoxyacetate

A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(3-hydroxyphenoxy)propylamino]propy]phenoxyacetate (140 mg, 0.36 mmol) in 8 mL of dioxane and 5 mL of a 2 m sodium hydroxide solution was stirred at room temperature under argon for five hours. The pH of the solution was adjusted to 9 with 2 M hydrochloric acid, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with from 0 to 5% isopropanol in water to give the title compound as a colorless solid, mp 136°C; [a]D<25>-11° (c=0.16, 50% isopropanol/50% water).

5<1>HX270MHz, d<8->DMSO/D20): 7.1-6.9 (3H, m), 6.70 (2H, d, J=8.5Hz), 6.35-6, 25 (3H7m), 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

A solution of (S,R)-methyl-4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetate (140 mg, 0.36 mmol) in 8 mL of dioxane and 5 ml of a 2 M sodium hydroxide solution was stirred at room temperature under argon for 18 hours. The pH of the solution was adjusted to 9 with 2 m hydrochloric acid, after which the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with from 0 to 20% isopropanol in water to give the title compound as a colorless solid, mp 119°C; [a]D<25->15° (c=0.34, 70% isopropanol/ 30% water).

5<1>H (270MHz, d<6->DMSO/D20): 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 (1H, m) and 0.90 (3H, d, J=6.3Hz) ppm.

Example 4: (S,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphosphonic acid, diethyl ester

A solution of (S,R)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benzodioxasilynan-6-yloxy)-2-hydroxypropylamine]propyl}phenoxymethylphosphonic acid diethyl ester (270 mg, 0.424 mmol) in 10 mL tetrahydrofuran in a plastic container at room temperature under argon, 5 drops of a hydrogen fluoride pyridine complex were added. After 15 minutes, 220 mg of aluminum oxide was added, and stirring was continued for 30 minutes. The reaction mixture was then filtered through a thin cake of celite, after which the solvent was evaporated. The crude product was purified by reverse phase chromatography over C1.8 silica and eluted with 20% ethanol in water, which gave the title compound as a pale beige foam.

8<1>H (400MHz, d<6->DMSO): 8.81 (s, exchanged with D 2 O); 7.18 (2H, d, J=10.7Hz); 6.95 (2H, d, J=10.7Hz); 6.92 (1H, d, j=2.4Hz); 6.70 (1H, d, J=9.6Hz); 6.65 (1H, 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 (1H, 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-hydroxymethyl-phenoxy)propylamino]propyl}phenoxymethyl)ethylphosphonate

(S,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino}-propyl)phenoxymethylphosphonic acid diethyl ester (220 mg, 0.443 mmol) and 5 mL of 1 M lithium hydroxide in 5 mL of 1 ,4-dioxane was stirred at room temperature for 24 hours under argon. The solution was adjusted to pH 9 by adding solid carbon dioxide, after which the solvents were evaporated. The residue was purified by reverse phase chromatography over C18 silica eluting with from 0 to 10% ethanol in water to give a white powder, mp 120°C to 121°C.

5<1>H (400MHz, d<6->DMSO): 9.95 (s, br, exchanged with D 2 O); 7.07 (2H, d, J=10.7Hz); 6.9 (1H, d, J=2.0Hz); 6.78 (2H, d, J=10.7Hz); 6.71 (1H, d, J=10Hz); 6.5 (1H, d, J=10.5Hz and 2.1Hz); 5.2 (s, br, exchanged with D20); 4.45 (2H, s); 4.07 (1H, 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}phenoxymethylcarboxylic acid methyl ester

A solution of (S,R)-4-{2-[3-2,2-di-tert-butyl-4H-1,3,2-benzodioxasilian-6-yl-oxy)-2-hydroxypropylamine]propyl} phenoxymethylcarboxylic acid methyl ester (0.262 g, 0.469 mmol) in 10 ml of tetrahydrofuran in a plastic container, at room temperature under argon was added 5 drops of hydrogen fluoride pyridine complex. After 10 minutes, 250 mg of aluminum oxide was added, and stirring was continued for 30 minutes. The reaction mixture was filtered through a thin cake of celite, after which the solvent was evaporated in vacuo. The crude product was used in the next step.

8<1>H|400MHz, d<6->DMSO): 8.83 (s, br, exchanged with D 2 O); 7.15 (2H, d, J=9.8Hz); 6.89~(1H, d, J=2.6Hz); 6.83 (2H, d, J=9.6Hz); 6.66 (2H, m); 4.95 (s, br, exchanged with D20); 4.73 (2H, s); 4.46 (2H, s); 3.96 (1H, 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

-(^R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyljphenoxymethylcarboxylic acid methyl ester (0.16 g, 0.382 mmol) and 5 mL of 2 M sodium hydroxide in 5 mL of 1, 4-dioxane was stirred at room temperature for 20 hours under argon. The solution was adjusted to pH 9 by adding solid carbon dioxide, after which the solvents were evaporated. The residue was purified by reverse phase chromatography over C18 silica eluting with 0 to 20% ethanol in water to give white crystals, mp 140°C to 142°C. 6<1>H (400MHz, d<6->DMSO): 9.0 (s, br, exchanged with D 2 O); 6.94 (3H, m); 6.81-6.62 (4H, m); 4.48 (2H, s); 4.41 (2H, s); 4.18 (1H, m); 3.87 (2H, m); 3.25 (2H, m); 2.94 (1H, m); 2.82 (1H, m); 2.34 (1H, m); 0.94 (3H, d, J=7.5Hz). Example 8: (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)-propylamino]propyl}phenoxyacetic acid

The title compound was prepared from (S,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphosphonic acid, methyl ester by a modification of the method described in Example 7 Acidification to pH 7 with 1 M hydrochloric acid followed by reverse phase chromatography and freeze drying gave the title compound.

Example 9: (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)-propylamino]propyl}phenoxymethylphosphonic acid, ethyl ester

The title compound was prepared from (S,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphosphonic acid diethyl ester by a modification of the method described in example 5. Acidification to pH 7 with 1 M dilute hydrochloric acid followed by reverse phase chromatography and freeze drying gave the title compound.

Example 10: (SR)-4-{2-[3-(3,4-dihydroxyphenoxy)-2-hydroxy-propylamino]propyl}phenoxyacetic acid, methyl ester, hydrochloride

A solution of (SR)-4-{2-[3-(3,4-dibenzyloxyphenoxy)-2-hydroxypropylamino] propyljphenoxyacetic acid, methyl ester (230 mg, 0.4 mmol) in 30 mL of methanol containing 71 mg of palladium (II) chloride (0.4 mmol) was hydrogenated at room temperature and pressure for 18 h. The mixture was filtered through a cake of a filter medium, after which the filter cake was washed with methanol, and the combined filtrates were evaporated. The residue was dissolved in water and the solution was freeze-dried to give the title compound as a colorless solid.

8(D25):7",28 (2H, d, J=8.6Hz), 6.94 (2H, d, J=8.6Hz), 6.85 (1H, d, J=8.7Hz) , 6.51 (1H, d, J=3Hz), 6.40 (1H, dd, J=8.7Hz), 4.72 (2H, s), 4.3-4.25 (1H, m) , 4.05-3.97 (2H, m), 3.82 (3H, s), 3.68 (1H, dd, J=13.8, 6.9Hz), 3.4-3.36 ( 2H, m), 3.05 (1H, dd, J=13.1, 7Hz), 2.94 (1H, dd, J=13.8, 7.6Hz), 1.34 (3H, d, J =6.6Hz).

Example 11: (SR)-4-{2-[3-(3,4-dihydrophenoxy)-2-hydroxypropylamino] propyl}phenoxyacetic acid, hydrochloride

A solution of (SR)-4-{2-[2-hydroxy-3-(3,4-dihydrophenoxy)propylamino]propyl}phenoxyacetic acid, methyl ester, hydrochloride (78 mg, 0.17 mmol) in 2 mL of water containing 0 .5 ml of 1 M hydrochloric acid (0.51 mmol), was kept at 100°C under argon for three hours. After cooling to room temperature, the solution was freeze-dried, whereby the title compound was prepared as a colorless solid. 6 (d<8->DMSO)+D20): 7.16 (2H, d, J=8.6Hz), 6.86 (2H, d, J=8.6Hz), 6.64 (1H, d , J=8.5Hz), 6.42 (1H, d, J=3Hz), 6.21 (1H, dd, J=8.5, 3Hz), 4.65 (2H, s), 4.25 (1H, m), 3^9-3.8 (2H, m), 3.5 (1H, m), 3.3-3.2 (2H, m), 3.05 (1H, dd, J =12.5, 9.7Hz), 2.60_(1H, 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}-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester

The title compound was prepared from (SR)-5-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl}-1 ,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester using the method described in example 4.

8(d<6->DMSO+D2O): 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]propyl}-1,3-benzodioxole-2,2-dicarboxylic acid, dilithium salt

A solution of (SR)-5-{2-[3-(4-hydroxy-3-hydroxymethylphenoxy)-2-hydroxypropylamino]propyl}-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester (520 mg, mMol ) in 10 mL of dioxane and 3 mL of water and 6 mL of a 1 M lithium hydroxide solution (6 mmol), was stirred at room temperature under argon for 24 h. The pH of the solution was adjusted to 9 with dilute hydrochloric acid, after which the solvent was evaporated. The residue was purified by reverse phase chromatography and eluted with water-methanol mixtures to give the title compound as a colorless solid.

5(de<->DMSO+D2O): 6.90 (1H, d, J=2.2Hz), 6.76-6.58 (4H, m), 6.49 (1H, d, J=7f ?Hz), 4.42 (2H, s), 4.1-4.0 (1H, m), 3.84-3.81 (2H, m), 3.2-2.8 (4H, m ), 2.45-2.38 (1H, 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

The title compound was prepared from (S)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]ethyl} phenoxymethylphosphonic acid, diethyl ester using an experimental procedure corresponding to that described in Example 4. The title compound was prepared and isolated as a white foam. 5<1>H (200MHz, d<6->DMSO): 7.20 (2H, br D), 6.95 (3H, m), 6.67 (2H, m), 5.10 (1H, br t), 4.45 (4H, m), 4.15 (7H, m), 3.88 (2H, m), 2.8-3.2 (4H, m), 1.25 (6H, t, J=6.5Hz). Example 15: (S)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]ethyl}phenoxymethylphosphonate, ethyl ester, monolithium salt

The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]ethyl}phenoxymethylphosphonic acid, diethyl ester using a procedure similar to that used in Example 5 , after which the product was isolated as a solid after freeze-drying.

S<1>hT(250MHz, d<6>^DMSO): 7.0 (2H, d, J=8Hz), 6.70 (4H, m), 6.25 (1H, dd, J=8Hz and 2.3Hz), 4.42 (2H, s), 4.20 (1H, br s), 3.75 (5H, m), 3.55 (1H, 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-hydroxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester

(SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilynan-6-yl-oxy)-2-hydroxy-propylaminojpropyljphenoxymethylphosphonic acid, bis-(3 -benzyloxypropyl)ester (0.49 g, 0.56 mmol) was converted to the title compound by the procedure described in Example 4. 5<1>H (250MHz, CDCl3): 7.25 (10H, m), 7.05 (2H, d), 6.73 (2H, d), 6.62 (1H, 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 (1H, 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

The JT-ittel compound was prepared by the same method as described in example 5 from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]-2-propyl}phenoxymethylphosphonic acid, bis-(3-benzyloxypropyl)ester (0.314 g, 0.43 mmol).

5<1>H (400MHz, CD3OD): 7.15 (5H, m), 6.97 (2H, d), 6.74 (3H, m), 6.55 (1H, d), 6.48 (1H, 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 (1H, dd), 1.78 (2H, m), 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

The title compound was prepared from (SR)-4-{2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl}phenoxymethylphosphonic acid, bis-(3 -hydroxypropyl)ester (0.248 g, 0.36 mmol) by the same procedure as described in example 4.

5<1>H (200MHz, CDjOD): 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 (1H, m), 3.25 ( 3H, m), 2.74 (1H, m), 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-hydipoxypropyl)ester, lithium salt

The title compound was prepared by hydrolysis of (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethyl)phosphonic acid, bis-(3-hydroxypropyl)ester ( 0.198 g, 0.356 mmol), using the procedure described in Example 5.

5<1>H (250MHz, CD3OD): 7.11 (2H, d), 6.90 (3H, m), 6.70 (1H, d), 6.60 (1H, 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 (1H, dd), 1.83 (2H, m), 1.08 (3H, d).

Example 20: (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (SR)-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]propyl}phenoxy- methyphenylphosphinic acid, ethyl ester (0.906 g, 1.35 mmol) by the same method as described in Example 4, and the compound was obtained as a colorless 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

The title compound was prepared as a white foam after freeze-drying, from (SR)-4-{2-[4-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester (0.715 g, 1.35 mMol) by the same procedure as described in Example 5, except that methanol was used as a co-solvent instead of 1,4-dioxane.

5<1>H (250MHZ, CD3OD): 7.89 (2H, m), 7.40 (3H, m), 7.08 (2H, d), 6.91 (1H, d), 6.84 (2H, d), 6.70 (1H, d), 6.64 (1H, dd), 4.62 (2H, s), 4.20-4.00 (3H, m), 3.91 ( 2H, m), 3.37-2.85 (4H, m), 2.62 (1H, 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

The title compound was prepared from (S)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]ethyl}phenoxymethyl- (3-benzyloxypropyl)phosphinic acid, n-butyl ester using the method described in Example 4. The crude product was used without further purification.

5(d<6->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); 1.66-1.61 (2H, m); 1.44-1.39 (2H, m); 0.94 (3H, t, J=7.4Hz).

Example 23: (S)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]ethyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid

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 by a modification by the procedure described in Example 5. Acidification to pH 3.5 with 1M hydrochloric acid followed by C18 reverse phase chromatography and elution with 30% water in methanol and freeze drying of the resulting foam gave the title compound as a solid.

δ(d<8->DMSO+D 2 O): 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, m); 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]propyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester

The title compound was prepared from (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl}phenoxymethyl- (3-benzyloxypropyl)phosphinic acid, n-butyl ester using the method described in Example 4. The crude product was used without further purification.

δ(CD 13 +CD 3 OD): 7.44-7.30 (5H, m); 7.17 (2H, d, J=8.53Hz); 6.82 (2H, d, J=8^7Hz); 6.76-6.68 (2H, m); 6.65-6.59 (1H, m); 4.75 (2H, s); 4.51 (2H, s); 4.20-3.8617H, 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, m); 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)phosphonic acid, hydrochloride salt

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 by a modification of the procedure from example 5. Acidification to pH 3.5 with 1 M hydrochloric acid followed by C18 reverse phase chromatography and elution with water-methanol (30%) and freeze drying of the resulting foam gave the title compound as a solid.

8(d<6->DMSO+D 2 O): 7.33-7.23 (5H, m); 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 (3Hjd, J=6.12Hz).

Example 26: (S)-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (S)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilynan-6-yloxy)-2-hydroxypropylamino]ethyl}phenoxymethyl cyclohexylphosphinic acid , n-butyl ester using the method described in example 4. The crude product was used without further purification.

δ(dr<->DMSO+D 2 O): 7.18 (2H, d, J=8.25 Hz); 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 (D20 eclipses 1H 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}phenoxymethylcyclohexylphosphinic acid, lithium salt

The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Example 5, as a solid after C18 reverse phase chromatography and elution with water-methanol (30%) and lyophilization of the resulting foam.

6(CD 3 OD): 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 (1H, d, J=8.75Hz); 4.62 (2H, s); 4.04J2H, s); 4.09-4.00 (1H, m); 3.97 (1H, dd, J=10.45, 6.70Hz); 3.90 (1H, dd, J=f<c>f; 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

Peat solution of (S)-4-{2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylamino]ethyl} phenoxymethylcyclohexylphosphinic acid, n-butyl ester (1.0 g, 1.64 mmol) 100 ml methanol containing 50 mg 10% palladium on charcoal, was hydrogenated at 40°C and a pressure of about 3 kg per cm<2> for 24 hours. After cooling to room temperature, the suspension was filtered through a cake of filter media, after which the filtrate was evaporated to give the title compound.

8(d<6->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), 2.01-1.2 (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

The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy)propylaminoethylphenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Example 5.

8(d<6->DMSO+D20): 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, m), 2.8-2.5 (6H, m), 1, 95-1.0 (11H, m).

Example 30: (S)-4-[2-{2-hydroxy-3-(3-hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (S)-4-{2-[2-hydroxy-3-(3-benzyloxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Example 28.

5(d<6->DMSO+D2O): 7.19 (2H, d, J=8.5Hz), 7.05-6.98 (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

The title compound was prepared from (S)-{2-[2-hydroxy-3-(3-hydroxyphenoxy)propylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Example 5. 5(d^DMSO+ D20): 7.01 (2H, d, J=8.5Hz), 6.98 (1H, t, J=8Hz), 6.78 (2H, d, J=8.5Hz), 6.48 ( 1H, 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 (11H, m). Example 32: (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]propyl}phenoxymethyl cyclohexylphosphinic acid , n-butyl ester using the method described in example 4. The crude product was used without further purification.

_8.(CDCl 3 +D 2 O): 7.19 (2H, d, J=8.80 Hz); 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 (1H, 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);

1.25l3H, 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

The title compound was prepared from (SR)-4{2-[2-hydroxy-3-[(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester by the method described in Example 5, as a solid after C18 reverse phase chromatography and elution with water-methanol (30%) and lyophilization of the resulting foam.

8(D 2 O): 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-hexylphosphinic acid, n-butyl ester

The title compound was prepared from (SR)-4-{2-[3-(2,2-di-f-butyl-4H-1,3,2-benzodioxasilynan-6-yloxy)-2-hydroxypropylamino]propyl}phenoxy- methyl-n-hexylphosphinic acid, n-butyl ester using the method described in Example 4. The crude product was used without further purification.

5(d<6->DMSO+D 2 O): 7.15 (2H, d, J=8.50 Hz); 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, p, ); 4.35-4.28 (2H, m); 4.05-3.90 (4H, m); 3.86-3.81 (1H, m); 2.97-2.90 (1H, m); 2.89 (3H, m); 2.50-2.45 (1H, 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

The title compound was prepared from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydoxymethylphenoxy)propylamino]propyl}phenoxymethyl-n-hexylphosphinic acid, n-butyl ester by the method described in Example 5, as a solid after C18 reverse phase chromatography and elution with water-methanol (30%) and lyophilization of the resulting foam.

8(d<6->DMSO+D 2 O): 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 (1H, 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}phenoxymethyl-n-hexylphosphinic acid, n-butyl ester

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 by the method described in example 28.

_8(d<6->DMSO+D20): 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, m).

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-hexylphosphinic acid, n-butyl ester by a modification of the procedure described in Example 25. Acidification to pH 6 with 1 M hydrochloric acid followed by C18 reverse phase chromatography and freeze drying afforded the title compound as a solid.

5(d<6->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, m), 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

The title compound was prepared from (R)-4-{2-[3-(2,2-di-f-butyl-4H-1,2,3-ben2bdioxasilinan-6-yloxy)-2-(S)-hydroxypropylamino] propyl}phenoxymethyl phosphonic acid, bis-(2-phenylethyl)ester using the method described in Example 4. The crude product was used in the next step 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

The title compound was prepared from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphosphonic acid, bis-(2-phenylethyl)ester by the method of described in example 5, as a solid after chromatography on C18 reverse phase silica gel and elution with 40% methanol in water, and lyophilization of the resulting foam.

8(d<8->DMSO+D 2 O): 9.44 (1H, exchanged with D 2 O); 7.15-7.26 (5H, complex m); 7.03^7.05 (2H, d); 6.81-6.82 (1H, d); 6.67-6.78 (2H, d); 6.67-6.69 (2H, d); 6.35-6.38 (1H, dd); 5.08 (1H, t); 4.43-4.44 (2H, d); 3.94-3.99 (2H, q); 3.65-3.76 (5H, corn neck 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-[3-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]propyl}phenoxymethylphosphinic 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}phenoxymethylbenzyl phosphinic acid , n-butyl ester using the method described in Example 5. The compound was used in the next step without further purification.

δ(CDCl 3 +D 2 O): 7.24-7.26 (5H, s); 7.05-7.09 (2H, d); 6.65-6.72 (3H, complex m); 6.40-3.62 (3H, complex m); 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}phenoxymethylbenzylphosphinic 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 by the method described in Example 5, followed by acidification to pH 3.5 with 1 M hydrochloric acid, which gave a solid (m.p. 180°C to 183°C) after chromatography on C18 reverse phase silica gel and eluting with 40% methanol in water.

6(d<6->DMSO+D 2 O): 7.00-7.24 (7H, complex m); 6.94-6.95 (1H, d); 6.69-6.81 (2H,

d); 6.70-6.72 (1H, d); 6.61-6.69 (1H, m); 4.46 (2H, s); 4.14-4.17 (1H, m); 3.83-3.91 (1H, m); 3.64-3.69 (2H, d); 3.25-3.30 (1H, 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-hydroxymethylphenoxy)propylamino]ethyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (S)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benzodioxasilinan-6-yloxy)-2-hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid , ethyl ester (0.926 g, 14.1 mmol) by a procedure corresponding to that described in Example 4, and the compound was obtained as a colorless gum.

m/z: MHT 516 (60%)

Example 43: (S)-4-{2-[3-(4-hydroxy-3-hydroxymethylphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid, lithium salt

The title compound was prepared as a white foam (after freeze-drying) from (S)-4-{2-[3-(4-hydroxy-3-hydroxymethylphenoxy)-2-hydroxypropylamio]ethyl}-phenoxymethylphenylphosphinic acid, ethyl ester (483 mg, 0, 94 mmol) by the same method as described in example 21.

8<1>H (250MHz, CD3OD): 7.89 (2H, m), 7.41 (3H, m), 7.09 (2H, d), 6.90 (1H, d), 6.82 (2H, <J,), 6.69 (1H, d), 6.63 (1H, dd), 4.62 (2H, s), 4.05 (3H, m), 3.87 (2H, m), 3.05-2.63 (6H, m).

Example 44: (S)-4-{2-[3-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}-phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid ethyl ester using the procedure of Example 28.

6<1>H (250MHz, CD3OD): 7.92 (2H, m); 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 (1H, 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-hydroxyphenoxy9-2-hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid, lithium salt

The title compound was prepared from (S)-4-{2-[3-(4-hydroxyphenoxy)-2-_hydroxypropylamino]ethyl}phenoxymethylphenylphosphinic acid, ethyl ester using the method described in Example 5.

5<1>H (250MHz, CD3OD): 7.94 (2H, m); 7.41 (3H, m); 7.08 (2H, d, J=8.4Hz); 6.82 (2H7*J, 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-hydroxypropylamino]propyl}-phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (S,R)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester by the method described in Example 28.

8<1>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 (1H, m), 3.35-3.08 (3H, m); 2.7 (1H, m); 1.4 (3H, t, J=7.4Hz); 1.22 (3H, d, J=7.7Hz).

Example 47: (S,R)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, lithium salt

The title compound was prepared from (S,R)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester using the method described in Example 5.

5<1>H (250MHz, CD3OD): 7.9 (2H, m); 7.42 (3H, m); 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, m); 3.1-2.55 (5H, m); 1.08 (3H, d, J=7.7Hz).

Example 48: (S,R)-4-{2-[3-(4-hydroxy-3-methanesulfonylamiophenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (S,R)-4-{2-[3-(4-benzyloxy-3-methanesulfonylaminophenoxy)-2-hydroxypropylamino]propyl}phenylphosphinic acid, ethyl ester according to the method described in example 28.

6<1>H (250MHz, d<6->DMSO): 7.8 (2H, m); 7.68 (1H, m); 7.61 (2H, m); 7.16 (2H, d, J=8.2Hz); 7.01 (1H, d, J=1.40Hz); 6.94 (2H, d, J=7.9); 6.84 (1H, d, J=8.4Hz); 6.71 (1H, m); 4.52 (2H, m); 4.17 (3H, m); 3.96 (2H, m); 3.3-3.14 (4H, m); 2.94 (3H, s); 2.71 (1H, 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}phenoxymethylphenylphosphinic acid, hydrobromide salt

The title compound was prepared from (S,R)-4-{2-[3-(4-hydroxy-3-methanesulfonylaminophenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphenyl phosphinic acid, ethyl ester by the method described by D.M.Walkeret. eel. J. Chem. Soc. Chem. Commun., (1987) 22, 1710.

6<1>H (250MHZ, CD3OD): 7.9 (2H, m); 7.48 (3H, m); 7.13 (2H, d); 7.0 (1H, d); 6.89 (2H, d); 6.83 (1H, d); 6.68 (1H, dd); 4.20 (3H, m); 3.95 (2H, m); 3.5-2.9 (4H, m); 2.93 (3H, s); 2.72 (1H, m); 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

A solution of (S) 4-{2-[3-(4-f-butyldimethylsilyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-buphyl ester (199 mg, 0.28mMol) in 10 mL dichloromethane and 1 M hydrogen chloride in diethyl ether, was stirred at room temperature for two hours. The solution was then concentrated to give the title compound as a solid.

5<1>H (d<6->DMSO+D20): 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, m), 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

The title compound was prepared from (S) 4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethyl(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride by the method described in Example 5.

81H (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, m), 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

A solution of (S,R) 4-{2-[4-t-butyldimethylsilyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester (525 mg, 0.74 mmol) in 50 ml of methanol was treated with 2.70 ml of acetyl chloride. The reaction mixture was stirred for eight hours at room temperature, after which the solvent was removed to give the title compound.

5<1>H (d<6->DMSO): 7.37-6.67 (13H, m), 4.45 (2H, s), 4.33 (2H, m), 4.18 (1H , brs), 4.04-3.83 (4H, m), 3.48 (2H, t), 3.35 (1H, m), 3.18 (2H, m), 3.06 (1H, m), 2.60 (H, 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

The title compound was prepared from (S,R) 4-{2-[4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethyl-(3-benzyloxypropyl)phosphinic acid, n-butyl ester, hydrochloride by the method described in Example 5 .

5<1>H (d<6->DMSO): 7.32-6.50 (13H, m), 4.41 (2H, s), 3.80-3.69 (5H, m), 3 .45 (2H, t), 2.95^.50 (5H, m), 1.75 (2H, m), 1.44 (2H, m), 0.95 (3H, d).

Example 54: (S,R) 4-{2-[4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester

The title compound was prepared from (S,R) 4-{2-[4-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester using the method described in Example 28.

5<1>H (CDCl3): 7.10-6.45 (8H, m), 4.25-3.80 (7H, m), 3.20-2.75 (5H, m), 2, 15-1.15 (-18Hrm),0.93(3H,d).

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-hydroxypropylamino]propyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester using the method described in Example 5.

5<1>H (d<6->DMSO+D2O): 7.20 (2H, d), 6.80 (2H, d), 6.71 (4H, m), 4.11 (1H, m ), 3.84-3.77 (4H, m), 3.08-2.82 (5H, m), 1.88-1.23 (11H, m), 0.98 (3H, d).

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-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylhexylphosphinic acid, n-butyl ester by the method described in Example 28.

5<1>H (d<6->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 (1H, 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

- The Tiffel compound was prepared from (S,R) 4-{2-[4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylhexylphosphinic acid, n-butyl ester using the method described in example 5. 8<1>H Cd<6->DMSO): 7.04-6.41 (8H, m), 3.80-3.63 (5H, m), 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

A solution of (S)-4-{2-[3-(4-benzyloxy-3-fluorophenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester (0.88 g, 1.36 mmol) in 50 mL methanol containing 20 mg of palladium (II) chloride, was hydrogenated at room temperature and atmospheric pressure for four hours. The suspension was filtered through a cake of filter media and the filtrate was evaporated to give the title compound.

8<1>H (CDCl3+D2O9. 7.10 (2H, d, J=8.5Hz), 6.88, 6.78 (3H, m), 6.54 (1H, dd, J=12, 2, 2.8Hz), 6.36-6.32 (1H, m), 4.16-3.98 (5H, m), 3.84 (2H, d, J=5.08Hz), 3, 06-2.77 (6H, m), 2.02-1.23 (15H, m), 0.92 (3H, t, J=7.3Hz).

Example 59: (S)-4-{2-[3-(3-fluoro-4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, lithium salt

The title compound was prepared from (S)-4-{2-[3-(3-fluoro-4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylcyclohexylphosphinic acid, n-butyl ester using the method described in Example 5.

8<1>H (d<6->DMSO+D20): 7.04 (2H, d, J=8.6Hz), 6.89 (1H, dd, J=10.2, 8.9Hz), 6.75 (2H, d, J=8.6Hz), 6.60 (1H, dd, J=12.9, 2.9Hz), 6.08 (1H, 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 (11H, m).

Example 60: (S)-4-{2-[3-(4-hydroxy-3-hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3-phenylpropyl)phosphinic acid, n-butyl ester

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 by the method of described in Example 28. The crude product was used without further purification.

Mass Spectr. 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

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 by the method described in example 5. The crude product was purified by chromatography over C18 reverse phase silica and eluted with water/methanol mixtures.

5<1>H (d 6 -DMSO+D 2 O): 7.26-7.22 (2H, m); 7.16-7.12 (3H, m); 7.06 (2H, d, J=8.63Hz); 6.89 (1H, d, J=2.95Hz); 6.79 (2H, d, J=8.63Hz); 6.69 (1H, d, J=8.67Hz); 6.55 (1H, dd, J=8.67, 3.07Hz); 4.45 (2H, s); 4.10-4.00 (1H, 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, m); 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

The title compound was prepared from (S)-4-{2-[3-(4-benzyloxy-3-hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester by the method described in Example 28. The crude product was used without further purification.

8'H (CDCl 3 +D 2 O): 7.30-7.24 (3H, m); 7.12 (2H, d, J=8.52Hz); 6.97-6.74 (6H, m); 6.53 (1H, 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

The title compound was prepared from (S)-4-{2-[3-(4-hydroxy-3-hydroxymethyl)phenoxy-2-hydroxypropylamino]ethyl}phenoxymethyl(3-phenoxypropyl)phosphinic acid, ethyl ester by the method described in example 25. The crude product was purified by chromatography over C18 reverse phase silica and eluted with water/methanol mixtures.

8<1>Hia<6->DMSO+D 2 O): 7.23 (2H, t, J=7.7Hz), 6.94 (2H, d, J=8.8Hz); 6.93 (1H, s);

6.89-6.86 (3H, m); 6.72 (2H, d, J=8.6Hz); 6.67 (1H, d, J=8.64Hz); 6.56 (1H, dd, J=2.9, 8.6Hz); 4.44 (2H, s); 4.18-4.16 (1H, m); 3.97 (2H, t, J=6.5Hz); 3.87-3.79 (4H, m): 3.08 (1H, d, J=10.3Hz); 2.97-2.90 (3H, m); 2.83-2.81 (2H, m); 1.97-1.87 (2H, m); 1.61-1.53 (2H, m).

Example 64: (S,R)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphosphonic acid, bis-cyclohexyl ester, hydrochloride salt

The title compound was prepared from (S,R)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]propyl}phenoxymethylphosphonic acid, bis-cyclohexyl ester by the method described in method 9. The crude product was purified by crystallization of the hydrochloride salt from dichloromethane, which gave a solid with a melting point of 187°C to 189°C.

8<1>H (CDCl 3 +D 2 O): 7.18-7.21 (2H, d), 6.87-6.90 (2H, d); 6.26-6.28 (2H, d), 6.20-6.22 (2H, d), 4.68-4.72 (1H, m), 4.45-4.58 (2H, m ), 4.18-4.22 (2H, d), 4.00-4.06 (1H, m), 3.88-3.93 (1H, m), 3.11-3.48 (4H , m), 3.28-3.33 (1H, dd), 1.27-2.00 (20H, m), T.35-1.37(3H, d).

Example 65: (S)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester

The title compound was prepared from (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester using the method described in procedure 9. The title compound was obtained as a white solid.

5<1>H (d<6->DMSO+D 2 O): 6.72-7.41 (28H, complex); 4.32-4.66 (7H, m); 3.81-4.20 (4H, m); 2.72-2.99 (6H, m).

Example 66: (S)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2-phenylethyl)ester

The title compound was prepared from (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2-phenylethyl)ester by the method described in method 9. solid produced was crystallized from a 1:1 mixture of methanol and dichloromethane to give the title compound with a melting point of 75°C to 76°C. 5<1>H (d 6 -DMSO+D 2 O): 6.83-7.40 (18H, m); 3.80-4.72 (9H, m); 2.66-3.05 (10H, m). Example 67: (RR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester

The title compound was prepared from (RR)-4-{2-[3-(2,2-di-tert-butyl-4H-1,3,2-benz6"dioxasilinan-6-yl-oxy)-2-hydroxypropylamino] propyl}phenoxymethylphenylphosphinic acid, ethyl ester (140 mg, 0.21 mmol) by a method similar to that described in Example 4. The crude product obtained as a gray gum was used without further purification. m/z:MH+530 ( 18%). Example 68: (R,R)-4-{2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, lithium salt

The title compound was prepared from (RR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethylphenoxy)propylamino]propyl}phenoxymethylphenylphosphinic acid, ethyl ester

(110 mg, 0.21 mmol) by the same procedure as described in Example 21, and the product was isolated as a white powder after freeze-drying.

8<1>H (250MHz, CD3OD): 7.90 (2H, m); 7.42 (3H, m); 7.11 (2H, d); 6.95 (1H, d); 6.87 (2H, d); 6.69 (2H, d); 4.64 (2H, s); 4.19 (1H, m); 4.08 (2H, d); 3.97 (2H, m); 3.48 (1H, m); 3.36 (1H, m, partially obscured by MeOH signal); 3.20-3.02 (2H, m); 2.69 (1H,m) and 1.23 (3H,d).

Example 69: (S)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, 2-phenylethyl ester, hydrochloride salt dihydrate

The title compound was prepared from (S)-4-{2-[3-(4-hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2-phenylethyl ester) by the cfcn procedure described in Example 25, as a white solid 8<1>H (d<6->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 (1H, 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: (S)-4-{2-[3- (4-Hydroxyphenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, (2,2-diphenylethyl)ester, hydrochloride salt

The title compound was prepared from (S)-4-{2-[3-(4-hydrophenoxy)-2-hydroxypropylamino]ethyl}phenoxymethylphosphonic acid, bis-(2,2-diphenylethyl)ester by the method described in Example 25, as a white solid.

Pharmacological data: The activity of the present compounds was investigated using the following methods: Antagonist and agonist activity at human p^, p2- and p3-adrenoceptors: Subclones of CHO cells were stably transfected with each of the human p^, p2- and β3-adrenoceptors<1.>The cells were then broken up by immersion in an ice-cold dissolution buffer (10 mM TRIS, 2 mM EDTA, pH 7.4) containing the protease inhibitors leupeptin and benzamidine (5 ug per ml) and soybean rtrypsin inhibitor (10^ g per ml). The membranes were processed using the method described by Bouvier et. al.<2>and stored in 1 ml portions in liquid N2 for further use. β3-adrenoceptor-directed adenylyl cyclase activity: Adenylyl cyclase activity was assayed by the method of Kirkham et. åJ.<3>by adding 40 µl (70-80 µg protein) to the incubation medium of the above-mentioned CHO cell plasma membranes transfected with the human β3-adrenoceptor. cAMP produced within 20 minutes was separated from ATP by the method of Salomon et. al.<4>Agonist EC50 values and intrinsic activities were expressed as the concentration of agonist that produces 50% activation of adenylyl cyclase, and the maximum response produced by each agonist relative to that produced by (-)isoprenaline, respectively. Antagonist binding at pr and β2-adrenoceptors: Replacement of [<125>1]-iodocyanopindolol from CHO cell plasma membranes transfected with either the human pr or β2-adrenoceptor was performed by the method of Blin et. al.<5>Ki values (nM) were calculated from the binding IC50 curve for each agonist using the Cheng-Prusoff equation. Results:

References

1. T. Frielle et. al., Proc. Natl. Acad. Sci., 1987, 84, 7929; B. Kobilka, Proe. Nati. 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 (1)

1. Compound, characterized by formula I: or a pharmaceutically acceptable salt or solvate thereof, where R° is an aryl group optionally substituted with one, two or three substituents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulfonamido, arylsulfonamido, formamido, halogen, alkoxy and allyl; X is 0 or S; R<1> and R<1a> are independently hydrogen or an alkyl group; R- is OCH2 CO2 H or an ester or an amide of this group, or R2 is a group of formula (b): hior R <4> is hydrogen, alkyl, hydroxyalkyl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl or cycloalkyl and where R <5> is hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, aryloxyalkyloxy, arylalkyloxy or cycloalkyloxy, or R <5> is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, or R <5> together with OR <4> is 0(CH2 )n O, where n is 2, 3 or 4; and R <3> is hydrogen, halogen, alkyl or alkoxy, or R <3> forms together with R <2> a group of formula (c): or an ester or an amide of this group; provided that 4-[2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]propyl]phenoxyacetic acid and its salts and esters, and the compounds of examples 1 to 36 as described in EP0328251, are excluded from the group of compounds indicated with formula (I). 2. - Compound according to claim 1, characterized in that R° is a phenyl group optionally substituted with hydroxy and/or hydroxymethyl. 3. Compound according to claim 1 or 2, characterized in that R° is 4-hydroxy-3-hydroxymethylphenyl, 3- and 4-hydroxyphenyl groups, 3-hydroxyphenyl or 4-hydroxyphenyl. 4. Compound according to each of claims 1 to 3, characterized in that R<1> is an alkyl group and R<1a> is hydrogen. 5. A compound according to each of claims 1 to 3, characterized in that R <1> o^ R <1a> are both hydrogen. 6. Compound according to each of claims 1 to 5, characterized in that R<3> together with R2 is a group of formula (c), or R<2> is a group of formula (b) and R<3> is hydrogen, halogen, alkyl or alkoxy. 7. Compound according to each of claims 1 to 6, characterized in that R<2> is a group of formula (b). 8. Compound according to each of claims 1 to 7, characterized in that R<2> is a group of formula (b). 9. A compound according to each of claims 1 to 8, characterized in that R<4> is hydrogen, alkyl, hydroxyalkyl, phenylalkyl, benzyloxyalkyl or cycloalkyl. 10. Compound according to each of claims 1 to 9, characterized in that R<4> is hydrogen, ethyl, n-butyl, hydroxypropyl, phenylpropyl or benzyloxyethyl. 11. Compound according to each of claims 1 to 0, characterized by R <4> being hydrogen or alkyl. 127 A compound according to each of claims 1 to 11, characterized in that R <5> is hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkyloxyalkyloxy or cycloalkyl, preferably hydroxy, hydroxyalkyloxy or arylalkyloxy. 13_ Compound according to each of claims 1 to 12, characterized by that R 5 is hydrogen, phenyl, n-hexyl, cyclohexyl, ethoxy, n-butoxy, phenylpropyloxy, benzyloxypropyloxy, 2-hydroxyethyloxy or 3-hydroxypropyloxy. 14. Compound according to each of claims 1 to 13, characterized in that R<5> is n-hexyl or phenyl. 15. Compound according to claim 1, characterized in that it is selected from the group consisting of the title compounds from examples 1 to 70 as described here, or a pharmaceutically acceptable acid addition salt or pharmaceutically acceptable solvate of such a compound. 16. Compound according to each of claims 1 to 15, characterized in that the asymmetric carbon atom indicated by ( <*> ) has S configuration, while the asymmetric carbon atom indicated by ( <*> ) has R configuration . 17. Process for the preparation of a compound of formula (I) or one of its pharmaceutically acceptable acid addition salts or solvates, characterized in that: (a) a compound of formula (II): where X is as defined in relation to formula (I), and R <0> ' is R° as defined in relation to formula (I) or a protected form thereof, is reacted with a compound of formula (III): where R<1> , R<1> a,R<2> and R3 are as defined in relation to formula (I) and T° is a hydrogen atom or a protecting group; or (b) a compound of formula (I) where R <1a> is hydrogen, is prepared by reducing a compound of formula (XXI): where R°, R <1> , R <3> and X are as defined in relation to formula (I), and R <2>' is R<2> as defined in relation to formula (I) or a protected form of this; or (c) a compound of formula (XXIII): where R1 , R<1> a and X are as defined in relation to formula (I), R<0>' is as defined in relation to formula (II), T5 is a protecting group, R <2a> is R2 or a group or an atom which can be converted to R <2> , and R3a is R3 or a group or an atom which can be converted to R <3> , and where R <2> and R <3> are each as defined in relative to formula (I), is reacted with a reagent capable of converting R <2a> to R <2> , and/or a reagent capable of converting R <3a> to R <3> ; and then, if desired, perform one or more of the following possible steps: (i) converts a compound of formula (I) into another compound of formula (I); (ii) _ removes an optional protecting group; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or one of its pharmaceutically acceptable solvates. 18. Pharmaceutical preparation, characterized in that it contains a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates and a pharmaceutically acceptable carrier. 19. Method for the treatment of hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, intestinal disorders or for the treatment of stomach ulcers in humans and animals, characterized by the addition of an effective, non-toxic amount of a compound of formula (I) or one of its pharmaceutical acceptable salts or solvates, to a human or animal in need of said treatment. 20. Method for strengthening the weight gain and/or improving the utilization effect and/or increasing the body mass and/or reducing the birth mortality and increasing the survival rate after birth in domestic animals, characterized by supplying the domestic animals with an effective non-toxic amount of a compound of formula (I ) or one of its veterinary acceptable salts or solvates. 21. Veterinary-acceptable premix preparation, characterized by containing a compound of formula (I) or one of its veterinary-acceptable salts or solvates together with a veterinary-acceptable carrier. 22. Compound characterized by formula (XXI): where R°, R <1> , R <3> and X are as defined in connection with formula (I) in claim 1, and R2 is R2 as defined in connection with formula (I), or a protected form thereof . 23. Compound characterized by formula (XXIII): where R <1> , R1a and X are as defined in relation to formula (I) in claim 1, R° is R° as defined in relation to formula (I) in claim 1 or a protected form of this compound, T < 5> is a protecting group, R <2a> is R <2> or a group or atom which can be converted to R <2> , and R <3a> is R <3> or a group or atom which can be converted into R <3> , and where R <2> and R <3> are each as defined in connection with formula (I) in claim 1.