Phenylethanolamine derivatives as beta-2 agonists

0001This invention relates to β2 agonists of general formula: <chemistry id="chem0001" num="0001"><img file="EP1577291A1_D0001.tif" /></chemistry> in which R¹ R², n and Q¹ have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

0002Adrenoceptors are members of the large G-protein coupled receptor super-family. The adrenoceptor subfamily is itself divided into the α and β subfamilies with the β sub-family being composed of at least 3 receptor subtypes: β1, β2 and β3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas β3 adrenergic receptors are mainly expressed in fat tissues (therefore β3 agonists could potentially be useful in the treatment of obesity and diabetes) and β1 adrenergic receptors are mainly expressed in cardiac tissues (therefore β1 agonists are mainly used as cardiac stimulants).

0003The pathophysiology and treatments of airway diseases have been extensively reviewed in the literature (for reference see Barnes, P.J. Chest, 1997, 111:2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9:1, pp25-42) and therefore only a brief summary will be included here to provide some background information.

0004Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anticholinergics and β2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled β2 agonists. Short acting, rapid onset β2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.

0005Bronchodilation is mediated via agonism of the β2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because β2 receptors are so widely distributed in the airway, β2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how β2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, β2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.

0006In addition to the airways, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and thus β2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

0007However, numerous β2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at β2 adrenoreceptors expressed outside the airways (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class.

0008Accordingly, there is still a need for novel β2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, duration of action and/or pharmacodynamic properties. In this context, the present invention relates to novel β2 agonists. EP 0654534 B1 and EP0939134 B1 disclose a process for the preparation of compounds of formula (XI): <chemistry id="chem0002" num="0002"><img file="EP1577291A1_D0002.tif" /></chemistry> These compounds are disclosed as anti-obesity and anti-diabetic agents having specific β3 activity. US5,561,142 discloses selective β3 agonists of formula <chemistry id="chem0003" num="0003"><img file="EP1577291A1_D0003.tif" /></chemistry> EP0236624 discloses compounds of formula <chemistry id="chem0004" num="0004"><img file="EP1577291A1_D0004.tif" /></chemistry> having anti-obesity and/or anti-hyperglycaemic activity coupled with good selectivity from cardiac side-effects.

0009The invention relates to compounds of general formula (1): <chemistry id="chem0005" num="0005"><img file="EP1577291A1_D0005.tif" /></chemistry> wherein the (CH₂)_n-C(=O)Q¹ group is in meta or para position, <ul id="ul0001" list-style="dash"><li>R¹ and R² are independently selected from H and C₁-C₄ alkyl,</li><li>n is 0, 1 or 2,and,</li><li>Q¹ is a group selected from: <chemistry id="chem0006" num="0006"><img file="EP1577291A1_D0006.tif" /></chemistry></li></ul><ul id="ul0002" list-style="none" compact="compact"><li>* -NH-C₁-C₄alkyl, and a group *-N(R⁸)-Q²-A, wherein <ul id="ul0003" list-style="dash"><li>Q² is a single bond or a C₁-C₄ alkylene,</li><li>R⁸ is H or C₁-C₄ alkyl,</li><li>p is 1 or 2, and</li><li>A is a C₃-C₇ cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably by one or two carbon atoms, pyridyl, or a group of formula</li></ul></li></ul><chemistry id="chem0007" num="0007"><img file="EP1577291A1_D0007.tif" /></chemistry><ul id="ul0004" list-style="dash"><li>R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and are selected from H, C₁-C₄ alkyl, OR⁹, SR⁹, halo, CF₃, OCF₃, COOR⁹, SO₂NR⁹R¹⁰, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR¹⁰;</li><li>R⁹ and R¹⁰ are the same or different and are selected from H or C₁-C₄ alkyl and the * represents the attachment point to the carbonyl group;</li></ul> or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that, when n is 1 or 2, then: <ul id="ul0005" list-style="none"><li>1) Q¹ is *-NH-C₁-C₄alkyl, or *-N(R³)-Q²-A where A is C₃-C₇ cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, and/or,</li><li>2) when one of R¹ and R² is H, the other is not CH₃.</li></ul> It has now been found that the compounds of formula (1) are agonists of the β2 receptors, that are particularly useful for the treatment of β2-mediated diseases and/or conditions, and show good potency, in particular when administered via the inhalation route.

0010In the present invention, the term "potent" means that the compounds of formula (1) show an agonist potency for the β2 receptor, which is less than 10 nM as measured by the cell-based assay described herein. Preferably, the compounds of the invention are selective agonists of the β2 receptor receptors. Preferably, the compounds of the invention show an agonist potency for the β2 receptor, which is at least about 100-fold higher as for the β3 receptor and at least about 500-fold higher as for the β1 receptor.

0011In the here above general formula (1), C₁-C₄ alkyl and C₁-C₄ alkylene denote a straight-chain or branched group containing 1, 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in O-(C₁-C₄)alkyl radicals, S-(C₁-C₄)alkyl radicals etc.... Examples of suitable (C₁-C₄)alkyl radicals are methyl, ethyl, <i>n</i>-propyl, <i>iso</i>-propyl, <i>n</i>-butyl, <i>iso</i>-butyl, <i>sec</i>-butyl, <i>tert-</i>butyl.... Examples of suitable O-(C₁-C₄)alkyl radicals are methoxy, ethoxy, <i>n</i>-propyloxy, <i>iso-</i>propyloxy, <i>n</i>-butyloxy, <i>iso</i>-butyloxy, <i>sec</i>-butyloxy and <i>tert</i>-butyloxy.... The term "C₃-C₇ cycloalkyl", includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are cyclohexyl and cycloheptyl. The C₃-C₇ cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include adamantanyl, bicyclo[3.1.1]heptane, bicydo[2.2.1]heptane, bicyclo[2.2.2]octane.

0012Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro. In the following, the free bond on the phenyl group such as in the structure below, <chemistry id="chem0008" num="0008"><img file="EP1577291A1_D0008.tif" /></chemistry> means that the phenyl can be substituted in the meta or para position.

0013The compounds of the formula (1) <chemistry id="chem0009" num="0009"><img file="EP1577291A1_D0009.tif" /></chemistry> can be prepared using conventional procedures such as by the following illustrative methods in which Q¹, Q², A and n are as previously defined for the compounds of the formula (1) unless otherwise stated.

0014The amide derivatives of the formula (1) may be prepared by coupling an acid of formula (2): <chemistry id="chem0010" num="0010"><img file="EP1577291A1_D0010.tif" /></chemistry> with an amine of formula *-NH-C₁-C₄alkyl, *-N(R⁸)-Q²-A (3), <chemistry id="chem0011" num="0011"><img file="EP1577291A1_D0011.tif" /></chemistry> wherein R⁸, Q², A, p and R³ to R⁶ are as previously defined for compounds of formula (1). The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or <i>N</i>, <i>N</i>'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. <i>N</i>-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.

0015Said amine (3), (3') or (3") is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, protection, deprotection etc...) from commercially available material.

0016The acid of formula (2) may be prepared from the corresponding ester of formula (4): <chemistry id="chem0012" num="0012"><img file="EP1577291A1_D0012.tif" /></chemistry> wherein Ra is a suitable acid protecting group, preferably a (C₁-C₄)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.

0017The ester of formula (4) may be prepared by reaction of an amine of formula (5) : <chemistry id="chem0013" num="0013"><img file="EP1577291A1_D0013.tif" /></chemistry> wherein Ra and n are as previously defined, with a bromide of formula (6) : <chemistry id="chem0014" num="0014"><img file="EP1577291A1_D0014.tif" /></chemistry>

0018In a typical procedure, the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulphoxide, toluene, <i>N,N</i>-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.

0019The bromide of formula (6) may be prepared from the ester of formula (7) : <chemistry id="chem0015" num="0015"><img file="EP1577291A1_D0015.tif" /></chemistry> according to any method well-known to the one skilled in the art to prepare an alcohol from an ester, without modifying the rest of the molecule.

0020In a typical procedure, the ester of formula (7) is reduced with borane dimethylsulfide complex in tetrahydrofuran at a reflux for a period of 2 hours.

0021The alcohol of formula (7) may be prepared as either the (<i>R</i>) or (<i>S</i>) enantiomer according to methods well described in the literature (Tetrahedron Letters 1994, 35(50), 9375).

0022The amine of formula (5) may be prepared as either the (<i>R</i>) or (<i>S</i>) enantiomer from the corresponding protected amine of formula (8) : <chemistry id="chem0016" num="0016"><img file="EP1577291A1_D0016.tif" /></chemistry> wherein Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be α-methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-Interscience Publication, 1981.

0023The amine of formula (8) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (9): <chemistry id="chem0017" num="0017"><img file="EP1577291A1_D0017.tif" /></chemistry> wherein Ra, Rb, Rc and n are as previously defined.

0024In a typical procedure, the reaction of the ketone of formula (9) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH₃ or sodium triacetoxyborohydride of formula Na(OAc)₃BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (8) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (8) as a single diastereomer.

0025The ketone of formula (9) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (10): <chemistry id="chem0018" num="0018"><img file="EP1577291A1_D0018.tif" /></chemistry> wherein Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent.

0026In a typical procedure, the aryl halide of formula (10) is reacted with a tin enolate generated in-situ by treatment of isoprenyl acetate with tri-n-butyltin methoxide of formula BU₃SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-<i>ortho</i>-tolylphosphine of formula Pd(OAc)₂/P(o-Tol)₃) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80°C and 110°C for 6 to 16 hours.

0027The aryl halide of formula (10) may be obtained by esterification of the corresponding acid of formula (11): <chemistry id="chem0019" num="0019"><img file="EP1577291A1_D0019.tif" /></chemistry> wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.

0028In a typical procedure, the acid of formula (11) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours.

0029The acid of formula (11) is a commercial product. The amine of formula (5), where R¹ and R² are both the same C₁-C₄ alkyl, may be prepared according to the following scheme: <chemistry id="chem0020" num="0020"><img file="EP1577291A1_D0020.tif" /></chemistry> wherein R¹, R² and Ra are as previously defined.

0030In a typical procedure, the ester of formula (12) is reacted with an "activated" alkyl (organometallic alkyl such as R²MgBr, R²MgCl or R²Li) to give the corresponding tertiary alcohol of formula (13) using the method described above.

0031Said tertiary alcohol of formula (13) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5).

0032Alternatively, the amine of formula (5), where R¹ are R² both the same C₁-C₄ alkyl and n=0, may be prepared according to the following scheme: <chemistry id="chem0021" num="0021"><img file="EP1577291A1_D0021.tif" /></chemistry> wherein R¹, R² and Ra are as previously defined.

0033In a typical procedure, the ester of formula (14) is reacted with an "activated" alkyl (organometallic alkyl such as R²MgBr, R²MgCl or R²Li) to give the corresponding tertiary alcohol of formula (15) using the method described above.

0034Said tertiary alcohol of formula (15) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks to give the bromo amine (16).

0035The resulting bromo amine (16) is treated with a suitable palladium catalyst (e.g. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).

0036The ketone of formula (9) where n=2 may be prepared by reduction of an alkene of formula (17) : <chemistry id="chem0022" num="0022"><img file="EP1577291A1_D0022.tif" /></chemistry>

0037In a typical procedure, a solution of the olefin of formula (17) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium on charcoal) and stirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature between room temperature and 60°C for 8-24 hours.

0038The alkene of formula (17) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (18): <chemistry id="chem0023" num="0023"><img file="EP1577291A1_D0023.tif" /></chemistry>

0039In a typical procedure, the aryl halide (18) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh₃)₄, palladium acetate/tri-<i>ortho</i>-tolylphosphine of formula Pd(OAc)₂/P(o-tol)₃ or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCl₂) in a sutiable solvent (e.g. acetonitrile, <i>N, N</i>-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40°C and 110°C for 8 to 24 hours.

0040The ketone of formula (18) is a commercial product. The amine of formula (5), where R¹ and R² are both H and n is 1, may be prepared according to the following scheme: <chemistry id="chem0024" num="0024"><img file="EP1577291A1_D0024.tif" /></chemistry> wherein R¹, R² and Ra are as previously defined.

0041In a typical procedure, the acid of formula (19) is preferentially reduced to the corresponding alcohol (20) in the presence of the ester. This may be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.

0042Said primary alcohol of formula (20) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile. The preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine. For some of the steps of the here above described process of preparation of the compounds of formula (1), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. GREENE <i>(Protective Groups in Organic Synthesis,</i> A. Wiley-Interscience Publication, 1981) or by P. J. Kocienski <i>(Protecting groups,</i> Georg Thieme Verlag, 1994), can be used.

0043All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

0044Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography. Preferred compounds of formula (I) are those wherein Q¹ is *-NH-C₁-C₄alkyl, preferably NH-isopropyl, or *-N(R⁸)-Q²-A where A is C₃-C₇ cycloalkyl, preferably cyclohexyl, or adamantanyl. Other preferred compounds of formula (I) are those wherein n is 0. Preferably n is 0 and Q¹ is a group of formula <chemistry id="chem0025" num="0025"><img file="EP1577291A1_D0025.tif" /></chemistry> or *-N(R⁸)-Q²-A, wherein Q² is a single bond or a C₁-C₄ alkylene, R⁸ is H and A is naphthyl or <chemistry id="chem0026" num="0026"><img file="EP1577291A1_D0026.tif" /></chemistry> wherein R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and are selected from H, C₁-C₄ alkyl, OR⁹, SR⁹, halo, CF₃, OCF₃, COOR⁹, SO₂NR⁹R¹⁰, CONR⁹R¹⁰, NR⁹R¹⁰, NHCOR¹¹, wherein at least 2 of R³ to R⁷ are equal to H; wherein R⁹ and R¹⁰ are the same or different and are selected from H or C₁-C₄ alkyl, R¹¹ is C₁-C₄ alkyl and the * represent the attachment point to the carbonyl group. In the above groups of compounds,, the following substituents are preferred: <ul id="ul0006" list-style="none" compact="compact"><li>R¹ and R² are both CH₃ or,</li><li>R¹ is H and R² is CH₃ or CH₂-CH₃ or,</li><li>R¹ and R² are both H.</li></ul> Preferably Q¹ is <chemistry id="chem0027" num="0027"><img file="EP1577291A1_D0027.tif" /></chemistry> or a group *-N(R⁸)-Q²-A, wherein Q² is a single bond or a C₁-C₄ alkylene, R⁸ is H or C₁-C₄ alkyl, and A is a C₃-C₇ cycloalkyl, adamantanyl, naphtyl or a group of formula <chemistry id="chem0028" num="0028"><img file="EP1577291A1_D0028.tif" /></chemistry> wherein R³, R⁴, R⁵, R⁶ and R⁷ are as defined above. Preferably, when A is a group of formula <chemistry id="chem0029" num="0029"><img file="EP1577291A1_D0029.tif" /></chemistry> R³, R⁴, R⁵, R⁶ and R⁷ are selected from H, C₁-C₄ alkyl, OR⁹, SR⁹, Cl, F, CF₃, OCF₃, COOR⁹, SO₂NR⁹R¹⁰, and at least 2 of R³ to R⁷ represent H, wherein R⁹ and R¹⁰ are the same or different and are selected from H or C₁-C₄ alkyl. Preferably, R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and are selected from H, CH₃, OH, OCH₃, SCH₃, OCH₂CH₃, Cl, F, CF₃, OCF₃, COOH, SO₂NH₂, and at least 2 of R³ to R⁷ represent H. Preferably, R³, R⁴, R⁵, R⁶ and R⁷ are the same or different and are selected from H, CH₃, OH, OCH₃, OCH₂CH₃, Cl, F, CF₃, OCF₃, COOH, SO₂NH₂, and at least 3 of R³ to R⁷ are represent H. Preferably, R⁸ is H, methyl or ethyl, more preferably H. Preferably, Q² is selected from -CH₂-, -(CH₂)₂-, -(CH₂)₃-, -C(CH₃)₂-CH₂-, -CH₂-C(CH₃)₂-, and -CH(CH₃)-. Preferably n is 0 or 1.

0045Particularly preferred are the compounds of the formula (1) as described in the Examples section hereafter, i.e. : <ul id="ul0007" list-style="none" compact="compact"><li><i>N</i>-cycloheptyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cyclohexylmethyl )-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-methylacetamide;</li><li><i>N</i>-[(1<i>S</i>)-1-cyclohexylethyl]-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li>2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-isopropylacetamide;</li><li><i>N</i>-cyclopentyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cyclobutylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cyclopentylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-cyclohexyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-cyclobutyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cyclohexylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cyclopropylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(cycloheptylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-1-adamantyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(1-adamantylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N-2</i>-adamantyl-2-{3-[(2<i>R)-2</i>-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N-(2</i>-cyclohexylethyl)-2-{3-[(2<i>R</i>)<i>-</i>2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-methylacetamide;</li><li><i>N</i>-cycloheptyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-methylacetamide;</li><li><i>N</i>-cyclohexyl-<i>N</i>-ethyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(2-cyclohexylethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;</li><li><i>N</i>-(4-chlorobenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-(2,6-dimethoxybenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-benzyl-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li>4-{(1<i>R</i>)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1<i>H</i>)-yl)-2-oxoethyl]phenyl}-1,1-dimethylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;</li><li><i>N</i>-[2-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-(2,6-dichlorobenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li>2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-<i>N</i>-[2-(methylthio)benzyl]acetamide;</li><li><i>N</i>-(2,3-dimethylbenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li>2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-<i>N</i>-[3-(trifluoromethyl)benzyl]acetamide;</li><li><i>N</i>-[4-chloro-3-(trifluoromethyl)benzyl]-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-[2-chloro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-[3,5-bis(trifluoromethyl)benzyl]-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-[3-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide;</li><li><i>N</i>-[2-(4-chlorophenyl)ethyl]-3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzamide;</li><li>3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}-<i>N</i>-[2-(4-methylphenyl)ethyl]benzamide;</li><li>3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methyl-propyl}-<i>N</i>-[2-(4-trifluoromethylphenyl)ethyl]benzamide;</li><li><i>N</i>-[2-(3,4-dichlorophenyl)ethyl]-3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide;</li><li><i>N</i>-[2-(3,4-dimethylphenyl)ethyl]-3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}benzamide;</li><li>3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-<i>N</i>-(2-naphthalen-2-yl-ethyl)benzamide;</li><li><i>N</i>-(1,1-dimethyl-2-phenylethyl)-3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}benzamide;</li><li>3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}-<i>N</i>-(2-methyl-2-phenylpropyl)benzamide;</li><li><i>N</i>-(4-chlorobenzyl)-3-{2-[(2<i>R</i>)-2-hydroxy-2-(4-hydroxy-3-hyd roxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide;</li><li><i>N</i>-(2,6-dimethoxybenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;</li><li><i>N</i>-(3,4-dichlorobenzyl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;</li><li><i>N</i>-benzyl-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;</li><li><i>N</i>-(2,3-dihydro-1<i>H</i>-inden-2-yl)-2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide;</li><li>2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-<i>N</i>-(2-phenylethyl)acetamide;</li><li>2-{3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-<i>N</i>-(3-phenylpropyl)acetamide;</li><li><i>N</i>-benzyl-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-(3,4-dichlorobenzyl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-[2-fluoro-5-(trifluoromethyl)benzyl]-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-(2,6-dimethoxybenzyl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-[2-(4-chlorophenyl)ethyl]-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-(2,3-dihydro-1<i>H</i>-inden-2-yl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li>3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-<i>N</i>-(2-phenylethyl)benzamide;</li><li>3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-<i>N</i>-[(1<i>R</i>)-1-phenylethyl]benzamide;</li><li>3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-<i>N</i>-(3-phenylpropyl)benzamide;</li><li>4-[(1<i>R</i>)-2-({(1<i>R</i>)-2-[3-(3,4-dihydroisoquinolin-2(1<i>H</i>)-ylcarbonyl)phenyl]-1-methylethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;</li><li><i>N</i>-(2,3-dimethylbenzyl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-(5,6-diethyl-2,3-dihydro-1<i>H</i>-inden-2-yl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li><i>N</i>-(4-chlorobenzyl)-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide;</li><li>3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-<i>N</i>-phenylbenzamide, and,</li><li><i>N</i>-[4-(aminosulfonyl)benzyl]-3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide.</li></ul> According to one aspect of the present invention, the compounds of formula (1) wherein the (CH₂)_n-C(=O)Q¹ group is in position meta are generally preferred.

0046The compounds of formula (1) may also be optionally transformed into pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the compounds of the formula (1) include the acid addition and the base salts (including disalts) thereof.

0047Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen,, saccharate, stearate, succinate, D- and L-tartrate, 1-hydroxy-2-naphthoate and tosylate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002). Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods: <ul id="ul0008" list-style="none" compact="compact"><li>(i) by reacting the compound of formula (1) with the desired acid or base;</li><li>(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (1) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or</li><li>(iii) by converting one salt of the compound of formula (1) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.</li></ul> All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). Hereinafter all references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. The compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (1). As indicated, so-called 'pro-drugs' of the compounds of formula (1) are also within the scope of the invention. Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include: <ul id="ul0009" list-style="none"><li>(i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaced by (C₁-C₈)alkyl;</li><li>(ii) where the compound of formula (1) contains an alcohol functionality (- OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1) is replaced by (C₁-C₆)alkanoyloxymethyl; and</li><li>(iii) where the compound of formula (1) contains a primary or secondary amino functionality (-NH₂ or -NHR where R ≠H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) is/are replaced by (C₁-C₁₀)alkanoyl.</li></ul> Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1). Also included within the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed <i>in vivo</i> upon administration of the drug. Some examples of metabolites in accordance with the invention include <ul id="ul0010" list-style="none"><li>(i) where the compound of formula (1) contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ → -CH₂OH):</li><li>(ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR → -OH);</li><li>(iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² → -NHR¹ or -NHR²);</li><li>(iv) where the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂);</li><li>(v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph → -PhOH); and</li><li>(I).(vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ → COOH).</li></ul> Compounds of formula (1) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric <i>cisltrans</i> (or Z/E) isomers are possible. Where the compound contains, for example, a keto orstructural isomers are interconvertible <i>via</i> a low oxime group or an aromatic moiety,energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, <i>d</i>-lactate or <i>I</i>-lysine, or racemic, for example, <i>dl</i>-tartrate or <i>dl-</i>arginine.. <i>Cis</i>/<i>trans</i> isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

0048According to one aspect of the present invention, the (R,R)-stereoisomer of the formula below wherein R¹ is hydrogen and R² is C₁-C₄ alkyl, preferably methyl, and n and Q¹ are as defined above, is generally preferred: is generally preferred: <chemistry id="chem0030" num="0030"><img file="EP1577291A1_D0030.tif" /></chemistry> wherein n and Q¹ are as defined above for compounds of formula (1). The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S. Certain isotopically-labelled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, <i>i</i>.<i>e</i>. ³H, and carbon-14, <i>i</i>.<i>e</i>. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, <i>i</i>.<i>e</i>. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased <i>in vivo</i> half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

0049The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the β2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

0050The compounds of formula (1) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy and/or prophylaxis. They can be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which as active constituent contain an efficacious dose of at least one compounds of formula (1), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives. The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose. The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The compound of formula (1) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (1) may be in the form of multiparticulate beads. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma <i>et al</i> (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLApoly(<i>dl</i>-lactic-coglycolic)acid (PGLA) microspheres. The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (<i>e.g.</i> Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1<i>µ</i>g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1<i>µ</i>l to 100<i>µ</i>l. A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 0.001 mg to 10mg of the compound of formula (1). The overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day. The compounds of formula (1) are particularly suitable for an administration by inhalation The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (<i>e.g</i>. absorbable gel sponges, collagen) and non-biodegradable (<i>e.g.</i> silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, <i>i</i>.<i>e</i>. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148. Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require from 0.001 mg to 40mg. The total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

0051According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough. The second and more additional therapeutic agents may also be a compound of formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more β2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.

0052As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following: <ul id="ul0011" list-style="bullet"><li>simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,</li><li>substantially simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,</li><li>sequential administration of such combination compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and</li><li>sequential administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlapingly administered at the same and/or different times by said patient,</li></ul> where each part may be administered by either the same or different route.

0053Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to : <ul id="ul0012" list-style="none" compact="compact"><li>(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,</li><li>(b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄,</li><li>(c) Histamine receptor antagonists including H1 and H3 antagonists,</li><li>(d) α₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use,</li><li>(e) muscarinic M3 receptor antagonists or anticholinergic agents,</li><li>(f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,</li><li>(g) Theophylline,</li><li>(h) Sodium cromoglycate,</li><li>(i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),</li><li>(j) Oral and inhaled glucocorticosteroids,</li><li>(k) Monoclonal antibodies active against endogenous inflammatory entities,</li><li>(l) Anti-tumor necrosis factor (anti-TNF-α) agents,</li><li>(m)Adhesion molecule inhibitors including VLA-4 antagonists,</li><li>(n) Kinin-B₁ - and B₂ -receptor antagonists,</li><li>(o) Immunosuppressive agents,</li><li>(p) Inhibitors of matrix metalloproteases (MMPs),</li><li>(q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,</li><li>(r) Elastase inhibitors,</li><li>(s) Adenosine A2a receptor agonists,</li><li>(t) Inhibitors of urokinase,</li><li>(u) Compounds that act on dopamine receptors, e.g. D2 agonists,</li><li>(v) Modulators of the NF_κβ pathway, e.g. IKK inhibitors,</li><li>(w) modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase,</li><li>(x) Agents that can be classed as mucolytics or anti-tussive, and</li><li>(y) Antibiotics.</li></ul>

0054According to the present invention, combination of the compounds of formula (1) with : <ul id="ul0013" list-style="dash" compact="compact"><li>H3 antagonists,</li><li>Muscarinic M3 receptor antagonists,</li><li>PDE4 inhibitors,</li><li>glucocorticosteroids,</li><li>Adenosine A2a receptor agonists,</li><li>Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or,</li><li>Leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄,</li></ul> are preferred.

0055According to the present invention, combination of the compounds of formula (1) with : <ul id="ul0014" list-style="dash"><li>glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or</li><li>muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine,</li></ul> are further preferred.

0056It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The description, which follows, concerns the therapeutic applications to which the compounds of formula (1) may be put.

0057The compounds of formula (1) have the ability to interact with the β2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the β2 receptor plays in the physiology of all mammals.

0058Therefore, a further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the β2 receptor is involved. More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : <ul id="ul0015" list-style="bullet"><li>asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,</li><li>chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema,</li><li>obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,</li><li>bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,</li><li>acute lung injury,</li><li>bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.</li></ul>

0059A still further aspect of the present invention also relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a β2 agonist activity. In particular, the present inventions concerns the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of β2-mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.

0060As a consequence, the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a β2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of a compound of formula (1), its pharmaceutically acceptable salts and/or derived forms. The following examples illustrate the preparation of the compounds of the formula (1):

Example 1:

<b>N</b>

-cycloheptyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0061<chemistry id="chem0031" num="0031"><img file="EP1577291A1_D0031.tif" /></chemistry> Ammonium fluoride (98mg, 2.64mmol) was added in one portion to a stirred solution of 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-([<i>tert-</i>butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cycloheptylacetamide (Preparation 1) (150mg, 0.26mmol) in methanol (3ml) and water (1.5ml) at room temperature. The reaction was heated at 40°C for 18 hours and then allowed to cool to room temperature. The solvent was removed <i>in vacuo</i> and the residue dissolved in ethyl acetate (30ml) and water (20ml), the organic layer was separated, washed with brine (10ml), dried (magnesium sulfate) and the solvent removed <i>in vacuo</i> to yield a clear oil. This was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: ammonia (90:10:1 by volume) to furnish the title compound as a white foam (87mg). ¹H NMR (400MHz, CD₃OD): δ = 7.25-7.00 (6H, m), 6.85 (1H, d), 4.58 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.95 (2H, m), 2.75 (2H, m), 2.58 (1H, m), 1.83 (2H, m), 1.70-1.40 (10H, m), 1.05 (3H, d) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 477, [M-H]^- 453.

Example 2:

<b>N</b>

-(cyclohexylmethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-methylacetamide

0062<chemistry id="chem0032" num="0032"><img file="EP1577291A1_D0032.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cyclohexylmethyl)-<i>N</i>-methylacetamide (Preparation 2) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.21 (2H, m), 7.00 (4H, m), 6.68 (1H, d), 4.61 (3H, m), 3.71 (2H, s), 3.31 (2H, m), 3.20 (2H, m), 2.91 (5H, m), 2.71 (2H, m), 2.60 (1H, m), 1.70 (5H, m), 1.22 (4H, m), 1.04 (3H, d), 0.95 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 469, [M+Na]⁺ 491.

Example 3:

<b>N</b>

-[(1

<b>S</b>

)-1-cyclohexylethyl]-2-{3-[(

<b>2R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0063<chemistry id="chem0033" num="0033"><img file="EP1577291A1_D0033.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-[(1<i>S</i>)-1-cyclohexylethyl]acetamide (Preparation 3) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.20 (4H, m), 7.01 (2H, dd), 6.71 (1H, d), 4.60 (3H, m), 3.62 (1H, m), 3.48 (1H, d), 3.41 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, dd), 1.60 (5H, m), 1.40-1.02 (10H, m), 0.93 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 469, [M+Na]⁺ 491.

Example 4: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-isopropylacetamide

0064<chemistry id="chem0034" num="0034"><img file="EP1577291A1_D0034.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-isopropylacetamide (Preparation 4) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 3.97-3.90 (1H, m), 3.41 (2H, s), 2.98-2.93 (1H, q), 2.91-2.86 (1H, dd), 2.74-2.70 (2H, dd), 2.60-2.55 (1H, dd), 1.13-1.11 (6H, d), 1.08-1.07 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 401, [M-H]^- 399.

Example 5:

<b>N</b>

-cyclopentyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0065<chemistry id="chem0035" num="0035"><img file="EP1577291A1_D0035.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cyclopentylacetamide (Preparation 5) using the method for example 3 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.04-6.98 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 4.10-4.04 (1H, m), 3.42 (2H, s), 2.98-2.93 (1H, q), 2.90-2.85 (1H, dd), 2.74-2.69 (2H, dd), 2.60-2.55 (1H, dd), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.54 (2H, m), 1.47-1.39 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]⁺ 427, [M-H]^- 425. CHN analysis : found C 68.48%, H 8.20%, N 6.35%; C₂₅H₃₄N₂O₄+0.66H₂O requires C 68.49%, H 8.12%, N 6.39%.

Example 6:

<b>N</b>

-(cyclobutylmethyl)-2-(3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0066<chemistry id="chem0036" num="0036"><img file="EP1577291A1_D0036.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cyclobutylmethyl)acetamide (Preparation 6) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.62-4.59 (3H, m), 3.44 (2H, s), 3.18-3.17 (2H, d), 2.97-2.92 (1H, q), 2.90-2.85 (1H, dd), 2.73-2.69 (2H, dd), 2.60-2.55 (1H, dd), 2.50-2.43 (1H, m), 2.04-1.97 (2H, m), 1.92-1.78 (2H, m), 1.72-1.63 (2H, m), 1.08-1.06 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]⁺ 427, [M-H]^- 425. CHN analysis : found C 68.24%, H 8.09%, N 6.39%; C₂₅H₃₄N₂O₄+0.75H₂O requires C 68.23%, H 8.13%, N 6.37%.

Example 7:

<b>N</b>

-(cyclopentylmethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0067<chemistry id="chem0037" num="0037"><img file="EP1577291A1_D0037.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert-</i>butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cyclopentylmethyl)acetamide (Preparation 7) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22 (1H, d), 7.19-7.17 (1H, d), 7.12-7.11 (1H, d), 7.08 (1H, s), 7.04-7.00 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 3.44 (2H, s), 3.10-3.08 (2H, d), 2.98-2.94 (1H, q), 2.90-2.85 (1H, dd), 2.74-2.70 (2H, dd), 2.60-2.55 (1H, dd), 2.07-2.00 (1H, m), 1.73-1.66 (2H, m), 1.62-1.46 (4H, m), 1.22-1.12 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]⁺ 441, [M-H]^- 439. CHN analysis : found C 69.12%, H 8.19%, N 6.26%; C₂₆H₃₆N₂O₄+0.62H₂O requires C 69.13%, H 8.31 %, N 6.20%.

Example 8:

<b>N</b>

-cyclohexyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0068<chemistry id="chem0038" num="0038"><img file="EP1577291A1_D0038.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cyclohexylacetamide (Preparation 8) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22 (1H, d), 7.19-7.17 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.64-4.60 (3H, m), 3.64-3.56 (1 H, m), 3.42 (2H, s), 3.00-2.94 (1H, q), 2.91-2.86 (1H, dd), 2.76-2.72 (2H, dd), 2.61-2.56 (1H, dd), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.65-1.59 (1H, m), 1.38-1.28 (2H, m), 1.25-1.15 (3H, m), 1.09-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]⁺ 441, [M-H]^- 439. CHN analysis : found C 68.49%, H 8.27%, N 6.14%; C₂₆H₃₆N₂O₄+0.85H₂O requires C 68.50%, H 8.34%, N 6.14%.

Example 9:

<b>N</b>

-cyclobutyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0069<chemistry id="chem0039" num="0039"><img file="EP1577291A1_D0039.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cyclobutylacetamide (Preparation 9) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.21 (1H, d), 7.18-7.16 (1H, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.03-6.98 (2H, t), 6.70-6.68 (1H, d), 4.62-4.59 (3H, m), 4.29-4.21 (1H, m), 3.40 (2H, s), 2.88-2.43 (1H, q), 2.90-2.85 (1H, dd), 2.73-2.68 (2H, m), 2.61-2.56 (1H, dd), 2.29-2.21 (2H, m), 1.98-1.89 (2H, m), 1.76-1.66 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]⁺ 413, [M-H]^- 411. CHN analysis : found C 67.18%, H 7.75%, N 6.51%; C₂₄H₃₂N₂O₄+0.93H₂O requires C 67.15%, H 7.95%, N 6.53%.

Example 10:

<b>N</b>

-(cyclohexylmethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0070<chemistry id="chem0040" num="0040"><img file="EP1577291A1_D0040.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cyclohexylmethyl)acetamide (Preparation 10) using the method for example 1 to give the title compound as a yellow foam. ¹H NMR (400MHz, CD₃OD): δ = 7.21-7.20 (1H, m), 7.18-7.16 (1H, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.02-6.98 (2H, t), 6.70-6.68 (1H, d), 4.61-4.58 (3H, m), 3.44 (2H, s), 2.99-2.98 (2H, d), 2.94-2.83 (2H, m), 2.71-2.67 (2H, q), 2.58-2.53 (1H, dd), 1.70-1.60 (5H, m), 1.49-1.40 (1H, m), 1.26-1.12 (3H, m), 1.06-1.05 (3H, d), 0.93-0.83 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 455, [M+Na]⁺ 477, [M-H]^- 453. CHN analysis : found C 70.07%, H 8.50%, N 6.17%; C₂₇H₃₈N₂O₄+0.45H₂O requires C 70.09%, H 8.47%, N 6.05%.

Example 11:

<b>N</b>

-(cyclopropylmethyl)-2-(3-[(2

<b>R</b>

)-2-(((2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0071<chemistry id="chem0041" num="0041"><img file="EP1577291A1_D0041.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cyclopropylmethyl)acetamide (Preparation 11) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.21-7.16 (2H, m), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.02-6.98 (2H, m), 6.70-6.68 (1H, d), 4.61-4.58 (3H, m), 3.45 (2H, s), 3.03-3.01 (2H, d), 2.95-2.83 (2H, m), 2.71-2.67 (2H, m), 2.59-2.54 (1H, m), 1.07-1.06 (3H, d), 0.97-0.90 (1H, m), 0.48-0.43 (2H, q), 0.19-0.15 (2H, q) ppm. LRMS (electrospray) : m/z [M+H]⁺ 413, [M+Na]⁺ 435, [M-H]^- 411. CHN analysis : found C 67.85%, H 7.82%, N 6.48%; C₂₄H₃₂N₂O₄+0.70H₂O requires C 67.80%, H 7.92%, N 6.59%.

Example 12:

<b>N</b>

-(cycloheptylmethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0072<chemistry id="chem0042" num="0042"><img file="EP1577291A1_D0042.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(cycloheptylmethyl)acetamide (Preparation 12) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.24-6.95 (6H, m), 6.72-6.69 (1H, d), 4.62 (2H, s), 4.62-4.59 (1H, m), 3.26 (2H, s), 3.00-2.97 (2H, d), 2.98-2.54 (m, 5H), 1.70-1.02 (m, 13H), 1.05 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 469.

Example 13:

<b>N</b>

-1-adamantyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0073<chemistry id="chem0043" num="0043"><img file="EP1577291A1_D0043.tif" /></chemistry> Prepared from <i>N</i>-1-adamantyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i> -butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide (Preparation 13) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.96 (6H, m), 6.68-6.65 (1H, d), 4.63-4.59 (3H, m), 3.38 (2H, s), 2.98-2.92 (1H, q), 2.88-2.54 (4H, m), 2.02 (3H, s), 2.00 (6H, s), 1.68 (6H, s), 1.05-1.03 (3H, d) ppm. LRMS (electrospray) : m/z [M-H]^- 491.

Example 14:

<b>N</b>

-(1-adamantylmethy))-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0074<chemistry id="chem0044" num="0044"><img file="EP1577291A1_D0044.tif" /></chemistry> Prepared from <i>N</i>-(1-adamantylmethyl)-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i> -butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide (Preparation 14) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-7.12 (5H, m), 7.06-7.00 (1H, t), 6.72-6.70 (1H, d), 4.62-4.59 (1H, m), 4.61 (2H, s), 3.46 (2H, s), 2.98-2.92 (1H, q), 2.91-2.54 (6H, m), 2.90 (3H, s), 1.68-1.56 (6H, m), 1.42 (6H, s), 1.06-1.04 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 507, [M+Na]⁺ 529.

Example 15:

<b>N</b>

-2-adamantyl-2-(3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0075<chemistry id="chem0045" num="0045"><img file="EP1577291A1_D0045.tif" /></chemistry> Prepared from <i>N</i>-2-adamantyl-2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl (dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) propyl]phenyl}acetamide (Preparation 15) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.24-7.10 (5H, m), 7.05-6.98 (1H, t), 6.70-6.68 (2H, d), 4.61 (2H, s), 4.62-4.58 (1H, m), 3.94 (1H, s), 3.54 (2H, s), 2.96-2.52 (5H, m), 1.96-1.75 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d) ppm. LRMS (electrospray) : m/z [M-H]^- 491.

Example 16:

<b>N</b>

-(2-cyclohexylethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-methylacetamide

0076<chemistry id="chem0046" num="0046"><img file="EP1577291A1_D0046.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(2-cyclohexylethyl)-<i>N</i> methylacetamide (Preparation 16) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.23-7.00 (6H, m), 6.71-6.68 (1H, d), 4.61 (2H, s), 4.61-4.57 (1H, m), 3.71-3.68 (2H, m), 4.61-4.57 (1H, m), 3.71-3.68 (2H, m), 3.43-3.26 (2H, m), 2.97-2.52 (8H, m), 1.78-0.82 (13H, m), 1.08-1.06 (3H, d) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 505, [M-H]^- 491.

Example 17:

<b>N</b>

-cycloheptyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-methylacetamide

0077<chemistry id="chem0047" num="0047"><img file="EP1577291A1_D0047.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cycloheptyl-<i>N</i>-methylacetamide (Preparation 17) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.23-6.96 (6H, m), 6.72-6.64 (1H, dd), 4.62-4.60 (2H, d), 4.61-4.58 (1H, m), 4.58-4.51 (0.5H, m), 3.70-3.63 (0.5H, m), 3.75-3.67 (2H, d), 2.95-2.50 (5H, m), 2.82-2.78 (3H, d), 1.72-1.20 (12H, m), 1.02-1.00 (3H, 2d) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 491.

Example 18:

<b>N</b>

-cyclohexyl-

<b>N</b>

-ethyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0078<chemistry id="chem0048" num="0048"><img file="EP1577291A1_D0048.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-cyclohexyl-<i>N</i>-ethylacetamide (Preparation 18) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.25-6.98 (6H, m), 6.70-6.67 (1H, d), 4.61 (2H, s), 4.60-4.57 (1H, m), 3.72 (2H, s), 3.65-3.61 (1H, m), 3.30-3.24 (2H, q), 2.95-2.50 (5H, m), 1.84-1.08 (10H, m), 1.12-1.08 (3H, t), 1.04-1.02 (3H, d) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 491.

Example 19:

<b>N</b>

-(2-cyclohexylethyl)-2-(3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0079<chemistry id="chem0049" num="0049"><img file="EP1577291A1_D0049.tif" /></chemistry> Prepared from 2-{3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-<i>N</i>-(2-cyclohexylethyl)acetamide (Preparation 19) using the method for example 1 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.98 (6H, m), 6.68-6.66 (1H, d), 4.61 (2H, s), 4.60-4.58 (1H, m), 3.42 (2H, s), 3.20-3.16 (2H, t), 2.96-2.56 (5H, m), 1.73-1.60 (5H, m), 1.40-1.35 (2H, q), 1.30-1.12 (4H, m), 1.07-1.05 (3H, d), 0.92-0.81 (2H, m) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 491.

Example 20:

<b>N</b>

-(4-chlorobenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0080<chemistry id="chem0050" num="0050"><img file="EP1577291A1_D0050.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.37-7.36 (1H, d), 7.32-7.17 (8H, m), 7.13-7.11 (1H, d), 6.82-6.80 (1H, d), 4.75-4.71 (1H, m), 4.70 (2H, s), 4.37 (2H, s), 3.58 (2H, s), 3.02-2.96 (1H, m), 2.93-2.89 (1H, m), 2.86-2.78 (2H, m), 1.16 (3H, s), 1.14 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 497, [M+Na]⁺ 519, [M-H]^- 495.

Example 21:

<b>N</b>

-(2,6-dimethoxybenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl)ethyl}amino)-2-methylpropyl]phenyl}acetamide

0081<chemistry id="chem0051" num="0051"><img file="EP1577291A1_D0051.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.39-7.38 (1H, d), 7.32-7.13 (6H, m), 6.83-6.81 (1H, d), 6.66 (1H, s), 6.64 (1H, s), 4.80-4.77 (1H, m), 4.70 (2H, s), 4.46 (2H, s), 3.80 (6H, s), 3.52 (2H, s), 3.15-3.00 (2H, m), 2.88 (2H, m), 1.21 (3H, s), 1.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 523, [M+Na]⁺ 545, [M-H]^- 521.

Example 22:

<b>N</b>

-benzyl-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0082<chemistry id="chem0052" num="0052"><img file="EP1577291A1_D0052.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.38-7.37 (1H, d), 7.33-7.17 (9H, m), 7.12-7.11 (1H, m), 6.82-6.80 (1H, d), 4.75-4.72 (1H, dd), 4.70 (2H, s), 4.40 (2H, s), 3.58 (2H, s), 3.02-2.96 (1H, m), 2.93-2.89 (1H, m), 2.86-2.78 (2H, m), 1.16 (3H, s), 1.15 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M-H]^- 461.

Example 23: 4-{(1

<b>R</b>

)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1

<b>H</b>

)-yl)-2-oxoethyl]phenyl}-1,1-dimethylethyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol

0083<chemistry id="chem0053" num="0053"><img file="EP1577291A1_D0053.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.36-7.35 (1H, d), 7.29-7.24 (1H, m), 7.22-7.13 (5H, m), 7.12-7.09 (2H, m), 7.04-7.02 (1H, d), 6.80-6.78 (1H, m), 4.74 (1H, s), 4.71-4.66 (4H, m), 3.90-3.89 (2H, m), 3.86-3.82 (1H, m), 3.78-3.75 (1H, m), 2.94-2.86 (2H, m), 2.81-2.66 (4H, m), 1.08-1.01 (6H, m) ppm. LRMS (electrospray) : m/z [M+ H]⁺ 489, [M+Na]⁺ 511, [M-H]^- 487.

Example 24:

<b>N</b>

-[2-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0084<chemistry id="chem0054" num="0054"><img file="EP1577291A1_D0054.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.62-7.58 (1H, m), 7.56-7.54 (1H, m), 7.33-7.32 (1H, d), 7.28-7.12 (5H, m), 7.08-7.06 (1H, d), 6.78-6.76 (1H, d), 4.70-4.67 (1H, m), 4.65 (2H, s), 4.46 (2H, s), 3.55 (2H, s), 2.96-2.91 (1H, m), 2.86-2.81 (1H, m), 2.80-2.72 (2H, m), 1.10 (3H, s), 1.09 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 549, [M+Na]⁺ 571, [M-H]^- 547.

Example 25:

<b>N-</b>

(2

<b>,</b>

6-dichlorobenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0085<chemistry id="chem0055" num="0055"><img file="EP1577291A1_D0055.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.45-7.43 (2H, m), 7.39-7.38 (1H, d), 7.34-7.27 (2H, m), 7.23-7.19 (3H, m), 7.14-7.12 (1H, m), 6.83-6.81 (1H, d), 4.79-4.76 (1H, m), 4.71 (2H, s), 4.70 (2H, s), 3.55 (2H, s), 3.09-2.97 (2H, m), 2.88 (2H, s), 1.22 (3H, s), 1.21 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 531, [M+Na]⁺ 553, [M-H]^- 529.

Example 26: 2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-

<b>N</b>

-[2-(methylthio)benzyl]acetamide

0086<chemistry id="chem0056" num="0056"><img file="EP1577291A1_D0056.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.36-7.10 (10H, m), 6.81-6.79 (1H, d), 4.73-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1H, m), 2.89-2.84 (1H, m), 2.81-2.76 (2H, m), 2.48 (3H,s), 1.15 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 509, [M+Na]⁺ 531, [M-H]^- 507.

Example 27:

<b>N</b>

-(2,3-dimethylbenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0087<chemistry id="chem0057" num="0057"><img file="EP1577291A1_D0057.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD3OD): <i>δ</i> = 7.37-7.36 (1H, m), 7.30-7.16 (4H, m), 7.12-7.01 (4H, m), 6.82-6.80 (1H, d), 4.74-4.71 (1H, m), 4.69 (2H, s), 4.40 (2H, s), 3.56 (2H, s), 3.01-2.96 (1H, m), 2.92-2.88 (1H, m), 2.86-2.77 (2H, m), 2.29 (3H, s), 2.18 (3H, s), 1.16 (3H, s), 1.14 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 491, [M+Na]⁺ 513, [M-H]^- 489.

Example 28: 2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-

<b>N</b>

-[3-(trifluoromethyl)benzyl]acetamide

0088<chemistry id="chem0058" num="0058"><img file="EP1577291A1_D0058.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.56-7.47 (4H, m), 7.36-7.35 (1H, m), 7.28-7.15 (4H, m), 7.11-7.09 (1H, d), 6.80-6.78 (1H, d), 4.73-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1H, m), 2.89-2.85 (1H, m), 2.84-2.75 (2H, m), 1.14 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 531, [M+Na]⁺ 553, [M-H]^- 529.

Example 29:

<b>N</b>

-[4-chloro-3-(trifluoromethyl)benzyl]-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0089<chemistry id="chem0059" num="0059"><img file="EP1577291A1_D0059.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.64-7.63 (1H, m), 7.54-7.52 (1H, m), 7.47-7.45 (1H, m), 7.34-7.33 (1H, m), 7.27-7.14 (4H, m), 7.09-7.08 (1H, d), 6.80-6.78 (1H, d), 4.71-4.67 (1H, m), 4.69 (2H, s), 4.43 (2H, s), 3.58 (2H, s), 2.96-2.91 (1H, m), 2.84-2.80 (1H, m), 2.81-2.72 (2H, m), 1.12 (3H, s), 1.09 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 565, [M+Na]⁺ 587, [M-H]^- 563.

Example 30:

<b>N</b>

-[2-chloro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl)acetamide

0090<chemistry id="chem0060" num="0060"><img file="EP1577291A1_D0060.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD3OD): δ = 7.63-7.56 (3H, m), 7.36-7.35 (1H, d), 7.30-7.21 (3H, m), 7.18-7.16 (1H, dd), 7.12-7.11 (1H, d), 6.81-6.79 (1H, d), 4.73-4.69 (1 H, m), 4.69 (2H, s), 4.54 (2H, s), 3.62 (2H, s), 3.03-2.91 (1H, m), 2.89-2.84 (1H, m), 2.86-2.75 (2H, m), 1.14 (3H, s), 1.12 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 565, [M+Na]⁺ 587, [M-H]^- 563.

Example 31:

<b>N</b>

-[3,5-bis(trifluoromethyl)benzyl]-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0091<chemistry id="chem0061" num="0061"><img file="EP1577291A1_D0061.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.86-7.84 (3H, m), 7.35 (1H, s), 7.28-7.15 (4H, m), 7.11-7.09 (1H, d), 6.81-6.79 (1H, d), 4.71-4.68 (1H, m), 4.69 (2H, s), 4.54 (2H, s), 3.60 (2H, s), 2.96-2.91 (1H, m), 2.83-2.79 (1H, m), 2.80-2.71 (2H, m), 1.10 (3H, s), 1.08 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 599, [M+Na]⁺ 621, [M-H]^- 597.

Example 32:

<b>N</b>

-[3-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

0092<chemistry id="chem0062" num="0062"><img file="EP1577291A1_D0062.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.40 (1H, s), 7.36-7.16 (7H, m), 7.13-7.11 (1H, d), 6.82-6.80 (1H, d), 4.74-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.60 (2H, s), 3.01-2.94 (1H, m), 2.91-2.87 (1H, m), 2.85-2.77 (2H, m), 1.15 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 549, [M+Na]⁺ 571, [M-H]^- 547.

Example 33:

<b>N</b>

-[2-(4-chlorophenyl)ethyl]-3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide

0093<chemistry id="chem0063" num="0063"><img file="EP1577291A1_D0063.tif" /></chemistry> 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}-<i>N</i>-[2-(4-chlorophenyl)ethyl]benzamide (Preparation 38) (470mg, 0.77mmol) and ammonium fluoride (280mg, 7.70mmol) in methanol (3ml) and water (1.7ml) were heated to 43°C for 18 hours. The solvent was removed <i>in vacuo</i> and the product purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume). The resulting compound was taken up in methanol and evaporated (×3) to yield a white foam (320 mg). A small sample was recrystallised (hexane:ethyl acetate) to give a white solid (mp 139-140 °C). ¹H NMR (400MHz, CD₃OD) δ = 7.64-7.60 (2H, m), 7.37-7.20 (7H, m), 7.11 (1H, dd), 6.74 (1H, d), 4.68-4.65 (3H, m), 3.57 (2H, m), 2.98-2.87 (4H, m), 2.77-2.70 (2H, m), 1.12 (3H, s), 1.05 (3H, s). LRMS (electrospray) m/z 497 [M+H]⁺, 519 [M+Na]⁺ Analysis for C₂₈H₃₃CIN₂O₄.0.5 H₂O 0.3 C₄H₁₀O Calc. (Found) C 66.63 (66.39), H 6.95 (7.06), N 5.31 (5.30) %.

Example 34: 3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}-

<b>N</b>

-[2-(4-methylphenyl)ethyl]benzamide

0094<chemistry id="chem0064" num="0064"><img file="EP1577291A1_D0064.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-<i>N</i>-[2-(4-methylphenyl)ethyl]benzamide (Preparation 39) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.69-7.65 (2H, m), 7.37-7.30 (3H, m), 7.14-7.06 (5H, m), 6.75 (1H, d), 4.67-4.64 (3H, m), 3.59-3.54 (2H, m), 2.96-2.84 (4H, m), 2.77-2.69 (2H, m), 2.28 (3H, s), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 477 [M+H]⁺, 499 [M+Na]⁺ Analysis for C₂₉H₃₆N₂O₄-0.5 H₂O 0.3 C₄H₁₀O Calc. (Found) C 71.42 (71.62), H 7.94 (7.88), N 5.52 (5.57) %.

Example 35: 3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methyl -propyl}-

<b>N</b>

-[2-(4-trifluoromethylphenyl)ethyl]benzamide

0095<chemistry id="chem0065" num="0065"><img file="EP1577291A1_D0065.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-<i>N</i>-[2-(4-trifluoromethylphenyl)ethyl]benzamide (Preparation 40) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.68-7.62 (1H, m), 7.61 (1H, bs), 7.66 (2H, d), 7.42 (2H, d), 7.38-7.30 (3H, m), 7.12 (1H, dd), 6.75 (1H, dd), 4.68-4.65 (1H), 4.65 (2H, s), 3.61 (2H, m), 3.00 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.73 (1H, dd), 2.69 (1H, d), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 531 [M+H]⁺ HRMS for C₂₉H₃₄F₃N₂O₄ 531.2447 [M+H]⁺ found 531.2465.

Example 36:

<b>N</b>

-[2-(3,4-dichlorophenyl)ethyl]-3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide

0096<chemistry id="chem0066" num="0066"><img file="EP1577291A1_D0066.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-<i>N</i>-[2-(3,4-dichlorophenyl)ethyl]benzamide (Preparation 41) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.62 (1H, d), 7.60 (1H, s), 7.42-7.40 (2H, m), 7.38-7.31 (3H, m), 7.18-7.11 (2H, m), 6.75 (1H, d), 4.68-4.66 (1H), 4.65 (2H, s), 3.56 (2H, m), 2.86-2.97 (4H, m), 2.69-2.77 (2H, m), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 531 [M+H]⁺ HRMS for C₂₈H₃₃Cl₂N₂O₄ 531.1801 [M+H]⁺ found 531.1812.

Example 37:

<b>N</b>

-[2-(3,4-dimethylphenyl)ethyl]-3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}benzamide

0097<chemistry id="chem0067" num="0067"><img file="EP1577291A1_D0067.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3,4-dimethylphenyl)ethyl]benzamide (Preparation 42) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.63 (1H, m), 7.61 (1H, bs), 7.38-7.31 (3H, m), 7.12 (1H, dd), 7.02-6.99 (2H, m), 6.92 (1H, dd), 6.75 (1H, d), 4.67-4.64 (1H, m), 4.65 (2H, s), 3.53 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.82 (2H, t), 2.72 (1H, dd), 2.69 (1H, d), 2.20 (6H, s), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 491 [M+H]⁺ HRMS for C₃₀H₃₉N₂O₄ 491.2905 [M+H]⁺ found 491.2892.

Example 38: 3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-

<b>N</b>

-(2-naphthalen-2-yl-ethyl)benzamide

0098<chemistry id="chem0068" num="0068"><img file="EP1577291A1_D0068.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-<i>N</i>-(2-naphthalen-2-yl-ethyl)benzamide (Preparation 43) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ 7.80-7.75 (3H, m), 7.68 (1H, bs), 7.62 (1H, m), 7.57 (1H, bs), 7.44-7.29 (6H, m), 7.12 (1H, dd), 6.75 (1H, d), 4.67-4.63 (1H, m), 4.66 (2H, s), 3.67 (2H, m), 3.06 (2H, t), 2.90 (1H, dd), 2.82 (1h, d), 2.71 (1H, dd), 2.66 (1H, d), 1.08 (3H, s), 1.01 (3H, s). LRMS (electrospray) m/z 513 [M+H]⁺ HRMS for C₃₂H₃₇N₂O₄ 513.2748 [M+H]⁺ found 513.2726.

Example 39:

<b>N</b>

-(1,1-dimethyl-2-phenylethyl)-3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxy-methylphenyl)-ethylamino]-2-methylpropyl}benzamide

0099<chemistry id="chem0069" num="0069"><img file="EP1577291A1_D0069.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-<i>N</i>-(1,1-dimethyl-2-phenylethyl)benzamide (Preparation 44) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.64 (1H, m), 7.60 (1H, bs), 7.35-7.27 (3H, m), 7.24-7.15 (5H, m), 7.06 (1H, dd), 6.72 (1H, d), 4.64 (2H, s), 4.64-4.61 (1H, m), 3.20 (1H, d), 3.12 (1H, d), 2.86 (1H, dd), 2.81 (1H, d), 2.73-2.69 (2H, m), 1.42 (3H, s), 1.39 (3H, s), 1.09 (3H, s), 1.05 (3H, s). LRMS (electrospray) m/z 491 [M+H]⁺ HRMS for C₃₂H₃₇N₂O₄ 491.2905 [M+H]⁺ found 491.2885.

Example 40: 3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}-

<b>N</b>

-(2-methyl-2-phenylpropyl)benzamide

0100<chemistry id="chem0070" num="0070"><img file="EP1577291A1_D0070.tif" /></chemistry> Prepared from 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}-<i>N</i>-(2-methyl-2-phenylpropyl)-benzamide (Preparation 45) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ 7.53 (1H, m), 7.60 (1H, bs), 7.43 (1H, dd), 7.34-7.28 (5H, m), 7.20-7.16 (1H, m), 7.10 (1H, dd), 6.74 (1H, d), 4.65 (2H, s), 4.65-4.61 (1H, dd), 3.57 (2H, s), 2.87 (1H, dd), 2.79 (1H, d), 2.75-2.69 (2H, m), 1.38 (6H, s), 1.07 (3H, s), 1.03 (3H, s). LRMS (electrospray) m/z 491 [M+H]⁺ HRMS for C₃₀H₃₉N₂O₄ 491.2905 [M+H]⁺ found 491.2897.

Example 41:

<b>N</b>

-(4-chlorobenzyl)-3-{2-[(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide

0101<chemistry id="chem0071" num="0071"><img file="EP1577291A1_D0071.tif" /></chemistry> Prepared from 3-{(2<i>R</i>)-2-[2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-<i>N</i>-(4-chlorobenzyl)benzamide (Preparation 46) using the method for example 33 to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.74-7.70 (3H, m), 7.40-7.29 (7H, m), 7.07 (1H, dd), 6.71 (1H, d), 4.67-4.63 (1H, dd), 4.63 (2H, s), 4.60 (2H, dd), 2.96-2.88 (2H, m), 2.76-2.70 (2H, m), 1.12 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 481/483 [M+H]⁺ HRMS for C₃₀H₃₂CIN₂O₄ 483.2045 [M+H]⁺ found 483.2038.

Example 42:

<b>N</b>

-(2,6-dimethoxybenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide

0102<chemistry id="chem0072" num="0072"><img file="EP1577291A1_D0072.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.26-7.19 (3H, m), 7.11-7.07 (4H, m), 6.74-6.72 (1H, d), 6.61-6.59 (2H, d), 4.70-4.67 (1H, m), 4.63 (2H, s), 4.41 (2H, s), 3.75 (6H, s), 3.45 (2H, s), 2.91-2.75 (6H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 495, [M+Na]⁺ 517, [M-H]^- 493. CHN analysis : found C 66.15%, H 6.89%, N 5.53%; C₂₈H₃₄N₂O₆+0.75H₂O requires C 66.19%, H 7.04%, N 5.51%.

Example 43:

<b>N</b>

-(3,4-dichlorobenzyl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide

0103<chemistry id="chem0073" num="0073"><img file="EP1577291A1_D0073.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.43-7.41 (1H, d), 7.36-7.35 (1H, d), 7.26-7.23 (2H, m), 7.15-7.06 (5H, m), 6.74-6.72 (1H, d), 4.70-4.66 (1H, m), 4.63 (2H, s), 4.32 (2H, s), 3.53 (2H, s), 2.94-2.75 (6H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 503, [M+Na]⁺ 525, [M-H]^- 501. CHN analysis : found C 59.26%, H 5.52%, N 5.20%; C₂₆H₂₈N₂O₄Cl₂+1.35H₂O requires C 59.17%, H 5.86%, N 5.31 %.

Example 44:

<b>N</b>

-benzyl-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide

0104<chemistry id="chem0074" num="0074"><img file="EP1577291A1_D0074.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-(2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.30-7.19 (7H, m), 7.15-7.14 (2H, m), 7.11-7.06 (2H, m), 6.74-6.72 (1H, d), 4.70-4.67 (1H, m), 4.63 (2H, s), 4.35 (2H, s), 3.52 (2H, s), 2.95-2.77 (6H, m) ppm. LRMS (efectrospray) : m/z [M+H]⁺ 435, (M+Na]⁺ 457, [M-H]^- 433. CHN analysis : found C 67.21 %, H 6.70%, N 5.99%; C₂₆H₃₀N₂O₄+0.45CH₂Cl₂ requires C 67.20%, H 6.59%, N 5.93%.

Example 45:

<b>N</b>

-(2,3-dihydro-1

<b>H</b>

-inden-2-yl)-2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide

0105<chemistry id="chem0075" num="0075"><img file="EP1577291A1_D0075.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.26 (1H, s), 7.24-7.17 (3H, m), 7.13-7.07 (6H, m), 6.74-6.72 (1H, d), 4.72-4.68 (1H, m), 4.63 (2H, s), 4.59-4.52 (1H, m), 3.45 (2H, s), 3.26-3.24 (1H, d), 3.22-3.20 (1H, d), 2.97-2.79 (8H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 461, [M+Na]⁺ 483, [M-H]^- 459. CHN analysis : found C 65.30%, H 6.57%, N 5.57%; C₂₈H₃₂N₂O₄+0.80CH₂Cl₂+0.10H₂O requires C 65.23%, H 6.42%, N 5.28%.

Example 46: 2-{3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}-

<b>N</b>

-(2-phenylethyl)acetamide

0106<chemistry id="chem0076" num="0076"><img file="EP1577291A1_D0076.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.27-7.26 (1H, d), 7.24-7.06 (10H, m), 6.74-6.72 (1H, d), 4.72-4.69 (1H, m), 4.64 (2H, s), 3.44-3.39 (4H, m), 3.00-2.92 (2H, m), 2.89-2.82 (4H, m), 2.79-2.75 (2H, t) ppm. LRMS (electrospray) : m/z [M+H]⁺ 449, [M+Na]⁺ 471, [M-H]^- 447. CHN analysis : found C 64.80%, H 6.70%, N 5.52%; C₂₇H₃₂N₂O₄+0.75CH₂Cl₂ requires C 65.07%, H 6.59%, N 5.47%.

Example 47: 2-{3-[2-({0(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)ethyl]phenyl)-

<b>N</b>

-(3-phenylpropyl)acetamide

0107<chemistry id="chem0077" num="0077"><img file="EP1577291A1_D0077.tif" /></chemistry> Prepared according to the procedure used for Preparation 1 using {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.25-7.19 (4H, m), 7.15-7.05 (7H, m), 6.74-6.72 (1H, d), 4.69-4.64 (3H, m), 3.47 (2H, s), 3.21-3.17 (2H, t), 2.96-2.74 (6H, m), 2.60-2.56 (2H, t), 1.75-1.73 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M-H]^- 461. CHN analysis : found C 68.54%, H 7.17%, N 5.80%; C₂₈H₃₄N₂O₄+0.40CH₂Cl₂+0.10 H₂O requires C 68.45%, H 7.08%, N 5.62%.

Example 48:

<b>N</b>

-benzyl-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0108<chemistry id="chem0078" num="0078"><img file="EP1577291A1_D0078.tif" /></chemistry> To a solution of 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (116mg, 0.22mmol) in DMF (2ml) was added triethylamine (62µl, 0.45mmol), benzylamine (29µl, 0.27mmol), HOBt (33mg, 0.25mmol) and WSCDI (47mg, 0.25mmol) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed <i>in vacuo</i> and the residue partitioned between saturated aqueous sodium hydrogen carbonate solution (5ml) and dichloromethane/methanol (95/5) (10ml). The aqueous layer was separated and extracted with further dichloromethane/methanol (95/5) (4×10ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated <i>in vacuo.</i> The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90:10:1, by volume) to give the title compound as a white foam (70mg). ¹H NMR (400MHz, CD₃OD): δ = 7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.29 (6H, m), 7.26-7.21 (1H, m), 7.21 (1H, s), 7.03-7.01 (1H, d), 6.69-6.67 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 4.58 (2H, s), 3.05-2.98 (1H, m), 2.92-2.86 (1H, dd), 2.84-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.68-2.63 (1H, dd), 1.10-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 435, [M+Na]⁺ 457, (M-H]^- 433. CHN analysis : found C 69.79, H 6.96, N 6.37; C₂₆H₃₀N₂0₄+0.7H₂0 requires C 69.84, H 7.08, N 6.26.

Example 49:

<b>N</b>

-(3,4-dichlorobenzyl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0109<chemistry id="chem0079" num="0079"><img file="EP1577291A1_D0079.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.69-7.67 (1H, d), 7.65 (1H, s), 7.51 (1H, s ), 7.48-7.46 (1H, d), 7.36-7.27 (3H, m), 7.21 (1H, s), 7.03-7.02 (1H, d), 6.69-6.66 (1H, d), 4.65-4.61 (1H, m), 4.61 (2H, s), 4.54 (2H, s), 3.02-2.97 (1H, m), 2.91-2.86 (1H, dd), 2.83-2.77 (1H, dd), 2.74-2.69 (1H, dd), 2.68-2.63 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 503, [M+Na]⁺ 525, [M-H]- 501.

Example 50:

<b>N</b>

-[2-fluoro-5-(trifluoromethyl)benzyl]-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-(4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0110<chemistry id="chem0080" num="0080"><img file="EP1577291A1_D0080.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.74-7.60 (4H, m), 7.38-7.29 (3H, m), 7.22 (1H, s), 7.04-7.02 (1H, d), 6.69-6.67 (1H, d), 4.67 (2H, s), 4.67-4.61 (1H, m) 4.61 (2H, s), 3.04-2.99 (1H, m), 2.93-2.80 (2H, m), 2.76-2.71 (1H, m), 2.68-2.63 (1H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 521, [M+Na]⁺ 543, [M-H]^- 519. CHN analysis : found C 60.88, H 5.58, N 5.58; C₂₇H₂₈F₄N₂O₄+0.7H₂O requires C 60.83, H 5.56, N 5.25.

Example 51:

<b>N</b>

-(2,6-dimethoxybenzyl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0111<chemistry id="chem0081" num="0081"><img file="EP1577291A1_D0081.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.58-7.55 (2H, m), 7.31-7.24 (3H, m), 7.19 (1H, s), 7.00-6.98 (1H, dd), 6.68-6.64 (3H, m), 4.63 (2H, s), 4.63-4.58 (1H, m) 4.60 (2H, s), 3.84 (6H, s), 3.00-2.94 (1H, m), 2.90-2.85 (1H, m), 2.78-2.61 (3H, m), 1.08-1.06 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 495, [M+Na]⁺ 517, [M-H]^- 493. CHN analysis : found C 65.52, H 6.89, N 5.43; C₂₈H₃₄N₂O₆+1.0H₂O requires C 65.61, H 7.08, N 5.46.

Example 52:

<b>N</b>

-[2-(4-chlorophenyl)ethyl]-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0112<chemistry id="chem0082" num="0082"><img file="EP1577291A1_D0082.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.60-7.58 (1H, d), 7.54 (1H, s), 7.35-7.23 (7H, m), 7.04-7.01 (1H, dd), 6.70-6.68 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 3.60-3.57 (2H, t), 3.02-2.96 (1H, m), 2.92-2.87 (3H, m), 2.83-2.78 (1H, m), 2.75-2.71 (1H, dd), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 483, [M+Na]⁺ 505, [M-H]^- 481. CHN analysis : found C 65.90, H 6.68, N 5.55; C₂₇H₃₁CIN₂O₄+0.5H₂O requires C 65.91, H 6.56, N 5.69 .

Example 53:

<b>N</b>

-(2,3-dihydro-1

<b>H</b>

-inden-2-yl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0113<chemistry id="chem0083" num="0083"><img file="EP1577291A1_D0083.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.66-7.63 (2H, m), 7.35-7.28 (2H, m), 7.22-7.21 (3H, m), 7.15-7.13 (2H, m), 7.03-7.02 (1H, dd), 6.70-6.68 (1H, d), 4.84-4.79 (1H, m), 4.64-4.60 (1H, m), 4.61 (2H, s), 3.37-3.30 (2H, dd), 3.03-2.97 (3H, m), 2.92-2.87 (1H, m), 2.84-2.78 (1H, m), 2.76-2.71 (1H, m), 2.68-2.63 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 461, [M+Na]⁺ 483, [M-H]^- 459. CHN analysis : found C 70.42, H 6.87, N 5.91; C₂₈H₃₂N₂O₄+0.9H₂O requires C 70.54, H 7.15, N 5.88 .

Example 54: 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-

<b>N</b>

-(2-phenylethyl)benzamide

0114<chemistry id="chem0084" num="0084"><img file="EP1577291A1_D0084.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.60-7.58 (1H, d), 7.56 (1H, s), 7.35-7.17 (8H, m), 7.05-7.02 (1H, dd), 6.70-6.68 (1H, d), 4.64-4.60 (1H, m), 4.62 (2H, s), 3.61-3.57 (2H, t), 3.03-2.97 (1H, m), 2.93-2.87 (3H, m), 2.84-2.78 (1H, m), 2.77-2.71 (1H, m), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 449, [M+Na]⁺ 471, [M-H]^- 447. CHN analysis : found C 70.10, H 7.16, N 6.09; C₂₇H₃₂N₂O₄+0.75H₂O requires C 70.18, H 7.31, N 6.06

Example 55: 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-

<b>N</b>

-[(1

<b>R</b>

)-1-phenylethyl]benzamide

0115<chemistry id="chem0085" num="0085"><img file="EP1577291A1_D0085.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.67-7.64 (2H, m), 7.41-7.39 (2H, d), 7.34-7.28 (4H, m), 7.24-7.21 (2H, m), 7.02-7.00 (1H, dd), 6.68-6.66 (1H, d), 5.26-5.21 (1H, q), 4.63-4.60 (1H, m), 4.60 (2H, s), 3.03-2.99 (1H, m), 2.91-2.86 (1H, dd), 2.83-2.78 (1H, dd), 2.74-2.70 (1H, dd), 2.69-2.63 (1H, dd), 1.57-1.55 (3H, d), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 449, [M+Na]⁺ 471, [M-H]^- 447. CHN analysis : found C 68.96, H 7.07, N 5.91; C₂₇H₃₂N₂O₄+1.2H₂O requires C 68.97, H 7.37, N 5.96

Example 56: 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-

<b>N</b>

-(3-phenylpropyl)benzamide

0116<chemistry id="chem0086" num="0086"><img file="EP1577291A1_D0086.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.63-7.61 (1H, d), 7.59 (1H, s), 7.35-7.21 (7H, m), 7.16-7.13 (1H, m), 7.03-7.01 (1H, dd), 6.69-6.67 (1H, d), 4.61 (3H, m), 3.42-3.39 (2H, t), 3.00-2.96 (1H, q), 2.91-2.86 (1H, dd), 2.81-2.76 (1H, dd), 2.74-2.61 (4H, m), 1.98-1.91 (2H, quin), 1.09-1.07 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M-H]^- 461.

Example 57: 4-[(1

<b>R</b>

)-2-({(1

<b>R</b>

)-2-[3-(3,4-dihydroisoquinolin-2(1

<b>H</b>

)-ylcarbonyl)phenyl]-1-methylethyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

0117<chemistry id="chem0087" num="0087"><img file="EP1577291A1_D0087.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD_sOD): δ = 7.39-7.36 (1H, m), 7.29-7.17 (6H, m), 7.12-7.01 (3H, m), 6.71-6.69 (1H, d), 4.62 (2H, s), 4.62-4.55 (2H, m), 3.96 (2H, s), 3.60-3.56 (1H, m), 3.11-2.64 (7H, m), 1.10-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 461, [M+Na]⁺ 483, [M-H]^- 459. CHN analysis : found C 71.65, H 7.12, N 6.39; C₂₈H₃₂N₂O₄+0.41 H₂O requires C 71.87, H 7.07, N 5.99.

Example 58:

<b>N</b>

-(2,3-dimethylbenzyl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0118<chemistry id="chem0088" num="0088"><img file="EP1577291A1_D0088.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.68-7.66 (1H, d), 7.64 (1H, s), 7.36-7.28 (2H, m), 7.21 (1H, d), 7.14-7.12 (1H, d), 7.08-6.99 (3H, m), 6.68-6.68 (1H, d), 4.63-4.59 (1H, m), 4.61 (2H, s), 4.59 (2H, s), 3.04-2.99 (1H, q), 2.92-2.89 (1H, dd), 2.83-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.69-2.64 (1H, dd), 2.30 (3H, s), 2.28 (3H, s), 1.11-1.09 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 463, [M+Na]⁺ 485, [M-H]^- 461. CHN analysis : found C 70.17, H 7.33, N 5.90; C₂₈H₃₄N₂O₄+0.90H₂O requires C 70.24, H 7.54, N 5.85.

Example 59:

<b>N</b>

-(5,6-diethyl-2,3-dihydro-1

<b>H</b>

-inden-2-yl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0119<chemistry id="chem0089" num="0089"><img file="EP1577291A1_D0089.tif" /></chemistry> Prepared according to the procedure used for example 49 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.65-7.63 (1H, d), 7.61 (1H, s), 7.34-7.26 (2H, m), 7.21 (1H, s), 7.03-7.01 (1H, m), 7.01 (2H, s), 6.69-6.67 (1H, d), 4.81-4.77 (1H, dd), 4.63-4.60 (1H, m), 4.61 (2H, s), 3.31-3.26 (2H, dd), 3.03-2.99 (1H, q), 2.97-2.92 (2H, dd), 2.92-2.87 (1H, dd), 2.83-2.78 (1H, dd), 2.75-2.71 (1H, dd), 2.68-2.61 (5H, m), 1.22-1.18 (6H, t), 1.10-1.09 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 517, [M+Na]⁺ 539, [M-H]^- 515. CHN analysis : found C 72.58, H 7.80, N 5.34; C₃₂H₄₀N₂O₄+0.7H₂O requires C 72.62, H 7.88, N 5.29.

Example 60:

<b>N</b>

-(4-chlorobenzyl)-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0120<chemistry id="chem0090" num="0090"><img file="EP1577291A1_D0090.tif" /></chemistry> To a solution of 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (120mg, 0.27mmol) in DMF (3ml) was added triethylamine (111µl, 0.79mmol), 4-chlorobenzylamine (39µl, 0.32mmol), and HBTU (110mg, 0.29mmol) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed <i>in vacuo</i> and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (93:7:0.7 changing to 90:10:1, by volume) to give the title compound as a white foam (97mg). ¹H NMR (400MHz, CD₃OD): δ = 7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.30 (6H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70-6.68 (1H, d), 4.67-4.64 (1H, dd), 4.62 (2H, s), 4.55 (2H, s), 3.15-3.07 (1H, m), 3.00-2.86 (2H, m), 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13-1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 469, [M+Na]⁺ 491, [M-H]^- 467.

Example 61: 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-

<b>N</b>

-phenylbenzamide

0121<chemistry id="chem0091" num="0091"><img file="EP1577291A1_D0091.tif" /></chemistry> Prepared according to the procedure used for example 60 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.77-7.74 (2H, m), 7.69-7.67 (2H, d), 7.41-7.33 (4H, m), 7.22 (1H, d), 7.16-7.12 (1H, t), 7.05-7.03 (1H, dd), 6.70-6.68 (1 H, d), 4.66-4.61 (1H, m), 4.62 (2H, s), 3.09-3.04 (1H, m), 2.96-2.84 (2H, m), 2.79-2.69 (2H, m), 1.14-1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 421, [M+Na]⁺ 443, [M-H]^- 419 CHN analysis : found C 67.98, H 6.64, N 6.48; C₂₅H₂₈N₂O₄+0.06CH₂Cl₂+0.95 H₂O requires C 67.99, H 6.83, N 6.33.

Example 62:

<b>N</b>

-[4-(aminosulfonyl)benzyl]-3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

0122<chemistry id="chem0092" num="0092"><img file="EP1577291A1_D0092.tif" /></chemistry> Prepared according to the procedure used for example 60 using 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine, substituting with dichloromethane :methanol:880 ammonia (85:15:2, by volume) as eluent to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.87-7.85 (2H, d), 7.71-7.69 (1H, d), 7.67 (1H, s), 7.53-7.50 (2H, d), 7.39-7.32 (2H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70-6.68 (1H, d), 4.67-4.65 (1H, m), 4.65 (2H, s), 4.62 (2H, s), 3.14-3.07 (1H, m), 2.97-2.92 (1H, dd), 2.91-2.86 (1H, dd), 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13-1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 514, [M+Na]⁺ 536, [M-H]^- 512. CHN analysis : found C 56.26, H 6.01, N 7.45; C₂₆H₃₁N₃O₆S+2.1 H₂O requires C 56.63, H 6.43, N 7.62.

Preparation 1: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cycloheptylacetamide

0123<chemistry id="chem0093" num="0093"><img file="EP1577291A1_D0093.tif" /></chemistry> A solution of (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) (250mg, 0.45mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94mg, 0.49mmol), hydroxybenzotriazole monohydrate (66mg, 0.49mmol) in <i>N</i>,<i>N</i>-dimethylformamide (4ml) was treated with triethylamine (0.12ml, 0.89mmol) and cycloheptylamine (56mg, 0.49mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed <i>in vacuo</i> and the residue partitioned between ethyl acetate (10ml) and saturated aqueous sodium bicarbonate (10ml). The organic phase was separated, and the aqueous phase extracted with further ethyl acetate (2×10ml). The combined organic extracts were washed with water (5ml), brine (5ml), dried (sodium sulfate) and the solvent removed <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give the title compound as a pale yellow oil (150mg). ¹H NMR (400MHz, CD₃OD): δ = 7.20-6.98 (6H, m), 6.68 (1H, d), 4.60 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, m), 1.80 (2H, m), 1.75-1.40 (10H, m), 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 569.

Preparation 2: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cyclohexylmethyl)-

<b>N</b>

-methylacetamide

0124<chemistry id="chem0094" num="0094"><img file="EP1577291A1_D0094.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert-</i>butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.20-6.95 (6H, m), 6.63 (1H, d), 4.60 (3H, m), 3.68 (2H, s), 3.20 (2H, m), 2.85 (5H, m), 2.63 (2H, m), 2.57 (1H, m), 1.60 (5H, m), 1.20 (4H, m), 1.03 (3H, d), 0.81 (11H, m), 0.00 (3H, s), -0.21 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 583.

Preparation 3: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-[(1

<b>S)-</b>

1-cyclohexylethyl]acetamide

0125<chemistry id="chem0095" num="0095"><img file="EP1577291A1_D0095.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.20 (3H, m), 7.03 (1H, s), 6.98 (2H, dd), 6.68 (1H, d), 4.60 (3H, m), 3.68 (1H, m), 3.42 (1H, d), 3.38 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, dd), 1.65 (4H, m), 1.40-0.83 (13H, m), ppm. LRMS (electrospray) : m/z [M+H]⁺ 583, [M+Na]⁺ 605, [M-H]^- 582.

Preparation 4: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyt)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-isopropylacetamide

0126<chemistry id="chem0096" num="0096"><img file="EP1577291A1_D0096.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.19-7.15 (2H, m), 7.11-7.10 (1H, d), 7.04 (1H, s), 6.99-6.96 (2H, t), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 3.96-3.90 (1H, m), 3.39 (2H, s), 2.93-2.84 (2H, m), 2.70-2.62 (2H, m), 2.56-2.52 (1H, m), 1.12-1.11 (6H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 515, [M-H]^- 513.

Preparation 5: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cyclopentylacetamide

0127<chemistry id="chem0097" num="0097"><img file="EP1577291A1_D0097.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 4.10-4.04 (1H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.62 (2H, m), 2.56-2.51 (1H, m), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.53 (2H, m), 1.47-1.39 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 541, [M-H]^- 539.

Preparation 6: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cyclobutylmethyl)acetamide

0128<chemistry id="chem0098" num="0098"><img file="EP1577291A1_D0098.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl)-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz. CD₃OD): δ = 7.19-7.15 (2H, m), 7.12-7.10 (1H, m), 7.04 (1H, s), 7.00-6.96 (2H, m), 6.69-6.67 (1H. d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 3.43 (2H, s), 3.19-3.17 (2H, d), 2.93-2.85 (2H, m), 2.70-2.62 (2H, m), 2.56-2.51 (1H, m), 2.48-2.43 (1H, m), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m), 1.72-1.65 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 541, [M-H]^- 539.

Preparation 7: 2-(3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cyclopentylmethyl)acetamide

0129<chemistry id="chem0099" num="0099"><img file="EP1577291A1_D0099.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert-</i>butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.18 (1H, s), 7.16-7.14 (1H, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.65-4.57 (2H, m), 3.43 (2H, s), 3.10-3.08 (2H, d), 2.93-2.85 (2H, m), 2.70-2.63 (2H, m), 2.56-2.51 (1H, m), 2.08-2.00 (1H, m), 1.74-1.67 (2H, m), 1.64-1.50 (4H, m), 1.22-1.14 (2H, m), 1.06-1.04 (3H, d), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 555, [M-H]^- 554.

Preparation 8: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cyclohexylacetamide

0130<chemistry id="chem0100" num="0100"><img file="EP1577291A1_D0100.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1H, d), 4.70-4.67 (1H, dd), 4.65-4.58 (2H, m), 3.65-3.57 (1H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.61 (2H, m), 2.56-2.51 (1H, m), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.64-1.59 (1H, m), 1.39-1.28 (2H, m), 1.24-1.15 (3H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 555, [M-H]^- 554.

Preparation 9: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cyclobutylacetamide

0131<chemistry id="chem0101" num="0101"><img file="EP1577291A1_D0101.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, d), 7.03 (1H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.65 (1H, dd), 4.62-4.61 (2H, d), 4.29-4.21 (1H, m), 3.39 (2H, s), 2.92-2.84 (2H, m), 2.68-2.61 (2H, m), 2.57-2.52 (1H, m), 2.29- 2.21 (2H, m), 1.98-1.87 (2H, m), 1.74-1.66 (2H, m), 1.05-1.03 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 527, [M-H]^- 525.

Preparation 10: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cyclohexylmethyl)acetamide

0132<chemistry id="chem0102" num="0102"><img file="EP1577291A1_D0102.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.18-7.14 (2H, m), 7.11-7.09 (1H, m), 7.03 (1H, s), 6.98-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.62-4.61 (2H, d), 3.43 (2H, s), 3.00-2.99 (2H, d), 2.91-2.84 (2H, m), 2.70-2.62 (2H, m), 2.55-2.50 (1H, m), 1.69-1.67 (5H, m), 1.49-1.43 (1H, m), 1.27-1.14 (3H, m), 1.05-1.03 (2H, m), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 569, [M+Na]⁺ 591, [M-H]^- 567.

Preparation 11: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cyclopropylmethyl)acetamide

0133<chemistry id="chem0103" num="0103"><img file="EP1577291A1_D0103.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.15-7.07 (3H, m), 7.01 (1H, s), 6.95-6.92 (2H, m), 6.65-6.63 (1H, d), 4.66-4.63 (1H, m), 4.58-4.57 (2H, d), 3.40 (2H, s), 3.00-2.98 (2H, d), 2.89-2.80 (2H, m), 2.65-2.57 (2H, m), 2.53-2.48 (1H, dd), 1.01-1.00 (3H, d), 0.93-0.87 (1H, m), 0.79 (9H, s), 0.44-0.40 (2H, q), 0.15-0.12 (2H, q), -0.04 (3H, s), -0.24 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 527, [M+Na]⁺ 549, [M-H]^- 525.

Preparation 12: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(cycloheptylmethyl)acetamide

0134<chemistry id="chem0104" num="0104"><img file="EP1577291A1_D0104.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.24-6.95 (6H, m), 6.70-6.67 (1H, d), 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.24 (2H, s), 3.02-2.99 (2H, d), 2.92-2.50 (5H, m), 1.72-1.08 (13H, m ), 1.06-1.04 (3H, d), 0.92 (9H, s), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 583, [M+Na]⁺ 605.

Preparation 13:

<b>N</b>

-1-adamantyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0135<chemistry id="chem0105" num="0105"><img file="EP1577291A1_D0105.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.20-6.93 (6H, m), 6.68-6.65 (1H, d), 4.74-4.68 (1H, m), 4.65-4.58 (2H, m), 3.40 (s, 2H), 2.96-2.85 (m, 2H), 2.72-2.54 (3H, m), 2.04 (3H, s), 2.01 (6H, s), 1.70 (6H, s), 1.07-1.05 (3H, d), 0.85 (9H, s), 0.02 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]^- 605.

Preparation 14:

<b>N</b>

-(1-adamantylmethyl)-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide

0136<chemistry id="chem0106" num="0106"><img file="EP1577291A1_D0106.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.96 (6H, m), 6.71-6.68 (1H, d), 4.75-4.67 (1H, m), 4.66-4.58 (2H, m), 3.26 (2H, s), 2.88-2.50 (5H, m), 2.84 (2H, s), 1.90 (3H, s), 1.74-1.58 (6H, m), 1.44 (6H, s), 1.08-1.06 (3H, d), 0.84 (9H, s), 0.01 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]^- 619.

Preparation 15:

<b>N</b>

-2-adamantyl-2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl (dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) propyl]phenyl}acetamide

0137<chemistry id="chem0107" num="0107"><img file="EP1577291A1_D0107.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.96 (6H, m), 6.70-6.68 (1 H, d), 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.95 (1H, s), 3.52 (2H, s), 2.94-2.50 (5H, m), 1.96-1.78 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), - 0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]^- 605.

Preparation 16: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(2-cyclohexylethyl)-

<b>N</b>

-methylacetamide

0138<chemistry id="chem0108" num="0108"><img file="EP1577291A1_D0108.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.98 (6H, m), 6.70-6.68 (1H, d), 4.75-4.71 (1H, m), 4.70-4.58 (2H, m), 3.70-3.64 (2H, m), 3.45-3.37 (2H, m), 2.98-2.52 (8H, m), 1.80-0.80 (25H, m), 0.04 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 619.

Preparation 17: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cycloheptyl-

<b>N</b>

-methylacetamide

0139<chemistry id="chem0109" num="0109"><img file="EP1577291A1_D0109.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.96 (6H, m), 6.72-6.64 (1H, dd), 4.72-4.65 (1H, m), 4.62-4.60 (2H, m), 4.58-4.51 (0.5H, m), 3.90-3.83 (0.5H, m), 3.77 (1H, s), 3.66 (1H, s), 2.96-2.50 (5H, m), 2.82-2.78 (3H, d), 1.76-1.20 (12H, m), 1.06-1.04 (3H, dd), 0.82-0.80 (9H, 2s), 0.01-0.00 (3H, 2s), -0.18- -0.19 (3H, 2s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 583, [M+Na]⁺ 605.

Preparation 18: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-cyclohexyl-

<b>N</b>

-ethylacetamide

0140<chemistry id="chem0110" num="0110"><img file="EP1577291A1_D0110.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.25-6.94 (6H, m), 6.70-6.66 (1H, d), 4.72-4.68 (1H, m), 4.64-4.58 (2H, m), 3.73 (2H, s), 3.70-3.60 (1H, m), 3.73 (2H, s), 3.70-3.60 (1H, m), 3.30-3.24 (2H, q), 2.95-2.48 (5H, m), 1.85-1.10 (10H, m), 1.12-1.08 (3H, t), 1.04-1.02 (3H, d), 0.92 (9H, s), 0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 605.

Preparation 19: 2-{3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-

<b>N</b>

-(2-cyclohexylethyl)acetamide

0141<chemistry id="chem0111" num="0111"><img file="EP1577291A1_D0111.tif" /></chemistry> Prepared according to the procedure used for preparation 1 using (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD): δ = 7.22-6.96 (6H, m), 6.68-6.66 (1H, d), 4.70-4.65 (1H, m), 4.64-4.58 (2H, m), 3.42 (2H, s), 3.21-3.17 (2H, t), 2.93-2.50 (5H, m), 1.74-1.60 (5H, m), 1.39-1.34 (2H, q), 1.30-1.12 (4H, m), 1.04-1.02 (3H, d), 0.96-0.91 (2H, m), 0.90 (9H, s), 0.00 (3H, s), -0.19 (3H, s)ppm. LRMS (electrospray) : m/z [M+Na]⁺ 605.

Preparation 20: (3-{(2

<b>R</b>

)-2-[(2

<b>R</b>

)-2-{[

<b>tert</b>

-Butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid

0142<chemistry id="chem0112" num="0112"><img file="EP1577291A1_D0112.tif" /></chemistry> A solution of methyl (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 21) (7.04g, 14.43mmol) in tetrahydrofuran (40ml) was treated with lithium hydroxide (28.9ml of a 1M aqueous solution, 28.9mmol) and the reaction left to stir at room temperature for 16 hours. Hydrochloric acid (28.9ml of a 1M aqueous solution, 28.9mmol) was added and then the tetrahydrofuran was removed <i>in vacuo.</i> The remaining aqueous layer was decanted and the residue washed with further water (10ml). The residue was redisolved in methanol (30ml) and the solvent removed <i>in vacuo</i> to give the title compound as a colorless foam (5.95g) which was used without further purification. ¹H NMR (400MHz, CD₃OD): δ = 7.32 (1H, s), 7.25-7.18 (2H, m), 7.13 (1H, s), 7.12-7.10 (1H, d), 7.02-7.01 (1H, d), 6.79-6.77 (1H, d), 4.98-4.95 (1H, m), 4.65-4.64 (2H, d), 3.48 (2H, s), 3.48-3.43 (1H, m), 3.28-3.23 (1H, dd), 3.13-3.09 (1H, dd), 2.98-2.93 (1H, dd), 2.77-2.72 (1H, dd), 1.23-1.21 (3H, d), 0.86 (9H, s), 0.06 (3H, s), -0.13 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 474, [M+Na]⁺ 496, [M-H]^- 472. CHN analysis : found C 64.15%, H 8.25%, N 2.84%; C₂₆H₃₉NO₅Si+0.7H₂O requires C 64.22%, H 8.37%, N 2.88%.

Preparation 21: methyl (3-{(2

<b>R</b>

)-2-[(2

<b>R</b>

)-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate

0143<chemistry id="chem0113" num="0113"><img file="EP1577291A1_D0113.tif" /></chemistry> A suspension of methyl (3-{(2<i>R</i>)-2-[(2<i>R</i>)-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 22) (5.27g, 9.12mmol) and 10% palladium on carbon (1.00g) in ethanol (50ml) was stirred under an atmosphere of hydrogen (60psi) at room temperature for 16 hours. The catalyst was filtered off through arbocel and the filtrate concentrated <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (96:4:0.4 changing to 95:5:0.5, by volume) to give the title compound as a pale yellow oil (1.99g) which was used without further purification. ¹H NMR (400MHz, CD₃OD): δ = 7.21-7.17 (2H, m), 7.11-7.09 (1H, d), 7.03-6.98 (3H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.62-4.61 (2H, d), 3.67 (3H, s), 3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m), 1.07-1.05 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 488, [M+Na]⁺ 510, [M-H]^- 486

Preparation 22: methyl (3-{(2

<b>R</b>

)-2-[(2

<b>R</b>

)-2-{[

<b>tert-</b>

butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate

0144<chemistry id="chem0114" num="0114"><img file="EP1577291A1_D0114.tif" /></chemistry> A solution of [2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (12.5g, 27.7mmol) and methyl {3-[(2<i>R</i>)-2-aminopropyl]phenyl}acetate (Preparation 25) (11.5g, 55.4mmol) in dichloromethane (130ml) was heated to 90°C, allowing the dichloromethane to evaporate. The resulting melt was left at 90°C for a further 16 hours. The reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound (12.1 g) as a white oil. ¹H NMR (400MHz, CD₃OD): δ = 7.47-7.45 (2H, m), 7.39-7.29 (4H, m), 7.19-7.15 (1H, t), 7.13-7.07 (2H, m), 7.03 (1H, s), 7.01-6.99 (1H, d), 6.93-6.91 (1H, d), 5.12 (2H, s), 4.76-4.73 (1H, t), 4.67-4.66 (2H, d), 3.66 (3H, s), 3.58 (2H, s), 2.95-2.80 (2H, m), 2.68-2.55 (3H, m), 1.06-1.05 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 578, [M+Na]⁺ 600.

Preparation 23: [2-(benzyloxy)-5-((1

<b>R</b>

)-2-bromo-1-{[

<b>tert</b>

-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol

0145<chemistry id="chem0115" num="0115"><img file="EP1577291A1_D0115.tif" /></chemistry> Borane dimethylsulfide complex (42.4ml of 10M solution in tetrahydrofuran, 424mmol) was added dropwise to a solution of methyl 2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}ethyl)benzoate (Preparation 24), (91.0g, 189mmol) in tetrahydrofuran (1600ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0°C before quenching with methanol (270ml). The mixture was left to stir at room temperature for 16 hours and then the solvent removed <i>in vacuo.</i> The residue was partitioned between dichloromethane (500ml) and water (500ml). The aqueous phase was separated and extracted with dichloromethane (500ml) and the combined organic extracts washed with saturated aqueous sodium chloride (500ml), dried (magnesium sulfate) and the solvent removed <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7g) as a colourless oil. ¹H NMR (400MHz, CDCl₃): δ = 7.42-7.36 (5H, m), 7.29-7.25 (3H, m), 6.94 (1H, d), 5.12 (2H, s), 4.84-4.81 (1H, m), 4.74 (2H, s), 3.48-3.40 (2H, m), 0.90 (9H, s), 0.11 (3H, s), -0.07 (3H, s) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 473 / 475.

Preparation 24: methyl 2-(benzyloxy)-5-((1

<b>R</b>

)-2-bromo-1-{[

<b>tert</b>

-butyl (dimethyl)silyl]oxy}ethyl)benzoate

0146<chemistry id="chem0116" num="0116"><img file="EP1577291A1_D0116.tif" /></chemistry> A solution of methyl 2-(benzyloxy)-5-[(1<i>R</i>)-2-bromo-1-hydroxyethyl]benzoate (71.05g, 195mmol), imidazole (18.52g, 272mmol), <i>tert</i>-butyldimethylsilyl chloride (32.23g, 214mmol) and 4-(<i>N,N</i>-dimethylamino)pyridine (0.44g, 3.6mmol) in <i>N,N</i>-dimethylformamide (270ml) was left to stir at room temperature under a nitrogen atmosphere for a period of 24 hours. The solvent was removed <i>in vacuo</i> and the residue partitioned between ethyl acetate (500ml) and water (500ml). The organic phase was separated and washed with 2N hydrochloric acid (2-fold 500ml), saturated aqueous sodium bicarbonate (2-fold 500ml) saturated sodium chloride (500ml), dried (magnesium sulfate) and the solvent removed <i>in vacuo</i> to give the title compound as a colourless oil (91.0g). ¹H NMR (400MHz, CDCl₃): δ = 7.81 (1H, bs), 7.51-7.30 (6H, m), 7.01 (1H, d), 5.19 (2H, s), 4.85-4.82 (1H, m), 3.91 (3H, s), 3.48-3.39 (2H, m), 0.90 (9H, s), 0.11 (3H, s), -0.08 (3H, s) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 501 / 503.

Preparation 25: methyl {3-[(2

<b>R</b>

)-2-aminopropyl]phenyl}acetate

0147<chemistry id="chem0117" num="0117"><img file="EP1577291A1_D0117.tif" /></chemistry> A solution of methyl [3-((2<i>R</i>)-2-{[(1<i>R</i>)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride (Preparation 26) (7.69g, 22mmol) and ammonium formate (6.94g, 110mmol) was heated to 75°C in the presence of 20% palladium hydroxide-on-charcoal (Pd(OH)₂/C, 2.00g). After 90 minutes the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated <i>in vacuo.</i> The residue was partitioned between dichloromethane (100ml) and 880 ammonia (100ml) and the organic phase separated. The aqueous phase was extracted dichloromethane (100ml) and the combined organic extracts dried (magnesium sulfate) and reduced <i>in vacuo</i> to give the title compound as a colourless oil (4.78g). ¹H NMR (400MHz, CD₃OD): δ = 7.27-7.23 (1H, t), 7.13-7.09 (3H, m), 3.67 (3H, s), 3.63 (2H, s), 3.12-3.05 (1H, m), 2.67-2.57 (2H, m), 1.06 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 208, [M+Na]⁺ 230.

Preparation 26: methyl [3-((2

<b>R</b>

)-2-{[(1

<b>R</b>

)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride

0148<chemistry id="chem0118" num="0118"><img file="EP1577291A1_D0118.tif" /></chemistry> A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 27) (8.5g, 41.2mmol), (<i>R</i>)-α-methyl benzylamine (4.8ml, 37.2mmol), sodium triacetoxyborohydride (11.6g, 56mmol) and acetic acid (2.2ml, 38mmol) in dichloromethane (400ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with dichloromethane (100ml). The combined organic extracts were dried (magnesium sulfate) and reduced <i>in vacuo.</i> Purification by flash column chromatography eluting with dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume) gave a 4:1 mixture of diastereomers (<i>R,R</i> major) as a pale yellow oil (8.71g). Treatment with hydrogen chloride (40ml of a 1M solution in methanol, 40mmol) followed by three successive crystallisations (diisopropylether/ methanol) gave the title compound as a white crystalline solid (5.68g). ¹H NMR (400MHz, CD₃OD): δ = 7.52-7.48 (5H, m), 7.28-7.25 (1H, m), 7.18-7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1 H, q), 3.62 (2H, s), 3.30 (3H, s), 3.30-3.25 (1H, m), 3.26-3.15 (1H, m), 2.66-2.60 (1H, m), 1.68 (3H, d), 1.18, (3H, d) ppm. LRMS (electrospray): m/z [M+H]⁺ 312, [M+Na]⁺ 334.

Preparation 27: methyl [3-(2-oxopropyl)phenyl]acetate

0149<chemistry id="chem0119" num="0119"><img file="EP1577291A1_D0119.tif" /></chemistry> Tributyltin methoxide (28.3 ml, 98mmol), preparation 30 (15.0g, 65mmol), isopropenyl acetate (10.8ml, 98mmol), palladium(II)acetate (750mg, 3.30mmol) and tri-<i>ortho</i>-tolylphosphine (2.0g, 6.5mmol) were stirred together in toluene (75ml) at 100°C under nitrogen for 5 hours. After cooling the reaction was diluted with ethyl acetate (150ml) and 4M aqueous potassium fluoride solution (90ml) and stirred for 15 minutes. The mixture was filtered through arbocel and the organic phase separated and reduced <i>in vacuo.</i> The residue was purified by flash column chromatography silica gel eluting with a solvent gradient of diethyl ether:pentane (0:100 to 25:75, by volume) changing to dichloromethane to give the title compound as a pale yellow oil (12.6g). ¹H NMR (400MHz, CDCl₃): δ = 7.30 (1H, t), 7.19 (1H, d), 7.13-7.10 (2H, m), 3.69 (5H, s), 3.61 (2H, s), 2.15 (3H, s) ppm. LRMS (electrospray) : m/z [M+NH₄]⁺ 224, [M+Na]⁺ 229.

Preparation 28: Methyl (3-bromophenyl)acetate

0150<chemistry id="chem0120" num="0120"><img file="EP1577291A1_D0120.tif" /></chemistry> Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromophenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at 0°C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed <i>in vacuo</i> and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated <i>in vacuo</i> to give the title compound as a colourless oil (20.6g). ¹H NMR (400MHz, CDCl₃): δ = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 253.

Preparation 29 : 1-(3-bromophenyl)-2-methylpropan-2-ol)

0151<chemistry id="chem0121" num="0121"><img file="EP1577291A1_D0121.tif" /></chemistry> Methylmagnesium bromide (3M solution in diethylether, 51.6ml, 155mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0g, 70mmol) in dry diethylether (200ml) at 0°C. The resulting mixture was left for 3 hours, then cooled to 0°C and slowly quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (sodium sulfate). The yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol (90:5:5 by volume to afford a pale yellow oil (13.26 g). ¹H NMR (400MHz, CDCl₃) δ = 7.40 (2H, m), 7.15 (2H, m), 2.74 (2H, s), 1.42 (1H, bs), 1.22 (6H, s).

Preparation 30:

<b>N</b>

-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide

0152<chemistry id="chem0122" num="0122"><img file="EP1577291A1_D0122.tif" /></chemistry> Chloroacetonitrile (6.63ml, 105mmol) was added to a stirred solution of 1-(3-bromophenyl)-2-methylpropan-2-ol) (Preparation 29) (12.0g, 52.0mmol) in acetic acid (25ml) at room temperature. The resulting solution was cooled to 0°C and concentrated sulfuric acid (25ml) was added keeping the temperature &lt;10°C. The resulting solution was left to stir for 1 hour and then poured onto ice and basified by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2×500ml), the organics combined and washed with water (50ml), dried (sodium sulfate) and the solvent removed <i>in vacuo</i> to afford the title compound as an orange solid (16.08 g). ¹H NMR (400MHz, CDCl₃) δ = 7.39-7.32 (1H, d), 7.26 (1H, s), 7.1-7.13 (1H, t), 7.08-7.03 (1H, d), 6.17 (1H, bs), 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s). CHN for C₁₂H₁₅BrCINO calc. (found): C 47.32 (47.26), H 4.96 (4.87), N 4.60 (4.65). LRMS (electrospray) m/z 306 [M+H]⁺

Preparation 31 : 2-(3-bromophenyl)-1,1-dimethylethylamine

0153<chemistry id="chem0123" num="0123"><img file="EP1577291A1_D0123.tif" /></chemistry> A solution of <i>N</i>-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide (Preparation 30) (32.0g, 105mmol), thiourea (9.60g, 126mmol) and acetic acid (50ml) in ethanol (250ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated <i>in vacuo</i> and basified using aqueous sodium hydroxide solution (1M, 450ml). The product was extracted with dichloromethane (2×500ml) and the combined organics washed with brine (50ml), dried (sodium sulfate) and the solvent removed <i>in vacuo</i> to afford the title compound as a black oil (23g). ¹H NMR (400MHz, CDCl₃) δ = 7.36-7.32 (2H, m), 7.16-7.08 (2H, m), 2.62 (2H, s), 1.84 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m/z 228 [M+H]⁺

Preparation 32: [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid

<b>tert</b>

-butyl ester

0154<chemistry id="chem0124" num="0124"><img file="EP1577291A1_D0124.tif" /></chemistry> 2-(3-bromophenyl)-1,1-dimethylethylamine (Preparation 31) (5.0g, 22mmol) was treated with di-<i>tert</i>-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (50ml) and stirred for 20 hours. The reaction mixture was washed with water (50ml) and the combined organics dried (sodium sulfate) and the solvent removed <i>in vacuo.</i> The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane to afford the title compound as a brown oil (7.23g). ¹H NMR (400MHz, CDCl₃) δ = 7.35 (1H, d), 7.30 (1H, s), 7.15-7.11 (1H, t), 7.05 (1H, d), 4.24 (1H, bs), 2.97 (2H, s), 1.50 (9H, s), 1.27 (6H, s). LRMS (electrospray) m/z 350 [M+NH₄]⁺

Preparation 33: 3-(2-

<b>tert</b>

-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester

0155<chemistry id="chem0125" num="0125"><img file="EP1577291A1_D0125.tif" /></chemistry> A solution of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid <i>tert</i>-butyl ester (Preparation 32) (7.0g, 21 mmol), [1,1'-<i>bis</i>(diphenylphosphino)ferrocene]dichloropalladium(II) (1.74g, 2.1 mmol) and triethylamine (5.94ml, 43mmol) in methanol (250ml) was heated to 100°C under 100psi carbon monoxide for 12 hours. The reaction mixture was filtered through arbocel and the filtrate concentrated <i>in vacuo</i> and purified by flash column chromatography on silica gel eluting with dichloromethane:pentane (50:50 by volume) to afford the title compound as a yellow solid (3.76g). ¹H NMR (400MHz, CDCl₃) δ = 7.92-7.90 (1H, m), 7.82 (1H, s), 7.35-7.34 (2H, m), 4.24 (1H, bs), 3.90 (3H, s), 3.05 (2H, s), 1.48 (9H, s), 1.26 (6H, s). LRMS (electrospray) m/z 208 [M+H-BOC]⁺

Preparation 34: 3-(2-amino-2-methylpropyl)benzoic acid methyl ester

0156<chemistry id="chem0126" num="0126"><img file="EP1577291A1_D0126.tif" /></chemistry> A solution of 3-(2-<i>tert</i>-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester (Preparation 33) (1.6g, 5.2mmol) in dichloromethane (160ml) at 0°C was treated with trifluoroacetic acid (13.6ml) and left to warm to room temperature over 2 hours. The solvent was removed <i>in vacuo</i> and the product purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to yield the title compound as an amber oil (1.06g). ¹H NMR (400MHz, CDCl₃) δ = 7.90-7.88 (1H, m), 7.84 (1H, s), 7.36-7.35 (2H, m), 3.90 (3H, s), 2.71 (2H, s), 1.67 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m/z 208 [M+H]⁺

Preparation 35: 3-{2-[(2

<b>R</b>

)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(

<b>tert</b>

-butyldimethyl-silanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester

0157<chemistry id="chem0127" num="0127"><img file="EP1577291A1_D0127.tif" /></chemistry> 3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36g, 6.60mmol), [2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (2.96g, 6.60mmol), sodium iodide (980mg, 6.60mmol) and diisopropylethylamine (3.44ml, 19.7mmol) in acetonitrile (10ml) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed <i>in vacuo</i> and saturated aqueous sodium hydrogen carbonate solution (20ml) added and the product extracted with ethyl acetate (3×30ml). The combined organics were washed with brine (3×20 ml), dried (sodium sulfate) and the solvent removed <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the purified product was dissolved in diethylether and evaporated (×3) to yield a white foam (1.70 g). ¹H NMR (400MHz, CDCl₃) δ = 7.89-7.84 (2H, m), 7.44-7.21 (9H, m), 6.88 (1H, d), 5.10 (2H, s), 4.73-4.69 (3H, m), 3.91 (3H, s), 2.83-2.62 (4H, m), 2.86 (1H, t), 1.05 (3H, s), 1.02 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.19 (3H, s). LRMS (electrospray) m/z 578 [M+H]⁺, 600 [M+Na]⁺

Preparation 36 : 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester

0158<chemistry id="chem0128" num="0128"><img file="EP1577291A1_D0128.tif" /></chemistry> 3-{2-[(2<i>R</i>)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(<i>tert</i>-butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 35) (2.12g, 3.70mmol) and palladium-on-carbon (10%, 300mg) in methanol (50ml) were hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through arbocel and the filtrate concentrated <i>in vacuo,</i> the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, this material was taken up in diethylether and evaporated (x3) to yield a white foam (1.50 g). ¹H NMR (400MHz, CDCl₃) δ = 7.89-7.86 (1H, m), 7.82 (1H, bs), 7.33-7.31 (2H, m), 7.13 (1H, dd), 6.96 (1H, d), 6.79 (1H, d), 4.81 (2H, dd), 4.66 (1H, dd), 3.91 (3H, s), 2.81-2.76 (1H, m), 2.67 (2H, dd), 2.58 (1H, dd), 1.06 (3H, s), 1.03 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.19 (3H, s). LRMS (electrospray) m/z 488 [M+H]⁺, 510 [M+Na]⁺

Preparation 37: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid

0159<chemistry id="chem0129" num="0129"><img file="EP1577291A1_D0129.tif" /></chemistry> 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 36) (1.50g, 3.08mmol), aqueous sodium hydroxide solution (5M, 3.07ml, 15.0mmol), water (2ml) and dioxane (20ml) were stirred at room temperature for 18 hours. The solvent was removed <i>in vacuo</i> and the residue dissolved in water (30ml) and acidified with aqueous hydrochloric acid (1N, 15.38ml). The resulting white precipitate was filtered off and dried <i>in vacuo</i> for 72 hours to furnish the title compound as a white solid (1.28g). ¹H NMR (400MHz, CD₃OD) δ = 7.88 (1H, d), 7.81 (1H, bs), 7.38-7.28 (3H, m), 7.10 (1H, dd), 6.77 (1H, d), 4.92 (1H, m, partially under solvent peak), 4.61 (2H, dd), 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s), -0.04 (3H, s), - 0.15 (3H, s). LRMS (electrospray) m/z 474 [M+H]⁺

Preparation 38: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-

<b>N</b>

-[2-(4-chlorophenyl)ethyl]benzamide

0160<chemistry id="chem0130" num="0130"><img file="EP1577291A1_D0130.tif" /></chemistry> 2-(4-Chlorophenyl)ethylamine (164mg, 1.06mmol) was added to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203mg, 1.06mmol), 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) (500mg, 1.06mmol), 1-hydroxybenzotriazloe hydrate (160mg, 1.06mmol) and triethylamine (440µl, 3.20mmol) in dichloromethane (30ml). The resulting solution was stirred for 48 hours under nitrogen. The solvent was removed <i>in vacuo</i> and the residue taken up in ethyl acetate (30ml), washed with water (20ml), sodium hydrogen carbonate (0.5 M, 2×20 ml), brine (2×20 ml), dried (sodium sulfate) and the solvent removed <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the resulting material was taken up in methanol and evaporated, then taken up in diethylether and evaporated to yield a white foam (480 mg). ¹H NMR (400MHz, CD₃OD) δ = 7.64-7.60 (2H, m), 7.36-7.19 (7H, m), 7.05 (1H, dd), 6.72 (1H, d), 4.71-4.67 (1H, m), 4.60 (2H, dd), 3.57 (2H, t), 2.93-2.61 (6H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s). LRMS (electrospray) m/z 611 [M+H]⁺, 633 [M+Na]⁺

Preparation 39: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-

<b>N</b>

-[2-(4-methylphenyl)ethyl]benzamide

0161<chemistry id="chem0131" num="0131"><img file="EP1577291A1_D0131.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CD₃OD) δ = 7.65-7.61 (2H, m), 7.36-7.30 (2H, m), 7.27 (1H, d), 7.14-7.06 (5H, m), 6.72 (1H, d), 4.71-4.68 (1H, m), 4.60 (2H, dd), 3.54 (2H, t), 2.90-2.83 (3H, m), 2.70 (2H, dd), 2.61 (1H, dd), 2.28 (3H, s), 1.09 (3H, s), 1.05 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (1H, s). LRMS (electrospray) m/z 591 [M+H]⁺, 613 [M+Na]⁺

Preparation 40: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-

<b>N</b>

-[2-(4-trifluoromethylphenyl)ethyl]benzamide

0162<chemistry id="chem0132" num="0132"><img file="EP1577291A1_D0132.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl)benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ = 7.66 (2H, d), 7.45 (1H, m), 7.38 (1H, s), 7.33 (2H, d), 7.29-7.22 (2H, m), 7.07 (1H, dd), 6.88 (1H, dd), 6.75 (1H, dd), 6.15 (1H, t), 4.75 (1H, dd), 4.57 (1H, t), 3.73-3.68 (2H, m), 2.99 (2H, t), 2.76 (1H, dd), 2.65 (2H, s), 2.58 (1H, dd), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (electrospray) m/z 646 [M+H]⁺

Preparation 41: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-

<b>N</b>

-[2-(3, 4-dichlorophenyl)ethyl]benzamide

0163<chemistry id="chem0133" num="0133"><img file="EP1577291A1_D0133.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (40OMHz, CDCl₃) δ = 7.45 (1H, d), 7.40-7.36 (2H, m), 7.33 (1H, d), 7.30-7.22 (2H, m), 7.05 (2H, m), 6.88 (1H, dd), 6.75 (1H, d), 6.17 (1H, t), 4.75 (1H, dd), 4.69 (1H, t), 3.63 (2H, m), 2.89 (1H, t), 2.76 (1H, dd), 2.66 (2H, s), 2.59 (1H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (electrospray) m/z 646 [M+H]⁺

Preparation 42: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3, 4-dimethylphenyl)ethyl]benzamide

0164<chemistry id="chem0134" num="0134"><img file="EP1577291A1_D0134.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ = 7.43 (1H, d), 7.37 (1H, s), 7.20-7.27 (2H, m), 7.06-7.09 (2H, m), 7.01 (1H, s), 6.94 (1H, d), 6.88 (1H, dd), 6.74 (1H, dd), 6.13 (1H, t), 4.75 (1H, dd), 4.59 (1H, t), 3.64 (1H, dd), 2.85 (1H, t), 2.77 (1H, dd), 2.65 (2H, s), 2.59 (1H, dd), 2.24 (3H, s), 2.23 (3H, s), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (APCI) m/z 606 [M+H]⁺

Preparation 43: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-

<b>N</b>

-(2-naphthalen-2-yl-ethyl)benzamide

0165<chemistry id="chem0135" num="0135"><img file="EP1577291A1_D0135.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ 7.77 (3H, m), 7.67 (1H, s), 7.48-7.35 (5H, m), 7.23-7.19 (2H, m), 7.06 (1H, dd), 7.37 (1H, dd), 6.74 (1H, d), 6.17 (1H, t), 4.74 (2H, dd), 4.67 (1H, t), 3.76 (2H, dd), 3.09 (2H, t), 2.75 (1H, dd), 2.62 (2H, s), 2.57 (1H, dd), 1.00 (3H, s), 0.97 (3H, s), 0.78 (9H, s), -0.05 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 628 [M+H]⁺

Preparation 44: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-

<b>N</b>

-(1,1-dimethyl-2-phenyl-ethyl)benzamide

0166<chemistry id="chem0136" num="0136"><img file="EP1577291A1_D0136.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ = 7.43 (1H, m), 7.36 (1H, s), 7.31-7.13 (7H, m), 7.08 (1H, dd), 6.84 (1H, dd), 6.75 (1H, d), 5.70 (1H, s), 4.73 (2H, dd), 4.68 (1H, t), 3.10 (2H, dd), 2.77 (1H, dd), 2.65 (2H, s), 2.68 (1H, dd), 1.45 (3H, s), 1.44 (3H, s), 1.06, (3H, s), 1.01 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 605 [M+H]⁺

Preparation 45: 3-{2-[(2

<b>R</b>

)-2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}-

<b>N</b>

-(2-methyl-2-phenylpropyl)-benzamide

0167<chemistry id="chem0137" num="0137"><img file="EP1577291A1_D0137.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert</i>-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ = 7.42-7.34 (4H, m), 7.29-7.15 (5H, m), 7.05 (1H, dd), 6.87 (1H, dd), 6.74 (1H, d), 5.73 (1H, t), 4.74 (2H, dd), 4.64 (1H, dd), 3.62 (2H, dd), 2.75 (1H, dd), 2.61 (2H, dd), 2.66 (1H, dd), 1.40 (6H, s), 1.00 (3H, s), 0.97 (3H, s), 0.79 (9H, s), -.05 (3H, s), -0.20 (3H, s). LRMS (electrospray) m/z 605 [M+H]⁺

Preparation 46: 3-{(2

<b>R</b>

)-2-[2-(

<b>tert</b>

-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-

<b>N</b>

-(4-chlorobenzyl)benzamide

0168<chemistry id="chem0138" num="0138"><img file="EP1577291A1_D0138.tif" /></chemistry> Prepared according to the procedure used for preparation 38 using 3-{2-[(2<i>R</i>)-2-(<i>tert-</i>butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. ¹H NMR (400MHz, CDCl₃) δ 7.55 = (1H, m), 7.49 (1H, m), 7.33-7.24 (4H, m), 7.06 (1H, dd), 6.88 (1H, dd), 6.74 (1H, d), 6.49 (1H, t), 4.73 (1H, dd), 4.57 (2H, dd), 2.75 (1H, dd), 2.66 (2H, s), 2.66 (1H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.78 (9H, s), -0.06 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 597/599 [M+H]⁺

Preparation 47: [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester

0169<chemistry id="chem0139" num="0139"><img file="EP1577291A1_D0139.tif" /></chemistry> A solution of {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (Preparation 48) (5.1 g, 18mmol), thiourea (1.6g, 21 mmol) and acetic acid (18ml) in ethanol (80ml) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was reduced <i>in vacuo,</i> the residue dissolved in ethanol (150ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The solvent was reduced <i>in vacuo</i> and the residue partitioned between ethyl acetate (200ml) and 5% aqueous sodium carbonate (200ml). The organic extract was washed with saturated sodium chloride (100ml), dried (sodium sulfate) and reduced <i>in vacuo.</i> The residue was purified by strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluent was concentrated <i>in vacuo</i> giving the title compound as a yellow oil (2.68g, 63%). ¹H NMR (400MHz, CDCl₃): δ = 7.29-7.04 (4H, m), 4.08 (2H, q), 3.64 (2H, s), 2.57 (2H, s), 1.18 (3H, t), 0.99 (6H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 236, [M+NH4]⁺ 258.

Preparation 48: {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid

0170<chemistry id="chem0140" num="0140"><img file="EP1577291A1_D0140.tif" /></chemistry> Concentrated sulphuric acid (21 ml) was added dropwise to a solution of [3-(2-hydroxy-2-methyl-propyl)-phenyl]-acetic acid (Preparation 49) (10.6g, 51.0mmol) and chloroacetonitrile (4.8ml, 76.0mmol) in glacial acetic acid (16ml) at 0°C. The reaction was allowed to warm to room temperature and after 2 hours was poured onto iced water (500ml). The aqueous was extracted with ethyl acetate (2×250ml) and the combined organics washed with brine (50ml), dried (sodium sulfate), and the solvent removed <i>in vacuo</i> to furnish the title compound as a golden oil (14.0g). ¹H NMR (400MHz, CDCl₃): δ = 7.31-7.06 (4H, m), 6.19 (1H, bs), 3.95 (2H, s), 3.62 (2H, s), 3.02 (2H, s), 1.36 (6H, s) ppm. LRMS (electrospray) : m/z [M-H]^- 282 / 284.

Preparation 49: [3-(2-hydroxy-2-methyl-propyl)-phenyl]-acetic acid

0171<chemistry id="chem0141" num="0141"><img file="EP1577291A1_D0141.tif" /></chemistry> Methyl magnesium chloride (51ml of a 3M solution in tetrahydrofuran, 153mmol) was added dropwise to a stirred solution of the ester (11.6g, 51mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 331) in tetrahydrofuran (300ml) at 0°C under nitrogen. The reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50ml) and 2N hydrochloric acid (80ml) were cautiously added. The aqueous was extracted with ethyl acetate (2×300ml) and the combined organics washed with brine (50ml), dried (sodium sulfate), and the solvent removed <i>in vacuo</i> to furnish the title compound as a golden oil (11.2g). ¹H NMR (400MHz, CDCl₃): <i>δ</i> = 7.30-7.12 (4H, m), 3.63 (2H, s), 2.75 (2H, s), 1.22 (6H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 209.

Preparation 50: {3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid

0172<chemistry id="chem0142" num="0142"><img file="EP1577291A1_D0142.tif" /></chemistry> Prepared according to the procedure used for preparation 20 using ethyl {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate (Preparation 68) to give the title compound as a cream solid. ¹H NMR (400MHz, CD₃OD): <i>δ</i> = 7.43-7.42 (1H, d), 7.37-7.22 (4H, m), 7.15-7.13 (1H, m), 6.85-6.83 (1H, d), 4.90-4.86 (1H, m), 4.71 (2H, s), 3.56-3.55 (2H, m), 3.25-3.13 (2H, m), 3.05-2.98 (2H, m), 1.40 (3H, s), 1.38 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 374, [M-H]^- 372.

Preparation 51: {3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid

0173<chemistry id="chem0143" num="0143"><img file="EP1577291A1_D0143.tif" /></chemistry> Prepared according to the procedure used for preparation 20 using ethyl {3-[2-({(2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetate (Preparation 52) to give the title compound as a white solid. ¹H NMR (400MHz, CD₃OD): δ 7.26 (1H, d), 7.20-7.16 (1H, t), 7.09-6.97 (5H, m), 6.74-6.72 (1H, d), 4.68-4.65 (1H, m), 4.44 (2H, s), 3.42 (2H, s), 2.95-2.71 (6H, m) ppm. LRMS (electrospray) : m/z [M-H]^- 344.

Preparation 52: ethyl {3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetate

0174<chemistry id="chem0144" num="0144"><img file="EP1577291A1_D0144.tif" /></chemistry> Prepared according to the procedure used for preparation 21 using ethyl {3-[2-({(2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetate (Preparation 53) to give the title compound as an orange oil. ¹H NMR (400MHz, CD₃OD): δ 7.25-7.20 (2H, m), 7.11-7.05 (4H, m), 6.73-6.71 (1H, d), 4.68-4.63 (3H, m), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.89-2.71 (6H, m), 1.24-1.21 (3H, t) ppm. LRMS (electrospray) : m/z[M+H]⁺ 374, [M-H]^- 372.

Preparation 53: ethyl {3-[2-({(2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetate

0175<chemistry id="chem0145" num="0145"><img file="EP1577291A1_D0145.tif" /></chemistry> A solution of ethyl (3-{2-[((2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate (Preparation 54) (2.39g, 4.14mmol) in methanol (15ml) and water (10ml) was treated with ammonium fluoride (1.53g, 41.4mmol) and the reaction heated to 40°C for 16 hours. The methanol was removed <i>in vacuo</i> and the aqueous residue extracted with dichloromethane (3×50ml). The combined organics were dried (sodium sulfate) and the sovent removed <i>in vacuo</i> and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97:3:0.3 changing to 95:5:0.5, by volume) to give the title compound as an orange gum (1.90g). ¹H NMR (400MHz, CD₃OD): δ = 7.45-7.34 (5H, m), 7.31-7.27 (1H, m), 7.24-716 (2H, m), 7.11-7.09 (3H, m), 2.96-2.94 (1H, d), 5.12 (2H, s), 4.72-4.68 (3h, M), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.91-2.74 (6H, m), 1.24-1.20 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]⁺ 464, [M-H]^- 462.

Preparation 54: ethyl(3-{2-[((2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate

0176<chemistry id="chem0146" num="0146"><img file="EP1577291A1_D0146.tif" /></chemistry> Prepared according to the procedure used for preparation 22 using [2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) and ethyl [3-(2-aminoethyl)phenyl]acetate (Preparation 58) to give the title compound as a yellow oil. ¹H NMR (400MHz, CD₃OD): δ = 7.44-7.43 (2H, d), 7.37-7.33 (3H, m), 7.30-7.27 (1H, t), 7.24-7.20 (1H, t), 7.15-7.08 (4H, m), 6.94-6.92 (1H, d), 5.10 (2H, s), 4.77-4.74 (1H, m), 4.67-4.66 (2H, d), 4.14-4.09 (2H, m), 3.58 (2H, s), 2.90-2.75 (5H, m), 2.66-2.62 (1H, m), 1.24-1.21 (3H, t), 0.78 (9H, s), -0.05 (3H, s), -0.22 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 578, [M-H]^- 576.

Preparation 55: ethyl [3-(2-hydroxyethyl)phenyl]acetate

0177<chemistry id="chem0147" num="0147"><img file="EP1577291A1_D0147.tif" /></chemistry> Carbonyl diimidazole (5.11g, 31.5mmol) was added in one portion to a stirred solution of the ester (International Journal of Peptide and Protein Research, 1987, 29(3), 331) (7.00g, 31.5mmol) in tetrahydrofuran (100ml) at room temperature under nitrogen. The reaction was stirred for 2 hours and water (26ml) was added and the reaction cooled to 0°C. Sodium borohydride (6.00g, 0.15mmol) was then added portionwise and the reaction allowed to warm to room temperature with continued stirring over 2 hours. Ethyl acetate (300ml) was added followed by dropwise addition of 2N aqueous hydrochloric acid (20ml). The organic layer was separated and the aqueous extracted with ethyl acetate (2×75ml), the combined organics were dried (sodium sulfate) and the solvent removed <i>in vacuo</i> to furnish a white solid which was purified by flash column chromatography on silica gel eluting with ethyl acetate:penatane (50:50, by volume) to give the title compound as a colourless oil (4.60g). ¹H NMR (400MHz, CDCl₃): δ = 7.28-7.24 (1H, m), 7.15-7.11 (3H, m), 4.17-4.08 (2H, m), 3.84-3.81 (2H, t), 3.59 (2H, s), 2.86-2.82 (2H, t), 1.29-1.23 (3H, t) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 231, [M-H]^- 207.

Preparation 56: ethyl (3-(2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate

0178<chemistry id="chem0148" num="0148"><img file="EP1577291A1_D0148.tif" /></chemistry> Methane sulfonyl chloride (2.78g, 24.3mmol) was added dropwise to a solution of ethyl [3-(2-hydroxyethyl)phenyl]acetate (Preparation 55) (4.60g, 22.1mmol) and triethylamine (3.40ml, 24.3mmol) in dichloromethane (250ml) at 0°C under nitrogen. The reaction was allowed to warm to room temperature over 1 hour and washed with saturated aqueous sodium hydrogen carbonate (75ml). The aqueous was washed with dichloromethane (2×100ml) and the combined organics washed with water (25ml), dried (sodium sulfate) and the solvent removed <i>in vacuo</i> to furnish the title compound as a colourless oil (6.2g). ¹H NMR (400MHz, CDCl₃): δ = 7.29-7.25 (1H, t), 7.17-7.12 (3H, t), 4.41-4.38 (2H, t), 4.16-4.10 (2H, m), 3.58 (2H, s), 3.04-3.00 (2H, t), 2.81 (3H, s), 1.26-1.22 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]⁺ 578, [M-H]^- 576.

Preparation 57: ethyl [3-(2-azidoethyl)phenyl]acetate

0179<chemistry id="chem0149" num="0149"><img file="EP1577291A1_D0149.tif" /></chemistry> Sodium azide (2.82g, 43.3mmol) was added in one portion to a stirred solution of ethyl(3-{2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate (Preparation 56) (6.20g, 21.7mmol) in <i>N,N</i>-dimethylformamide (400ml) at room temperature. The reaction was heated at 60°C for 1 hour and then allowed to cool to room temperature and the solvent removed <i>in vacuo.</i> Ethyl acetate (200ml) and water (75ml) was added and the organics separated, the aqueous was washed with ethyl acetate (2x100ml) and the combined organics evaporated <i>in vacuo</i> to yield an oil that was purified by flash column chromatography on silica gel eluting with ethyl acetate:penatane (5:95, by volume) to give the title compound as a colourless oil (4.65g). ¹H NMR (400MHz, CDCl₃): δ = 7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06 (2H, m), 3.60 (2H, s), 3.51-3.47 (2H, t), 2.87-2.84 (2H, t), 1.24-1.20 (3H, t) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 256, [M-H]^- 232.

Preparation 58: ethyl[3-(2-aminoethyl)phenyl]acetate

0180<chemistry id="chem0150" num="0150"><img file="EP1577291A1_D0150.tif" /></chemistry> Triphenylphosphine (3.88g, 23.3mmol) was added in one portion to a stirred solution of ethyl [3-(2-azidoethyl)phenyl]acetate (Preparation 57) (3.88g, 16.6mmol) in tetrahydrofuran (100ml) at room temperature under nitrogen. The reaction was stirred for 18 hours and water (5ml) added and the reaction heated at 50°C for 4 hours, the reaction was cooled to room temperature and the solvent removed <i>in vacuo.</i> The residue was dissolved in saturated aqueous sodium hydrogen carbonate (40ml) and the aqueous extracted with dichloromethane (3×50ml). The combined organics were dried (sodium sulfate), the solvent removed <i>in vacuo</i> and the residue purified by flash column chromatography on silica gel eluting with dichlromethane:methanol (95:5, by volume) to give the title compound as a colourless oil (3.11 g). ¹H NMR (400MHz, CDCl₃): δ = 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16-4.11 (2H, m), 3.58 (2H, s), 2.96-2.93 (2H, t), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]⁺208, [M+Na]⁺ 230, [M-H]^- 206.

Preparation 59: 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid

0181<chemistry id="chem0151" num="0151"><img file="EP1577291A1_D0151.tif" /></chemistry> To a solution of methyl 3-[(2<i>R</i>)-2-(((2<i>R</i>)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate (Preparation 60) (5.12g, 14.24mmol) in tetrahydrofuran (35ml), was added aqueous lithium hydroxide solution (1 M, 29ml, 29mmol) and the solution left to stir at room temperature for 18 hours. Aqueous hydrochloric acid (1 M, 29ml, 29mmol) was added and the tetrahydrofuran/water removed <i>in vacuo</i> to give the title compound as an off-white solid (5.87g) that was used without further purification. ¹H NMR (400MHz, CD₃OD): δ = 7.86-7.84 (1H, d), 7.82 (1H, s), 7.37-7.30 (3H, m), 7.17-7.15 (1H, dd), 6.79-6.77 (1H, d), 4.89-4.85 (1H, m), 4.65 (2H, s), 3.60-3.50 (1H, m), 3.21-3.15 (3H, m), 2.84-2.78 (1H, dd), 1.25-1.23 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 346, [M+Na]⁺ 368, [M-H]^- 344. CHN analysis : found C 50.29, H 6.07, N 3.07; C₁₉H₂₃NO₅+2.0LiCl+1.3H₂O requires C 50.31, H 5.69, N 3.09.

Preparation 60: methyl 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate

0182<chemistry id="chem0152" num="0152"><img file="EP1577291A1_D0152.tif" /></chemistry> A suspension of methyl 3-[(2<i>R</i>)-2-({(2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate (Preparation 61) (6.83g, 15.2mmol) and 10% palladium on carbon (683mg) in ethanol (100ml) was stirred under an atmosphere of hydrogen (60psi) at room temperature for 18 hours. The catalyst was filtered off through arbocel and the filtrate concentrated <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5 changing to 90:10:1, by volume) to give the title compound as a pale yellow gum (5.12g). ¹H NMR (400MHz, CD₃OD): δ = 7.85-7.83 (1H, m), 7.79 (1H, s), 7.36-7.35 (2H, m), 7.20 (1H, s), 7.02-6.99 (1H, dd), 6.68-6.65 (1H, d), 4.61-4.58 (1H, m), 4.60 (2H, s), 3.90 (3H, s), 2.97-2.87 (2H, m), 2.80-2.62 (3H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 360, [M+Na]⁺ 382, [M-H]^- 358

Preparation 61: methyl 3-[(2

<b>R</b>

)-2-({(2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate

0183<chemistry id="chem0153" num="0153"><img file="EP1577291A1_D0153.tif" /></chemistry> A solution of methyl 3-{(2<i>R</i>)-2-[((2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate (Preparation 62) (10g, 17.74mmol) and ammonium fluoride (6.57g, 177mmol) in methanol (180ml) and water (60ml) was heated at 40°C for 18hrs. The methanol was removed <i>in vacuo</i> and the remaining aqueous layer extracted with dichloromethane (2×100ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated <i>in vacuo.</i> The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5, by volume) to give the title compound (6.83g) as a pale yellow gum. ¹H NMR (400MHz, CD₃OD): δ = 7.83-7.82 (1H, d), 7.78 (1H, s), 7.47-7.45 (2H, m), 7.39-7.28 (6H, m), 7.11-7.10 (1H, d), 6.89-6.87 (1H, d), 5.11 (2H, s), 4.65 (2H, s), 4.65-4.62 (1H, m), 3.88 (3H, s), 2.98-2.89 (2H, m), 2.79-2.64 (3H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 450, [M+Na]⁺ 472, [M-H]^- 448.

Preparation 62: methyl 3-{(2

<b>R</b>

)-2-[((2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate

0184<chemistry id="chem0154" num="0154"><img file="EP1577291A1_D0154.tif" /></chemistry> A solution of [2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (9.23g, 20.5mmol) and methyl {3-[(2<i>R</i>)-2-aminopropyl]phenyl}acetate (Preparation 63) (8.48g, 40.9mmol) in dichloromethane (70ml) was heated to 90°C, allowing the dichloromethane to evaporate. The resulting melt was left at 90°C for a further 18 hours. The reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97.5:2.5:0.25, by volume) to give the title compound (10g) as an orange oil. ¹H NMR (400MHz, CD₃OD): δ = 7.84-7.82 (1H, m), 7.79 (1H, s), 7.47-7.43 (2H, m), 7.39-7.30 (6H, m), 7.08-7.06 (1H, d), 6.89-6.86 (1H, d), 5.10 (2H, s), 4.74-4.71 (1H, t), 4.65-4.64 (2H, d), 3.88 (3H, s), 2.97-2.87 (2H, m), 2.69-2.68 (2H, d), 2.65-2.61 (1H, dd), 1.08-1.07 (3H, d), 0.80 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 564, [M+Na]⁺ 586.

Preparation 63: methyl {3-[(2

<b>R</b>

)-2-aminopropyl]phenyl}acetate

0185<chemistry id="chem0155" num="0155"><img file="EP1577291A1_D0155.tif" /></chemistry> A solution of methyl [3-((2<i>R</i>)-2-{[(1<i>R</i>)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate (Preparation 64) (13.65g, 40.9mmol) and ammonium formate (12.9g, 204mmol) in ethanol (200ml) was heated at reflux in the presence of 20% of palladium hydroxide on charcoal (Pd(OH)₂/C, 1.36g). After 3 hours the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated <i>in vacuo.</i> The residue was partitioned between dichloromethane (200ml) and 880 ammonia (100ml) and the organic phase separated. The aqueous phase was extracted with further dichlorormethane (3×100ml) and the combined organic extracts washed with brine (100ml), dried (sodium sulfate) and reduced <i>in vacuo</i> to give the title compound (8.48g) as a pale yellow oil. ¹H NMR (400MHz, CDCl₃): δ = 7.90-7.87 (2H, m), 7.38-7.34 (2H, m), 3.90 (3H, s), 3.26-3.17 (1H, m), 2.78-2.73 (1H, dd), 2.64-2.59 (1H, dd), 1.14-1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 194.

Preparation 64: methyl [3-((2

<b>R</b>

)-2-{[(1

<b>R</b>

)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hyrdrochloride

0186<chemistry id="chem0156" num="0156"><img file="EP1577291A1_D0156.tif" /></chemistry> A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 65) (45.3g, 236mmol), (R)-α-methyl benzylamine (27.6ml, 214mmol), sodium triacetoxyborohydride (68.1g, 321mmol) and acetic acid (14.7ml, 257mmol) in dichloromethane (1500ml) was stirred at room temperature for 18 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (600ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (2×100ml). The combined organic extracts were washed with brine (100ml), dried (sodium sulfate), filtered through celite and reduced <i>in vacuo</i>. The oil was dissolved in methanol (200ml), treated with 1M hydrogen chloride in methanol (300ml) and reduced <i>in vacuo</i> to give a 4:1 mixture of diastereomers (<i>R,R</i> major) as an off-white, hydrochloride salt. Two successive crystallisations (diisopropylether/methanol) gave the title compound (27.3g) as a colourless crystalline solid. ¹H NMR (400MHz, CD₃OD): δ = 7.92-7.90 (1H, d), 7.75 (1H, s), 7.55-7.49 (5H, m), 7.45-7.42 (1H, dd), 7.35-7.33 (1H, d), 4.68-4.63 (1H, q), 3.90 (3H, s), 3.43-3.38 (1H, dd), 3.25-3.19 (1H, m), 2.71-2.65 (1H, dd), 1.71-1.69 (3H, d), 1.17-1.16, (3H, d) ppm.

Preparation 65: methyl [3-(2-oxopropyl)phenyl]acetate

0187<chemistry id="chem0157" num="0157"><img file="EP1577291A1_D0157.tif" /></chemistry> Tributyltin methoxide (80.3ml, 279mmol), methyl 3-bromobenzoate (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(II)acetate (2.6g, 11.6mmol) and tri-<u>o</u>-tolylphosphine (7.1 g, 23.2mmol) were stirred together in toluene (350ml) at 100°C under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced <i>in vacuo.</i> The residue was purified by flash column chromatography on silica gel eluting with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil. ¹H NMR (400MHz, CDCl₃): δ = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 215, [M-H]^- 191.

Preparation 66: ethyl (3-{2-[((2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[

<b>tert</b>

-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate

0188<chemistry id="chem0158" num="0158"><img file="EP1577291A1_D0158.tif" /></chemistry> Prepared according to the procedure used for preparation 22 using [2-(benzyloxy)-5-((1<i>R</i>)-2-bromo-1-{[<i>tert</i>-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) and [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester (Preparation 47) to give the title compound as a yellow oil. ¹H NMR (400MHz, CD₃OD): δ = 7.48-7.05 (11H, m), 7.04-6.96 (1H, d), 5.10 (2H, s), 4.80-4.74 (1H, m), 4.78-4.63 (2H, q), 4.16-4.05 (2H, q), 3.60 (2H, s), 2.89-2.63 (2H, m), 2.70-2.62 (2H, m), 1.24-1.20 (3H, t), 1.07-1.04 (6H, d), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]⁺ 606, [M-H]^- 604.

Preparation 67: ethyl {3-[2-({(2

<b>R</b>

)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)-2-methylpropyl]phenyl}acetate

0189<chemistry id="chem0159" num="0159"><img file="EP1577291A1_D0159.tif" /></chemistry> Prepared according to the procedure used for preparation 53 using ethyl (3-{2-[((2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[<i>tert</i>-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate (Preparation 66) to give the title compound as an oil. ¹H NMR (400MHz, CD₃OD): δ = 7.47-7.03 (11H, m), 6.98-6.95 (1H, d), 5.14 (2H, s), 4.68 (2H, s), 4.68-4.66 (1H, m), 4.15-4.10 (2H, q), 3.60 (2H, s), 2.90-2.64 (4H, m), 1.26-1.22 (3H, t), 1.08-1.05 (6H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 492, [M-H]^- 490.

Preparation 68: ethyl {3-[2-({(2

<b>R</b>

)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate

0190<chemistry id="chem0160" num="0160"><img file="EP1577291A1_D0160.tif" /></chemistry> Prepared according to the procedure used for preparation 21 using ethyl {3-[2-({(2<i>R</i>)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyl}amino)-2-methylpropyl]phenyl}acetate (Preparation 67) to give the title compound as a colourless oil. ¹H NMR (400MHz, CD₃OD): δ = 7.30-7.02 (6H, m), 6.77-6.75 (1H, d), 4.62 (2H, s), 4.62-4.60 (1H, m), 4.17-4.09 (2H, q), 3.65-3.50 (2H, m), 2.90-2.63 (4H, m), 1.14-1.10 (3H, t), 1.08-1.05 (6H, d) ppm. LRMS (electrospray) : m/z [M+H]⁺ 402, [M-H]^- 400.

<b>Abbreviations</b>

0191TBDMS = <i>tert</i>-butyl(dimethyl)silyl

<i><b>In vitro</b></i><b>activity of the compounds of formula (1)</b>

0192The ability of the compounds of the formula (1) to act as potent β2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips.

Guinea-pig trachea

0193Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO₂ asphyxiation and exsanguination from the femoral artery and the trachea is isolated. Four preparations are obtained from each animal, starting the dissection immediately below the larynx and taking 2.5 cm length of trachea. The piece of trachea is opened by cutting the cartilage opposite the trachealis muscle, then transverse sections, 3-4 cartilage rings wide, are cut. The resulting strip preparations are suspended in 5 ml organ baths using cotton threads tied through the upper and lower cartilage bands. The strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 µM Indomethacin (Sigma 17378), 10 µM Guanethidine (Sigma G8520) and 10 µM Atenolol (Sigma A7655), heated at 37°C and gassed with 95% O₂/5% CO₂, before applying an initial tension of 1 g. The preparations are allowed to equilibrate for a further 30-45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals. Changes in tension are recorded and monitored via standard isometric transducers coupled to a data-collection system (custom-designed at Pfizer). Following the tensioning equilibration, the tissues are subjected to electrical field stimulation (EFS) using the following parameters : 10 s trains every 2 minutes, 0.1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts) continuously throughout the length of the experiment. EFS of post-ganglionic cholinergic nerves in the trachea results in monophasic contractions of the smooth muscle and twitch height is recorded. The organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period.

Experimental protocol for assessment of potency and efficacy

0194Following equilibration to EFS, the peristaltic pump is stopped and the preparations 'primed' with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximal response in terms of inhibition of the contractile EFS response. The isoprenaline is then washed out over a period of 40 minutes. Following the priming and wash-out recovery, a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1^e-9 to 1^e/3^e-6 M. At the end of the isoprenaline curve the preparations are washed again for 40 minutes before commencing a second curve, either to isoprenaline (as internal control) or a beta-2 agonist according to the present invention. Beta-2 agonist responses are expressed as percentage inhibition of the EFS response. Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1. The EC₅₀ value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect. Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC₅₀ beta-2 agonist)/(EC50 Isoprenaline).

Confirmation of beta-2 mediated functional activity

0195Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective β₂ antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.

0196According to another alternative, the agonist potency for the β2 receptor of the compounds of the formula (1) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC₅₀) for the β2 receptor.

Compound Preparation

019710 mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted to required top dose in 4 % DMSO. This top dose is used to construct a 10-point semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, l-5627) was used as a standard in every experiment and for control wells on each plate. Data was expressed as % Isoprenaline response.

Cell Culture

0198CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2) were grown in Dulbeccos MEM/NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 µg/ml geneticin (Sigma, G7034) and 10 µg/ml puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

Assay Method

019925 µl / well each dose of compound was transferred into a cAMP- Flashplate® (NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenaline as max controls. This was diluted 1:2 by the addition of 25 µl / well PBS. Cells were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give 1×10⁶ cells / ml CHOhB2. Compounds were incubated with 50 µl / well cells for 1 hour. Cells were then lysed by the addition of 100 µl / well detection buffer (NEN, SMP004B) containing 0.18 µCi / ml ¹²⁵l-cAMP (NEN, NEX-130) and plates were incubated at room temperature for a further 2 hours. The amount of ¹²⁵l-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. Dose-response data was expressed as % Isoprenaline activity and fitted using a four parameter sigmoid fit. It has thus been found that the compounds of formula (1) according to the present invention that have been tested show a β2 cAMP EC₅₀ below 10nM.