MXPA06010629A - Phenylaminoethanol derivates as beta2 receptor agonists - Google Patents

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

DERIVATIVES OF FENILAMINOETANOL AS AGENTS OF THE BETA2 RECEIVER DESCRIPTIVE MEMORY The present invention relates to β2 agonists of the general formula: wherein R1, R2, Q1, Q2 'Q3 and Q4 have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and uses of, such derivatives. The adrenorreceptores are members of the great superfamily of receptors coupled to the protein G. The subfamily of adrenorreceptores divides in itself in the subfamilies to and ß, being the subfamily ß composed of at least 3 subtypes of receptors: ß1, ß2 and ß3 . These receptors exhibit differential expression patterns in tissues of different systems and organs of mammals. Β2 adrenergic receptors (β2) are mainly expressed in smooth muscle cells (eg vascular, bronchial, uterine or intestinal smooth muscle), whereas β3 adrenergic receptors are expressed mainly in fatty tissues (therefore, ß3 agonists may be potentially useful in the treatment of obesity and diabetes) and ß1 adrenergic receptors are mainly expressed in cardiac tissues (therefore, ß1 agonists are used mainly as cardiac stimulants). The pathophysiology and treatments of respiratory diseases have been extensively reviewed in the literature (for reference see Barnes, PJ Chest, 1997, 111: 2, pp. 17S-26S and Bryan, SA et al, Expert Opinion on research drugs, 2000, 9: 1, pp. 25-42) and therefore in this document only a brief summary will be included to provide some background information. Glucocorticosteroids, anti-leukotrienes, theophylline, chromones, anticholinergics, and β2-agonists are classes of drugs that are currently used to treat allergic and nonallergic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Treatment guidelines for these diseases include inhaled short and long-acting ß2 agonists. Short-acting, rapid onset β2 agonists are used to "rescue" bronchodilation, while long-acting forms provide sustained relief and are used for maintenance therapy. Bronchodilation is mediated via ß2 adrenoreceptor agonism expressed in the smooth muscle cells of the respiratory tract, which produces relaxation and consequently bronchodilation. Therefore, as functional antagonists, β2-agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelin. Since ß2 receptors are distributed so widely in the respiratory tract, ß2 agonists can also affect other types of cells that play a role in asthma. For example, it has been reported that ß2 agonists can stabilize mast cells. Inhibition of the release of bronchoconstrictor substances may be the way in which ß2 agonists block allergen-induced bronchoconstriction, exercise, and cold air. Likewise, ß2 agonists inhibit cholinergic neurotransmission in the human respiratory tract, which may produce a reduction in cholinergic-reflex bronchoconstriction. In addition to the respiratory tract, it has also been established that β2-adrenoreceptors are also expressed in other organs and tissues and, therefore, 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 delivery, congestive heart failure, depression, inflammatory and allergic dermal diseases, psoriasis, proliferative skin diseases, glaucoma and gastric and peptic ulcer. However, numerous ß2 agonists are limited in their use due to their low selectivity or adverse effects produced by a high systemic exposure and mainly mediated by action on ß2 adrenoreceptors expressed outside the respiratory tract (muscle tremors, tachycardia, palpitations, restlessness) . Therefore, there is a need for improved agents of this class. Accordingly, there is still a need for new β2 agonists having 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 new β2 agonists. International publications EP 0654534 B1 and EP0939134 B1 describe a process for the preparation of compounds of formula (XI): These compounds are described as antiobesity and antidiabetic agents that have specific β3 activity. These compounds are described as antiobesity and antidiabetic agents that have specific β3 activity. International publication US 5,561, 142 describes the selective β3 -agonist of formula The international publication EP0236624 describes compounds of formula which have anti-obesity and / or anti-hyperglycemic activity together with good selectivity of cardiac side effects. The invention relates to the compounds of the general formula (1): wherein the group CH2-C (= 0) NH-benzyl-Q1-Q2-Q3-Q4 is in the meta or para position, and - R1 and R2 are independently selected from H and C4 alkyl; - Q1 is - (CH2) n-, wherein n is an integer selected from 0 and 1; - Q2 is a group selected from -NH-, -C (= 0) NH-, -NHC (= 0) -, -NH-C (= O) -NH- and -SO2NH-; - Q3 is a single bond or a C4alkylene optionally substituted with OH; - Q4 is selected from: wherein * represents the point of attachment to Q3 and R3, R4, R5, R6 and R7 are independently selected from H, C 1 -C 4 alkyl, phenyl, phenoxy, OR 8, SR 8, halo, CN, CF 3, OCF 3, COOR9, S02NR $ R9, CONRBR9, NR8R9, NHCOR9, CH2-NHC (= O) NH-R9; wherein R8 and R9 are independently selected from H or C4 alkyl; or, if appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations. It has now been observed that the compounds of formula (1) are β2 receptor agonists which are particularly useful for the treatment of diseases and / or frames mediated by β2 and show good potency, in particular when administered by the inhalation route. In the present invention, the term "potent" means that the compounds of formula (1) show an agonist potency for the β2 receptor 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 receptors. More preferably, the compounds of the invention show an agonist potency for the β2 receptor, which is at least about 100 times higher than for the β3 receptor and at least about 500 times higher than for the β1 receptor. In the general formula (1) set forth above (1), C- | C alkyl and C C4 alkylene denote a straight or branched chain group containing 1, 2, 3 or 4 carbon atoms. This also applies if they carry substituents or are present as substituents of other radicals, for example in radicals = 0-alkyl (C C); S-alkyl radicals (C C4), etc. Examples of suitable (C C4) alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tere-butyl. Examples of suitable O-alkyl radicals (C C) are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy. Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro. The compounds of the formula (1) wherein the group CH2-C (= 0) NH-benzyl-01-Q2-Q3-Q4 is in the meta or para position, can be prepared using conventional procedures such as those of the following illustrative methods in which R1, R2, Q1, Q2, Q3 and Q4 are as previously defined for the compounds of the formula (1), unless otherwise indicated.

The compounds of the formula (1) can be prepared by deprotection of the compounds of the formula (2): wherein the group CH2-C (= 0) NH-benzyl-Q1-Q2-Q3-Q4 is in the meta or para position, in which PG represents a suitable alcohol protecting group, typically an alkyl silyl group such as TBDMS or TMS, and preferably TBDMS. The deprotection can be carried out according to the methods described in the standard textbooks such as "Protective Groups in Organic Synthesis" by TWGreene, A. Wiley-lnterscience Publication, 1981. In a typical procedure, in which PG represents TBDMS, the compound of formula (2) is treated with 10-20 eq of ammonium formate in aqueous methanol, at about 40 ° C between 18 and 42 hours, or with aqueous acetic acid in tetrahydrofuran between TA and about 65 ° C , between 18 and 100 hours. The amide derivatives of formula (2) can be prepared by coupling an acid of formula (3): (3 > wherein the group CH 2 -C (= 0) OH is in the meta position or to an amine of formula (4): 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 N, N'-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. -methylmorpholine, triethylamine or N-diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate, and at a temperature between 10 ° C and 40 ° C (room temperature) for a period of time. from 1-24 hours. In a typical procedure, the acid of formula (3) is treated with an excess of amine of formula (4) (1.1-1.2 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1-1.3 eq) , 1-hydroxybenzotriazole hydrate (1.1-1.3 eq) and triethylamine (2-3 eq) in N, N-dimethylformamide at RT over a period of 18 hours. Said amine of formula (4) is either commercially available or can be prepared by conventional methods known to the person skilled in the art (eg, reduction, oxidation, alkylation, protection, deprotection, etc.) from a material existing in the the market. The acid of formula (3) can be prepared from the corresponding ester of formula (5): wherein the group CH2-C (= 0) ORa is in the meta or para position, wherein Ra is an acid protecting group, preferably an alkyl group (C- | -C4) including, but not limited to methyl and ethyl, according to any known method for preparing an acid from an ester, without modifying the remainder of the molecule. For example, the ester can be hydrolyzed by treatment with an aqueous acid or base (for example, hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (for example, water, 1,4-dioxane, tetrahydrofuran / water), at a temperature between 20 ° C and 100 ° C, for a period of 1 to 40 hours. In a typical procedure, the ester of formula (5) is treated with an excess of lithium hydroxide (2 eq) in aqueous tetrahydrofuran at RT for about 16 hours. The ester of formula (5) can be prepared by deprotection of the compounds of formula (6): wherein the group CH2-C (= 0) ORa is in the meta or para position, in which PG2 is a group phenol protector, typically an alkyl group, typically a methyl or benzyl group and preferably a benzyl group. The deprotection can be carried out according to the methods described in the standard textbooks such as "Protective Groups in Organic Synthesis" by TWGreene, A. Wiley-lnterscience Publication, 1981. In a typical procedure, in which PG2 is benzyl, the compound of formula (6) is hydrogenated in the presence of 10% palladium on carbon in ethanol as a solvent at 60 psi H2, for about 16 hours at room temperature. The ester of formula (6) can be prepared by reaction of an amine of formula (7): wherein the group CH2-C (= O) ORa is in the meta or para position and in which Ra is as previously defined, with a bromide of formula (8): In a typical procedure, the amine of formula (7) is reacted with a bromide of formula (8) optionally in the presence of a solvent or mixture of solvents (eg, dimethyl sulfoxide, toluene, N, N-dimethylformamide, acetonitrile), optionally in the presence of a base suitable (eg, triethylamine, N-diisopropylethylamine or potassium carbonate) at a temperature between 80 ° C and 120 ° C, for 12 to 48 hours. Preferably, the amine of formula (7) (2 eq) and the bromide of formula (8) are reacted at 90 ° C in the absence of solvent for about 16 hours. The bromide of formula (8) can be prepared by deprotection of the compounds of formula (9): according to any method known to those skilled in the art to prepare an alcohol from an ester, without modifying the remainder of the molecule.

In a typical procedure, the ester of formula (9) is reduced with borane dimethylsulfide complex in tetrahydrofuran at reflux for a period of 2 hours. The alcohol of formula (8) can be prepared in the form of the (R) or (S) enantiomer according to the methods described in the literature (Tetrahedron Letters 1994, 35 (50), 9375). When neither R1 nor R2 represent H, the amine of formula (7) can be prepared as the (R) or (S) enantiomer from the corresponding protected amine of formula (10): wherein the group CH2-C (= O) ORa is in the meta or para position and Ra is as previously defined, and Rb and Rc represent any suitable substituent, so that HNRbRc is a chiral amine (e.g., Rb can be hydrogen and Rc can be an a-methylbenzyl), provided that the bonds between N and Rb, and N and Rc can be easily cleaved to produce the free amine of formula (7) using standard methodology to cleave protective groups of nitrogen, like those found in the TW textbook GREENE, Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981. In a typical procedure, the amine of formula (10) is treated with 20% palladium hydroxide on carbon in the presence of an excess of ammonium formate in ethanol at room temperature for about 2 hours. The amine of formula (10) can be prepared as a single diastereomer by reaction with an amine of formula HNRbRc with a ketone of formula (11): wherein the group CH2-C (= O) ORa is in the meta or para position, and Ra, Rb and Rc are as previously defined. In a typical procedure, the reaction of the ketone of formula (11) with the amine of formula HNRbRc leads to a chiral intermediate which in turn is reduced by a suitable reducing agent (e.g., sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride of the formula Na (OAc) 3BH) optionally in the presence of a drying agent (eg, molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (eg, acetic acid) to produce the amine of formula (10) as a mixture of diastereomers. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature between 20 ° C and 80 ° C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallized from a suitable solvent or solvent mixture (e.g., isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) to produce (10) as a simple diastereomer. In particular, the ketone of formula (11) can be prepared by palladium mediated coupling of an aryl halide of formula (12): wherein the group CH2-C (= 0) ORa is in the meta or para position and Ra is as previously defined and Hal represents a halogen atom including, but not limited to, bromine and iodine, with a enolate or enolate equivalent. In a typical procedure, the aryl halide of formula (12) is reacted with a tin enolate generated in situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu3SnOMe in the presence of a suitable palladium catalyst (palladium / tri-ortho-tolylphosphine acetate of formula Pd (OAc) 2 / P (o-Tol) 3) in a non-polar solvent (eg, toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature between 80 ° C and 110 ° C for 6 to 16 hours. The aryl halide of formula (12) can be obtained by esterification of the corresponding acid of formula (13): wherein the CH2-C (= 0) OH group is in the meta or para position and Hal is as previously defined, according to any method known to those skilled in the art to prepare an ester from a acid, without modifying the rest of the molecule. In a typical procedure, the acid of formula (13) is reacted with an alcohol solvent of formula RaOH, wherein Ra is as defined above, 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. The acid of formula (13) is a product available in the market. The amine of formula (7), wherein R1 and R2 are both C4 alkyl, can be prepared according to the following scheme: SCHEME 1 (?) wherein the group CH2-C (= O) OH is in the meta or para position and R1, R2 and Ra are as previously defined.

In a typical procedure, the ester of formula (14) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R Li) to produce the corresponding tertiary alcohol of formula (15), using the method described above . The ester of formula (14) can be prepared from the corresponding (commercial) diacid precursor according to the procedure described in International Journal of Peptide and Protein Research 1987, 29 (3), 331. Said tertiary alcohol of formula (15) is then treated with an alkyl nitrile (e.g., chloroacetonitrile) in the presence of an acid (eg, sulfuric acid, acetic acid) to produce a protected intermediate which in turn is cleaved using standard methodology for cleaving the nitrogen protective group such as those mentioned in the textbooks. The resulting amino acid is then esterified using the method described herein to produce the amine of formula (7). The compounds of formula (2), in which Q1 represents - (CH2) n and n represents 0, and Q2 represents -C (= 0) NH-, can alternatively be prepared by coupling an acid of formula (16): wherein the group CH2-C (= O) NH-CH2-Phenyl-COOH is in the meta or para position and the group Ra is in the meta position or para with an amine of formula H2N-Q3-Q4 (17) The acid of formula (16) is reacted with the amine of formula (17), with a conventional coupling agent (e.g., 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or N, N '-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., N- methylmorpholine, triethylamine or N-diisopropylethylamine). The reaction can be carried out in a suitable solvent such as plridine, N, N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at a temperature comprised between 10 ° C and 40 ° C (room temperature) for a period of time. from 1-24 hours. In a typical procedure, the acid of formula (16) is treated with the amine of formula (17) (1 eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 eq), 1-hydroxybenzotriazole hydrate (1.1 eq) and triethylamine (3 eq) in N, N-dimethylformamide at RT over a period of 18 hours. The amine of formula (17) is either commercially available or can be prepared by conventional methods known to the person skilled in the art (eg, reduction, oxidation, alkylation, protection, deprotection, etc.) from a material existing in the the market. The acid of formula (16) can be prepared from the corresponding ester of formula (18): wherein the group CH2-C (= 0) NH-CH2-Phenyl-COORa is in the meta or para position and Ra is a suitable acid protecting group, preferably a (C1-C4) alkyl group including, but not limited thereto, methyl and ethyl, according to any method known to the person skilled in the art to prepare an acid from the ester, without modifying the remainder of the molecule. For example, the ester can be hydrolyzed by treatment with an aqueous acid or base (for example, hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (for example, water, 1,4-dioxane, tetrahydrofuran / water), at a temperature between 20 ° C and 100 ° C, for a period of 1 to 40 hours. In a typical procedure, the ester of formula (18) is treated with an excess of lithium hydroxide (2 eq) in aqueous tetrahydrofuran at RT for about 7 hours. The ester of formula (18) can be prepared by coupling the acid of formula (3) with the amine of formula (19): by analogy with the previously described methods for the synthesis of the compound of formula (2). The amine of formula (19) is marketed. The amine of formula (7), wherein R1 and R2 are both H, can be prepared according to the following scheme: SCHEME 2 (20.) (21) wherein R1, R2 and Ra are as previously defined In a typical procedure, the acid of formula (20) is preferably reduced to the corresponding alcohol (21) in the presence of the ester. it can be carried out by forming the imidazole acyl or mixed anhydride and subsequent reduction with sodium borohydride or other suitable reducing agent, said primary alcohol of formula (21) then being converted to a leaving group such as mesylate, tosylate, bromide or iodide and it is displaced with the appropriate amine nucleophile.The preferred nucleophile is an 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 supply the amine. For some of the steps of the process described hereinabove for the preparation of the compounds of formula (1), it may be necessary to protect the potential reactive functions that are not desired to be reacted, and to cleave said protecting groups accordingly. In such a case, any compatible protective radical can be used. In particular, the protection and deprotection methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994). All of the above reactions and preparations of novel starting materials used in the foregoing methods are conventional and appropriate reagents, and those skilled in the art will know with reference to the preceding literature and examples and preparations cited therein, the reaction conditions for its modality or preparation, as well as the procedures to isolate the products. Preferred compounds of formula (1) are those in which Q1 is (CH2) n, wherein n is 0 and Q2 is -S02NH- or C (= O) NH-. Other preferred compounds of formula (1) are those in which Q1 is (CH2) n, where n is I and Q2 is -NH-C (= O) - or -NH-C (= O) -NH- . In the above compounds of formula (1), the following substituents are also preferred: Preferably, R1 and R2 are both CH3. Preferably, R and R2 are both H. Preferably, R1 is H and R2 is CH3. More preferably, R1 is H and R2 is CH3. Preferably, Q3 is a bond, -CH2-, - (CH2) 2-, -C (CH3) 2-CH2-, -CH (CH3) -CH (OH) - or CH2-CH (CH3) -. Preferably Q4 is wherein R3, R4, R8, R6 and R7 are selected from H, C-1-C4 alkyl, phenyl, phenoxy OR8, SR8, halo, CF3, OCF3, COOR9, SO2NR8R9, CONR8R9, NHR8R9, NHCOR9, CH2-NHC (= o) NH-R8; and at least two of R3 and R7 represent H. More preferably Q4 is wherein R3, R4, R5, R6 and R7 are selected from H, C4 alkyl, phenyl, phenoxy OR8, halo, CF3, OCF3; and at least two of R3 and R7 represent H. Particularly preferred are the compounds of the formula (1) as described in the Examples section below, ie: N- (4-tert-butylbenzyl) -4 -. { [( { 3 - [(2 ^) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl .}. acetyl) amino] methyl} benzamide; N- (2-ethoxybenzyl) -4-. { (( { 3 - [(2f?) - 2- ( { (2f?) - 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl.}. Amino) propyl] phenyl.}. acetyl) amino] methylbenzamide; 4 { [( { 3 - [(2R) -2- ( { (2 /?) - 2-hydroxy-2- [4-hydroxy] -3- (hydroxymethyl) phenyl] ethyl.}. Amino) propyl] phenyl}. Acetyl) amino] methyl.} - N- [4- (trifluoromethoxy) benzyl] benzamide; N- (3,4-dichlorobenzyl) -4- { [( { 3 - [(2 /?) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl) amino) propyl] phenyl ..}. acetyl) amino] methyl} benzamide; N- [2-fluoro-5- (trifluoromethyl) benzyl-4-. { [( { 3 - [(2R) -2- ( { (2R) -2-hydrox¡-2- [4-hydroxy-3- (hydroxymethyl) pheny] ethyl}. propyl] phenyl.} acetyl) amino] methyl} benzamide; N- [3,5-bis (trifluoromethyl) benzyl] -4-. { [( { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl} benzamide; 4-. { [( { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl .}. acetyl) amino] methyl} -N- (4-phenoxybenzyl) benzamide; N- (1,1-dimethyl-2-phenylethyl) -4-. { [( { 3 - [(2f?) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl .}. acetyl) aminojmethyl} benzamide; N- [2- (4-ethylphenyl) ethyl] -4-. { [( { 3 - [(2 /?) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) aminojmethyl} benzamide; N (2- (4-chlorophenyl) ethyl] -4-. {[[( { 3 - [(2 /?) - 2- ( { (2R) -2-hydroxy2- (4-hydroxy) 3- (hydroxymethyl) phenyl] ethyl} amino) propylphenyl} acetyl aminojmethyl benzamide; N- [2- (4-ethoxyphenyl) ethyl] -4-. {[[(. {3- [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl benzamide; N- [2- (1, 1'-biphenyl-4-yl) ethyl] -4- { [( { 3 - [(2 /?) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxylmethyl) phenol] ethyl} amino) propyl] phenyl} acetyl) aminoj methyl} benzamide; - { [( { 3 - [(2f?) - 2- ( { (2fí) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl}. ) propyl] phenyl} acetyl) amino] methyl.}. - N- (4-hydroxy-3-methoxybenzyl) benzamide; N- (1,1-biphenyl-3-yl-methyl) -4-. { [( { 3 - [(2f?) - 2- ( { (2f?) - 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl}. Amino) propyl ] phenyl.} acetyl) amino.} methyl.} benzamide; 4 { [( { 3 - [(2 /?) - 2- ( { (2) -2-hydroxy) 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl.}. Amino) propyl] f enyl} acetyl) amino] methyl} -N- [2- (3-methoxyphenyl) ethyl] benzamide; N- [2- (3,4-dichlorophenyl) ethyl] -4-. { [( { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl} benzamide; 4-. { [( { 3 - [(2 /?) - 2- ( { (2f?) - 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl}. Amino) propyl ] phenyl} acetyl) amino] methyl} -N [(2S) -2-phenylpropylbenzamide; 4-. { [( { 3 - [(2R) -2- ( { (2f?) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl}. Amino) propyljphenyl .}. acetyl) amino] methyl} -N - [(1 R, 2 S) -2-hydroxy-1-methyl-2-phenylethyl] benzamide; 4-ethoxy-N (4 { [( { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl.}. amino) propyl] phenyl}. acetyl) amino] methyl.} benzyl) benzamide; N- (4-. {[[( { 3 - [(2R) -2- ( { (2R) -2-hydroxy! 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl.} benzyl) -1-naphthamide; N- (4- { [( { 3 - [(2f?) - 2- ( { (2?) - 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl) ] ethyl.}. amino) propyl] phenyl}. acetyl) amino] methyl.} benzyl) -2,2-diphenylacetamide; N- (4- { [( { 3 - [(2 /?) - 2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl.} benzyl) -4-phenoxybenzamide; N- (4 - [(benzhydrylamino) methyl] benzyl.} -2- { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy] 3- (hydroxymethyl) phenyl] ethyl.}. Amino) propyl] phenyl} acetamide; N {3 - [(benzylamino) sulfonyl] benzyl.} -2- { 3 - [(2R) -2- (. {(2?) - 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide; 2- { 3 - [( 2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-. {4 - (( { [(3-phenoxybenzyl) amino] carbonyl.}. Amino) methyl] benzyl.} Acetamide, and N- (3,4-dimethoxybenzyl) -4- { [( { 3 - [(2R) -2- ( { (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetyl) amino] methyl.} benzamide.

According to one aspect of the present invention, the compounds of formula (1), wherein the group -CH2-C (= 0) NH-benzyl-Q1-Q2-Q3-Q4 is in the meta position, in general they are preferred. The compounds of formula (1) can also be optionally transformed into pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the compounds of the formula (1) include their acid and base addition salts (including disalts). Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include salts of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate, D and L-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, phosphate / dihydrogen phosphate, saccharate, stearate, succinate, D and L-tartrate, 1-hydroxy-2-naphthoate and tosylate. Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. The hemispheres of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

For a review of the appropriate salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002). The pharmaceutically acceptable salts of the compounds of formula (1) can be prepared by one or more of three methods: (i) by reacting the compound of formula (1) with the desired acid or base; (ii) removing a protecting group of acid or labile base 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 appropriate acid or base; or (iii) converting one salt of the compound of formula (1) into another by reaction with a suitable acid or base or by a suitable ion exchange column. The three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in both solvated and unsolvated 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 used when said solvent is water. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which unlike the aforementioned solvates, the drug and the host are present in stoichiometric and non-stoichiometric amounts. Also included are drug complexes that contain two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288 of Haleblian (August 1975). From here on, all references to the compounds of formula (1) include references to their salts, solvates and complexes and to the solvates and complexes of their salts. The compounds of the invention include the compounds of formula (1) as defined herein, including all polymorphisms and their crystalline habits, prodrugs and their isomers (including optical, geometric and tautomeric isomers) as defined below in the present and isotopically-labeled compounds of formula (1). As indicated above, the so-called 'prodrugs' of the compounds of formula (1) are also within the scope of the invention. Therefore, certain derivatives can, by themselves, when administered to the organism, become compounds of formula (1) having the desired activity, for example, hydrolytic cleavage. Said derivatives are referred to as "prodrugs". More information on the use of prodrugs can 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 according to the invention may, for example, be produced by replacing the appropriate functionalities present in the compounds of formula (1) with certain residues known to those skilled in the art as 'pro-residues' as described, for example, by example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the invention include: (i) wherein the compound of formula (1) contains a carboxylic acid functionality (-COOH), its ester, for example a compound in which the hydrogen of the functionality of carboxylic acid of the compound of formula (1) is replaced with alkyl (CrC8); (ii) wherein the compound of formula (1) contains an alcohol functionality (-OH), its ether, for example a compound in which the hydrogen of the alcohol functionality of the compound of formula (1) is replaced with alkanoyloxymethyl ( CrC6); and (iii) wherein the compound of formula (1) contains a primary or secondary amino functionality (-NH2 or -NHR where R? H), its amide, for example, a compound in which, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) are replaced or replaced with alkanoyl (CC? o). Other examples of substitution groups can be found according to the preceding example and examples of other types of prodrugs in the aforementioned references. In addition, certain compounds of formula (1) can by themselves act as prodrugs of other compounds of formula (1). Also included within the scope of the invention are the metabolites of compounds of formula (1), ie, compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include (i) where the compound of formula (1) contains a methyl group, its hydroxymethyl derivative (-CH3? -CH2OH): (ii) wherein the compound of formula (1) contains an alkoxy group, its hydroxy derivative (-OR? -OH); (iii) wherein the compound of formula (1) contains a tertiary amino group, its secondary amino derivative (-NR1R2? -NHR1 or -NHR2); (iv) wherein the compound of formula (1) contains a secondary amino group, its primary derivative (-NHR1? -NH2); (v) wherein the compound of formula (1) contains a phenyl residue, its phenol derivative (-Ph? -PhOH); Y (I) (vi) wherein the compound of formula (1) contains an amide group, its carboxylic derivative (-CONH2? COOH).

The compounds of formula (1) containing one or more carbon atoms can exist as two or more stereoisomers. If a compound of formula (1) contains an alkenyl or alkenylene group, the geometric cis / trans (or Z / E) isomers are possible. If the compound contains, for example, a keto or the structural isomers are interconvertible via an oxime group or an aromatic moiety, a tautomeric isomerism ('tautomerism') with an energy barrier can occur. This may be in the form of proton tautomerism in compounds of formula (1) containing, for example, a methyl group, keto or oxime, or the so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound can have more than one type of isomerism. Included within the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds that exhibit more than one type of isomerism, and mixtures of one or more of them. Also included are acid or base addition salts in which the counter ion is optically active, eg, cf-lactate or / -lysine, or racemic, eg, d / -tartrate or a7-arginine.

The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis of 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). racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acid or base moiety, an acid or base as tartaric acid or 1-phenylethylamine The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer (s) by means known to a person skilled in the art. The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form. chromatography, typically HPLC, in an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing between 0 and 50% by volume of isopropanol, typically between 2% and 20%, and between 0 and 5 % by volume of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture. Stereoisomeric conglomerates can 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). According to one aspect of the present invention, the (f?, F?) - stereoisomer of the formula below is preferred, wherein R1 is hydrogen and R2 is C1-C4 alkyl, preferably methyl, and Q1, Q2, Q3 and Q4 are as defined above: The present invention includes all isotopically-labeled pharmaceutically-acceptable compounds of formula (1) in which one or more atoms are replaced with atoms having the same atomic number but a mass or atomic mass number different from the mass or number of atomic mass that predominates in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen isotopes, as H and 3H, carbon, as 11C, 13C and 14C, chlorine, as 36CI, fluorine, as 18F, iodine, as 123l and 25l, nitrogen, as 13N and 15N, oxygen, as 15O, 17O and 18O, phosphorus, like 32P, and sulfur, like 35S. Certain isotopically-labeled compounds of formula (1), for example those incorporating a radioactive isotope, are useful in tissue distribution studies. The radioactive isotopes tritium, ie 3H and carbon 14, ie 14C, are especially useful for this purpose since they are easily incorporated and detection means are available. Substitution with heavier isotopes such as deuterium, Le 2H, may produce certain therapeutic advantages brought about for greater stability, eg, increased in vivo half-life or reduced dose requirements and, accordingly, may be preferred in some circumstances. Substitution with positron emission isotopes, such as 11C, 18F 15O and 13N, may be useful in positron emission topography (PET) studies to examine the occupancy of a receptor by a substrate. The isotopically-labeled compounds of formula (1) in general can be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagent previously employed. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted isotopically, for example D20, d6-acetone and d6-DMSO. The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatives are valuable pharmaceutically active compounds, suitable for the therapy and prophylaxis of various disorders in which the β2 receptor is involved or in which the agonism of this receptor can induce benefits, in particular in allergic and non-allergic respiratory diseases but also in the treatment of other diseases such as, but not limited to, those of the nervous system, premature delivery, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative dermal diseases, glaucoma and in cases in which there is an advantage in reducing gastric acidity, particularly in gastric and peptic ulcers. The compounds of formula (1) and their pharmaceutically acceptable salts and derivatives, as mentioned above, can be administered according to the invention to animals, preferably mammals, and in particular to humans, as pharmaceuticals for therapy and / or prophylaxis. They can be administered by themselves, mixed together or in the form of pharmaceutical preparations containing, as active constituent, an effective dose of at least one compound of formula (1), its pharmaceutically acceptable salts and / or derivatives, in addition to pharmaceutically acceptable excipients and / or customary additives. The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatives can be lyophilized, spray-dried or dried by evaporation to provide a solid plug, powder or film of amorphous crystalline material. For this purpose, radio frequency or microwave drying may be used. The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatives can 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 depend to a large extent on the particular mode of administration. The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the digestive tract, or buccal or sublingual administration can be used through 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 (even filled with liquid), chewing gum, multi and nano-particulates, gels, solid solution, liposomes, films, ovules , aerosols and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be employed as fillers in hard or soft capsules and typically comprise a car, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet. The compounds of the invention can also be used in rapidly dissolving, rapid disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001). For dosage forms of tablets, depending on the dose, the drug can constitute from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form . In addition to the drug, the tablets generally contain a disintegrant. Examples of disgregates include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. In general, the disintegrant would be from 1% by weight to 25% by weight, preferably from 5% by weight to 20% of the dosage form. Binders are generally used to impart cohesion qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The 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.

The tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may constitute 0.2 wt% to 5 wt% of the tablet, and the glidants may constitute 0.2 wt% to 1 wt% of the tablet. The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants generally constitute from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and flavor masking agents. Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight of disintegrant and from about 0.25% by weight to about 10% by weight of lubricant. The tablet mixtures can be compressed directly or by means of a roller to form tablets. Blends of tablets or portions of mixtures may, alternatively, be wet, dry, or melt granulated, coagulated in the molten state, or extruded prior to the formation of the tablets. The final formulation may comprise one or more layers and may be coated or uncoated; it can even be encapsulated. Tablet formulation is described in "Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980.) Oral consumption films for human or veterinary use are dosage forms. thin-film water-soluble or water-expandable, typically flexible that can rapidly dissolve or adhere to mucous membranes and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer , a stabilizer or an emulsifier, a viscosity modifying agent and a solvent Some components of the formulation can perform more than one function The compound of formula (1) can be soluble or insoluble in water. from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight of the solutes.The less soluble compounds can constitute a greater proportion of the composition, typically up to 88% by weight of the solutes. Alternatively, the compound of formula (1) can be in the form of multiparticulate spheres. The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulating agents, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants and flavor masking agents. The films according to the invention are typically prepared by evaporative drying thin aqueous films applied as a coating on a release support or release paper. This can be done in a drying oven or tunnel, typically a combined coater-dryer or by means of lyophilization or vacuum. Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed release, controlled, directed and programmed. Modified release formulations suitable for the purposes of the invention are disclosed in U.S. Patent No. 6,106,864. In Pharmaceutical Technology On-line, 25 (2), 1-14, by Verma et al (2001) are details of other suitable release technologies such as high energy dispersions and osmotic and coated particles. In WO 00/35298 the use of a chewing gum to achieve controlled release is described.

The compounds of the invention can also be administered directly into the blood stream, into the muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle), needleless injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but for some applications, may be more adequately formulated as a non-aqueous, sterile or a dry form that has to be used together with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be carried out easily using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (1) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of agents that increase solubility. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this manner, the compounds of the invention can be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted reservoir that provides for the modified release of the active compound. Examples of such formulations include drug-coated stents and PGLApoli (dl-lactic-coglycolic) acid microspheres (PGLA). The compounds of the invention can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powder, dressings, film foams, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles 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 injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture, for example, in a dry mixture with lactose, or as a mixed particulate component, for example , mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1,1,1,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound or compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or extending the release of the active, a propellant or propellants as a solvent and a 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 micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable crushing method, such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (made, for example, from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture 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 can be anhydrous or in monohydrated form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer that uses electrodynamics to produce a fine mist can contain between 1 μg and 20 mg of the compound of the invention per actuation and the actuation volume can vary between 1 μl and 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol or sweeteners, such as saccharin or sodium saccharin may be added to the formulations of the invention intended for administration by inhalation / intranasal.

Formulations for inhaled / intranasal administration can be formulated for immediate and / or modified release using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that supplies a measured quantity. The units according to the invention are typically administered at a metered dose or "discharge" containing between 0.001 mg and 10 mg of the compound of formula (1) The total daily dose will typically be in the range of 0.001 mg to 40 mg, which can be administered in a single dose or, more usually, as divided doses throughout the day The compounds of formula (1) are particularly suitable for administration by inhalation The compounds of the invention can be administered rectally or vaginally, For example, in the form of a suppository, ovum or enema, cocoa butter is a traditional suppository base, but different alternatives may be used, as appropriate.Rectal / vaginal administration formulations can be formulated to be immediate release and Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. The invention may also be administered directly to the eyes or ears, typically in the form of drops of a suspension or micronized solution in sterile, pH-adjusted, isotonic saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable implants (eg, sponges with absorbable gel, collagen) and non-biodegradable implants (eg, silicone), wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes A polymer such as a crosslinked poly (acrylic acid), polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, may be incorporated by example gellan gum, together with a preservative such as benzalkonium chloride. These formulations can also be supplied by iontophoresis. Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. Modified release formulations include: delayed, sustained, pulsed, controlled, directed or programmed release. The compounds of the invention can be combined with soluble macromolecular substances, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for its use in any of the modes of administration mentioned above. For example, it is found that drug-cyclodextrin complexes in general are useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct the complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a vehicle, diluent or solubilizer. Alpha-, beta- and gamma cyclodextrins are the most commonly used for these purposes, examples of which can be found in the international patent applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148. To the extent that it may be 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 may conveniently be combined, one of which at least contains a compound according to the invention, in the form of a kit suitable for the co-administration 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) according to the invention, and means for retaining separate the compositions, such as a container, divided bottle or Aluminum package divided. An example of such a case is the ordinary blister for packaging tablets, capsules and the like. The kit of the invention is particularly suitable for administering different administration forms, for example parenteral, for administering the separate compositions in different dose ranges, or for titrating the compositions separated from each other. To assist in monitoring the treatment, the kit typically comprises instructions for administration and may have a so-called reminder. For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.001 mg to 5000 mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require between 0.001 mg and 40 mg. The total daily dose may be administered in single or divided doses and may, at the discretion of the physician, be outside the typical range described herein. These dosages are based on an average human subject weighing approximately 65 kg to 70 kg. The doctor can easily determine doses of subjects whose weights are outside this range, such as children and the elderly. To avoid doubts, the references in this report to "treatment" includes references to curative, palliative and prophylactic treatment. According to another embodiment of the present invention, the compounds of formula (1), or their pharmaceutically acceptable salts, derivatives or compositions, can also be used as a combination with one or more additional therapeutic agents that are 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 dyspnea, cough. The second and further additional therapeutic agent can also be a compound of formula (1), or its pharmaceutically acceptable salt, derivatives or compositions, or one or more β2 agonists known in the art. More typically, the second and subsequent therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "co-administration", "co-administered" and the term "in combination with", with reference to the compounds of formula (1) and one or more other therapeutic agents, have as an end and refer and include the following: • simultaneous administration of said combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when said components are formulated together in a only form of administration that releases said components at virtually the same time to said patient, • practically simultaneous administration of said combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when said components are formulated separately from each other in separate dosage forms that the patient takes at about the same time, after which said components are released at almost the same time to said patient. tea, • sequential administration of said combination compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when said components are formulated separately from each other, which the patient takes in consecutive schedules with a significant time interval between each administration; whereupon said components are released at practically different times to said patient; and • sequentially administering said combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when said components are formulated together in a single administration form that releases said components into a controlled mode, after which the patient takes it concurrently, consecutively and / or superimposed at the same times and / or at different times, where each part can be administered by the same route or by a different route. Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of formula (1), or their pharmaceutically acceptable salts, derivatives or compositions include, but are not limited to, (a) 5-lipoxygenase inhibitors. (5-LO) or antagonists of the 5-lipoxygenase activating protein (FLAP), (b) Leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 and LTE4 antagonists, (c) Histamine receptor antagonists including antagonists of H1 and H3, (d) Sympathomimetic vasoconstrictor agents agonists of ai and a2 adrenoreceptors for decongestant use, (e) M3 muscarinic receptor antagonists or anticholinergic agents, (f) PDE inhibitors, eg inhibitors of PDE3, PDE4 and PDE5, (g) Theophylline, (h) Sodium cromoglycate, (i) COX inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j) Oral or inhaled glucocorticosteroids, (k) Monoclonal antibodies active ales against endogenous inflammatory entities, (I) Antitumor necrosis factor (anti-TNF-α) agents, (m) Adhesion molecule inhibitors including VLA-4 antagonists, (n) Quinine receptor antagonists-Bi and B2, (o) Agents immunosuppressants, (p) matrix metalloprotease inhibitors (MMPs), (q) tachykinin receptor antagonists NK-i, NK2 and NK3, (r) elastase inhibitors, (s) adenosine A2A receptor agonists, (t) Urokinase inhibitors, (u) Compounds that act on dopamine receptors, p. eg, D2 agonists, (v) Modulators of the NF? ß >pathway; p. eg, inhibitors of IKK, (w) Modulators of cytokine signaling pathways such as p38 MAP kinase or syk kinase, (x) Agents that can be classified as mucolytic or antitussive, and (and) Antibiotics. According to the present invention, the combination of the compounds of formula (1) with H3 antagonists, - Muscarinic M3 receptor antagonists, - PDE4 inhibitors, - glucocorticosteroids, - Adenosine A2a receptor agonists, - Modulators of the cytokine signaling pathways such as p38 MAP kinase or syk kinase, or, - leukotriene antagonists (LTRAs), including LTB4, LTC4, LTD4 and LTE4 antagonists, In accordance with the present invention, the combination of the compounds of formula ( 1) with: - 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 - muscarinic receptor antagonists M3 or anticholinergic agents which include, in particular, ipratropium salts, namely bromide, tiotropium salts, namely bromide, salts of oxitropium, namely bromide, perenzepine and telenzepine, are most preferred. It must be taken into account that all the references in this document for treatment include a curative, palliative and prophylactic treatment. The following description relates to therapeutic applications in which the compounds of formula (1) can be used. The compounds of formula (1) have the ability to interact with the β2 receptor and, therefore, have a wide range of therapeutic applications, as described in more detail below, due to the essential function of the β2 receptor. in the physiology of all mammals. Therefore, another aspect of the present invention relates to the compounds of formula (1), or their pharmaceutically acceptable salts, derivatives or compositions, for use in the treatment of diseases, disorders and conditions in which the β2 receptor is involved. . More specifically, the present invention also relates to the compounds of formula (1), or their pharmaceutically acceptable salts, derivatives or compositions, for use in the treatment of diseases, disorders and conditions selected from the group consisting of: any type, etiology or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, topical bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused for pathophysiological disorders, 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, infectious asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, s newborn wheezing syndrome and bronchiolitis, • chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema, • obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular any obstructive or Inflammatory airway 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 a progressive and irreversible airway obstruction, respiratory distress syndrome in adults (ARDS), exacerbation of airway hyperreactivity resulting from other drug therapy and respiratory disease associated with pulmonary hypertension, • bronchitis of any type, etiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, laryngotracheobronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, bronchitis due to staphylococci or streptococci and bronchopneumonia, • acute lung injury, • bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis which is a member selected from the group consisting of cylindrical bronchiectasis, saccule bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, bronchiectasis cystic, dry bronchiectasis and follicular bronchiectasis. Even another aspect of the present invention also relates to the use of the compounds of formula (1) or their pharmaceutically acceptable salts, derivatives or compositions for the manufacture of a drug having β2 agonist activity. In particular, the present invention relates to the use of the compounds of formula (1), or their pharmaceutically acceptable salts, derivatives or compositions, for the manufacture of a drug for the treatment of diseases and / or conditions mediated by β2, in particular , the diseases and / or tables mentioned above. Therefore, the present invention provides a particularly interesting method for treating a mammal, including a human, with an effective amount of a compound of formula (1) or its pharmaceutically acceptable salt, derivative or composition. More precisely, the present invention provides a particularly interesting method for the treatment of diseases and / or frames mediated by β 2 in a mammal, including a human being, in particular the diseases and / or tables mentioned above, which comprises administering said mammal an effective amount of a compound of formula (1), its pharmaceutically acceptable salts and / or derivatives. The following examples illustrate the preparation of the compounds of formula (1): EXAMPLES 1 TO 12 A solution of ammonium fluoride in water (15 eq, 20 mgml "1) was added to a solution of the protected compound of preparations 38-3, 45-46, 48-49 and 52-53 (1 eq) in methanol ( 45-100 mlmmol "1) and the reaction was stirred at 40 ° C for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography, using a Biotage® silica gel cartridge using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.3 to 93: 7: 0.7) as the eluent. The product was triturated with ether to yield the title compound as a solid.

EXAMPLES 13 TO 18 Ammonium fluoride (10-15 eq) was added to a solution of the protected compound of preparations 38, 44, 47, 50-51 and 53 (1 eq) in methanol (40-44 mlmmor1) and water (17-25mLmmol). 1) and the reaction was stirred at 40 ° C. for 18 hours.The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1) as the eluent The product was triturated with ether or pentane to produce the title compound as a solid.

The A-tlc analysis after 18 hours, showed that there was still starting material, so that additional ammonium fluoride (5-6 eq) was added and the reaction was stirred for another 18 hours at 40 ° C. Compound B was purified using a Biotage® silica gel cartridge and dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 95: 5: 0.5) as the eluent.

EXAMPLES 19 TO 23 The compounds of the aforementioned general formula were prepared from the preparations of compounds 30-34, following the procedure described for examples 13 to 18.

The A-tic analysis, after 18 hours, showed that there was still starting material, so that additional ammonium fluoride (5-6 eq) was added and the reaction was stirred for another 18 hours at 40 ° C.

EXAMPLE 24 N-3-R (Benzylamino) sulfonylbenz H > -2-f3 - ((2 /?) -2- ( { (2 /?) -2-hydroxy-2-r4-hydroxy-3- (hydroxymethyphenethyl) .amino) propynyl} acetamide Ammonium fluoride (134 mg, 3.61 mmol) was added to a solution of the compound of preparation 36 (132 mg, 0.18 mmol) in water (4 ml) and methanol (7 ml), and the reaction was stirred at 40 ° C for 18 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (93: 7: 0.5) to produce a colorless gum. This was triturated with ether and the mixture was evaporated under reduced pressure to yield the title compound as a white solid, 55 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.06 (d, 3 H), 2.55- 2.60 (dd, 1 H), 2.67-2.73 (m, 2 H), 2.84-2.89 (m, 1 H), 2.93-2.98 ( m, 1 H), 3.53 (s, 2H), 3.98 (s, 2H), 4.40 (s, 2H), 4.59-4.63 (m, 3H), 6.69 (d, 1 H), 6.98-7.03 (, 2H), 7.08 (s, 1 H), 7.13-7.24 (m, 8H), 7.44 (d, 2H), 6.67-7.72 (m, 2H). LRMS: m / z ES + 618 [MH +] Microanalysis found: C, 64.50; H, 6.47; N, 6.54. C34H39N3O6S + 0.85H2O requires C, 64.51; H, 6.48; N, 6.64%.

EXAMPLE 25 2-f3-((2 /)) -2 - (((2 /)) -2-Hydroxy-2-r4-hydroxy-3- (hydroxymethylphenmethyl > amino) propylphenyl > -N - { 4-r ((r (3-phenoxybenzyl) amino-1-carbonyl) amino} -methylphenyl-acetamide The title compound was prepared from the compound of preparation 55 (157 mg, 0.192 mmol) as a white solid in 54% yield, following the procedure described in the previous example. 1 H NMR (CD 3 OD, 400 MHz) d: 1.05 (d, 3 H), 2.52-2.57 (dd, 1 H), 2.65-2.71 (m, 2 H), 2.82-2.93 (m, 2 H), 3.48 (s, 2 H) ), 4.22-4.30 (m, 6H), 4.61 (s, 3H), 6.66-6.70 (d, 1 H), 6.83 (d, 1 H), 6.92-7.33 (m, 18H). LRMS: m / z ES + 703 [MH +] Microanalysis found: C, 70.04; H, 6.81; N, 7.82. C42H4SN406 + 0.95H2O requires C, 70.07; H, 6.71; N, 7.78%.

EXAMPLE 26 N- (3,4-Dimethoxybenzyl-4- (r (. {3-r (2 /?) -2 - (((2?) - 2-hydroxy-2-r4-hydroxy-3 - (hydroxymethyl) pheninet? l> amino) propylphenyl> acetyl) amino) methyl &benzamide A solution of the compound of Preparation 35 was stirred (170 mg, 0.23 mmol) in tetrahydrofuran (2 ml), water (2 ml) and acetic acid (6 ml), at 65 ° C for 18 hours, and another 72 hours at room temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol 1: 0.88 ammonia (95: 5: 0.5 to 90: 10: 1). The resulting gum was triturated with ether to yield the title compound as a white solid, 61 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.06 (d, 3 H), 2.55-2.61 (dd, 1 H), 2.66-2.75 (m, 2 H), 2.82-2.98 (m, 2 H), 3.52 (s, 2 H) ), 3.80 (s, 6H), 4.40 (s, 2H), 4.48 (s, 2H), 4.61 (m, 3H), 6.69 (d, 1 H), 6.89 (s, 2H), 6.96 (s, 1 H), 7.01 (d, 2H), 7.08 (s, 1 H), 7.13 (m, 1 H), 7.19 (m, 2H), 7.30 (d, 2H), 7.77 (d, 2H). LRMS: m / z ES + 618 [MH +] [aJD = -17.20 (c = 0.10, MeOH) PREPARATION 1 Methyl 2- (benzyloxy) -5- (l7ff) -2-bromo-1-. { rterc-butyl (dimethyl) silinoxyl} ethyl) benzoate A solution of methyl 2- (benzyloxy) -5 - [(7f? -2-bromo-1-hydroxyethylbenzoate (Tett. Lett. 1994, 35 (50), 9375) (71.05 g, 195 mmol), imidazo! (18.52 g, 272 mmol), tert-butyldimethylsilyl chloride (32.23 g, 214 mmol) and 4-dimethylaminopyridine (0.44 g, 3.6 mmol) in N, N-dimethylformamide (270 mL) at room temperature under nitrogen atmosphere for 24 hours The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 ml) and water (500 ml) The organic phase was separated and washed with 2N hydrochloric acid (2 x 500 ml), sodium bicarbonate saturated aqueous (2 x 500 ml), saturated sodium chloride (500 ml), dried (magnesium sulfate) and the solvent was removed in vacuo to yield the title compound as a colorless oil (91.0 g). (400 MHz, CDCI3): d -0.08 (s, 3H), 0.11 (s, 3H), 0.90 (s, 9H), 3.39-3.48) m, 2H), 3.91 (s, 3H), 4.82-4.85 (m, 1 H), 5.19 (s, 2H), 7.01 (d, 1 H), 7.30-1 7.51 (m , 6H), 7.81 (br s, 1 H). LRMS: m / z ES + 501, 503 [M + Na] + PREPARATION 2 r 2 - (Benzyloxy) -5- (f'7 /?) - 2-bromo-1 - ((tert-butyl (dimethyl) silinoxy > ethyl) phenanmethanol Borane dimethylsulfoxide complex (42.4 ml of ~ 10M solution, 424 mmol) was added dropwise to a solution of preparation 1 (91.0 g, 189 mmol) in tetrahydrofuran (1600 ml). Then, the resulting mixture was heated to reflux for 2 hours and then cooled to 0 ° C before being quenched with methanol (270 ml). The mixture was allowed to stir at room temperature for 16 hours and then the solvent was removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with dichloromethane (500 ml) and the combined organic solutions were washed with saturated aqueous sodium chloride (500 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel, eluting with cyclohexane: ethyl acetate (100: 0 changing to 80:20, by volume) to yield the title compound (68.7 g) as a colorless oil. 1 H NMR (400 MHz, CDCl 3): d -0.07 (s, 3H), 0.11 (s, 3H), 0.90 (s, 9H), 3.40-3.48 (m, 2H), 4.74 (s, 2H), 4.81 -4.84 (m, 1 H), 5.12 (s, 2H), 6.94 (d, 1 H), 7.25-7.29 (m, 3H), 7.36-7.42 (m, 5H). LRMS: m / z ES + 473, 475 [M + Naf PREPARATION 3 (3-bromo-phenyl) -acetic acid methyl ester Acetyl chloride (0.7 mL, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl) -acetic acid (20.08, 93 mmol) in methanol (500 mL) at 0 ° C under nitrogen and the reaction allowed to warm gradually to room temperature for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane, dried (sodium sulfate) and concentrated under reduced pressure to yield the title compound as a colorless oil, 20.6g. 1 H NMR (CDCl 3, 400 MHz) d: 3.59 (s, 2 H), 3.70 (s, 3 H), 7.17-7.24 (m, 2 H), 7.37-7.45 (m, 2 H) LRMS: m / z ES + 253 [M + Na] + PREPARATION 4 [3- (2-Oxo-propyl) -phene-acetic acid methyl ester A mixture of the bromide from Preparation 3 (15.0 g, 65.0 mmol), tributyltin methoxide (28.3 mL, 98.0 mmol), isopropenyl acetate (10.8 mL, 98.0 mmol), palladium (II) acetate (750 mg, 3.30 mmol) and tri-ortho-tolylphosphine (2.0 g, 6.5 mmol) in toluene (75 ml) at 100 ° C under nitrogen for 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 ml) and aqueous 4M potassium fluoride solution (90 ml), and the mixture was stirred for 15 minutes. The mixture was filtered through Arbocel® and the organic phase was separated and reduced under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of diethyl ether: pentane: dichloromethane (0: 100: 0 to 25: 75: 0 to 0: 0: 100, by volume) to produce the title compound as a pale yellow oil, 12.69. 1 H NMR (CDCl 3, 400 MHz) d: 2.15 (s, 3 H), 3.61 (s, 2 H), 3.69 (m, 5 H), 7.10-7.13 (m, 2 H), 7.19 (d, 1 H), 7.30 ( did, 1 H. - LRMS: m / z ES + 224 [M + NH4] + PREPARATION 5 Acid methyl ester hydrochloride { 3 - ((2 /?) - 2- (ff? H -phenyl-ethylamino) - propin-phenyl.

A solution of the ketone from Preparation 4 (8.5 g, 41.2 mmol), f?) - a-methyl benzylamine (4.8 mL, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 was stirred. ml, 38 mmol) in dichloromethane (400 ml) at room temperature for 48 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution (200 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic solutions were dried (magnesium sulfate) and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with dichloromethane: methanol: 88 ammonia (99: 1: 0.1 to 95: 5: 0.5 by volume) yielded a 4: 1 mixture of diastereomers (R, main R) as a pale yellow oil (8.71 g). Treatment with excess 1 M hydrogen chloride, followed by three consecutive crystallizations (diisopropyl ether / methanol) afforded the title compound as a colorless crystalline solid, 5.68 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1.18 (d, 3 H), 1.68 (d, 3 H), 2.60- 2.66 (m, 1 H), 3.15-3.26 (m, 1 H), 3.25-3.30 (m, 1 H), 3.30 (s, 3 H), 3.62 (s, 2 H), 4.59 (q, 1 H), 7.00 (m, 2 H), 7.17 (m, 1 H), 7.27 (m, 1 H), 7.50 (m, 5H), LRMS: m / z ES + 312 (M + H) + PREPARATION 6 Methyl f3-f (2 /?) -2-aminopropylphenyl > acetate A solution of the compound of preparation 5 was heated (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) in ethanol (40 ml) up to 75 ° C in the presence of 20% palladium hydroxide on carbon (Pd (OH) 2 / C, 2.00 g ). After 90 minutes, the reaction mixture was cooled to room temperature, filtered through Arbocel® and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 0.88 ammonia (100 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts were dried over magnesium sulfate and reduced in vacuo to yield the title compound as a colorless oil (4.78 g). 1 H NMR (400 MHz, CD 3 OD): d 1.06 (d, 3 H), 2.57-2.67 (m, 2 H), 3. 05-3.12 (m, 1 H), 3.63 (s, 3 H), 3.67 (s, 3 H), 7.11 (m, 3 H), 7.25 (m, 1 H). LRMS: m / z ES + 208 [M + H] + PREPARATION 7 Methyl (3 - ((2 /?) - 2-r (2f?) -2- (fterc-butyl (dimethyl) silinoxy) -2- (4 -benzenoxy-3-3-hydroxymethyl-phenyl) -ethylamino-1-propyl.} -phenyl) -acetate A solution of the bromide from Preparation 2 (12.5 g, 27.7 mmol) and the amine from Preparation 6 (11.5 g, 55.4 mmol) in dichloromethane (130 mL) was heated at 90 ° C, allowing the dichloromethane to evaporate. The resulting mixture was left at 90 ° C for another 16 hours. The reaction mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2 to 97: 3: 0.3, by volume) to yield the title compound. title (12.1 g) as a colorless oil. 1 H NMR (400 MHz, CD3OD): d -0.19 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H), 1.05 (d, 3H), 2.55-2.68 (m, 3H), 2.80- 2.95 (m, 2H), 3.58 (s, 2H), 3.66 (s, 3H), 4.67 (d, 2H), 4.74 (t, 1 H), 5.12 (s, 3H), 6.92 (d, 1 H) , 7.00 (d, 1 H), 7.03 (s, 1 H), 7.07-7.13 (m, 2H), 7.15-7.19 (m, 1 H), 7.29-7.39 (m, 4H), 7.46 (m, 2H ). LRMS: m / z ES + 578 [M + H] + PREPARATION 8 Methyl (3 { (2?) - 2-r (2?) -2-frtercbutyl (dimethyl) silinoxy -2- (4-hydroxy) 3- hydroxymethyl-phenyl) -ethylamino-1-propyl) -phenyl) -acetate A suspension of the compound of preparation 7 (5.27 g, 9.12 mmol) and 10% palladium on carbon (1.00 g) in ethanol (50 ml) was stirred under a hydrogen atmosphere (60 psi) at room temperature for 16 hours. The catalyst was filtered through Arbocel® and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia (96: 4: 0.4 to 95: 5: 0, by volume) to afford the title compound as a pale yellow oil (1.99 g). 1 H NMR (400 MHz, CD 3 OD): d -0.20 (s, 3H), -0.01 (s, 3H), 0.82 (s, 9H), 1.06 (d, 3H), 2.55-2.69 (m, 3H), 2.86. -2.96 (m, 2H), 3.59 (s, 2H), 3.67 (5, 3H), 4.62 (d, 2H), 4.70 (t, 1 H), 6.68 (d, 1 H), 6.98-7.03 (m , 3H), 7.10 (d, 1 H), 7.19 (m, 2H). LRMS: rn / z ES + 488 [M + H] + PREPARATION 9 Acid (3- { (2 /?) - 2-r (2 /?) - 2-nerc-Butyl (dimethylsilynoxy | -2- (4-hydroxy-3-hydroxymethyl-phen »l) -ethylamino-propyl.} -phenyl) -acetic An ester solution of preparation 8 (7.04 g, 14. 43 mmol) in tetrahydrofuran (40 ml) with lithium hydroxide (28.9 ml of a 1 M aqueous solution, 28.9 mmol) and the reaction was allowed to stir at room temperature for 16 hours. Hydrochloric acid (28.9 ml of a 1 M aqueous solution, 28.9 mmol) was added and the tetrahydrofuran was removed in vacuo. The remaining aqueous layer was decanted and the residue was further washed with water (10 ml). The residue was redissolved in methanol (30 ml) and the solvent in vacuo to yield the title compound as a colorless foam (5.95 g). 1 H NMR (400 MHz, CD 3 OD): -0.13 (s, 3 H), 0.06 (s, 3 H), 0.86 (s, 9 H), 1.22 (d, 3 H) 2.72-2.77 (dd, 1 H), 2.93-2.98 (dd, 1 H), 3.09-3.13 (dd, 1 H), 3.23-3.28 (dd, 1 H) 3.43-3.48 (m, 1 H), 3.48 (s, 2H), 4.64 (d, 2H), 4.97 (m, 1 H), 6.78 (d, 1H), 7.02 (d 1 H), 7.11 (d, 1 H), 7.13 (s, 1 H), 7.18-7.25 (m, 2H), 7.32 (s) , 1 HOUR). LRMS: ES + m / z 474 [M + H] + Microanalysis found: C 64.15, H 8.25, N 2.84; C26H39NO5Si + 0.7H2O requires 64.22, H 8.37, N 2.88%.

PREPARATION 10 Methyl 4-. { r ((3-r (2 /?) - 2 - (((2?) - 2- { rterc-butyl (dimethyl) sililloxy> -2-r4-hydroxy (hydroxymethyl) phenylethyl} amino) propyl} phenyl } acetyl) amino1 methyl) benzoate 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.44 g, 9.28 mmol) was added to a mixture of the acid from preparation 9 (4.0 g, 8.22 mmol), methyl 4- (aminomethyl) benzoate (1.54 g, 9.28 mmol), 1-hydroxybenzotriazole hydrate (1.25 g, 9.28 mmol) and triethylamine (3.538, 25.3 mmol) in N, N-dimethylformamide (60 mL), and the reaction was stirred at room temperature for 64 hours. The mixture was concentrated under reduced pressure and the oily residue was partitioned between dichloromethane (50 ml) and sodium bicarbonate solution (50 ml), and the layers were separated. The aqueous solution was extracted with more dichloromethane (3 x 75 ml), the combined organic solutions were washed with water (30 ml) and brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as the eluent to afford the title compound as a white solid, 3.03 g. 1 H NMR (CD 3 OD, 400 MHz) d: -0.18 (s, 3 H), 0.02 (s, 3 H), 0.84 (s, 9H), 1.04 (d, 3H), 2.53 (m, 1 H), 2.60-2.70 (m, 2H), 2.82-2.94 (m, 2H), 3.52 (s, 2H), 3.86 (s, 3H), 4.42 (s, 2H), 4.61 (d, 2H), 4.66 (m, 1 H), 6.64-6.70 (d, 1 H), 6. 86-7.02 (br d, 2H), 7.04 (s, 1 H), 7.17 (d, 1 H), 7.20 (m, 2H), 7.24-7.36 (d, 2H), 7. 86-7.92 (d, 2H). LRMS: m / z 621 [M + H] + PREPARATION 11 Acid 4-ffl. { 3,4 (2?) -2- ( { (2R) -2- (rterc-butyl (dimethyl) silinoxy) -2-r4-hydroxy-3- (hydroxymethyl) phenylethyl}. amino) propylphenyl) acetyl) amino1 methyl) benzoic An aqueous solution of lithium hydroxide (9.76 ml, 1 M, 9.76 mmol) was added to a solution of the ester of preparation 10 (3.03 g, 4.88 mmo!) In tetrahydrofuran (20 ml) and the reaction was stirred at room temperature for 7 hours. The mixture was cooled on ice and neutralized by the addition of 1 M hydrochloric acid (9.76 ml, 1 M, 9.76 mmol). The tetrahydrofuran was removed in vacuo, and the remainder of the aqueous solution decanted. An azeotrope with methanol was formed with the residue to yield the title compound as a white solid, 2.96 g. 1 H NMR (CD 3 OD, 400 MHz) d: -0.17 (s, 3 H), 0.07 (s, 3 H), 0.86 (s, 9 H), 1.17 (d, 3 H), 2.66-2.72 (dd, 1 H), 2.98 -3.03 (dd, 1 H), 3.13 (dd, 1 H), 3.24 (m, 1 H), 3.40 (m, 1 H), 3.55 (s, 2H), 4.40 (s, 2H), 4.67 (d) , 2H), 4.97-5.00 (m, 1 H), 6.79 (d, 1 H), 7.09-7.15 (m, 3H), 7.20-7.36 (m, 5H), 7.87-7.89 (d, 2H). LRMS: m / z 607 [M + H] + PREPARATION 12 tert-Butyl (4-. {((3,4-dimethoxybenzyl) aminolcarbonyl) benzyl) carbamate A mixture of 4- (tert-butoxycarbonylamino-methyl) -benzoic acid (1.0 g, 4 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (920 mg, 4.8 mmol), hydrate 1- was stirred. hydroxybenzotriazo! (600 mg, 4.4 mmol), 3,4-dimethoxybenzylamine (730 mg, 4.4 mmol) and N-ethyldiisopropylamine (2.5 m!, 14 mmol) in N, N-dimethylformamide (20 ml) at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with 1N hydrochloric acid (2x), sodium bicarbonate solution (2x) and sodium chloride solution. This solution was dried over magnesium sulfate and evaporated under reduced pressure to yield the title compound as a colorless solid, 1.69. 1 H NMR (CDCl 3, 400 MHz) d: 1.44 (s, 9 H), 3.84 (s, 6 H), 4.35 (s, 2 H), 4.58 (d, 2 H), 4.98 (br S, 1 H), 6.42 (s) , 1 H), 6.81 (d, 1 H), 6.88 (m, 2 H), 7.36 (d, 2 H), 7.76 (d, 2 H). LRMS: m / z APCI + 401 [M + H +] PREPARATION 13 tert-Butyl (4-fr (4-phenoxybenzoyl) aminolmethyl} benzyl) carbamate 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (722 mg, 4.65 mmol) was added to a solution of 1-hydroxybenzotriazole hydrate (628 mg, 4.65 mmol), 4-phenoxybenzoic acid (996 mg, 4.65 mmol) , tert-butyl 4-aminomethylbenzyl carbamate (1.0 g, 4.23 mmol) and triethylamine (1.79 mL, 12.7 mmol) in N, N-dimethylformamide (50 mL) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and water (20 ml) and the layers were separated. The aqueous solution was further extracted with ethyl acetate (5x50ml) and the combined organic solutions were washed with water (20ml), the aqueous solution was dried with sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 98: 2) to yield the title compound as a white solid, 647 mg. 1 H NMR (CD 3 OD, 400 MHz) d: 1.44 (s, 9 H), 4.19 (s, 2 H), 4.54 (s, 2 H), 7.00 (d, 2 H), 7.05 (d, 2 H), 7.16-7.24 (m , 3H), 7.30 (d, 2H), 7.40 (m, 2H), 7.84 (d, 2H). LRMS: m / z 455 [M + Na +] PREPARATION 14 tert -Butyl (4-1 (1-naphthoylamino) metH1benzyl}. Carbamate The title compound was obtained as a pale brown solid in 79% yield from 1-naphthoic acid and tert-butyl 4-aminomethylbenzyl carbamate, following the procedure described in Preparation 13. 1H NMR (DMSO-d6, 400MHz ) d: 1.37 (s, 9H), 4.10 (d, 2H), 4.50 (d, 2H), 7.21 (d, 2H), 7.31-7.39 (m, 3H), 7.53 (m, 3H), 7.62 (d) , 1 H), 7.93-8.02 (m, 2H), 8.17 (m, 1H), 9.05 (m, 1 H).

PREPARATION 15 tert-Butyl (4-. {F (4-ethoxybenzoyl) amino-1-methyl} benzyl) carbamate A solution of 4-ethoxybenzoyl chloride (702 mg, 3.80 mmol) in dichloromethane (5 ml) was added dropwise to an ice-cooled solution of tert-butyl 4-aminomethylbenzyl carbamate (1.0 g, 4.23 mmol) and triethylamine ( 1.60 mL, 11.4 mmol) in dichloromethane (45 mL). Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 18 hours. The reaction was washed with sodium bicarbonate solution (25 ml) and the aqueous solution was re-extracted with dichloromethane (4 x 50 ml). The combined organic solutions were washed with water (2 x 25 ml), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (99: 1) to yield the title compound as a white solid, 656 mg. 1 H NMR, (DMSO-d 6,400MHz) d: 1.30-1.36 (m, 12H), 4.03-4.09 (m, 4H), 4.40 (d, 2H), 6.95 (d, 2H), 7.15 (d, 2H) , 7.22 (d, 2H), 7.33 (m, 1 H), 7.83 (d, 2H), 8.82 (m, 1 H).

PREPARATION 16 N-f4- (aminomethyl) benzyl) -4-ethoxybenzamide hydrochloride A solution of the compound of Preparation 15 (656 mg, 1.88 mmol) in 4M hydrochloric acid in dioxane (4.71 mL, 18.8 mmol) was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to yield the title compound as a white solid. 1 H NMR (DMSO-d 6, 400MHz) d: 1.32 (t, 3H), 3.95 (m, 2H), 4.03-4.09 (q, 2H), 4.43 (d, 2H), 6.95 (d, 2H), 7.32 ( d, 2H), 7.40 (d, 2H), 7.84 (d, 2H), 5.37 (m, 3H), 8.95 (m, 1 H). LRMS: m / z APCf 285 [M + H + j PREPARATIONS 17 TO 18 The following examples of general formula: were prepared from the corresponding protected amines, following a procedure similar to that described in preparation 16.

PREPARATION 19 4- (Aminomethyl) -N- (3,4-dimethoxybenzyl) benzamide hydrochloride Hydrogen chloride was bubbled through an ice-cooled solution of the compound of preparation 12 (1.6 g, 4.0 mmol) in dichloromethane (30 ml) until saturation was achieved. The solution was then stirred at room temperature for 2 hours. The solution was evaporated under reduced pressure and the residue was triturated well with ether and the resulting solid filtered and dried to yield the title compound, 1.04 g. 1 H NMR (CD 3 OD, 400 MHz) d: 3.82 (s, 6 H), 4.19 (s, 2 H), 4.52 (s, 2H), 6.92 (s, 2H), 6.99 (s, 1 H), 7.68 (d, 2H), 7.96 (d, 2H). LRMS: m / z APCl + 301 [M + H] PREPARATION 20 Benzyl f4- (aminomethyl) benzylcarbamate A solution of benzylchloroformate (10.48 ml, 74 mmol) in dichloromethane (250 ml) was added to an ice-cooled solution of 4-aminomethyl benzylamine (10 g, 74 mmol) and triethylamine (9.77 ml, 74 mmol), in dichloromethane ( 480 ml) for 90 minutes. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (450 ml) and 1 M sodium hydroxide solution (300 ml). The resulting mixture was filtered, the layers were separated and the organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate, the solution was cooled in an ice bath, the resulting solid was filtered and the filtrates were evaporated under reduced pressure to yield the title compound as a white solid, 7.44 g. 1 H NMR (DMSO-de, 400MHz) d: 3.63 (s, 2H), 4.18 (s, 2H), 5.01 (s, 2H), 7.12-7.39 (m, 9H), 7.77 (s, 1 H). LRMS: m / z ES + 271 [M + Na +] PREPARATION 21 Benzyl (4- (f (diphenylacetyl) aminomethyl) benzyl) carbamate 1- (3-Dimethylaminopropyl) -3-ethylcarbodumide hydrochloride (0.39 g, 2.03 mmol) was added to a solution of 1-hydroxybenzotriazole hydrate (270 mg, 2.03 mmol), triethylamine (0.52 mL, 3.70 mmol), the amine of Preparation 20 (500 mg, 1.85 mmol) and diphenylacetic acid (450 mg, 2.03 mmol) in dichloromethane (7 mL) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and water (10 ml) and the layers were separated. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hot dichloromethane, the solid was filtered and the filtrate was evaporated under reduced pressure to provide the title compound as a white solid, 291 mg. 1 H NMR (DMSO-de, 400MHz) d: 4.17 (d, 2H), 4.22 (s, 2H), 4.98 (s, 1 H), 5.02 (s, 2H), 7.04-7.39 (m, 19H), 7.75 (m, 1 H), 8.70 (m, 1 H). LRMS: m / z EN '463 [M-H] PREPARATION 22 N-f4- (Aminomethyl) benzyl-2,2-diphenylacetamide A mixture of the compound of preparation 21 (200 mg, 0.43 mmol) and 10% palladium on carbon (40 mg) in ethanol (15 ml) and ethyl acetate (a few drops) was hydrogenated at 50 ° C and 60 psi for 3 hours. hours. The reaction mixture was filtered through Arbocel®, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (98: 2 to 90:10) to yield the title compound as a white solid, 87 mg. 1 H NMR (DMSO-de, 400MHz) d: 3.63 (s, 2H), 4.24 (s, 2H), 5.00 (s, 2H), 7.08-7.37 (m, 14H), 8.70 (s, 1 H).

PREPARATION 23 4-. { f (Diphenylmethyl) amino1methyl} benzonitrile A mixture of para-cyanobenzyl bromide (13.72 g, 70 mmol), benzhydrylamine (13.79 g, 70 mmol) and potassium carbonate (16.8 g, 70 mmol) in ethanol (200 ml) was stirred at reflux for 5 hours. The mixture was allowed to cool, the resulting precipitate was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from 80-100 petrol / isopropanol to yield the title compound as an oil, 14.5 g. m.p. 75-75 ° C.

PREPARATION 24 [4- (Aminomethyl) benzyl) (diphenylmethyl) amine dihydrochloride A solution of the compound of Preparation 23 (10.43 g, 35 mmol) in tetrahydrofuran (100 m!) Was added dropwise over 20 minutes to a solution of lithium aluminum (2.66 g, 70 mmol) in tetrahydrofuran (80 mL). . Once the addition was complete, the reaction was allowed to stir at reflux for 5 hours, then allowed to cool to room temperature. Water (27 ml) was added cautiously with stirring, then 2M sodium hydroxide solution (2.7 ml) followed by more water (8.1 ml). The resulting mixture was filtered, the filtrate was evaporated under reduced pressure, the residue was dissolved in chloroform and the solution was dried over sodium sulfate and evaporated under reduced pressure. The residue was treated with ethereal hydrochloric acid and the product was recrystallized from isopropanol / methanol to yield the title compound, 3.6 g. Microanalysis found: 67.50, H, 6.40; N, 7.55. C2? H22N2 + 2HCl-requires C, 67.20; H, 6.45; N, 7.46%.

PREPARATION 25 N-Benzole-3-cyanobenzenesulfonamide Benzylamine (1.17 g, 10 mmol) was added to a solution of 3-cyanobenzenesulfonyl chloride (2 g, 10 mmol) and triethylamine (3.45 mL, 25 mmol) in tetrahydrofuran (30 mL) and the mixture was stirred at room temperature. environment for 18 hours. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The organic extract was dried over sodium sulfate and evaporated under reduced pressure to yield the title compound as a solid, 2.53 g. 1 H NMR (CD 3 OD, 400 MHz) d: 4.17 (s, 2 H), 7.17 (m, 5 H), 7.62 (dd, 1 H), 7.88 (d, 1 H), 8.02 (m, 2 H). LRMS: m / z APCI + 271 [M + H +] PREPARATION 26 3- (aminomethyl) -? / - benzylbenzenesulfonamide hydrochloride Sodium borohydride (3.23 g, 100 mmol) was added dropwise over 20 minutes to an ice-cooled cobalt chloride solution. (2.22 g, 17.2 mmol) and the nitrile from Preparation 25 (2.33 g, 8.5 mmol) in methanol (120 mL) and once the addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction was quenched by the addition of hydrochloric acid (3N, 15 ml), then 0.88 ammonia (20 ml) was added. The mixture was concentrated under reduced pressure and the residue was pre-adsorbed on silica gel. This was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.5 to 90: 10: 1) to produce an oil. The oil was treated with methanolic hydrochloric acid (1 M) and the solution was evaporated under reduced pressure to yield the title compound as a white solid, 2.42 g. 1 H NMR (CD 3 OD, 400 MHz) d: 4.09 (s, 2 H), 4.19 (s, 2 H), 7.20 (m, 5 H), 7.61 (m, 1 H), 7.68 (m, 1 H), 7.86 (m , 1H), 7.94 (s, 1 H). LRMS: m / z APCI + 277 [M + H] + PREPARATION 27 tert -Butyl (4-. {F (1f-imidazol-1-iicarbonyl) amino methyl) benzyl carbamate A mixture of N, N-carbonyl diimidazole (1.51 g, 9.31 mmol) and tert-butyl 4-aminomethylbenzyl carbamate (2 g, 8.45 mmol) in tetrahydrofuran (60 ml) was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml) and the layers were separated. The aqueous solution was further extracted with ethyl acetate (2 x 30 ml) and the combined organic solutions were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as the eluent to afford the title compound as a colorless oil. 1 H NMR (CD3OD, 400MHz) d: 1.44 (s, 9H), 4.20 (s, 2H), 4.51 (s, 2H), 7.05 (s, 1 H), 7.25 (d, 2H), 7.32 (d, 2H) ), 7.62 (s, 1 H), 8.26 (s, 1 H). LRMS: m / z ES + 353 [M + Na +] PREPARATION 28 tert-Butyl. { 4-f ( { F (3-phenoxybenzyl) amino1carbonyl > amino) metinbenzyl} carbamate A mixture of the compound of Preparation 27 (500 mg, 1.51 mmol), 3-phenoxybenzylamine (EP 0313397, pg 16) (345 mg, 1.59 mmol) and triethylamine (0.64 mL, 4.53 mmol) in toluene (20 mL) was stirred. at 60 ° C for 18 hours. The cooled mixture was concentrated under reduced pressure and the resulting residue was purified by Isolute® SC! Gel column chromatography using methanol as the eluent to yield the title compound as a white solid, 342 mg. 1 H NMR (DMSO-de, 400MHz) d: 1.38 (s, 9H), 4.17 (s, 2H), 4.20 (s, 4H), 6.82 (dd, 1 H), 6.90 (s, 1 H), 7.00 ( m, 2H), 7.14 (m, 4H), 7.22-7.40 (m, 6H). LRMS: ES + 460 [M-H] " PREPARATION 29 N- (4- (amnomethyl) benzyl- (3-phenoxybenzyl) urea hydrochloride A solution of the compound of Preparation 28 (451 mg, 0.98 mmol) in 4M hydrochloric acid in dioxane (2.44 mL, 9.77 mmol) was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to yield the title compound as a white solid. 1 H NMR (CD 3 OD, 400 MHz) d: 4.07 (s, 2 H), 4.29 (d, 2 H), 4.35 (s, 2 H), 6.93 (m, 3 H), 7.08 (dd, 1 H), 7.26 (d, 2H), 7.31 (d, 1 H), 7.34-7.42 (m, 6H). LRMS: m / z 362 [M + H] + PREPARATIONS 30 TO 34 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.1-1.3 eq) was added to a solution of 1-hydroxybenzotriazole hydrate (1.1-1.3 eq), the acid of preparation 9 (1 eq), the amine or the appropriate amine salt (1.1-1.2 eq) and triethylamine (2-3 eq) in N, N-dimethylformamide (8-40mlmmol "1), and the reaction was stirred at room temperature for 18 hours. at reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution The layers were separated, the aqueous one was extracted with more dichloromethane and the combined organic solutions were dried over sodium sulfate and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel, using dichloromethane: methanol 0.83 ammonia (95: 5: 0.5) as the eluent to produce the title compounds.

PREPARATION 35 4- (r «3 - ((2?) - 2- ((2?) -2- (rterc-Butyl (dimethyl) silinoxy-2-r4-hydroxy-3- (hydroxymethyl) phenylethyl}. propylphenyl) acetyl) amino1 methyl) -A 3,4-dimethoxybenzyl p-benzamide The title compound was obtained as a white foam in 71% yield, from the compounds of Preparations 9 and 19, following the procedure described for Preparations 30 to 34. 1 H NMR (CD 3 OD, 400 MHz) d: -0.19 (s, 3 H), -0.01 (s, 3 H), 0.83 (s, 9 H), 1.03 (d, 3 H), 2.56 (dd, 1 H), 2.64 ( m, 2H), 2.90 (m, 2H), 3.54 (s, 2H), 3.80 (s, 6H), 4.40 (s, 2H), 4.50 (s, 4H), 4.62 (m, 1 H), 4.70 ( m, 1 H), 6.68 (d, 1 H), 6.90 (s, 2H), 6.99 (d, 2H), 7.05 (s, 1 H), 7.12-7.21 (m, 3H), 7.31 (d, 2H) ), 7.77 (d, 2H). LRMS: m / z APCI + 756 [M +] PREPARATION 36 N-. { 3 - ((Benzylamino) sulfoninbenzyl> -2- (3-r (2R) -2 - (((2R) -2- (tert-butyl (dimethyl) silinoxy) -2-r4-hydroxy-3- (hydroxyethyl) L) phenylethyl, amino) propylphenyl, acetamidate The title compound was obtained as a white solid with 53% yield from the compounds of preparations 9 and 26, following the procedure described for preparations 30 to 34. 1H NMR (CD3OD, 400 MHz) d: -0.19 (s, 3H), 0.00 (s, 3H ), 0.83 (s, 9H), 1.04 (d, 3H), 2.53 (dd, 1 H), 2.70 (m, 2H), 2.85-2.98 (m, 2H), 3.52 (s, 2H), 3.97 (s) , 2H), 4.40 (s, 2H), 4.61 (q, 2H), 4.72 (m, 1 H), 6.69 (d, 1 H), 6.99 (m, 2H), 7.05 (s, 1 H), 7.13 -7.23 (m, 8H), 7.44 (m, 2H), 7.69 (m, 2H). LRMS: m / z ES + 732 [M +] PREPARATIONS 37 TO 54 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.1 eq) was added to a solution of 1-hydroxybenzotriazole hydrate (1.1 eq), amine (RNH2 1 eq), acid from preparation 11 (1 eq) and triethylamine (3 eq) in N, N-dimethylformamide (12-40 mlmmol "1) and the reaction was stirred at room temperature for 18 hours.The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water and the layers were The aqueous solution was further extracted with dichloromethane and the combined organic solutions were dried over sodium sulfate and evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia ( 100: 0: 0 to 95: 5: 0.5) to produce the title compounds.

PREPARATION 55 2- (3-r (2 /?) - 2 - (((2?) - 2- rterc-Butyl (dimethyl) silinoxy> -2-r4-hydroxy-3- (hydroxymethyl) phenylethyl) amino) prop Hyphenyl) -? / - (4-r ((r (3-phenoxybenzyl) amino-1-carbonyl) amino) metip-benzyl) -acetamide The title compound was obtained as a clear gum with 41% yield from the acid of preparation 11 and the amine of preparation 29, following the procedure described for preparations 37 to 54. 1 H NMR (CD3OD, 400 MHz) d: -0.20 (s, 3H), 0.01 (s, 3H), 0.82 (s, 9H), 1.03 (d, 3H), 2.49-2.58 (m, 1H), 2.60-2.72 (m, 2H), 2.82 -2.94 (m, 2H), 3.50 (s, 2H), 3.80 (s, 2H), 4.34 (s, 4H), 4.60 (d, 2H), 4.67 (m, 1 H), 6.67 (d, 1 H) ), 6.90-7.36 (m, 19H). LRMS: m / z ES + 839 [M + Na +] In vitro activity of the compounds of formula (1) The ability of the compounds of formula (1) to act as potent β2 agonists, consequently mediating smooth muscle relaxation, can be determined by measuring the effect of beta receptor stimulation -2 adrenergic in electrically stimulated contraction of guinea pig trachea strips.

Cobaya Trachea Dunkin-Hartley male guinea pigs (475-525g) are sacrificed by asphyxiation of C02 and exsanguination of the femoral artery, and the trachea is isolated. Four preparations of each animal are obtained, beginning the dissection immediately below the larynx and taking a trachea length of 2.5 cm. The trachea piece is opened by cutting the cartilage opposite the trachealis muscle, and then cross sections are cut with a width of 3-4 rings of cartilage. 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, the tension is removed for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μM Indometacin, (Sigma 17378), 10 μM Guanetidin (Sigma G8520) and 10 μM Atenolol (Sigma A7655), heated at 37 ° C and gasified with 95% 0215% C02, before applying an initial tension of 19. The preparations are allowed to equilibrate for another 30-45 minutes, during which time tension is reapplied (up to 1 g) twice in 15 minute intervals. Changes in tension are recorded and controlled by means of conventional isomc transducers coupled to data collection systems (custom designed in Pfizer). After tension equilibrium, the tissues are subjected to electric field stimulation (EFS) using the following parameters. 10 voltages every 2 minutes, pulse amplitude of 0.1 ms, 10 Hz and semi-maximum voltage (25 Volts) continuously throughout the entire experiment. The SAI of the post-ganglionic cholinergic nerves of the trachea produces monophasic smooth muscle contractions and a shortening of the height is recorded. The organ baths are constantly perfused with the Krebs Ringer buffer described above by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception that when a beta-2 agonist according to the present invention, the pump is stopped for the period of time from the cumulative dosing to the bath and starts again after reaching the maximum response for the washout period.

Experimental protocol for evaluation of potency and efficacy After equilibration in EFS, the peristaltic pump is stopped and the preparations are "primed" with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximum response in terms of inhibition of a contractile EFS response. The isoprenaline is then removed by washing for a period of 40 minutes. After priming and recovery from washout, a standard curve is made to soprenaline in all tissues (isoprenaline curve 1) by cumulative bolus addition to the bath, using half the concentration of logarithmic increments. The concentration range used is 1e "9 a 1e / 3e" 6 M. At the end of the isoprenaline curve, the preparations are washed again for 40 minutes before beginning a second curve, with respect to isoprenaline (as internal standard) or a beta-2 agonist according to the present invention. Responses to the beta-2 agonist are expressed as percent inhibition of the response to the EFS. The data for the beta-2 agonist are normalized by expressing the inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1. The EC50 value for the beta-2 agonist according to the present invention refers to the concentration of compound necessary to produce a semi-maximal effect. The data for the beta-2 agonists according to the present invention are then expressed as the relative potency for isoprenaline defined by the ratio (EC54 beta-2 agonist) / (EC50 Isoprenaline).

Confirmation of functional activity mediated by beta-2 Beta-2 agonist activity of test compounds is confirmed using the protocol discussed above, however, before constructing the curve for the beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with ICI 300 nM 118551 (a selective β2 antagonist) which produces, in the case of an effect mediated by beta-2, a shift to the right of the dose response curve of the test compound. According to another alternative, the β2 receptor agonist potency of the compounds of formula (1) can also be determined by measuring the concentration of the compound according to the present invention required to produce the half maximal effect (EC50) for the β2 receptor.

Preparation of compounds A 10 mM stock solution / DMSO (dimethyl sulfoxide) is diluted 100% compound up to the higher dose required in 4% DMSO. This higher dose is used to construct a semilogarithmic dilution curve of 10 points, all in 4% DMSO. Isoprenaline (Sigma, 1-5627) is used as a standard in each experiment and to control the wells of each plate. The data are expressed as% isoprenaline response.

Cell Culture CHO (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- were cultured. 139 1988 CHOhß2) in Dulbeccos MEM / NUT MIX F12 (Gibco, 21331-020) enriched with 10% fetal bovine serum (Sigma, F4135, Lot 90K84O4 Exp 09104), 2 mM glutamine (Sigma, G7513), 500 μg / ml geneticin (Sigma, G7034) and 10 μg / ml puromycin (Sigma, P8833). The cells are seeded to give a confluence of about 90% for the assay.

Test method Each dose of 25 μl / well of the compound was transferred to a cAMP-Flashplate® (NEN, SMPO04B), with 1% DMSO as baseline controls and 100 nM Isoprenaline as maximum controls. This was diluted 1: 2 by the addition of 25 μl / PBS per well. The cells were subjected to the action of trypsin (0.25% Sigma, T4049), were washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMPO04B) to produce 1x106 cells / ml CHOhB2. The compounds were incubated with 50 ul / cells per well for 1 hour. The cells were then used by addition of 100 μl / well detection buffer (NEN, SMPO04B) containing 0.18 PCi 1 ml 1 61-cAMP (NEN, NEX-30) and the plates were incubated at room temperature for another 2 hours . The amount of 1261-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal count efficiency for 1 minute. The dose response data are expressed as% isoprenaline activity and adjusted using a four-parameter sigmoid fit. It has been found, therefore, that the compounds of formula (1) according to the present invention that have been tested demonstrate an EC50 for β2 cAMP of less than 1 nM.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I): wherein the group CH2-C (= 0) NH-benzyl-Q1-Q2-Q3-Q4 is in the meta or para position, and R1 and R2 are independently selected from H and C-? -C alkyl; Q1 is - (CH2) n-, wherein n is an integer selected from 0 and 1; Q2 is a group selected from -NH-, -C (= 0) NH-, -NHC (= 0) -, -NH-C (= 0) -NH- and -S02NH-; Q3 is a single bond or C44 alkylene optionally substituted with OH; Q4 is selected from: wherein * represents the point of attachment to Q3, and R3, R4, R5, R6 and R7 are independently selected from H, C - - C alkyl, phenyl, phenoxy, OR8, SR8, halo, CN, CF3, OCF3 , COOR9, S02NR $ R9, CONRBR9, NR8R9, NHCOR9, CH2-NHC (= 0) NH-R9; wherein R 8 and R 9 are independently selected from H or C C alkyl; or, if appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations.

2. The compound according to claim 1, further characterized in that Q1 is (CH2) n, wherein n is 0 and Q2 is -S02NH- or C (= 0) NH-.

3. The compound according to claim 1, further characterized in that Q1 is (CH2) n, wherein n is 1 and Q2 is -NH- C (= 0) - or -NH-C (= 0) - NH-.

4. The compound according to any of claims 1 to 3, further characterized in that Q3 is a bond, - CH2-, - (CH2) 2-, -C (CH3) 2 -CH2-, -CH (CH3) -CH (OH) - or CH2-CH (CH3) -.

5. The compound according to any of claims 1 to 4, further characterized in that Q4 is wherein R 3, R 4, R 5, R 6 and R 7 are selected from H, C 4 alkyl, phenyl, phenoxy OR 8; SR8, halo, CF3, OCF3, COOR9, S02NR8R9, CONR ° R9, NHR8R9, NHCOR9, CH2-NHC (== 0) NH-R9; and at least two of R3 and R7 represent H.

6. The compound according to any of claims 1 to 5, further characterized in that R1 and R2 are independently selected from H and CH3.

7. - The (f?, /?) - stereoisomer of a compound of any of claims 1 to 6.

8. The compound according to any of claims 1 to 7, further characterized in that the group CH2-C (= 0 ) NH-benzyl-Q1-Q2-Q3-Q4 is in the meta position.

9. The compound according to claim 1, further characterized in that it is selected from the group consisting of examples 1 to 26.

10. The use of a compound of formula (1) as described in any one of claims 1 to 9 or its pharmaceutically acceptable salt, derivative or composition, for the manufacture of a drug for the treatment of diseases, disorders and conditions selected from the group consisting of asthma of any kind, etiology or pathogenesis, in particular asthma is a member selected from the group consisting of atopic asthma, non-atopic asthma. allergic asthma, topical bronchial IgE mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, 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, infectious asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, newborn wheezing syndrome and bronchiolitis, bronchoconstriction chronic or acute, chronic bronchitis, obstruction of the small airways and emphysema, obstructive or inflammatory diseases of the respiratory tract of any kind, etiology or pathogenesis, in particular any obstructive or inflammatory airway disease that is a selected member among the group consisting of tire chronic eosinophilic ony, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD characterized by progressive and irreversible airway obstruction, respiratory distress syndrome in adults (ARDS), exacerbation of airway hyperreactivity secondary to other drug therapy and respiratory disease associated with pulmonary hypertension, bronchitis of any kind, etiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, laryngotracheobronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis and bronchopneumonia, acute lung injury, bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis which is a member selected from the group consisting of cylindrical bronchiectasis, saccule bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

11. A combination of a compound according to any of claims 1 to 9 with a therapeutic agent selected from: (a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein antagonists (FLAP) ), (b) Leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 and LTE4 antagonists, (c) Histamine receptor antagonists including H1 and H3 antagonists, (d) Sympathomimetic vasoconstrictor agents, adrenoreceptor agonists a- \ and a2 for decongestant use, (e) M3 muscarinic receptor antagonists or anticholinergic agents, (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors, (g) Theophylline, (h) Sodium cromoglycate, (i) inhibitors of COX, both selective or non-selective COX-1 or COX-2 inhibitors (NSAIDs), (j) Oral or inhaled glucocorticosteroids, such as DAGR (dissociated corticosteroid receptor agonists), (k) Monoclonal antibodies active against inflammatory entities endogenous agents, (I) Antitumor necrosis factor agents (anti-TNF-a), (m) Inhibitors of adhesion molecules including VLA-4 antagonists, (n) Quinine receptor antagonists B1 and B2, (or ) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin receptor antagonists NK-i, NK2 and NK3, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, ( t) Urokinase inhibitors, (u) Compounds that act on dopamine receptors, p. eg, D2 agonists, (v) Modulators of the NF path? ß_ p. eg, inhibitors of IKK, (w) modulators of cytokine signaling pathways such as p38 MAP kinase or syk kinase, (x) agents that can be classified as mucolytic or antitussive, (and) antibiotics, (z) inhibitors of HDAC, and (aa) PI3 inhibitors kinase