MXPA00009351A - &bgr;2-ADRENERGIC RECEPTOR AGONISTS - Google Patents

Abstract

Disclosed are multibinding compounds which are&bgr;2-adrenergic receptor agonists and are useful in the treatment and prevention of respiratory diseases such as asthma, bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

Description

AGOt STAS OF ADEERGIC BETA2 RECEIVERS.

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to novel multiple binding compounds (agents) which are β2 adrenergic receptor agonists and pharmaceutical compositions comprising such compounds. Accordingly, the multiple-binding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature delivery.

References The following publications are cited in this application as superscript numbers: REF .: 121940 1 Hardman, J. G., et al. "The Pharmacological Basis of Therapeutics", McGraw-Hill, New York, (1996). 2 Strosberg, A. D. "Structure, Function, and Regulation of Adrenergic Receptors "Protein Sci. 2, 1198-1209 (1993). 3 Beck-Sickinger, A. G. "Structure Characterization and Binding Sites of G- Protein-coupled Receptors" DDT, 1, 502-513, (1996). 4 Hein, L. & Kobilka, B. K. "Adrenergic Receptor Signal Transduction and Regulation" Neuropharmacol, 34, 357-366, (1995).

Strosberg, A. D. & Pietri-Rouxel, F. "Function, and Regulation of β3-Adrenoceptor" TiPS, 17, 373-381, (1996). 6 Barnes, P. J. "Current Therapies for Asthma" CHEST, 111: 17S-26S. (1997). 7 Jack, D. A. "A way of Looking at Agonis and .Antagonism: Lessons from Salbutamol, Salmeterol and other β-Adrenoceptor Agonists" Br. J. Clin. Pharmac. 31, 501-514, (1991). 8 Kissei Pharmaceutical Co. Ltd. "2-.Amino-l- (4-hydroxy-2-methyl-phenyl) propanol derivatives" JP-10152460 (Publication date June 9, 1998).

All of the above publications are incorporated herein by reference entirely to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference entirely.

State of the Art A receptor is a biological structure with one or more binding domains that forms a reversible complex with one or more ligands, where that complex has biological consequences. The receptors may exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular environment and the cytosol), or entirely within the cell (intracellular receptors). They can also function independently of a cell (for example, lump formation). The receptors inside the cell membrane allow a cell to communicate with the space outside its edges (for example signaling) as well as to function in the transport of molecules and ions in and out of the cell.

A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively it may be a synthetic ligand for the receptor as a drug, a drug candidate or a pharmacological tool.

The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of receptors attached to the membrane that communicate changes that occur outside the edges of the cell inside, activating a cellular response when appropriate. G proteins, when activated, affect a wide range of cascading effector systems both positively and negatively (eg, ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).

Adrenergic receptors (AR) are members of the G protein-coupled receptors that are composed of a family of three receptor subtypes: al (A, B, D) 2 (A, E, C), and ß (i, 2) , 3) X ~ 5 These receptors are expressed in tissues of various systems and organs of mammals and the proportions of the a and b receptors are tissue dependent. For example, tissues of bronchial smooth muscle express several ß2-AR while those of cutaneous blood vessels contain only subtypes -AR.

It has been established that the ß2-.AR subtype is involved in respiratory diseases such as asthma, 6 chronic bronchitis, nervous system damage, and premature delivery8. Currently, several drugs for example, albuterol, formoterol, isoprenolol, or salmeterol that have β2-AR agonist activities are being used to treat asthma. However, these drugs have limited utility because they are either non-selective and therefore cause adverse side effects such as muscle tremor, tachycardia, palpitations, and agitation, 6 or have a short duration of action and / or a short time of action attack. Accordingly, there is a need for β2-selective αAR agonists which have a rapid action and have an increased potency and / or longer duration of action.

The multiple-binding compounds of the present invention satisfy this need.

B. DESCRIPTION OF THE INVENTION This invention is directed to novel multiple binding compounds (agents) that are agonists or partial agonists of the β2 adrenergic receptor and are therefore useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature delivery.

Accordingly, in one of its compositional aspects, this invention provides a multiple-linking compound of Formula (I): (L) p (X) q (I) where: p is an integer from 2 to 10; q is an integer from 1 to 20; X is a linker; and L is a ligand where: One of the ligands, L, is selected from a compound of formula (a): (a) where : Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; W is a covalent bond linking the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa- (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n (where n is an integer from 0 to 2), -CO-, - PRb- (wherein Rb is alkyl), - P (0) 2-, and -OP (0) 0- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that at least one of Ar1, Ar2, R1, R2, or W binds the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): -Q-Ar3 (b) where : Ar 3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa - (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -0-, -S (0) n- (where n is an integer from 0 to 2), -CO-, -PRb- (where RD is alkyl), -P (0) 2-, and -OP (0) 0-; Y pharmaceutically acceptable salts thereof provided that: (i) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then both W and X are not alkylene or alkylene-O-; (ii) when the multiple-linking compound of Formula (I) is a compound of the formula: Ar 1 is 4-hydroxy-2-ethylphenyl, Ar 2 is aryl, Ar 3 is aryl or heterocyclyl, W is styrene, Q is a covalent bond, R 1 is alkyl, then the X linker is not linked to the group Ar3 through an oxygen atom; Y (iii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, is alkylene, Ar is aryl or cycloalkyl, Q is a covalent bond, then X is not -alkylene-O-.

More preferably, each linker, X, in the multiple-linking compound of Formula (I) independently has the formula: -X to -Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C (O) -, -C (0) 0-, -OC (O) -, -C (0) NR-, -NRC (O) -, C (S), -C (S) 0-, -C (S) NR-, -NRC (S) -, or a covalent bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; Each Ya to each separate occurrence is selected from the group consisting of -O-, -C (O) -, -0C (0) -, -C (0) 0-, -NR-, -S (0) n-, ~ C (0) NR'-, -NR'C (O) -, -NR 'C (0) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR' -, -NR'-C (= NR ') -, -0C (0) -NR'-, -NR'-C (0) -0-, -N = C (Xa) -NR'-, -NR '-C (Xa) = N-, -P (0) (OR') -0-, -0-P (0) (OR ') -, -S (0) nCR'R "-, -S ( 0) n-NR'-, -NR'-S (0) n-, -SS-, and a covalent bond, where n is O, lo 2; R, R 'and R "at each separate occurrence are selected of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, and Xa is as defined above.

Preferably, q is less than p in the multiple-binding compounds of this invention.

In yet another aspect of these compositional aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multiple-linking compound of Formula (I): (L) p (X) q (I) where: p is in whole from 2 to 10; q is an integer from 1 to 20; X is a linker; Y L is a ligand where: One of the ligands, L, is selected from a compound of formula (a): (to) where: Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; W is a covalent bond joining the -NR-- to Ar2, alkylene or substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa - (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n (where n is an integer from 0 to 2), -CO-, -PR- (where Rb is alkyl), -P (0) 2-, and -OP (O) O- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that minus one of Ar1, Ar2, R1, R2, or W binds the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): -Q-Ar3 (b) where: Ar 3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n- (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -OP (O) O-; Y pharmaceutically acceptable salts thereof provided that: (i) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then both W and X are not alkylene or alkylene-O-; (ii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 is 4-hydroxy-2-methylphenyl, Ar2 is aryl, Ar3 is aryl or heterocyclyl, W is stylene, Q is a covalent bond, R1 is alkyl, then linker X is not linked to the group Ar3 through an atom of oxygen; Y (iii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1, Ar2, Ar3, R1, R2 are as defined above, W is alkylene, and Q is a covalent bond, then X is not -alkylene-O-.

More preferably, each linker, X, in the multiple-linking compound of Formula (I) independently has the formula: -X to -Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C (0) -, -C (0) 0-, -0C (0) -, -C (0) NR-, -NRC (O) -, C (S), -C (S) 0-, -C (S) .NR-, -NRC (S) -, OR a covalent bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; Each Ya to each separate occurrence is selected from the group consisting of -0-, -C (0) -, -0C (0) -, -C (0) 0-, -NR-, -S (0) n-, -C (0) NR'-, -NR'C (O) -, -NR 'C (0) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR' -, -NR'-C (= NR ') -, -0C (0) -NR'-, -NR'-C (0) -0-, -N = C (Xa) -NR'-, -NR '-C (Xa) = N-, -P (0) (OR') -0-, -0-P (0) (0R ') -, -S (0) nCR'R "-, -S ( 0) n-NR'-, -NR'-S (0) n-, -SS-, and a covalent bond, where n is 0, so 2; R, R 'and R "at each separate occurrence are selected of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, and Xa is as defined above.

In yet another aspect, this invention provides a method for treating diseases mediated by a β2 adrenergic receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Multiple linkage of Formula (I): (L) p (X) q (I) where: p is in whole from 2 to 10; q is an integer from 1 to 20; X is a linker; Y L is a ligand where: One of the ligands, L, is selected from a compound of formula (a): (to) where; Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; W is a covalent bond linking the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa- (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -0-, -S (0) n (where n is an integer from 0 to 2), -CO-, - PRb- (wherein Rb is alkyl), -P (0) 2-, and -OP (0) 0- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that at least one of Ar1, Ar2, R1, R2, or W binds the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): - Q-Ar3 (b) where : Ar 3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n_ (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -O-P (O) O-; Y pharmaceutically acceptable salts thereof provided that: (iv) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then as much as X are not alkylene or alkylene-O-; (v) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 is 4-hydroxy-2-methylphenyl, Ar2 is aryl, Ar3 is aryl or heterocyclyl, W is stylene, Q is a covalent bond, R1 is alkyl, then linker X is not linked to the group Ar3 through an atom of oxygen; Y (vi) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1, Ar2, Ar3, R1, R2 are as defined above, W is alkylene, and Q is a covalent bond, then X is not -alkylene-O-.

More preferably, each linker, X, in the multiple-linking compound of Formula (I) independently has the formula: -X to -Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C (O) -, -C (0) 0-, -OC (O) -, -C (0) NR-, -NRC (O) -, C (S), -C (S) 0-, -C (S) NR-, -NRC (S) -, or a covalent bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; Each Ya to each separate occurrence is selected from the group consisting of -O-, -C (O) -, -OC (O) -, -C (0) 0-, -NR-, -S (0) n- / -C (0) NR'-, -NR'C (O) -, -NR 'C (O) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR' -, -NR'-C (= NR ') -, -OC (0) -NR'-, -NR'-C (0) -0-, -N = C (Xa) -NR'-, -NR '-C (Xa) = N-, -P (O) (OR') -O-, -0-P (0) (OR ') -, -S (0) nCR'R "-, -S ( 0) n-NR'-, -NR'-S (0) "-, -SS-, and a covalent bond, where n is 0, lo 2; R, R 'and R" at each separate occurrence are selected of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, and Xa is as defined above.

In yet another aspect, this invention is directed to general synthetic methods for the generation of large libraries of various multimeric compounds whose multimeric compounds are candidates for the possession of multiple binding properties with the adrenergic β2 receptor. The various libraries of multimeric compounds provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide a library of multimeric compounds wherein both the linker and the ligand have complementary functional groups that allow a covalent linkage. The library of linkers is selected such that it has various properties such as valence, length of the linker, geometry and rigidity of the linker, hydrophilicity or hydrophobicity, amphiphilicity, acidity, alkalinity and polarization. The library of ligands is selected such that they have various binding sites in the same ligand, different functional groups in the same site, otherwise the same ligand, and the like.

This invention is also directed to libraries of various multimeric compounds whose multimeric compounds are candidates for the possession of multiple binding properties with the adrenergic β2 receptor. These libraries are prepared via the methods described above and allow the rapid and efficient evaluation of any molecular coercion that imparts multiple binding properties to a ligand or a class of ligands that have a preference for a receptor.

Accordingly, in one of these aspects of the method, this invention is directed to a method for the identification of multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor whose method comprises: (a) the identification of a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of ligands wherein each linker of said library comprises at least two functional groups that have complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stegeometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the functional groups complementary ones react to form a covalent bond between said linker and at least two of said ligands; Y (d) the assay of multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor.

In another of these aspects of the method, this invention is directed to a method for identifying multimeric ligand compounds possessing multiple binding properties with the adrenergic β2 receptor whose method comprises: (a) identification of a library of ligands wherein each ligand contains at least one reactive functionality; (b) the identification of a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the groups complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; Y (d) the assay of multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor.

The library preparation of multimeric ligand compounds is completed either by the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b).

Sequential addition is preferred when a mixture of different ligands is employed to ensure that the heterodimeric or multimeric compounds are prepared. The concurrent addition of the ligands occurs when at least a portion of the multimeric compounds prepared are homomultimeric compounds.

The assay protocols recited in (d) can be carried out in the library of multimeric ligand compounds produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).

In one of these aspects of composition, this invention is directed to a library of multimeric ligand compounds which may possess multivalent properties with the β2 adrenergic receptor whose library is prepared by the method comprising: (a) the identification of a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker of said library comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the functional groups Complementaries react to form a covalent linkage between said linker and at least two of said ligands.

In another of these aspects of composition, this invention is directed to a library of multimeric ligand compounds which may possess multivalent properties with the adrenergic β2 receptor whose library is prepared by the method comprising: (a) identification of a library of ligands wherein each ligand contains at least one reactive functionality; (b) the identification of a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the groups Complementary functional groups react to form a covalent bond between said linker and at least two of said ligands.

In a preferred embodiment, the library of linkers employed either in the methods or aspects of the library of this invention is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acid linkers , basic linkers, linkers of different polarization and amphiphilic linkers. For example, in one embodiment, each of the linkers in the linker library may comprise linkers of different chain length and / or having different complementary reactive groups. Such lengths of the linkers may preferably fall within the range from about 2 to 100 Á.

In another preferred embodiment, the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands in order to provide a range of orientations of said ligand in said multimeric ligand compounds. Such reactive functionality includes, by way of example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides and precursors thereof. It is understood, of course, that the reactive functionality in the ligand is selected to be complementary to at least one of the reactive groups in the linker such that a covalent linkage can be formed between the linker and the ligand.

In other embodiments, the multimeric ligand compound is homomeric (e.g., each of the ligands is the same, although it may be linked at different points) or heterodimeric (e.g., at least one of the ligands is different from the other ligands).

In addition to the combinatorial methods described herein, this invention stipulates an integrative process for the rational evaluation of which molecular constraints impart multiple binding properties to a class of multimeric compounds or ligands that exhibit affinity for a receptor. Specifically, this aspect of the method is directed to a method for the identification of multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor whose method comprises: (a) the preparation of a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which have affinity for a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand e wherein said contact is carried out under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (b) testing said first collection or iteration of multimeric compounds to assess which of said multimeric compounds possess multiple binding properties with the adrenergic β2 receptor if they have them; (c) repeating the process of (a) and (b) above until it is found that at least one multimeric compound possesses multiple binding properties with the adrenergic β2 receptor; (d) the evaluation of which molecular coactions impart multiple binding properties with the adrenergic β2 receptor to the multimeric compound or compounds found in the first iteration recited in (a) - (c) above; (e) the creation of a second collection or iteration of multimeric compounds which are elaborated on the particular molecular constraints that impart multiple binding properties to the compound or multimeric compounds found in said first iteration; (f) the evaluation of which molecular constraints impart enhanced multiple binding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above; (g) the optional repetition of Steps (e) and (f) to elaborate further on said molecular constraints.

Preferably, Steps (e) and (f) are repeated at least twice, more preferably from 2-50 times, still more preferably from 3 to 50 times, and even more preferably at least 5-50 times.

B.REV? DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates examples of multiple binding compounds comprising 2 ligands attached in different formats to a linker.

FIG. 2 illustrates examples of multiple binding compounds comprising 3 ligands attached in different formats to a linker.

FIG. 3 illustrates examples of multiple binding compounds comprising 4 ligands attached in different formats to a linker.

FIG. 4 illustrates examples of multiple binding compounds comprising > 4 ligands attached in different formats to a linker.

FIGs. 5-13 illustrate the synthesis of compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions This invention is directed to multiple binding compounds which are β2 adrenergic receptor agonists, pharmaceutical compositions containing such compounds and methods for the treatment of diseases mediated by the β2 adrenergic receptor in mammals. When such compounds, compositions or methods are discussed, the following terms have the following meanings unless indicated otherwise. Any of the undefined terms have their meanings recognized in the state of the art.

The term "alkyl" refers to a branched saturated hydrocarbon chain with a monoradical or unbranched which preferably has from 1 to 40 carbon atoms, more preferably from 1 to 10 carbon atoms, and even more preferably from 1 to 6 carbon atoms of carbon. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term "substituted alkyl" refers to an alkyl group as defined above, having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxyamino, nitro , -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl and -S02-heteroaryl. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.

The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably from 1 to 10 carbon atoms and even more preferably from 1 to 6 carbon atoms of carbon. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH (CH3) CH2-) and the like.

The term "substituted alkylene" refers to an alkylene group, as defined above, having 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxy ino, alkoxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-alkyl substituted, -S02-aryl and -S02-heteroaryl. Additionally, such substituted alkylene groups include those wherein 2 substituents on the alkylene group are fused to form one or more substituted cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring-shaped structures.

The term "alkaryl" or "aralkyl" refers to the groups -alkylene-aryl and -alkylene-substituted-aryl where the alkylene, the substituted alkylene and the aryl are as defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.

The term "heteroaralkyl" refers to the groups -alkylene-heteroaryl and -alkylene-substituted-heteroaryl wherein the alkylene, the substituted alkylene and the heteroaryl are as defined herein. Such heteroaralkyl groups are exemplified by pyridine-3-methyl, pyridine-3-ylmethyloxy, and the like.

The term "alkoxy" refers to the alkyl-0-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O- groups, wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are it is defined here. Preferred akoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy , 1,2-dimethylbutoxy, and the like.

The term "substituted alkoxy" refers to the alkyl-0-substituted, alkenyl-O-substituted, cycloalkyl-O-substituted, cycloalkenyl-O-substituted, and alkynyl-O-substituted groups where the substituted alkyl, the substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

The term "alkenyl" refers to a monoradical of a group of branched or unbranched unsaturated hydrocarbons preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms. carbon and having at least 1 and preferably 1-6 vinyl restoration sites. Preferred alkenyl groups include ethenyl (-CH = CH2), n-propenyl (-CH2CH = CH2), iso-propenyl (-C (CH) 3 = CH2), and the like.

The term "substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl substituted, acyl, acylamino, acyloxy, amino, amino substituted, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02 -aryl and -S02-heteroaryl.

The term "alkenylene" refers to a diradical of a group of branched or unbranched unsaturated hydrocarbons preferably having from 2 to 40 carbon atoms, more preferably from 2 to 10 carbon atoms and even more preferably from 2 to 6 carbon atoms. carbon and having at least 1 and preferably 1-6 vinyl restoration sites. This term is exemplified by groups such as ethenylene (-CH = CH-), propenylene isomers (for example, -CH 2 CH = CH-, -C (CH 3) = CH-), and the like.

The term "substituted alkenylene" refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl substituted, acyl, acylamino, acyloxy, amino, amino substituted, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -SO? -substituted alkyl, - S02-aryl and -S02-heteroaryl. Additionally, such substituted alkenylene groups include those wherein 2 substituents on the alkenylene group are fused to form one or more substituted cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.

The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon having preferably from 2 to 40 carbon atoms, more preferably from 2 to 20 carbon atoms and even more preferably from 2 to 6 carbon atoms and having at least less 1 and preferably 1-6 sites of installation (triple bond) of acetylene. Preferred alkynyl groups include ethynyl (-C = CH), propargyl (-CH2C = CH) and the like.

The term "substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl substituted, acyl, acylamino, acyloxy, amino, amino substituted, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, - S02-aryl and -S02-heteroaryl.

The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon having preferably from 2 to 40 carbon atoms, more preferably from 2 to 10 carbon atoms and even more preferably from 2 to 6 carbon atoms and having less 1 and preferably 1-6 sites of installation (triple bond) of acetylene. Preferred alkynylene groups include ethynylene (-C = C-), propargylene (-CH2C = C-) and the like.

The term "substituted alkynylene" refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl substituted, acyl, acylamino, acyloxy, amino, amino substituted, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S 2-aryl and -S02-heteroaryl.

The term "acyl" refers to the groups HC (O) -, alkyl-C (O) -, alkyl-C (O) -substituted, alkenyl-C (O) -, alkenyl-C (O) -substituted, cycloalkyl-C (O) -, C (O) -substituted cycloalkyl, cycloalkenyl-C (O) -, cycloalkenyl-C (O) -substituted, aryl-C (O) -, heteroaryl-C (O) - and heterocyclic-C (O) - wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "acylamino" or "aminocarbonyl" refers to the group -C (0) NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group ( example, morpholino) wherein the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "sulfonylamino" refers to the group -NRS02Ra where R is hydrogen, alkyl, substituted alkyl, aralkyl, or heteroaralkyl, and Ra is alkyl, substituted alkyl, amino, or substituted amino wherein the alkyl, substituted alkyl, aralkyl, heteroaralkyl and substituted amino are as defined herein.

The term "inactivate" refers to the group -NRC (0) R wherein each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic wherein alkyl, alkyl substituted, alkenyl, substituted alkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term "aminoacyloxy" or "alkoxycarbonylamino" refers to the group -NRC (0) 0R wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic they are as defined here.

The term "acyloxy" refers to the groups alkyl-C (0) 0-, alkyl-C (0) 0 -substituted, cycloalkyl-C (O) O-, cycloalkyl-C (0) 0 -substituted, aryl- C (0) 0-, heteroaryl-C (0) 0-, and heterocyclic-C (0) 0- wherein the alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term "aryl" refers to an unsaturated aromatic carbocyclic group having from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., naphthyl or anthryl) fused (fused). Optionally, the aryl group can be fused with a heterocyclic or cycloalkyl group. Preferred aryls include phenyl, naphthyl and the like. Unless otherwise required by the definition of the aryl substituent, such aryl groups may be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, sulfonylamino, alkaryl, aryl, aryloxy, azido, carboxyl , carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, - SO-substituted alkyl, -SO-aryl, -SO-heteroaryl , -S02- alkyl, -S02-substituted alkyl, -S02-aryl, -S02- heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups also as defined above.

The term "arylene" refers to the diradical derived from the aryl (including the substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and similar.

The term "amino" refers to the group -NH2.

The term "substituted amino" refers to the group -NRR wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl , aryl, heteroaryl and heterocyclic provided that both R 's are not hydrogen.

The term "carboxyalkyl" or "alkoxycarbonyl" refers to the groups "-C (0) O-alkyl", "-C (0) O-substituted alkyl", "-C (0) 0 -cycloalkyl", " -C (0) O-substituted cycloalkyl "," -C (O) O-alkenyl "," -C (0) O-substituted alkenyl "," -C (0) 0-alkynyl "and" -C (0) O-substituted alkynyl "wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl are as defined herein.

The term "cycloalkyl" refers to cyclic alkyl groups of 3 to 20 carbon atoms having a single cyclic ring or multiple fused rings, said cycloalkyl group may be optionally fused to an aryl or heteroaryl group. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multi-ring structures such as adamantanyl, and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, cycloalkyl. substituted, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02- substituted alkyl, -S02-aryl and -S02-heteroaryl.

The term "cycloalkenyl" refers to cyclic alkenyl groups having from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, cycloalkyl. substituted, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxyamino, nitro, -S0-alkyl, -SO-substituted alkyl, -SO-aryl, -S0-heteroaryl, -S02-alkyl, -S02- substituted alkyl, -S02-aryl and -S02-heteroaryl.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "heteroaryl" refers to an aromatic group having from 1 to 15 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). The heteroaryl ring may be optionally fused to a cycloalkyl or heterocyclyl ring. Unless otherwise required by the definition of the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocycle, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -S0-alkyl, -SO-substituted alkyl, -SO-aryl, -S0-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl and trihalomethyl. Preferred heteroaryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl. The term "heteroaryloxy" refers to the heteroaryl-O- group.

The term "heteroarylene" refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridinylene, 1,2-quinolinylene, 1, 8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridinylene, 2,5-indolenyl, and the like.

The term "cycloalkylene" refers to the diradical group derived from the cycloalkyl, as defined above, and is exemplified by the groups 1, 6-cyclohexylene, 1,3-cyclopentylene, and the like.

The term "substituted cycloalkylene" refers to the diradical group derived from the substituted cycloalkyl, as defined above. The term "cycloalkenylene" refers to the diradical group derived from the cycloalkyl, as defined above.

The term "substituted cycloalkenylene" refers to the diradical group derived from the substituted cycloalkenyl, as defined above.

The term "heterocycle" or "heterocyclyl" refers to an unsaturated group of saturated onoradicals having a single ring or multiple fused rings, from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably from 1 to 4 heteroatoms, selected of nitrogen, sulfur, phosphorus, and / or oxygen within the ring and subsequently where one, two, or three of the ring carbon atoms can be optionally replaced with a carbonyl group (eg, a keto group). Unless otherwise defined by the definition of the heterocyclic substituent, such heterocyclic groups may be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, cycloalkyl. substituted, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocycloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02- substituted alkyl, -S02-aryl and -S? 2 ~ heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Preferred heterocyclics include morpholino, piperidinyl, and the like. Examples of heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofuranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles.

The term "heterocyclooxy" refers to the heterocyclic-O- group.

The term "thioheterocyclooxy" refers to the heterocyclic-S- group. The term "heterocycle" refers to the diradical group formed of a heterocycle, as defined herein, and is exemplified by the 2, 6-morpholino, 2, 5-morpholino groups and the like.

The term "oxyacylamino" or "aminocarbonyloxy" refers to the group -OC (0) NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic they are as defined here.

The term "cycloalkyl group adhered to spiro" refers to a cycloalkyl group attached to another ring via a carbon atom common to both rings.

The term "thiol" refers to the group -SH.

The term "thioalkoxy" or "alkylthio" refers to the group -S-alkyl.

The term "substituted thioalkoxy" refers to the group -S-substituted alkyl.

The term "thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above, optionally including the substituted aryl groups also defined above. The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally the substituted aryl groups also defined above.

As any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically not feasible. In addition, the compounds of this invention include all the stereochemical isomers that arise from the substitution of these compounds.

The term "pharmaceutically acceptable salt" refers to salts which retain the effectiveness and biological properties of the multiple-binding compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the multiple-binding compounds of this invention are capable of the formation of acid and / or alkali salts by virtue of the presence of amino and / or carboxyl groups or groups similar to these.

The pharmaceutically acceptable base addition salts can be prepared from organic and inorganic bases. Salts derived from inorganic bases, include by way of example only sodium, potassium, lithium, ammonium, calcium and magnesium salts. Bases derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di (substituted alkyl) amines, tri (substituted alkyl) ) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, alkenyl substituted amines, di (alkenyl substituted) amines, tri (alkenyl substituted) amines, cycloalkyl amines, di (cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkyl amines, cycloalkyl disubstituted amine, cycloalkyl trisubstituted amines, cycloalkenyl, di (cycloalkenyl) amines, tri (cycloalkenyl) amines, substituted cycloalkenyl amines, cycloalkenyl disubstituted amine, cycloalkenyl trisubstituted amines, aryl amines, diaryl amines triaryl amines heteroaryl amines diheteroarilo, triheteroarilo amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines s, di- and tri-amines mixed where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl , heteroaryl, heterocyclic, and the like. Also included are the amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri (isopropyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine. , procaine, hydrabamine, choline, botain, ethylenediamine, glucosamine, N-alkylglucamines, teobro ina, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.

The pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The term "pharmaceutically acceptable cation" refers to the cation of a pharmaceutically acceptable salt.

The term "library" refers to at least 3, preferably 102 to 109 and more preferably 102 to 104 multimeric compounds. Preferably, these compounds are prepared as a multiplicity of compounds in a simple solution or reaction of the mixture which allows a simple synthesis of these. In one embodiment, the library of multimeric compounds can be tested directly to demonstrate multiple binding properties. In another embodiment, each member of the library of multimeric compounds is first isolated and, optionally, characterized. This member is then tested to demonstrate multiple binding properties. The term "collection" refers to a set of multimeric compounds which are prepared either sequentially or concurrently (for example, combinatorially). The collection comprises at least two members; preferably from 2 to 109 members and even more preferably from 10 to 104 members.

The term "multimeric compound" refers to compounds comprising 2 to 10 ligands covalently linked through at least one linker whose compounds may or may not possess multiple binding properties (as defined herein).

The term "pseudohalide" refers to functional groups which react in displacement reactions in a manner similar to a halogen. Such functional groups include, by way of example, mesyl, tosyl, azido and cyano groups.

The term "protecting group" or "blocking group" refers to any group which when attached to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring in these groups and whose protective group can be removed by conventional chemical or enzymatic steps to re-establish the hydroxyl, thiol, amino or carboxyl group (See, 'TW Greene and PGH Wuts, "Protecti ve Groups in Organic Synthesis," 2nd Ed.). The particular removable blocking group employed is not critical and the removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be chemically introduced. in a hydroxyl functionality and then selectively removed either by chemical or enzymatic methods in low stringent conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like.

Preferred removable amino blocking groups include conventional substituents such as t-butyloxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC), and similar which can be removed by conventional conditions compatible with the nature of the product.

Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by conditions not very rigorous compatible with the nature of the product.

The term "optional" or "optionally" means that the event, circumstance or substituent subsequently described may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where it does not.

The term "ligand" or "ligands" as used herein denotes a compound that is a binding partner with a β2 adrenergic receptor and is bound to it by complementarity. Preferred ligands are those that are either agonists or antagonists of the β2 adrenergic receptor. The specific region or regions of the ligand that is (are) recognized by the receptor is designated as the "ligand domain". A ligand may be capable of either binding to the receptor itself, or may require the presence of one or more non-ligand components for binding (eg, Ca "2, Mg" 2 or a water molecule is required for the binding of a ligand to several ligand binding sites). Examples of the ligands useful in this invention are described herein. Those skilled in the art will appreciate that portions of the ligand structure that are not essential for specific molecular recognition and binding activity can be substantially varied, replaced or substituted with unrelated structures (eg, with auxiliary groups such as it is defined later) and, in some cases, completely omitted without affecting the binding interaction. The primary requirement of a ligand is that it has a ligand domain as defined above. It is understood that it is not intended to limit the term "ligand" to compounds that are known to be useful in their binding to the adrenergic β2 receptor (eg, known drugs). Those skilled in the art will understand that the term "ligand" can be applied in the same way to a molecule that is not normally associated with the β-adrenergic receptor binding properties. Furthermore, it should be noted that ligands that exhibit marginal activity or lack useful activity as monomers can be highly active as multivalent compounds because of the benefits conferred by multivalency.

The term "ligand" or "ligands" as used herein is intended to include the cluster forms of the ligands as well as the individual enantiomers and diastereomers and non-cluster mixtures thereof. The term "multiple binding agent or compound" refers to a compound that is capable of having multivalency, as defined below, and which has 2-10 ligands covalently bound to one or more linkers. In all cases, each ligand and linker in the multiple-bond compound is independently selected such that the multiple-bond compound includes both symmetric compounds (eg, where each ligand and each linker is identical) and asymmetric compounds (eg. example, wherein at least one of the ligands is different from the other ligand (s) and / or at least one linker is different from the other linker (s)). The multiple-binding compounds provide a greater therapeutic and / or biological effect than the aggregate of ligands without binding equivalent thereto which are made available for binding. That is to say that the biological and / or therapeutic effect of the ligands bound to the multiple binding compound is greater than that achieved by the same amount of unlinked ligands made available to bind to the ligand binding sites (receptors). The phrase "increased biological or therapeutic effect" includes, for example: increased affinity, increased target selectivity, increased target specificity, increased potency, increased efficacy, decreased toxicity, duration of activity or enhanced action, ability to kill such cells as pathogenic fungi, tumor cells, etc. increased, decreased side effects, increased therapeutic index, improved bioavailability, improved pharmacokinetics, enhanced activity spectrum, and the like. The multiple-binding compounds of this invention will exhibit at least one and preferably more than one of the aforementioned effects.

The term "univalence" as used herein refers to a simple binding interaction between a ligand as defined herein with a ligand binding site as defined herein. It should be noted that a compound having multiple copies of a ligand (or ligands) exhibits univability when only one ligand is interacting with a ligand binding site. The examples of univalent interactions are represented below.

The term "multivalence" as used herein refers to the concurrent binding of 2 to 10 ligands linked (which may be the same or different) and two or more corresponding receptors (ligand binding sites) which may be the same or different .

For example, two ligands connected through a linker that binds concurrently to two ligand binding sites would be considered as bivalence; three ligands thus connected would be an example of trivalence. An example of a trivalent linkage, illustrating a multiple-bond compound occupying three ligands against a monovalent binding interaction, is shown below: univalent interaction trivalent interaction It should be understood that not all compounds containing multiple copies of a ligand attached to a linker or linkers necessarily exhibit the phenomenon of multivalency, for example, that the biological and / or therapeutic effect of the multiple binding agent is greater than the sum of the aggregate of unbound ligands made available for binding to the ligand binding site (receptor). For multivalency to occur, ligands that are connected by a linker or linkers have to be presented to their ligand binding sites by the linker (s) in a specific manner in order to carry out the targeted result to the desired ligand. , and thus produce a multiple union event.

Thereafter, the multiple-binding compound of the present invention may be composed of ligands that are all β2-adrenergic receptor agonists or may be composed of ligands that are selected from the adrenergic β2-receptor agonists and antagonists provided that the multiple linkage exhibits a general activity agonist with the ß2 adrenergic receptor.

The term "potency" refers to the minimum concentration at which a ligand is capable of achieving a desirable biological or therapeutic effect. The potency of a ligand is typically proportional to its affinity for its ligand binding site. In some cases, the power may be correlated non-linearly with its affinity. By comparing the potency of two drugs, for example, a multiple binding agent and the aggregate of its unbound ligand, the dose-response curve of each is determined under identical test conditions (for example, in a test in vi). The discovery that the multiple binding agent produces a biological or therapeutic effect equivalent to a lower concentration than the unbound ligand is indicative of improved potency.

The term "selectivity" or "specificity" is a measure of the binding preferences of a ligand for different ligand binding sites (receptors). The selectivity of a ligand with respect to its target ligand binding site relative to another ligand binding site is given by the rate of the respective Kd values (eg, the dissociation constants for each ligand-receptor complex) or , in cases where a biological effect is observed less than Kd, the rate of the respective EC5o 's (for example, the concentrations that produce 50% of the maximum response for the ligand interacting with the two different ligand binding sites ( receivers)).

The term "ligand binding site" denotes the site on the β-adrenergic receptor that recognizes a ligand domain and provides a binding partner for the ligand. The ligand binding site can be defined by monomeric or multimeric structures. This interaction may be capable of producing a unique biological effect, for example, agonism, antagonism, and modulatory effects or may maintain a long-lasting biological effect, and the like.

It should be recognized that the ligand binding sites of the receptor that participates in the multivalent binding biological interactions are forced to varying degrees by their intra- and intermolecular associations. For example, ligand binding sites can be covalently linked to a single structure, non-covalently associated in a multimeric structure, immersed in a membrane or polymer matrix, and so on and therefore have less translational and rotational freedom than if the same structures were present as monomers in a solution.

The terms "agonism" and "antagonism" are well known in the state of the art. The term "modulatory effect" refers to the ability of the ligand to change the activity of an agonist or antagonist through its binding to a ligand binding site.

The term "inert organic solvent" or "inert solvent" means a solvent which is inert under the conditions of the reaction being described in conjunction with the inclusions, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform. , methylene chloride, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions described herein are inert solvents.

The term "treatment" refers to any treatment of a pathological condition in a mammal, particularly a human, and includes: (i) preventing the pathological condition from occurring in a subject who may be predisposed to the condition but has not yet been diagnosed with the condition and, therefore, the treatment constitutes the prophylactic treatment for the condition of the disease; (ii) the inhibition of the pathological condition, for example, stop its development; (iii) relief of the pathological condition, for example, by causing regression of the pathological condition; or (iv) relief of conditions mediated by the pathological condition.

The term "pathological condition which is modulated by treatment with a ligand" covers all disease states (eg, pathological conditions) which are generally recognized in the state of the art to be usefully treated with a ligand for the ß2 adrenergic receptor in general, and those disease states which have been found to be usefully treated with a specific multiple binding compound of our invention. Such disease states include, by way of example only, the treatment of a mammal affected with asthma, chronic bronchitis, and the like.

The term "therapeutically effective amount" refers to that amount of multiple binding compound which is sufficient to effect the treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and the condition of the disease being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can be determined quickly by someone of ordinary skills in the state of the art.

The term "linker", identified where appropriate by the symbol 'X', refers to a group or groups that covalently binds 2 to 10 ligands (as identified above) in a manner that provides a compound capable of presenting multivalency. Among other features, the linker is a ligand-oriented entity that allows the binding of at least two copies of a ligand (which may be the same or different) to it. Additionally, the linker can be either a chiral or achiral molecule. In some cases the linker can be a covalent bond that binds the ligands in a manner that provides a compound capable of presenting multivalency. Additionally, in some cases, the linker can itself be biologically active. The term "binder", however, does not extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the multiple-binding compounds of this invention can be adhered to a solid support if desired. For example, such adhesion to solid supports can be made for use in separation and purification processes and similar applications.

The spread to which the multivalent binding is made depends on the efficiency with which the linker or linkers that bind the ligands present these ligands to the formation of available ligand binding sites. Beyond presenting these ligands for multivalent interactions with ligand binding sites, the linker or linkers spatially encloses these interactions to occur within dimensions defined by the linker or linkers. Thus, the structural characteristics of the linker (valence, geometry, orientation, size, flexibility, chemical composition, etc.) are characteristics of multiple bonding agents that play an important role in the determination of their activities.

The linkers used in this invention are selected in such a way as to allow multivalent binding of ligands to the ligand binding sites of a β2 adrenergic receptor, whether such sites are located internally, or internally and at the periphery of the structure of the ligand. receiver, or in an intermediate position thereof.

Representative Compounds of the Formula (I) I. The representative bivalent multiple-linking compounds of Formula (I) wherein Ar 1 is 4-hydroxy-3-hydroxymethylphenyl, Ar 2 is 1,4-phenylene, R 1 and R 2 are hydrogen, X, W, Q, and Ar 3 are as defined below in Table A are: Table A Cpd. Stereochemistry W X -Q-ArJ # a * C (** = stereochemistry) ÍA (RS) - (CH 2) 2"bond -NH-CH2- ** CH (OH) phenyl ** = (S) 2A (RS) "(CH2) 2- bond -NH-CH2- ** CH (OH) phenyl ** = (R) 3A (RSi ~ (CH2) 2- bond -NH-CH2- ** CH (OH) phenyl ** = (RS) 4A (RS1; CH2) 2"-NH-CH2- ** CH (OH) - (4-hydroxy-3-hydroxymethyl) phenyl ** = (RS) A (RS) - (CH2) -60- bond link - (CH2) 3-0- (CH2) 6-NH- CH2 - ** CH (OH) - (4-hydroxy-3-hydroxyethyl) phenyl ** = (RS) A (RS) -CH2- linkage NH-CH2 - ** CH (OH) - (4-hydroxy-3-hydroxymethyl) phenyl ** = (RS) A (R) - (CH2) 2- bond -NH-CH2- ** CH (OH ) phenyl ** = (S) II. Representative bivalent multiple-linking compounds of Formula (I) wherein Ar 1 is 4-hydroxy-3-hydroxymethylphenyl, Ar 2 is 1,4-phenylene, R 1 and R 2 are hydrogen, X, W, Q, and Ar 3, are as defined below in Table B are: Table B III. Representative bivalent multiple-linking compounds of Formula (I) wherein Ar 1 is 4-hydroxy-3-hydroxy-methylphenyl, R 1 and R 2 are hydrogen, Ar 3 is (4-hydroxy-3-hydroxymethyl) phenyl, X, W, Q, and Ar2 are as defined below in Table C are: IV. The representative bivalent multiple-linking compounds of Formula (I) Ar1 and Ar3 are 4-hydroxy-3-hydroxymethylphenyl, R1 and R2 are hydrogen, Q is a bond, and W, Ar2, and X are as defined below in Table D are: Table D V. The representative bivalent multiple-linking compounds of Formula (I) wherein Ar1 is phenyl, R1 and R2 are hydrogen, W is - (CH2) 2-, and Ar2 is 1,4-phenylene and -Q-Ar3, is [2-hydroxy-2-phenyl] ethylamino, X is a bond as shown below in Table E: Table E VI. Miscellaneous compounds: 10 PRE.FERID.AS MODALITIES While the broader definition of this invention is stated in the Brief Summary of the Invention, certain compounds of Formula (I) are preferred.

(A) A preferred group is a bivalent multiple-bond compound of Formula (II): (10 (i) Within this group (A) is a more preferred group of compounds wherein: Ar1 is aryl, more preferably. Ar1 is: (a) a phenyl ring of formula (c): (c) where: R 4 is hydrogen, alkyl, halo, or alkoxy, preferably hydrogen, methyl, fluoro, chloro, or methoxy; R5 is hydrogen, hydroxy, halo, halo, amino, or -NHS02Ra where Ra is alkyl, preferably hydrogen, hydroxy, fluoro, chloro, amino, or -NHS02CH3; Y R6 is hydrogen, halo, hydroxy, alkoxy, substituted alkyl, sulfonylamino, to inoacil, or acylamino; preferably hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, -CH2S02CH3, -NHS02CH3, -NHCHO, CONH2, or -NHCONH2. (ii) Another most preferred decomposed group within group (A) is that where: Ar 1 is heteroaryl, more preferably Ar 1 is 2,8-dihydroxyquinolin-5-yl or 3-bromoisoxazol-5-yl. (iii) Still another group of compounds more preferred within group (A) is that where: Ar 1 is heterocyclic, more preferably Ar 1 is heterocyclic fused to an aryl ring, more preferably 6-fluorochokan-2-yl; W is a bond linking the group -NR2- to Ar2, alkylene, or a substituted alkylene group where one or more of the carbon atoms in the alkylene group is optionally replaced by -O-, preferably a covalent bond, methylene , ethylene, propylene, - (CH2) 6-0- (CH2) 3-, - (CH2) 6-0-, or -CH2CH (OH) CH2-0-; Y Ar2 is phenyl wherein the groups W and X are adhered at positions 1,2-, 1,3 and 1,4 of the phenyl ring; cyclohexyl optionally substituted with methyl and wherein groups W and X are adhered at the 1,3 and 1,4 positions of the cyclohexyl ring; or piperazine wherein the groups W and X are adhered at the 1,4 positions of the piperazine ring, preferably 1,4-phenylene.

Among the most preferred groups above, there are still more preferred groups of compounds wherein: (a) X is -0-, -O-alkylene, -0- (arylene) -NH- (substituted alkylene) -, -0- (alkylene) -0- (arylene) - (alkylene) -0- (alkylene) ) - NH- (substituted alkylene) -, -0- (alkylene) -0- (arylene) -, or - (alkylene) - (cycloalkylene) -NH- (substituted alkylene) -, preferably -0- (CH2) 4 -; CH2- (1, 4-cyclohexyl) -NH-CH2-CH (0H) -; -0- (1, 4-phenylene) - NH-CH2-CH (0H) - -0- (CH2)? O-0- (1,4-phenylene) - (CH2) 3-0- (CH2) 6 -NH-CH2-CH (0H) - -0- (CH2) 6-0- (1, 4-phenylene) - (CH2) 3-0- (CH2) 5-NH-CH2-CH (0H) - - 0- (CH2) 6-0- (1, 4-phenylene) -; Y Q is a covalent bond; or (b) X is a link; Y Q is a substituted alkylene group in which one or more of the carbon atoms in said substituted alkylene group is optionally replaced by a heteroatom such as -NRa- (where Ra is hydrogen, alkyl, or acyl) or -0-, preferably -NH-CH2-CH (0H) -; -NH-CH2- CH (0H) -CH2-0-; -NH-CH (CH20H) -; -CH2-NH-CH2-CH (OH) -; C (CH 3) 2 -NH-CH 2 -CH (0H) -; - (CH2) 3-NH-CH2-CH (OH) -; - (CH2) 3 ~ 0- (CH2) 6-NH-CH2-CH (OH) -; - (CH2) 2-NH-CH2-CH (OH) -; -0- (CH2) - CH (OH) -CH2-NH-CH2-CH (OH) -; -NH-CH2-CH (OH) -CH2-0-; more preferably -NH-CH2- * CH (OH) -; -NH- * CH (CH20H) -; (CH2) 3-0- (CH2) 6-NH-CH2- * CH (OH) -; -NH-CH2- * CH (OH) -CH2-0- (where * is R or S stereochemistry); Within the groups of the above-preferred, and more preferred, compounds, a particularly preferred group of compounds is that wherein: (i) Ar3 is the same as Ar1 as defined in the preferred embodiments (A) (i) - (iii) above.

Another group of compounds particularly preferred is that wherein: (ii) Ar is a phenyl ring of formula (d) R7 Rß () where: R7 is hydrogen, alkyl, alkenyl, substituted alkyl, halo, alkoxy, substituted alkoxy, hydroxy, aminoacyl, or heteroaryl, preferably hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, -CH2C02Me, hydroxy, -CH2CONH2, -NHCOCH3, -NHCHO, or imidazol-1-yl, l-methyl-4-trifluoromethylimidazol-2-yl; Y R8 is hydrogen, halo, alkoxy, substituted alkoxy, acylamino, preferably hydrogen, fluoro, chloro, methoxy, -CH2C02Me, -NHCHO, or -CONH2. (iii) Still another group of compounds particularly preferred is that wherein: Ar3 is naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5- (CH3C02CH20-) -1,2,3,4-tetrahydronaphthyl, lH-2-oxoindole, 2,3 , 4-trihydrotianaphthalene, 4-hydroxy-2-benzothiazolinone, or 4-oxo-2,3-dihydrotianaphthalene.

Within the above preferred, more preferred, and particularly preferred groups, an even more particularly preferred group is that wherein: Ar 1 is phenyl, 4-hydroxyphenyl, 3, -dihydroxyphenyl, 3,4-dichlorophenyl, 3,5-dihydroxyphenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3, -dihydroxyphenyl, 2-chloro-3, 5-dihydroxyphenyl, 2-fluoro-3, 5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3- (HCONH-) phenyl, 4-hydroxy-3- (NH2CO) -) phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4- (CH3S02NH-) -phenyl, 4-hydroxy-3- (CH3S02CH2-) phenyl, 4-hydroxy-3- (CH3S02NH-) phenyl, 4-hydroxy - 3- (NH2CONH-) phenyl, 3,5-dichloro-4-aminophenyl, preferably 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3- (HC0NH-) phenyl, 3,5-dichloro-4-aminophenyl, or ArJ is: Y = '! (Z-ClorH) (X = ClorF) (X-ClorF) -NHCONH,] -i-a NHSOjMe preferably, phenyl or 4-hydroxy-3-hydroxymethylphenyl.

GENERAL SYNTHETIC SCHEME The compounds of this invention can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in the preparation of these compounds are available from either commercial distributors such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA) or are prepared by methods known to those experts in the state of the art who follow procedures stated in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons , 1991); Rodd 's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March' s Advanced Organic Chemistry, (John Wiley and Sons , 4th Edition), and Larock 's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The start materials and the reaction intermediates can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Moreover, it will be appreciated that where typical conditions or preferred processes occur (e.g., reaction temperatures, times, mole rates of reagents, solvents, pressures, etc.), other process conditions may also be used less than Let it be said otherwise. The optimum reaction conditions can vary with the particular solvents or reagents used, but such conditions can be determined by one skilled in the art by means of rumba optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from going through undesired reactions. The choice of a suitable protecting group for a particular functional group as well as the appropriate conditions for protection and deprotection are well known in the state of the art. For example, numerous protective groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications can be made to these schemes and will be suggested in the state of the art having reference to this disclosure.

Preparation of a multiple-bond compound of the Formula (I) In general, a multiple-bond compound of Formula (I) can be prepared as illustrated and described below in Schemes A-D.

A bivalent multiple-binding compound of Formula (I) can be prepared by the covalent attachment of the ligands, L, wherein at least one of the ligands is selected from a compound of formula (a) as defined in Brief Summary of the Invention, to a linker, X, as shown in Scheme A below.

Scheme A Method (a) 2 1 / -FG1 FG '-FG' Method (b) -FG1 [intermediary] (II) unprotect -FG X -F FftGZS In method (a), a bivalent multiple binding compound of Formula (I) is prepared in a Step, by covalently linking the ligands, L, to a linker, X, where FG1 and FG2 represent a functional group such as it is halo, amino, hydroxy, thio, aldehyde, ketone, carboxy, carboxy derivatives such as acid halide, ester, amido, and the like.

This method is preferred for the preparation of compounds of Formula (I) wherein the ligands are the same.

In method (b), the compounds of Formula (I) are prepared in several Steps by the covalent attachment of one equivalent of a ligand, Li, to a ligand X where FG1 and FG2 represent a functional group as defined above, and FG2PG is a protected functional group to give an intermediate of formula (II). Deprotection of the second functional group in the ligand, followed by the reaction of a ligand L2, which may be or different than the ligand Li # then provides a compound of the Formula (I). This method is suitable for the preparation of compounds of Formula (I) wherein the ligands are non-identical.

The ligands are covalently linked to the linker using conventional chemical techniques that provide a covalent linkage of the ligand to the linker. The reaction chemistries that result in such bonds are well known in the state of the art and involve the use of complementary functional groups in the linker and ligand as shown below in Table I.

Table I Complementary Union Chemicals Representative First Reactive Group Second Union Reagent Group carboxyl amine amide halide sulfonyl amine sulfonamide hydroxyl alkyl / aryl / halide ether hydroxyl isocyanate urethane amine epoxide ß-hydroxyamine amine alkyl / aryl / halide alkylamine amine isocyanate urea hydroxyl carboxyl ester amine aldehyde amine The reaction between a carboxylic acid of either the linker or the ligand and a primary or secondary amine of the ligand or the linker in the presence of well-known and appropriate activating agents such as dicyclohexylcarbodiimide, results in the formation of an amide bond that binds covalently ligand the linker; the reaction between an amine group of either the ligand or the ligand and a sulfonyl halide of the ligand or the linker, in the presence of a base such as triethylamine, pyridine, and the like results in the formation of a sulfonamide bond that binds covalently ligand the linker; and the reaction between an alcohol or phenol group of either the ligand or the linker and an alkyl or aryl halide of the ligand or the linker in the presence of a base such as triethylamine, pyridine, and the like, results in the formation of an ether bond that binds covalently to the ligand with the linker. A bivalent multiple-linking compound of Formula (I) wherein the second ligand Ar3 is the same as Ar1, X is a bond, and Q is the 2-hydroxyethylamino group, and the ligands are linked through the group Ar2 can be prepared of an acetophenone derivative of formula 1 as shown below in Scheme B.

Scheme B reduction (I) (Ar1 * Ar3) The condensation of an acetophenone derivative of the formula 1 with a diamine of the formula 2 in an ether solution such as tetrahydrofuran provides an imine of the formula 3. Reduction of the imine with an appropriate reducing agent such as borane provides a compound of the Formula (I). Suitable reaction solvents are tetrahydrofuran, and the like. Compound 1 where Ar1 is phenyl is prepared by heating acetophenone in 48% hydrobromic acid in dimethyl sulfoxide.

The compounds of the formula 1 ^ can be prepared by methods well known in the state of the art. For example, α, α-dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone can be prepared by heating the 5-acetylsalicylic acid methyl ester in 48% hydrobromic acid.

Alternatively, a bivalent multiple-linking compound of Formula (I) wherein the second ligand Ar3 is the same as Ar1, X is a bond, and Q is a 2-hydroxyethylamino group, and the ligands are linked through the group Ar2 can be prepared from an acetophenone derivative of formula 1 as shown below in Scheme C.

Scheme C (I) (Ar1 = Ar3) A compound of (I) can be prepared by the reaction of an epoxide of formula 4 with a diamine of formula 2. Epoxides 4 are either commercially available or can be prepared by the methods described in Kierstead, R. W. et. to the. J. Med. Chem. 26, 1561-1569, (1983) or Hett, R. et. to the. Tet. Lett. , 9345-9348 (1994).

Another method for the preparation of a bivalent multiple-binding compound of Formula (I) wherein the second ligand Ar3 is the same as Ar1, X is a bond, and Q is a 2-hydroxyethylamino group, and the ligands are linked through of the group Ar2 can be prepared from an acetophenone derivative of formula 1 as shown below in Scheme D.

Scheme D reduction 6 Z 8 (!) (Ar1 = Ar3) Bromination of an acetophenone derivative of formula 5 with bromide in a halogenated organic solvent such as chloroform provides an a-bromoacetophenone derivative of formula 6. Treatment of 6 with sodium azide followed by reduction of azido. resulting with an appropriate reducing agent such as lithium aluminum hydride provides an ethanolamine derivative of formula 8. Condensation of 2 equivalent of 8 with a dialdehyde compound 9 provides an imine of formula 1 ^) which is converted to a compound of Formula (I) as described above in Scheme A.

Any compound which is a β 2 -adrenergic receptor agonist can be used as a ligand in this invention. Typically, a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be rapidly coupled to the linker. Compounds having such functionality are either known in the art or can be prepared by modifying the rubaño of known compounds using reagents and conventional procedures.

The linkers can be adhered to different positions in the ligand molecule to achieve different orientations of the ligand domains, and therefore facilitate multivalency. While several of positions in the β-adrenergic modulating ligands are synthetic in their binding, it is preferred to preserve those ligand substructures which are more important for ligand-receptor binding. Currently, the aryl group and the side chain nitrogen are the preferred binding sites.

It will be apparent to one skilled in the art that the foregoing chemistries are not limited to the preparation of bivalent multiple-bond compounds of Formula (I) and that they can be used to prepare tri-, tetra-, etc., compounds. of multiple binding of the Formula (I). The linker is adhered to the ligand in a position that retains the ligand-ligand binding site interaction domain and specifically that allows the ligand domain of the ligand to orient itself to bind to the ligand binding site. Such synthetic positions and protocols for binding are well known in the state of the art. The term linker covers everything that is not considered to be part of the ligand.

The relative orientation in which the ligand domains are shown derives from the particular point or points of adhesion of the ligands to the linker, and in the geometry of the structure. The determination of where acceptable substitutions can be made in a ligand is typically based on prior knowledge of the structure-activity relationships (SAR) of the ligand and / or congeners and / or structural information about the ligand-receptor complexes (e.g. , X-ray crystallography, NMR, and the like). Such positions and synthetic methods for covalent adhesion are well known in the state of the art. After adhesion to the selected linker (or adhesion to a significant portion of the linker, for example 2-10 atoms of the linker), the univalent linker-ligand conjugate can be tested for retention of activity in the relevant assay.

The linker, when covalently bound to multiple copies of the ligands, provides a substantially non-immunogenic, biocompatible multiple-binding compound. The biological activity of the multiple-bond compound is highly sensitive to valence, geometry, composition, size, flexibility or rigidity, etc. of the linker and, in contrast, to the general structure of the multiple-bond compound, as well as the presence or absence of anionic or cationic charge, the relative hydrophobicity / hydrophilicity of the linker and the like in the linker. Accordingly, the linker is preferably chosen to maximize the biological activity of the multiple link compound. The linker can be chosen to improve the biological activity of the molecule. In general, the linker can be chosen from any organic molecule construction that directs two or more ligands to their ligand binding sites to allow multivalency. In this aspect, the linker can be considered as a "framework" in which the ligands are arranged in order to obtain the orientation result of the desired ligand, and thus produce a multiple-bond compound.

For example, different orientations can be achieved by inclusion in the groups of the structure containing mono- or polycyclic groups, including the aryl and / or heteroaryl groups, or structures that incorporate one or more multiple carbon-carbon bonds (groups alkenyl, alkenylene, alkynyl, or alkynylene). Other groups may also include oligomers and polymers which are branched-chain or straight-chain species. In preferred embodiments, the stiffness is imparted by the presence of cyclic groups (eg, aryl, heteroaryl, cycloalkyl, heterocyclic, etc.). In other preferred embodiments, the ring is a ring of six or ten members. In still more preferred embodiments, the ring is an aromatic ring such as, for example, phenyl or naphthyl.

The hydrophobic / hydrophilic characteristics of the linker as well as the presence or absence of charged portions can be quickly controlled by the skilled artisan. For example, the hydrophobic nature of a linker derived from hexamethylene diamine (H2N (CH2) eNH2) or related polyamines can be modified to be substantially more hydrophilic by replacing the alkylene group with a poly (oxyalkylene) group as found in the "Jeffaminas" commercially available.

The different structures can be designated to provide preferred orientations of the ligands. Such structures can be represented by using an array of points (as shown below) where each point can potentially be an atom, such as C, O, N, S, P, H, F, Cl, Br , and F or the point can alternatively indicate the absence of an atom in that position. To facilitate the understanding of the frame structure, the frame is illustrated as a two-dimensional arrangement in the following diagram, although clearly the frame is a three-dimensional arrangement in practice: 0 1 2 3 4 5 6 7 8 Each point is either an atom, chosen from carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, or halogen, or the point represents a point in space (for example, an absence of an atom). As is apparent to the skilled artisan, only certain atoms in the grid have the ability to act as an adhesion point for the ligands, called, C, 0, N, S, and P.

The atoms can be connected to each other via links (single, double or triple bonds with acceptable resonance and tautomeric forms), giving importance to the usual forces of chemical bonds. The ligands can be attached to the framework via single, double or triple bonds (with tautomeric and chemically acceptable resonance forms).

The multiple ligand groups (2 to 10) can be adhered to the scaffold in such a way that the shortest, minimum path distance between adjacent ligand groups does not exceed 100 atoms. Preferably, the linker connections with the ligand are selected in such a way that the maximum spatial distance between two adjacent ligands is not more than 100 Á.

An example of a linker as presented in the grid is shown below for a biphenyl construction.

The nodes (1,2), (2,0), (4,4), (5,2), (4,0), (6,2), (7,4), (9,4), (10.2), (9.0), (7.0) all represent carbon atoms. The node (10.0) represents a chlorine atom. All other nodes (or points) are points in space (for example, they represent an absence of atoms).

The nodes (1,2) and (9,4) are points of union. The hydrogen atoms are attached to the nodes (2,4), (4,4), (4,0), (2,0), (7,4), (10,2) and (7,0) . The nodes (5,2) and (6,2) are connected by a single link.

The carbon atoms present are connected by either a single or double bond, taking into consideration the principle of resonance and / or tautomerism.

The intersection of the frame (linker) and the ligand group, and in fact, the frame (linker) itself can have many different binding patterns. Examples of the acceptable patterns of three arrays of contiguous atoms are shown in the following diagram: CCC NCC OCC SCC PCC CCN NCN OCN SCN PCN CCO NCO OCO SCO PCO CCS NCS OCS SCS PCS CCP NCP OCP SCP PCP CNC NNC ONC SNC PNC CNN NNN ONN SNN PNN CNO NNO ONO ST D PNO CNS NNS ÜTTF SNS PNS CNP TTTTP ONP SNP PN P An expert in the state of the art would be able to identify the bonding patterns that would produce multivalent compounds. The production methods of these link arrangements are described in March, "Advanced Organic Chemistry," 4th Edition, Wiley-Interscience, New York, New York (1992). These arrangements are described in the grid of points shown in the scheme above. All possible arrangements are shown for the five most preferred atoms. Each atom has a variety of acceptable oxidation states. Arrays of underlined links are less acceptable and are not preferred.

Examples of molecular structures in which the above link patterns could be employed as components of the linker are shown below.

The identification of the geometry and size of an appropriate framework for the presentation of the ligand domain are important steps in the construction of a multiple link compound with enhanced activity. Systematic spatial search strategies can be used to help in the identification of preferred frameworks through an iterative process. Figure 3 illustrates a useful strategy for determining an optimal sample orientation of frameworks for the ligand domains. Various other strategies are known to those skilled in the art of molecular design and can be used for the preparation of compounds of this invention.

As shown in Figure 1, sample vectors around similar core structures such as a phenyl structure (Panel A) and a cyclohexane structure (Panel B) can be varied, as can the domain space. of ligand of the core structure (e.g., the length of the adhesion portion). It should be noted that core structures different from those shown here can be used for the determination of the optimal orientation of the frame sample of the ligands. The process may require the use of multiple copies of the same core structure or combinations of different types of cores shown.

The process described above can be extended to trimers (Figure 2) and to a higher valence compound (Figures 3 and 4).

The assays of each of the individual compounds of a generated collection described above will guide an alternate set of compounds with the desired enhanced activities (eg, potency, selectivity, etc.). The analysis of this alternative equipment using a technique such as the Ensemble Molecular Dynamics will provide an orientation of the framework that favors the desired properties. A wide variety of linkers is commercially available (see, for example, Available Chemical Directory (ACD)). Many of the linkers that are suitable for use in this invention fall into this category. Others can be rapidly synthesized by methods well known in the state of the art and / or are described below.

Since the geometry of the preferred framework was selected, the physical properties of the linker can be optimized by varying the chemical composition of these. The composition of the linker can be varied in various ways to achieve the desired physical properties for the multiple-bond compound.

Therefore it can be seen that there is a plethora of possibilities for the composition of a linker. Examples of the linkers include aliphatic portions, aromatic portions, steroid portions, peptides and the like. Specific examples are peptides or polyamides, hydrocarbons, aromatic groups, ethers, lipids, cationic or anionic groups, or a combination thereof.

The examples are given later, but it should be understood that several changes can be made and equivalents can be substituted without abandoning the scope and true spirit of the invention. For example, the properties of the linker can be modified by the addition or insertion of auxiliary groups in or on the linker, for example, to change the solubility of the multiple link compounds (in water, fats, lipids, biological fluids, etc.). ), hydrophobicity, hydrophilicity, flexibility of the linker, antigenicity, stability, and the like. For example, the introduction of one or more groups of poly (ethylene glycol) (PEG) on or into the linker improves the hydrophilicity and water solubility of the multiple link compound, increases both the molecular weight and the size of the molecule and, depending on the nature of the linker that does not contain PEG, it may increase the retention time in vivo. Later, the PEG can decrease its antigenicity and potentially improve the rigidity in general of the linker.

Auxiliary groups which improve the water solubility / hydrophilicity of the binder and, consequently, the resulting binder compounds are useful in the practice of this invention. Thus, it is within the scope of the present invention to use auxiliary groups such as, for example, small repeating units of ethylene glycols, alcohols, polyols (eg, glycerin, glycerol propoxylate, saccharides, including mono-, oligosaccharides, etc.). ), carboxylates (e.g., small repeating units of glutamic acid, acrylic acid, etc.), amines (e.g., tetraethylenepentamine, and the like) to improve the water solubility and / or hydrophilicity of the one-atom compounds of this invention . In the preferred embodiments, the auxiliary group used to improve water solubility / hydrophilicity will be a polyether.

The incorporation of lipophilic auxiliary groups within the linker structure to improve the lipophilicity and / or hydrophobicity of the multiple link compounds described herein is also within the scope of this invention. Lipophilic groups useful with the linkers of this invention include, by way of example only, the aryl and heteroaryl groups which, as above, may be either unsubstituted or substituted with other groups, but are at least substituted with a group which allows its covalent adhesion to the linker. Other lipophilic groups useful with the linkers of this invention include fatty acid derivatives which do not form bilayers in an aqueous medium until higher concentrations are reached.

Also within the scope of this invention is the use of auxiliary groups which results in the multiple binding compound being incorporated or anchored within a vesicle or other membranous structure such as a liposome or a micelle. The term "lipid" refers to any derivative of a fatty acid that is capable of forming a bilayer or micelle in such a way that a hydrophobic portion of the lipid material is oriented towards the bilayer while a hydrophilic portion is oriented towards the aqueous phase . The hydrophilic characteristics are derived from the presence of phosphate groups, carboxylic, sulfate, amino, sulfhydryl, nitro and the like are well known in the state of the art. Hydrophobicity could be conferred by the inclusion of groups including, but not limited to, saturated and unsaturated long chain aliphatic carbohydrate groups of up to 20 carbon atoms and such groups and such groups substituted by one or more group ( s) aryl, heteroaryl, cycloalkyl and / or heterocyclic. Preferred phosphoglycerides and sphingolipids lipids are, representative examples of which include fosfatidiIcolina, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylcholine palmitoileoil, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, phosphatidylcholine, dioleoyl, distearoyl phosphatidylcholine or dilinoleoylphosphatidylcholine could-be used. Other compounds lacking phosphorus, such as the families of sphingolipids and glycosphingolipids are also within the group designated as lipids.Amirably, the amphiphilic lipids described above can be mixed with other lipids including triglycerides and sterols.

The flexibility of the linker can be manipulated by the inclusion of auxiliary groups which are bulky and / or rigid. The presence of bulky or rigid groups can hinder free rotation near the links in the linker or links between the linker and the auxiliary group (s) or links between the linker and the functional groups. Rigid groups may include, for example, those groups whose conformational lability is restricted by the presence of rings and / or multiple bonds within the group, for example, the aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocyclic groups. Other groups which can impart rigidity include polypeptide groups such as oligo- or polyproline chains.

Stiffness can also be imparted electrostatically. Thus, if the auxiliary groups are charged either positively or negatively, the auxiliary groups loaded in a similar manner will force the presenting linker to a configuration that allows the maximum distance between each of the like charges. The energy cost of moving the groups of similar charges so that they are closer to one another will tend to hold the linker in a configuration that maintains the separation between the auxiliary groups of similar charges. Subsequent auxiliary groups that possess opposite charges will tend to be attracted to their counterparts of opposite charge and potentially can enter both inter- and intramolecular ionic bonds. This non-covalent mechanism will tend to hold the linker in a conformation which allows the link between the groups of opposite charge. The addition of auxiliary groups which are charged, or alternatively, possess a latent charge when unprotected, after addition to the linker, includes the deprotonation of a carboxyl, hydroxyl, thiol, or amino group because of a change in the pH, oxidation, reduction or other mechanisms known to those skilled in the art which results in the removal of the protecting group, is within the scope of this invention.

The rigidity can also be imparted by an internal hydrogen bond or by means of hydrophobic collapse.

Bulky groups may include, for example, large atoms, ions (eg, iodine, sulfur, metal ions, etc.) or groups containing large atoms, polycyclic groups, including aromatic groups, non-aromatic groups and structures incorporating one or more carbon-carbon multiple bonds (for example, alkenes and alkynes). The bulky groups also include oligomers and polymers which are branched or linear chain species. It is expected that species that are branched increase the stiffness of the structure more by gain of molecular weight units than by linear chain species.

In preferred embodiments, the stiffness is imparted by the presence of cyclic groups (eg, aryl, heteroaryl, cycloalkyl, heterocyclic, etc.). In other preferred embodiments, the linker comprises one or more six member rings. In still more preferred embodiments, the ring is an aryl group such as, for example, phenyl or naphthyl.

In view of the above, it is apparent that the appropriate selection of a linker group that provides the appropriate orientation, restricted / unrestricted rotation, the desired degree of hydrophobicity / hydrophilicity, etc. it is well within the skill of the state of the art. The elimination or reduction of the antigenicity of the multiple-bonding compounds described herein is also within the scope of this invention. In certain cases the antigenicity of a multiple-bond compound can be eliminated or reduced by the use of groups such as, for example, poly (ethylene glycol).

As explained above, the multiple binding compounds described herein comprise 2-10 ligands attached to a linker that binds the ligands such that they are presented to the enzyme for multivalent interactions with ligand binding sites that are in or on her. The linker spatially encloses these interactions to occur within dimensions defined by the linker. This and other factors increase the biological activity of the multiple-bond compound when compared to the same number of ligands made available in its mono-bond form.

The compounds of this invention are preferably represented by the empirical formula of (L) p (X) wherein L, X, p and q are as defined above. This is accomplished to include the various pathways in which ligands can be ligated with one another in order to achieve the goal of multivalency, and a more detailed explanation is described below.

As noted previously, the linker can be considered as a framework to which the ligands adhere. Thus, it should be recognized that the ligands can be adhered to any suitable position in this framework, for example, at the end of a linear chain or at any intermediate position.

The simplest and most preferred multiple-linking compound is a bivalent compound which may be represented as L-X-L, where each L is independently a ligand which may be the same or different and each X is independently the linker. Examples of such bivalent compounds are provided in FIG. 1 where each shaded circle represents a ligand. A trivalent compound could also be represented in a linear fashion, for example, as a sequence of repeated units LXLXL, in which L is a ligand and is the same or different in each occurrence, as X can be. However, a The trimer may also be a radial multiple-bond compound comprising three ligands adhered to a central core, and thus represented as (L) 3X, where the linker X could include, for example, an aryl or cycloalkyl group. The illustrations of trivalent and tetravalent compounds of this invention are found in FIGs. 2 and 3 respectively, where, once again, the shaded circles represent ligands. The tetravalent compounds can be represented in a linear array, for example, L-X-L-X-L-X-L in a branched array, for example, L-X-L-X-L i (a branched construction analogous to the isomers of butane-n-butyl, iso-butyl, sec-butyl, and t-butyl) or in a tetrahedral arrangement, for example, where X and L are as defined here. Alternatively, it could be represented by an alkyl, aryl or cycloalkyl derivative as above with four (4) ligands adhered to the core linker.

The same considerations apply to higher multiple-junction compounds of this invention containing 5-10 ligands as illustrated in FIG. 4 where, as before, shaded circles represent ligands. However, for multiple bonding agents attached to the central linker such as aryl or cycloalkyl, there is an obvious restriction that there must be sufficient adhesion sites in the linker to accommodate the number of ligands present; for example, a benzene ring could not directly accommodate more than 6 ligands, whereas a multiple-ring linker (eg, biphenyl) could accommodate a larger number of ligands.

The compounds described above can alternatively be represented as cyclic chains of the form: L ~ x X X and variants of it.

It is that all the above variations are within the scope of the invention defined by the formula (L) p (X) q.

With the above mentioned in mind, a preferred linker can be presented by the following formula: -Xa-Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa in each separate occurrence is selected from the group consisting of -O-, -S- -NR-, -C (O) -, -C (0) 0-, -OC (O) -, -C (0) NR -, -NRC (O) -, C (S) -, -C (S) 0-, -C (S) NR-, -NRC (S) -, OR a covalent bond where R is as defined below; Z in each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; each Ya in each separate occurrence is selected from the group consisting of -0-, -C (0) -, -0C (0) -, -C (0) 0-, -NR-, -S (0) "-, -C (0) NR'-, -NR'C (O) -, -NR 'C (0) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR' -, -NR'-C (= NR ') -, -0C (0) -NR'-, -NR'-C (0) -0- -N = C (Xa) -NR'-, -NR' -C (Xa) = N-, -P (0) (OR ') -0-, -0- P (0) (0R') -, -S (0) nCR'R "-, -S (0 ) n-NR'-, -NR'-S (0) n-, -SS-, and a covalent bond; where n is 0, 1 or 2; and R, R 'and R "in each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic Additionally, the linker portion can be optionally substituted at any atom it has by one or more substituted alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl groups , heteroaryl and heterocyclic.

In view of the above description of the linker, it is understood that the term "linker" when used in combination with the term "multiple link compound" includes both a covalently contiguous single linker (eg, LXL) and multiple linkers covalently non-contiguous (LXLXL) within the multiple-bond compound.

Combination Libraries The methods described above lend themselves to combinatorial approaches for the identification of multiple binding compounds which possess multiple binding properties.

Specifically, factors such as the appropriate juxtaposition of the individual ligands of a multiple-bond compound with respect to the relevant arrangement of binding sites on a target or targets is important in optimizing the interaction of the multiple-bond compound with its objective ( s) and to maximize the biological advantage through multivalency. One approach is to identify a library of candidate multiple-join compounds with key properties in the multiple-join parameters that are relevant to a particular objective. These parameters include: (1) the identity of the ligand (s), (2) the orientation of the ligands, (3) the valence of the construction, (4) the length of the linker, (5) the geometry of the linker, ( 6) the physical properties of the linker, and (7) the chemical functional groups of the linker.

Libraries of multimeric compounds that potentially possess multiple binding properties (eg, candidate multiple binding compounds) and that comprise a multiplicity of such variables are prepared and these libraries are then evaluated via conventional assays corresponding to the selected ligand and the parameters of multiple union desired. The considerations relevant to each of these variables are stated below: Selection of ligand (s): A single ligand or group of ligands is (are) selected for incorporation into the libraries of candidate multiple binding compounds whose library is directed against a particular biological target or targets eg, adrenergic β2 receptor. The only requirement for the chosen ligands is that they are able to interact with the selected target (s). Thus, the ligands may be known drugs, modified forms of known drugs, substructures of known drugs or substrates of modified forms of known drugs (which are competent to interact with the target), or other compounds. The ligands are preferably chosen based on the known favorable properties that may be projected to be transported or amplified in multiple bonding forms. Favorable properties include demonstrated safety and efficacy in human patients, appropriate PK / ADME profiles, synthetic accessibility, and desirable physical properties such as solubility, log P, etc. However, it is crucial to note that ligands which demonstrate an unfavorable property of those in the previous list can obtain a more favorable property through the process of formation of multiple binding compounds; for example, ligands should not necessarily be excluded with such bases. For example, a ligand that is not sufficiently potent in a particular target such that it is effective in a human patient can become highly potent and effective when presented in a multiple binding form. A ligand that is potent and effective but is not useful because a toxic side effect that is not related to a mechanism may have increased the therapeutic index (increased potency related to toxicity) as a multiple-binding compound. Compounds that exhibit short half-lives in vivo may have longer half-lives as multiple-bond compounds. The physical properties of the ligands that limit their utility (for example poor bioavailability due to low solubility, hydrophobicity, hydrophilicity) can be modulated in a rational manner in multiple bonding forms, providing compounds with physical properties consistent with the desired utility.

Orientation: selection of ligand adhesion points and binding chemistry: Several points are chosen in each ligand to which the ligand will be attached to the linker. The points selected in the ligand / linker for adhesion are functionalized to contain complementary reactive functional groups. This allows the probing of the effects of the presentation of the ligands to their receptor (s) in multiple relative orientations, an important multiple binding design parameter. The only requirement to choose the points of adhesion is that by adhering to at least one of these points it does not abrogate the activity of the ligand. Such points for adhesion can be identified by structural information when available. For example, inspection of a co-crystalline structure of a protease inhibitor attached to its target allows one to identify one or more sites where adhesion to the linker will not harm the enzyme: inhibitory interaction. Alternatively, the evaluation of the ligand / target binding by nuclear magnetic resonance will allow the identification of non-essential sites for ligand / target binding. See, for example, Fesik, et al., U.S. Patent No. 5,891,643. When such structural information is not available, the use of structure-activity relationships (SiR) for the ligands will suggest positions where substantial structural variations are and are not allowed. In the absence of structural and S.AR information, a library is merely selected with multiple adhesion points to allow the presentation of the ligand in different multiple orientations. Subsequent evaluation of this library will indicate which positions are appropriate for adherence.

It is important to emphasize that the adhesion positions that abrogate monomeric ligand activity can also be advantageously included in candidate multiple binding compounds in the library since such compounds carry at least one ligand attached in a manner which does not abrogate intrinsic activity . This selection derives from, for example, the heterobivalent interactions within the context of a simple target molecule. For example, consider a ligand antagonist of a receptor bound to its target receptor, and then consider modifying this ligand by adhering a second copy of this ligand with a linker which allows the second ligand to interact with the same receptor molecule at sites near the antagonist binding site, which includes receptor elements that are not part of the formal antagonist binding site and / or elements of the matrix surrounding the receptor such as the membrane. Here, the most favorable orientation for the interaction of the second ligand molecule with the receptor / matrix can be achieved by adhering it to the carrier in a position which abrogates the activity of the ligand at the formal antagonist binding site. Another way to consider this is that the SAR of individual ligands within the context of a multiple binding structure is often different from the SAR of those same ligands in monomeric form.

The aforementioned discussion focuses on bivalent interactions of dimeric compounds by transporting two copies of the same ligand bound with a single linker through different adhesion points, one of which can abrogate the binding activity of the monomeric ligand. It should also be understood that the bivalent advantage can also be obtained with heterodimeric constructs carrying two different ligands that bind to common or different targets. For example, a 5HT4 receptor antagonist and a selective muscarinic M3 antagonist of the bladder can be attached to a linker through adhesion sites which do not abrogate the binding activity of the monomeric ligands by their respective receptor sites. The dimeric compound can achieve improved affinity for both receptors due to favorable interactions between the 5HT ligand and M3 receptor elements near the formal M3 antagonist binding site and between the M3 ligand and 5HT4 receptor elements near the formal 5HT4 antagonist binding site . Thus, the dimeric compound may be more potent and selective antagonist of the overactive bladder and a superior therapy for incited urinary incontinence.

Once the ligand binding sites have been chosen, one identifies the types of chemical bonds that are possible at those points. The most preferred types of chemical bonds are those that are compatible with the overall structure of the ligand (or protected forms of the ligand) formed rapidly and generally, stable and innocuously safe under typical chemical and physiological conditions, and compatible with a larger number of available linkers. The amide, ether, amines, carbamates, ureas, and sulfonamide linkages are a few examples of preferred linkages.

Linkers: search for "" multiple binding parameters relevant through the selection of the valence, length of the linker, geometry of the linker, rigidity, physical properties, and chemical functional groups In the library of linkers used to generate the library of candidate multiple-union compounds, the selection of linkers used in this library of linkers takes into consideration the following factors: Valencia: In most cases the library of linkers is started with divalent linkers. The choice of ligands and appropriate juxtaposition of two ligands relative to their binding sites allows such molecules to exhibit their target binding affinities and specificities more than sufficient to confer biological advantage. Subsequently, divalent linkers or constructs are also typically modest in size such that they retain the desirable biodistribution properties of small molecules.

Length of the linker: The linkers are chosen from a range of lengths to allow the search of a range of inter-ligand distances that comprises the preferred distance for a given divalent interaction. In some cases the preferred distance can be estimated more precisely from high-resolution structural information of targets, typically enzymes and soluble receptor targets. In other cases where high-resolution structural information is not available (as in G7TM-coupled protein receptors), one can use simple models to estimate the maximum distance between the binding sites in either the adjacent receptors or in different locations in the same receiver. In situations where two binding sites are present in the same target (or target subunit for multiple subunit targets), the preferred distances of the linker are 2-20 A, with more preferred linker distances of 3-12 A. In situations where two binding sites reside in separate target sites, (eg, in protein) the preferred distances of the linker are 20-100 A, with more preferred distances of 30-70 A.

Geometry and rigidity of the linker: The combination of the ligand binding site, length of the linker, geometry of the linker, and rigidity of the linker determines the possible ways in which the ligands of the candidate compounds of multiple linkage can be deployed in three dimensions and thereby present to your union sites. The geometry and rigidity of the linker are usually determined by chemical composition and link model, which can be controlled and are systematically varied as another that covers the function in a multiple bond arrangement. For example, the geometry of the linker is varied by joining two ligands to the ortho, meta and par positions of the benzene ring, or in the cis or trans arrangements to the 1,1-vs positions. 1,2-vs. 1,3-vs. 1,4- around the cyclohexane nucleus or in cis or trans arrangements in an unsaturated ethylene unit. The rigidity of the linker is varied by controlling the number of relative energies of different possible conformational states for the linker. For example, a divalent compound carrying two ligands bound by the 1,8-octyl linker has many more degrees of freedom, and is therefore less rigid than a compound in which the two ligands are bound to the 4,4 positions. 'of the biphenyl linker.

Physical properties of the linker: The physical properties of the linkers are nominally determined by the chemical constitution and linker models of the linker, and the physical properties of the linker embed the total physical properties of the candidate multiple link compounds in which they are included. A percentage of linker compositions are typically selected to provide a percentage of physical properties (hydrophobicity, hydrophilicity, amphipathicity, polarization, acidity, and basicity) in the candidate multiple-binding compounds. The particular choice of the physical properties of the linker is made within the context of the physical properties of the ligands they bind and preferably the field is to generate molecules with favorable PK / ADME properties. For example, the linkers can be selected to avoid those that are so hydrophilic or so hydrophobic to be easily absorbed and / or distributed in vivo.

Chemical functional groups of the linker: The chemical functional groups of the linker are selected to be compatible with the chemistry chosen to connect the linkers to the ligands and to impart the percentage of physical properties sufficient to cover the initial examination of this parameter.

Combinatorial synthesis Having chosen a set n of ligands (n being determined by the sum of the number of different binding sites for each ligand chosen) and m linkers by the process underlined above, a library of divalent multiple-link compounds was prepared (n. ') m which covers multiple junction parameters designed for a particular purpose. For example, an array generated from two ligands, one that has two points of union (Al, A2) and one that has three points of union (Bl, B2, B3,) joined in all possible combinations provided by at least 15 possible combinations of multiple bonding compounds: Al-Al A1-A2 Al-Bl A1-B2 A1-B3 A2-A2 A2-B1 A2-B2 A2-B3 Bl-Bl B1-B3 B2-B2 B2-B3 B3-B3 When each of these combinations is linked by 10 different linkers, a library of 150 candidate multiple-binding compounds results.

Given the combinatorial nature of the library, common chemistries are preferably used to bind the reactive functionalities in the ligands with the complementary reactive functionalities in the ligands. The library therefore lends itself to efficient parallel synthetic methods. The combinatorial library can employ solid phase chemistries well known in the state of the art wherein the ligand and / or the linker binds to a solid support. Alternatively and preferably, the combinatorial library is prepared in the solution phase. After synthesis, the candidate multiple-binding compounds are optionally purified prior to assay for activity by, for example, chromatography methods (eg, HPLC).

Analysis of arrangement by biochemical, analytical, pharmacological and computational methods: Several methods were used to characterize the properties and activities of the candidate multiple-binding compounds in the library to determine which compounds possessed the multiple-binding properties. Physical constants such as solubility can be determined under various solvent conditions and logD / clogD. A combination of NMR spectroscopy and computational methods were used to determine the low energy conformations of the candidate multiple-binding compounds in fluid medium. The ability of library members to unite the desired objective and other objectives was determined by several standard methods, which include radioligand displacement assays for receptor and ion channel targets, and kinetic inhibition analysis for many enzyme targets . In vitro efficacy can also be determined, such as for agonist and antagonist receptor, ion channel blockers, and antimicrobial activity. The pharmacological data, including oral absorption, penetration of the intestines turned inside out, other pharmacokinetic parameters and efficacy data can be determined in appropriate models. In this way, structure-activity key ratios for design parameters were obtained. multiple union 'which are then used to direct future work.

Members of the library exhibiting multiple binding properties, as defined herein, can be easily determined by conventional methods. First, those members that exhibit multiple binding properties (both in vi tro and in vivo) are identified by conventional methods such as those described above, including conventional tests.

Second, the structure of those compounds that exhibit multiple binding properties can be fulfilled via recognized procedures in the state of the art. For example, each member of the library can be marked or labeled with appropriate information that allows the determination of the structure of relevant members at a later time. See, for example, Dower, et al., International Patent Application Publication No. WO 93/06121; Brener, et al., Proc. Nati Acad. Sci., USA, 89: 5181 (1992); Gallop, et al., U.S. Patent No. 5,846,839; each of which are incorporated herein by reference in its entirety. Alternatively, the structure of the relevant multivalent compounds can also be determined from soluble and unlabeled libraries of multivalent candidate compounds by methods known in the state of the art such as those described by Hindsgaul, et al., Canadian Patent Application No. 2,240,325 which was published on July 11, 1998. Such methods couple affinity front chromatography with mass spectroscopy to determine both the structure and the relative binding affinities of candidate multiple-binding compounds to receptors.

The process stated above for dimeric candidate multiple-bond compounds can, of course, be extended to trimeric candidate compounds and larger analogs thereof.

Consecutive synthesis and analysis of additional arrangement (s): Based on the information obtained through the analysis of the initial library, an optional component of the process is to find out one or more promising multiple link "leader" compounds as defined by related particular ligand orientations, lengths of the linkers, geometries of the linkers, etc. Additional libraries can then be generated around these guides to provide additional information regarding the structure for activity relationships. These arrays typically carry more concentrated variations in the structure of the linker in an effort to further optimize the affinity of the target and / or activity in the target (antagonism, partial agonism, etc.), and / or alter the physical properties. By iterative redesign analysis using the novel principles of multiple-junction design along with approaches to classical medicinal chemistry, biochemistry and pharmacology, someone is able to prepare and identify the optimal multiple-bond compounds that exhibit biological advantages towards their targets and as therapeutic agents. In addition to this process, suitable divalent linkers include, by way of example only, those derived from dicarboxylic acids, disulfonylaids, dialdehydes, diketones, dialdehydes, diisocyanates, diamines, diols, carboxylic acid mixtures, sulfonylaldehydes, aldehydes, ketones, halides, isocyanates, amines and diols. In each case, the functional group of the carboxylic acid, sulfonyla lide, aldehyde, ketone, halide, isocyanate, amine and diol is reacted with a functional complement in the ligand to form a covalent ligation. Such functional complementary is well known in the state of the art as illustrated in the following table: CHEMICALS OF COMPLEMENTARY UNION The exemplification of linkers includes the following linkers identified as X-1 through X-418 as stated below: Representative ligands for use in this invention include, by way of example, L-1 and L-2 as identified above wherein L-1 was selected from a compound of the formula (a) and L-2 was selected from a composed of the formula (b).

The combinations of ligands (L) and linkers (X) for this invention include, by way of example only, homo and hetero dimers wherein a first ligand was selected from L-1 and the second ligand and linker was selected from the following : L-2 / X-1- L-2 / X-2- L-2 / X-3- L-2 / X-4- L-2 / X-5- L-2 / X-6- L- 2 / X-7- L-2 / X-8-L-2 / X-9-L-2 / X-10-L-2 / X-11-L-2 / X-12-L-2 / X-13-L-2 / X-14-L-2 / X-15-L-2 / X-16-L-2 / X-17-L-2 / X-18-L-2 / X- 19- L-2 / X-20- L-2 / X-21- L-2 / X-22- L-2 / X-23- L-2 / X-23- L-2 / X-25- L-2 / X-26- L-2 / X-27- L-2 / X-28- L-2 / X-29- L-2 / X-30- L-2 / X-31- L- 2 / X-32-L-2 / X-33-L-2 / X-34-L-2 / X-35-L-2 / X-36-L-2 / X-37-L-2 / X-38-L-2 / X-39-L-2 / X-40-L-2 / X-41-L-2 / X-42-L-2 / X-43-L-2 / X- 44- L-2 / X-45- L-2 / X-46- L-2 / X-47- L-2 / X-48- L-2 / X-49- L-2 / X-50- L-2 / X-51- L-2 / X-52- L-2 / X-53- L-2 / X-54- L-2 / X-55- L-2 / X-56- L- 2 / X-57-L-2 / X-58-L-2 / X-59-L-2 / X-60-L-2 / X-61-L-2 / X-62-L-2 / X-63-L-2 / X-64-L-2 / X-65-L-2 / X-66-L-2 / X-67-L-2 / X-68-L-2 / X- 69- L-2 / X-70- L-2 / X-71- L-2 / X-72- L-2 / X-73- L-2 / X-74- L-2 / X-75- L-2 / X-76- L-2 / X-77- L-2 / X-78- L-2 / X-79- L-2 / X-80- L-2 / X-81- L- 2 / X-82-L-2 / X-83-L-2 / X-84-L-2 / X-85-L-2 / X-86-L-2 / X-87-L-2 / X-88- L-2 / X-89- L-2 / X-90- L-2 / X-91- L-2 / X-92- L-2 / X-93- L-2 / X- 94- L-2 / X-95- L-2 / X-96- L-2 / X-97- L-2 / X-98- L-2 / X-99- L-2 / X-100- L-2 / X-10 1- L-2 / X-102-L-2 / X-103-L-2 / X-104-L-2 / X-105-L-2 / X-106-L-2 / X-107- L-2 / X-108-L-2 / X-109-L-2 / X-110-L-2 / X-111-L-2 / X-112-L-2 / X-113-L- 2 / X-114-L-2 / X-115-L-2 / X-116-L-2 / X-117-L-2 / X-118-L-2 / X-119-L-2 / X-120-L-2 / X-121-L-2 / X-122-L-2 / X-123-L-2 / X-124-L-2 / X-125-L-2 / X- 126- L-2 / X-127- L-2 / X-128- L-2 / X-129- L-2 / X-130- L-2 / X-131- L-2 / X-132- L-2 / X-133-L-2 / X-134-L-2 / X-135-L-2 / X-136-L-2 / X-137-L-2 / X-138-L- 2 / X-139-L-2 / X-140-L-2 / X-141-L-2 / X-142-L-2 / X-143-L-2 / X-144-L-2 / X-145- L-2 / X-146- L-2 / X-147- L-2 / X-148- L-2 / X-149- L-2 / X-150- L-2 / X- 151- L-2 / X-152- L-2 / X-153- L-2 / X-154- L-2 / X-155- L-2 / X-156- L-2 / X-157- L-2 / X-158- L-2 / X-159- L-2 / X-160- L-2 / X-161- L-2 / X-162- L-2 / X-163- L- 2 / X-164-L-2 / X-165-L-2 / X-166-L-2 / X-167-L-2 / X-168-L-2 / X-169-L-2 / X-170-L-2 / X-171-L-2 / X-172-L-2 / X-173-L-2 / X-174-L-2 / X-175-L-2 / X- 176- L-2 / X-177- L-2 / X-178- L-2 / X-179- L-2 / X-180- L-2 / X-181- L-2 / X-182- L-2 / X-183-L-2 / X-184-L-2 / X-185-L-2 / X-186-L-2 / X-187-L-2 / X-188-L- 2 / X-189- L-2 / X-190- L-2 / X-191- L-2 / X-1 92- L-2 / X-193- L-2 / X-194- L-2 / X-195- L-2 / X-196- L-2 / X-197- L-2 / X-198- L-2 / X-199-L-2 / X-200-L-2 / X-201-L-2 / X-202-L-2 / X-203-L-2 / X-204-L- 2 / X-205-L-2 / X-206-L-2 / X-207-L-2 / X-208-L-2 / X-209-L-2 / X-210-L-2 / X-211-L-2 / X-212-L-2 / X-213-L-2 / X-214-L-2 / X-215-L-2 / X-216-L-2 / X- 217- L-2 / X-218- L-2 / X-219- L-2 / X-220- L-2 / X-221- L-2 / X-222- L-2 / X-223- L-2 / X-224-L-2 / X-225-L-2 / X-226-L-2 / X-227-L-2 / X-228-L-2 / X-229-L- 2 / X-230-L-2 / X-231-L-2 / X-232-L-2 / X-233-L-2 / X-234-L-2 / X-235-L-2 / X-236-L-2 / X-237-L-2 / X-238-L-2 / X-239-L-2 / X-240-L-2 / X-241-L-2 / X- 242- L-2 / X-243- L-2 / X-244- L-2 / X-245- L-2 / X-246- L-2 / X-247- L-2 / X-248- L-2 / X-249- L-2 / X-250- L-2 / X-251- L-2 / X-252- L-2 / X-253- L-2 / X-254- L- 2 / X-255-L-2 / X-256-L-2 / X-257-L-2 / X-258-L-2 / X-259-L-2 / X-260-L-2 / X-261- L-2 / X-262- L-2 / X-263- L-2 / X-264- L-2 / X-265- L-2 / X-266- L-2 / X- 267- L-2 / X-268- L-2 / X-269- L-2 / X-270- L-2 / X-271- L-2 / X-272- L-2 / X-273- L-2 / X-274- L-2 / X-275- L-2 / X-276- L-2 / X-277- L-2 / X-278- L-2 / X-279- L- 2 / X-280- L-2 / X-281- L-2 / X-282- L-2 / X- 283- L-2 / X-284- L-2 / X-285- L-2 / X-286- L-2 / X-287- L-2 / X-288- L-2 / X-289- L-2 / X-290-L-2 / X-291-L-2 / X-292-L-2 / X-293-L-2 / X-294-L-2 / X-295-L- 2 / X-296-L-2 / X-297-L-2 / X-298-L-2 / X-299-L-2 / X-300-L-2 / X-301-L-2 / X-302- L-2 / X-303- L-2 / X-304- L-2 / X-305- L-2 / X-306- L-2 / X-307- L-2 / X- 308- L-2 / X-309- L-2 / X-310- L-2 / X-311- L-2 / X-312- L-2 / X-313- L-2 / X-314- L-2 / X-315- L-2 / X-316- L-2 / X-317- L-2 / X-318- L-2 / X-319- L-2 / X-320- L- 2 / X-321-L-2 / X-322-L-2 / X-323-L-2 / X-324-L-2 / X-325-L-2 / X-326-L-2 / X-327-L-2 / X-328-L-2 / X-329-L-2 / X-330-L-2 / X-331-L-2 / X-332-L-2 / X- 333- L-2 / X-334- L-2 / X-335- L-2 / X336- L-2 / X-337- L-2 / X-338- L-2 / X-339- L- 2 / X-340-L-2 / X-341-L-2 / X-342-L-2 / X-343-L-2 / X-344-L-2 / X-345-L-2 / X-346-L-2 / X-347-L-2 / X-348-L-2 / X-349-L-2 / X-350-L-2 / X-351- L-2 / X-352-L-2 / X-353-L-2 / X-354-L-2 / X-355-L-2 / X-356-L-2 / X-357-L- 2 / X-358-L-2 / X-359-L-2 / X-360-L-2 / X-361-L-2 / X-362-L-2 / X-363-L-2 / X-364-L-2 / X-365-L-2 / X-366-L-2 / X-367-L-2 / X-368-L-2 / X-369-L-2 / X- 370-L-2 / X-371-L-2 / X-372-L-2 / X-373-L-2 / X-374-L-2 / X-375-L-2 / X-376- L-2 / X-377- L-2 / X-378- L-2 / X-379- L-2 / X-380-L-2 / X-381- L-2 / X-382- L- 2 / X-383-L-2 / X-384-L-2 / X-385-L-2 / X-386-L-2 / X-387-L-2 / X-388-L-2 / X-389-L-2 / X-390-L-2 / X-391-L-2 / X-392-L-2 / X-393-L-2 / X-394-L-2 / X- 395-L-2 / X-396-L-2 / X-397-L-2 / X-398-L-2 / X-399-L-2 / X-400-L-2 / X-401- L-2 / X-402-L-2 / X-403-L-2 / X-404-L-2 / X-405-L-2 / X-406-L-2 / X-407-L- 2 / X-408-L-2 / X-409-L-2 / X-410-L-2 / X-411-L-2 / X-412-L-2 / X-413-L-2 / X-414-L-2 / X-415-L-2 / X-416-L-2 / X-417-L-2 / X-418- UTILITY, PRUE.BA, AND JVDMINISTIÍACION Utility The multiple-binding compounds of this invention are β2-adrenergic receptor agonists. Accordingly, the multiple-binding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by adrenergic β2-receptor such as asthma, bronchitis, and the like. These are also "useful in the treatment of nervous system injuries and premature birth." It was also contemplated that the compounds of this invention are useful for the treatment of metabolic disorders such as obesity, diabetes, and the like.

Proof The agonist activity to the β2 adrenergic receptors of the compounds of the formula (I) can be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the assays described in the biological examples 1 and 2. They can also be assayed by the Ex vivo assays described in Ball, DI et al., "Salmterol at Novel, Long-acting beta-2 Adrenergic Agonist: Characterization of Pharmacological Activity in Vitro and in Vivo" Br. J. Pharmacol. , 104, 665-571 (1991); Linden, A et al., "Sameterol, Formoterol and Salbutamol in the Isolated Guinea-Pig Trachea: Differences in Maximum Relaxant Effect and Potency but not in Functional Antagonism, Thorax, 48, 547-553, (1993); I Bials, AT et al., Investigations into Factors Determining the Duration of Action of the Beta 2- Agonist Adrenoceptor, Salmateroal, Br. J. Pharmacol., 108, 505-515 (1993), or in in vivo assays such as those described in Ball, DI et al., "Salmterol at Novel, Long-acting beta 2-Adrenergic agonist: Characterization of Pharmacological Activity in Vitro and in Vivo" Br. J. Pharmacol., 104, 665-671 (1991); Kikkawa, H. et al. al., "RA-2005, to Novel, Long-acting, and) Selective Beta 2-Adrenoceptor Agonist: Characterization with other Beta 2-Agonists." Biol. Pharm. Bull., 17, 1047-1052, (1994); and Anderson, GP, "Formeterol: Pharmacology, Collective basis of Agonism and Mechanics of Long Duration of a Highly Potent and Selective Beta 2-Adrenoceptor Agonist Bronchodilator, Li Faith Sciences, 52, 2145-2160, (1993).

Pharmaceutical Formulations When employed as drugs, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as inhaled and oral injectable compositions. Such compositions are prepared in a manner well known in the state of the art and comprises at least one active compound.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or included within a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium) ointments containing, for example, up to 10 ounces. Weight% of an active compound, soft and hard gelatin, capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In the preparation of a formulation, it may be necessary to grind the active compound to provide the appropriate particle size prior to combination with the other ingredients. If the active compound is substantially insoluble, ordinarily it is ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup, and methyl cellulose The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; soaking agents; emulsifying and dispersing agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated such as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by use of procedures known in the art.

The compositions are preferably formulated in the form of a dosage unit containing from about 0.001 to about 1 g, more usually about 1 to about 30 mg, of the active ingredient. The term "dosage unit forms" refers to physically discrete units suitable as unit doses for human individuals and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutically suitable excipient. . Preferably, the compound of Formula (I) above was employed in no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being carrier (s) pharmaceutically inert.

The active compound is effective in a large percentage of dose and is generally administered in a pharmaceutically effective amount. It can be understood, however, that the amount of the compound currently administered will be determined by a physician, in light of the relevant circumstances, which include the condition to be treated, the chosen route of administration, the current compound administered and its relative activity. , the age, weight, and response of the patient individual, the severity of the patient's symptoms, and the like.

For the preparation of compositions such as tablets, the active main ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is proposed that the active ingredient is equally dispersed throughout the compositions so that the composition can be easily subdivided into equally effective dosage unit forms such as tablets, pills and capsules. This solid preformulation is then subdivided into dosage unit forms of the type described above that contain from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form that provides the long-acting advantage. For example, the tablet or pill may comprise an internal dose and external dose component, the second one being in the form of a wrap over the previous one. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric or coated layers, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as lacquers, cetyl alcohol, and cellulose acetate.

Liquid forms in which the novel compositions of the present invention can be incorporated for oral administration or injection include aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as corn oil, seed oil of cotton, sesame oil, coconut oil, or walnut oil, as well as elixirs and pharmaceutically similar vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in aqueous or organic solvents, or mixtures thereof, and pharmaceutically acceptable powders. The liquid or solid compositions may contain pharmaceutically acceptable acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions in pharmaceutically acceptable solvents can be atomized by the use of inert gases. The atomized solutions can be inhaled directly from the atomizing device or the nebulizer device can be attached to a chamber mask, or positive pressure breathing machine. Solutions, suspensions, or powder compositions may be administered preferably, orally or nasally, from devices that release the formulation in an appropriate manner.

EXAMPLES The following preparations and examples are given to enable those qualified in the state of the art greater clarity of understanding and to practice the present invention. These should not be considered as limiting the scope of the invention, but merely as being illustrative and representative of it.

In the examples below, the following abbreviations have the following meanings. Unless stated otherwise, all temperatures are in degrees Celsius. If an abbreviation is not defined this will have its generally accepted meaning. Á = .Angstroms cm = centimeter DCC = dicyclohexyl carbodiimide DMF = N, N-dimethylformamide DMSO = dimethylsulfoxide g = gram HPLC = high performance liquid chromatography MEM = minimal essential medium MIN = minute mL = milliliter mm = millimeter mmol = minimolar N = normal "" THF = tetrahydrofuran μL = microliters μm = microns rt = room temperature RF = retention faction NMR = nuclear magnetic resonance ESMS = electroaerosol mass spectrum ppm = parts per million Synthetic Examples E emplo 1 Synthesis of trans-1, -bis. { N- [2- (4-hydroxy-3-hydroxymethylphenyl) -2- Hydroxyethyl} Not me} cyclohexane (Figure 5 below) Stage 1 To a solution 11 of methyl ester 5-acetylsalicylic acid (5.0 g, 25.7 mmol) in dimethyl sulfoxide (44 mL) was added 48% hydrobromic acid. The resulting mixture was stirred at 55 ° C for 24 hours, and placed in a paste of ice and water (200 mL), precipitating a pale yellow solid. The solid was filtered, washed with water (200 mL), and dried to give 12 a, a-dihydroxy-4-hydroxy-3-methoxycarbonyl acetophenol. The product was resuspended in ethyl ether (-200 mL), filtered and dried to give (3.41 g, 59%) of pure product. Rf = 0.8 (10% MeOH / CH2Cl2).

HX-NMR (4 / ICDCL3 / CD3OD, 299.96 MHz): d (ppm) 8.73-8.72 (d, 1H), 8.28-8.24 (dd, 1H), 7.08-7.05 (d, 1H), 5.82 (s, 1H) ), 4.01 (s, 3H).

Stage 2 To a suspension 12 of, -dihydrixi-4-hydroxy-3-methoxycarbonyl-acetophenone (0.3 g, 1.3 mmol in THF (10 mL) was added a solution of trans-1,4-diaminocyclohexane (76 mg, 0.66 mmol). in THF (5mL), the resulting suspension was stirred for 3 hours at room temperature under nitrogen atmosphere, to which formation of an imine was completed and estimated by TLC analysis.After cooling the resulting solution in ice bath, it was added a surplus amount of 3M BH3-Me2S in hexane (4 L, 8 molar) to the previous solution The resulting mixture was slowly warmed to rt and refluxed for 4 hours under N2 stream After cooling the reaction of the mixture, MeOH (5 mL) was added to quench the excess amount of 2M BH3-Me2S.After stirring for 30 min, the final solution (or turbid solution was evaporated in vacuo, yielding a pale brown solid.The solid was washed with EtOAc hexane (1/2; mL), and dried. crude was dissolved in 50% MeCN / H20 containing 0.5% TFA, and purified by pre-scaling high performance liquid chromatography (HPLC) using a linear gradient (5% to 50% MeCN / H20 for 50 minutes, mL / min; detection at 254 nM). Fractions with UV absorption were analyzed by LC-MS to isolate 13 trans-1,4 bis. { N- [2- (4-hydroxy-3-hydroxymethyl-phenyl) -2-hydroxyethyl] amino} cyclohexane.

HX-NMR (CD30D, 299.96 MHz): 5 (ppm) 7.35 (d, 2H), 7.18 (dd.2H), 6.80-6.78 (d 2H), 4.88-4.86 (m, 2H), 4.65 (s, 4H ), 3.15 (br 4 H), 2.89 (m 2 H), 1.68-1.55 (br m, 4 H); ESMS (C2H34N206): caled. 446.5, obsd. 447.5 (M + H) ".

Compound 14: Proceeding as described above but substituting trans-1, -diamino-cyclohexane with 4,4 '-methylene bis (cyclohexylamine) dio bis. { 4, 4 '- [N- [2- (4-hydroxy-3-hydroxymethylphenyl-2-hydroxyethyl] amino] cyclohexane] methane ESMS (C3? H46? 206): caled, 542.7, obsd. 543.6 [M + H] ~ Compound 15: Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 1,3-cyclohexane bis (methylamine) gave 1,3-bis {N- [2- (4 -hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] aminomethyl] cyclohexane ESMS (C27H38? 206): caled 474.6, obs 475.3 [M + H] ".

Compound 16: Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 1,8-diamino-p-menthane gave 1,8-bis (? - (2- (4-hydroxy-3-hydroxymethylphenyl- 2-hydroxyethyl) amino) -p-menthane ESMS (C28H42? 206): caled, 502.6, obs 503.3 [M + H] ".

Compound 17: Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 1,4-bis (3-aminopropyl) piperazine gave 1,4-bis. { 3- [[N-2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] propyl} piperazine. ESMS (C28H44? 406): caled. 532.6, obsd. 533.3 [M + H] +, 550.0 (M +? A) ".

Compound 18: Proceeding as described above but substituting trans-1,4-diaminocyclohexane with p-xylylenediamine gave 1,4-bis. { N- [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] aminomethyl} benzene. ESMS (C26H32? 206): caled. 468.5, obsd. 469.3 [M + H] +, 492.0 [M +? A] +.

Compound 19: Proceeding as described above but substituting trans-1,4-diaminocyclohexane with m-xylylenediamine gave 1,3-bis. { N- [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] -aminomethyl} benzene. ESMS (C26H32? 20e): caled. 468.5, obsd. 469.3 [M + H] +, 492.0 [M +? A] +.

Compound 20: Which proceeds as described above but substituting trans-1,4-diamino-cyclohexane with 2-aminobenzylamine gave 1-. { N- [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] aminomethyl} -2- . { ? - [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino-benzene. ESMS (C25H3o? 206): calcd. 454.5, obsd. 455.3 [M + H] ".

Compound 21: Proceeding as described above substituting trans-1,4-diamino-cyclohexane with 2- (4-aminophenyl) ethylamine gave l-. { 2- [N-2- [(4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] ethyl} -2- . { N- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] benzene. ESMS (C26H32? 206) caled. 468.5, obsd. 469.3 [M + H] +.

Compound 22: Proceeding as described above but substituting trans-1,4-diamino-cyclohexane with 4, '-oxidianiline gave 4,4'-bis. { ? - [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] amino} phenyl ether. ESMS (C3oH32N207): caled. 532.6, obsd. 533.3 [M + H] +, 556.1 [M + Na] +.

Compound 23: Proceeding as described above but substituting trans-1,4-diaminocyclohexane with 2-aminobenzylamine gave 1-. { N- [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] aminomethyl} -4- . { N- [2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] amino} benzene. ESMS (C25H3o? 206): caled. 454.5. obs. 455.5 [M + H] +, 477.3 [M +? A] +.

Example 2 Synthesis of l-. { 2- [N-2- [(4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] ethyl} -4- . { N- [2-phenyl-2-hydroxyethyl] amino] benzene (Figure 6 below) To a suspension 12 of α, α-dihydroxy-4-hydroxy-3-methoxycarbonyl acetophenone, prepared in Example 1, Stage 1, above (0.3 g, 1.33 mmolar) in (10 mL) of THF was added a solution of 2- (4-aminophenyl) ethylamine (0.181 g, 1.33 mmol) in THF (5 mL). The resulting suspension was stirred for 3 hours at room temperature under a nitrogen atmosphere, followed by addition of 24 a, a-dihydroxy-acetophenone (0.2 g, 1.32 mmol). The reaction mixture was stirred for 3 hours at RT, at which imine formation was completed and evaluated by TLC analysis. The reaction mixture was cooled in an ice bath and an excess amount of 2M BH-Me2S in hexane was added (9mL; 18 mmolar). The resulting mixture was slowly warmed to rt, and refluxed for 4 hours under N2 stream. After cooling, MeOH (10 mL) was added to quench the excessive amount of BH3-Me2S. After stirring 30 min., At rt, the final solution (or turbid suspension) was evaporated in vacuo, to give a pale brown solid. The solid was washed with EtOAc / hexane (1/2, 20 mL), and dried. The crude product was dissolved in 50% MeCN / H20 containing 0.5% TFA, and purified by high performance liquid chromatography pre-scale (HPLC) using a linear gradient (5% at 50% MeCN / H20 for 50 min., 20 mL / min, detection at 254 nM).

Fractions with UV absorption were analyzed by LC-MS to locate 26 μl. { 2- [N-2- [(4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] -ethyl} -4- . { N- [2-phenyl-2-hydroxyethyl] amino] benzene. ESMS (C25H3oN204): caled. 422.5, obsd. 423.3 (M + H) ".

Compound 27: Proceeding as described above, but substituting a, a-dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone with a, a-dihydroxyacetoferione gave l-. { 2- [N- [2-phenyl-2-hydroxyethyl] aminoethyl} -4- [? - (2-phenyl-2-hydroxyethyl) amino] -benzene. ESMS ((C24H28? 208): caled 376. 5, obs 377. 0 (M + H). " Example 3 Synthesis of 1-. { 2- [N-2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] ethyl} -4- [N- (2-phenyl-2-hydroxyethyl) amino] enne (Figure 7 below) Stage 1 To a solution of 4- (2-aminoethyl) aniline (20 g, 147 mmol) in methanol (250 mL) was added (Boc) 20 (32.4 g, 148 mmol) in methanol (50 mL) at rt. After stirring for 24 hours, the reaction mixture was concentrated to dry to give a pale yellow oily residue. The oily material slowly solidified; thus, it was dissolved in 5% MeOH / CH2CL2 and subsequently column chromatography was applied in silica flash (3 to 10% MeOH / CH2CL2). After purification, 28-4 (N-Boc-2-aminoethyl) aniline was obtained as a pale yellow solid (32.95g, 95%): Rf = 0.6 in 10% MeOH / CH2CL2. 2H-NMR (CD3OD, 299.96 MHz): d (ppm) 6.96-6.93 (d, 2H), 6.69-6.65 (d, 2H), 3.20-3.13 (q, 2H), 2.63-2.58 (t, 2H) 1.41 (s, 9H).

Stage 2 28- (N-Boc-2-aminoethyl) aniline (1.25 g, 5.29 mmol) was dissolved in methanol (30 mL), followed by the addition of 24 phenylglyoxal (0.708 g 5.28 mmol). The reaction mixture was stirred for 1 hour at rt, prior to the addition of ? BC? BH3 (0.665 g, 10.6 mmol) The final mixture was stirred for 12 hours at rt, concentrated, and purified by silica flash column chromatography (2 to 5% MeOH / CH2CL2) to give N- (2- phenyl-2-hydroxyethyl) -4- (N-Boc-2-aminoethyl) -aniline as a pale yellow oil (1.71 g, 91%): Rf = 0.18 in 5% MeOH / CH2CL2. XH-? MR (CD3OD, 299.96 MHz): d (ppm) 7.4-7.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H) ), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s.9H).

Stage 3 A solution of N- (2-phenyl-2-hydroxyethyl) -4- (N-Boc-2-aminoethyl) aniline (1.7 g, 4.77 mmol) in methylene chloride (10 mL) was cooled in an ice bath, and TFA (10 mL) was slowly added under a stream of nitrogen in gas. The reaction mixture was stirred for 1 hour, and concentrated to yield a pale yellow oil. The crude material was purified by reverse phase HPLC (10% to 40% MeCN / H20 above 50 min, 20 mL / min) to give 29 N- (2-phenyl-2-hydroxyethyl) -4- (2- aminoethyl) aniline as TFA salt (1.1 g). ^ - MR (CD3OD, 299.96 MHz): d (ppm) 7.42-7.3 (m, 5H), 7.29-7.25 (d, 2H), 7.12-7.0 (d, 2H) 4.85- 4.82 (m, 1H), 3.45 -3.35 (m, 2H), 3.18-3.1 (t, 2H), 2.98- 2.94 (t, 2H); ESMS (C? 6H20? 2O?): Caled. 256.4, obs. 257.1 [M + H] +, 278.8 [M +? A] ", 513.4 [2M + H] +.

Stage 4 To a solution 29 of trifluoroacetate salt N- (2-phenyl-2-hydroxyethyl) -4- (2-aminoethyl) aniline (1.1 g, 2.3 mmolar) in methanol (10 mL) was added 5 M? AOH solution ( 0.93 mL): After stirring for 10 min., The solution was concentrated for drying. The residue was dissolved in (25 mL) THF, and 12 a, a-dihydroxy-4-hydroxy-3-methoxy-carbonylacetophenone (0.514 g, 2.27 mmol) was added. The reaction mixture was stirred for 12 hours at rt, cooled to 0 ° C, and BH3 / Me2S (1.14 mL, 10 M) was added under a nitrogen atmosphere. The reaction mixture was gradually warmed to rt, stirred for 2 hours at rt, and refluxed for 4 hours. The reaction mixture was cooled and methanol (10 mL) was added slowly. After stirring for 30 min. At rt, the reaction mixture was concentrated to give a solid residue, which was dissolved in MeOH (20 mL) containing 19% TFA. Evaporation of the organics yielded a pale yellow oil which was purified by reverse phase HPLC: 10% to 30% MeCN / H20 over 50 min., 20 mL / min to give 30 l-. { 2- [N-2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] -amino] ethyl} -4- [N- (2-phenyl-2-hydroxyethyl) -amino] benzene as the TFA salt (0.65 g). 1H-KMR (CD3OD, 299.96 MHz): d (ppm) 7.42-7.3 (m, 6H), 7.28-7.24 (d, 2H), 7.18-7.14 (dd.1H), 7.1-7.07 (d, 2H), 6.80-6.77 (d, 1H), 4.86-4.82 (m, 2H), 4.65 (s, 2H), 3.44-3.34 (m, 2H), 3.28-3.22 (m, 2H), 3.20-3.14 (m, 2H) ), 3.04-2.96 (m, 2H); ESMS (C25H3oN204): caled. 422.5, obsd. 423.1 [M + H] ", 404.7 [M-1H20]", 387.1 [M-2H20] ~.

Example 4 Synthesis of 1- (2- (N-2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] aminoethyl} -4- [N- (2-phenyl-2- (S) -hydroxyethyl) amino] benzene (Figure 8 below) Stage 1 A solution of 28 4- (N-Boc-2-aminoethyl) aniline (7.0 g, 29. 6 mmolar) in ethanol (100 mL) and (R) -oxidostyrene (3.56 g, 29.6 mmolar) was refluxed for 24 hours. The organics were removed to give a pale yellow solid. N- (2-phenyl-2- (S) -hydroxyethyl) -4- (N-Boc- 2-aminoethyl) aniline was removed by flash column chromatography on silica: 1/2 EtOAc / hexane at 3/1 EtOAc / hexane to 3% MeOH in 3/1 EtOAc / hexane: Rf = 0.39 in 3% MeOH / CHjCl.,.

Stage 2 A solution of N- (2-phenyl-2- (S) -hydroxyethyl) -4- (N-Boc-2-aminoethyl) -aniline (2.5 g, 7.0 mmolar) in CH2CL2 (15 mL) was cooled in a bath of ice under a stream of nitrogen and slowly added TFA (15 mL). The reaction mixture was stirred for 2 hours at 0 (g) C and then concentrated in vacuo. The crude product was dissolved in 20% MeC? / H20 and purified by preparative reverse phase HPLC (5 to 2% MeC? / H20 above 50 min; 254 nm; 20 mL / min.), To give 31 salt of trifluoroacetate aniline N- (2-phenyl-2- (S) -hydroxyethyl) -4- (2-aminoethyl) as a dye oil. ^ - MR (CD3OD, 299.96 MHz): d (ppm) 7.45-7.25 (m, 9H), 4.9 (dd, 1H), 3.55-3.45 (, 2H), 3.21-3.15 (t, 2H), 3.05-2.95 (t, 2H) ESMS (C? 6H20? 2O?): caled. 256.4, obs. 257.1 [M + H] +, 280.2 [M +? A] +.

Stage 3 To a solution 31 of aniline trifluoroacetate N- (2-phenyl-2- (S) -hydroxyethyl) -4- (2-aminoethyl) (0.144 g, 0.33 mmolar) in methanol (10 mL) was added aq. ? aOH (1.0 M, 0.625 mL). The solution was concentrated for drying and the residue was dissolved in anhydrous THF (5mL). 12 a, -Dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone (0.067 g, 0.3 mmol) was added and the reaction mixture was stirred for 12 hours at rt. BH3-Me2S (0.2 mL, 2M) was added at 0 ° C and the reaction mixture was heated to 75 ° C for 6 hours. After cooling the reaction mixture in an ice bath, MeOH (5 mL) was slowly added to quench the reaction, and the reaction mixture was stirred for 30 min., At rt. The organics were removed and the residue was dissolved in TFA / MeOH (1/9, 20 mL), and concentrated. The crude product was dissolved in 20% MeCN / H20, and purified by preparative HPLC: 5 to 20% MeCN / H20; 20 mL / min; 254 nm.) To give 33 l-. { 2- (N-2- (4-hydroxy-3-hydroxy-methylphenyl) -2-hydroxyethyl] amino] ethyl.} -4- [N- (2-phenyl-2- (S) -hydroxyethyl) -amino ]benzene.

XH-NMR (CD3OD, 299.96 MHz): d (ppm) 7.42-7.29 (, 8H), 7.22-7.18 (d, 2H), 7.17-7.14 (dd, 1H), 6.80-6.77 (d, 1H), 4.9 -4.85 (m, 2H), 4.65 (s, 2H), 3.5-3.34 (m, 2H), 3.28-3.25 (, 2H), 3.19-3.14 (m, 2H), 3.04-2.98 (m, 2H); ESMS (C25H3oN204): caled. 422.5, obsd. 423.1 [M + H] \ 446.1 [M + Na] +.

Proceeding as described above in Example 4 but substituting (R) - styrene oxide with (S) -oxide-styrene gave 34 l-. { 2- [N-2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] amino] ethyl} -4- [N- (2-phenyl-2- { R) -hydroxyethyl) amino] benzene.

-NMR (CD3OD, 299.96 .MHz): d (ppm) 7.42-7.28 (m, 8H), 7.20-7.1 (, 3H), 6.80-6.77 (d, 1H), 4.9-4.85 (m, 2H), 4.65 (s, 2H), 3.45-3.34 (m, 2H), 3.28-3.25 (m, 2H), 3.19-3.15 (m, 2H), 3.04-2.98 (m, 2H); ESMS (C25H3oN204): caled. 422.5, obsd. 423.1 [M + H] +, 446.1 [M + Na] +.

Example 5 Synthesis of 1,6-bis. { 4- (N- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl] aminoxyloxypropyl] phenoxy] hexane (Figure 9 below) Stage 1 A solution of 3- (4-hydroxyphenyl) -1-propanol (3.3 g, 21.7 mmol) and 1,2-di-iodohexane (3.5 g, 8.88 mmol) in dimethylsulfoxide (40 mL) was degassed and saturated with gas 2 and potassium carbonate (4.5 g, 32.56 mmolar) was added. The reaction of the mixture was stirred at 80 ° C for 18 hours under nitrogen atmosphere and then quenched with saline solution (150 mL). The product was extracted with RtOAc (200 mL) and the organic extracts were washed with 0.1 M NaOH and saline, and dried with MgSO4. The organics were removed in vacuo to give a pale brown solid. The solid was purified by silica flash column chromatography: 4/1 hexane / EtOAc to 5% MeOH in 1/1 hexane / EtOAc to give 36 1, 6-bis [4- (3-hydroxypropyl) phenoxy] hexane (Rf = 0.17 in 1/1 hexane / EtOAc) in 65% yield (2.23 g). XH-NMR (CD3OD, 299.96 MHz): d (ppm); 7.08-7.05 (d, 4H), 6.80-7.77 (d, 4H), 3.93-3.89 (t, 4H), 3.56-3.52 (t, 4H), 2.64-2.56 (t, 4H), 1.81-1.69 (, 8H), 1.44-1.21 (m, 4H).

Stage 2 A solution of 36 1, 6-bis [4- (3-hydroxypropyl) phenoxy] hexane (2.2 g, 5.69 mmol) in DMF (10 mL) containing NaH (0.57 g, 60% dispersion in mineral oil) was added to 0 ° C under nitrogen atmosphere and the reaction of the mixture was heated to 50 ° C. After 1 hour, 6-bromohexanonitrile (2.26 mL, 17 mmol) was added and the reaction of the mixture was heated to 80 ° C. 24 hours. The reaction of the mixture was quenched with saline (100 mL) and extracted with EtOAc (250 mL). The organic phase was washed with saline, dried with MgSO, and evaporated in vacuo, to give a pale yellow oil. Purification by silica gel column chromatography: 4/1 to 1/1 hexane / EtOAc gave 37 1, 6-bis [4- (5-cyanopentyloxypropyl) phenoxy] hexane product (Rf = 0.6 in 1/1 EtOAc / hexane ). XH-NMR (CDCl 3 OD, 299.96 MHz): d (ppm); 7.09-7.06 (d, 4H), 6.82-6.79 (d, 4H), 3.94-3.90 (t, 4H), 3.42-3.37 (m, 8H), 2.64-2.58 (t, 4H), 2.40-2.32 (m , 8H), 1.90-1.26 (m, 24H).

Stage 3 To 37 1, 6-bis [4- (5-cyanopentyloxypropyl) phenoxy] hexane (0.278 g, 0.48 mmolar) obtained in Step 2 above was added to a mixture of conc. HCl 810 mL) and AcOH (2 mL) and the reaction of the mixture was diluted with saline (50 mL), extracted with EtOAc (100 mL), and dried with MgSO4. Evaporation of the organic phase afforded 38-l, 6-bis [4- (5-carboxypentyl-oxypropyl) phenoxy] hexane as a pale yellow oily residue, which was used in the next Step without further purification. - "? - NMR (CDCl 3, 299.96 MHz): d (ppm); 7.09-7.07 (d, 4H), 6.82- 6.79 (d, 4H), 3.96-3.92 (t, 4H), 3.42-3.56 (m, 8H), 2.64-2.59 (t, 4H), 2.39-2.32 (m , 4H), 1.91-1.40 (m, 24H).

Stage 4 To a solution 39 2-hydroxy-2- (4-benzyloxy-3-hydroxymethylphenyl) -ethylamine (0.263 g, 0.96 mmolar) in DMF (8 mL) was added 1,6-bis [4- (5-carboxypentyloxypropyl) phenoxy] ] exano (-0.48 mmolar), obtained in Stage 3 above, HOBt (0.13 g, 0.96 mmolar), DIPEA (0.21"mL, 1.20 mmolar), and PyBOP (0.502 g, 0.96 mmolar) After stirring for 24 hours At rt, the reaction of the mixture was diluted with saline (20 mL) and extracted with EtOAc (50 mL) .The organic layer was washed with 0.1 M NaOH, 0.1 M HCl, and saline, and dried over MgSO 4 The organic solvents were removed in vacuo to give 1,6-bis [4- (5-amidopentioxypropyl) -phenoxy] hexane as a pale yellow oily residue (0.45 g).

Stage 5 A solution of 1,6-bis [4- (5-amidopentioxypropyl) -phenoxy] hexane (0.45 g, 0.4 mmol) obtained in Step 4 above, in anhydrous THF (10 mL) was added to a solution of LiAlH4 (0.16). g, 4.22 mmol) in anhydrous THF (49 mL) at 0 ° C. The reaction mixture was stirred for 4 hours at 80 ° C under nitrogen atmosphere and then quenched with 10% NaOH (1 mL at 0 ° C). C. After 30 min., The reaction of the mixture was precipitated and filtered and the precipitate was washed with 10% MeOH in THF (50 mL). The filtrates were combined and evaporated in vacuo to give a pale yellow oily residue. Purification by flash silica gel column chromatography: 5% MeOH / CH2Cl2 at 3% i-PrNH2 in 10% MeOH / CH2Cl2 gave 1,6-bis [4- (5 (aminoxyloxypropyl) -phenoxy] hexane. XH-NMR (CDC13, 299.96 MHz): d (ppm), 7.40-7.25 (m, 12H), 7.22-7.18 (d, 2H), 7.09-7.02 (d, 4H), 6.91-6.88 (d, 2H) , 6.81-6.75 (d, 4H), 5.01 (s, 4H), 4.8-4.75 (m, 2H), 4.70 (s, 4H), 3.96-3.83 (q, 4H), 3.4 2-3.34 (m, 8H), 2.84-2.64 (, 8H), 2.62- 2.56 (t, 4H), 1.84-1.75 (m, 8H), 1.57-1.50 (m, 10H), 1. 34-1.23 (m, 10H).

Stage 6 A solution of 1,6-bis [4- (5 (aminoxyloxypropyl) -phenoxy] hexane (0.16 g, 0.15 mmol) obtained in Step 5 above, in EtOH (40 mL) was hydrogenated under H 2 atmosphere (1 atm) with 10% Pd / C catalyst (100 mg) at rt for 24 hours The catalyst was filtered and the filtrate was concentrated to give the crude product as a pale yellow oil Purification by reverse phase HPLC: 10 to 50% MeCH / H20 over 40 min; 20 mL / min; 254 nm yields 40 1, 6-bis. {4- (N- [2- (4-hydroxy-3-hydroxymethyl-phenyl) -2-hydroxyethyl] (aminoxyloxypropyl) ] -phenoxy] hexane, H ^ NMR (CD3OD, 299.96 MHz): d (ppm), 7.35 (d, 2H), 7.18-7.15 (dd, 2H), 7.08-7.05 (d, 4H), 6.82-6.77 ( m, 6H), 4.65 (s, 4H), 3.96-3.92 (t, 4H), 3.45-3.34 (m, 8H), 3.12-3.01 (m, 6H), 2.94-2.89 (t, 2H), 2.62- 2.57 (t, 4H), 1.86-1.43 (m, 28H); ESMS (C54H8oN2O? O): caled, 917.1, Obs, 917.5 [M] ", 940.8 [M + Na] +.

Example 6 Synthesis of l-. { 2- [N-2- (4-hydroxy-3-hydroxymethylphenyl) -2- (R) -hydroxyethyl] aminoethyl} -4- [? - (2-phenyl-2- (S) -hydroxyethyl) amino] phenyl (Figure 10 below) Stage 1 A mixture of 4- (N-Boc-2-aminoethylaniline) was refluxed (10 g, 42.34 mmolar), benzaldehyde (4.52 mL, 44.47 mmolar), and molecular sieves of 4Á (10 g) in toluene (100 mL) at 95 ° C for 15 hours. The reaction of the mixture was filtered and the filtrate was concentrated in vacuo to give a dye oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and? AC? BH3 (2.79 g, 44.4 mmol) were added. The reaction of the mixture was stirred at 0 ° C for 1 hour and at rt for 2 hours and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash column chromatography on silica: 1/1 hexane / EtOAc gave 41 N-benzyl-4- (N-Boc-2-aminoethyl) aniline as a coloring oil (11.5 g, 83%). Rf = 0.75 in 1/1 hexane / EtOAc. H ^? MR (CD3OD, 299. 96 MHz): d (ppm); 7.38-7.2 (m, 5H), 6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H) ), 1.4 (s, 9H); ESMS (C20H26? 2O2): caled. 326.4, Obsd. 328 [M + H] +.

Stage 2 A mixture 41 of N-benzyl-4- (N-Boc-2-aminoethyl) aniline (10 g, 30.7 mmol) and (R) styrene oxide (3.51 mL, 30.7 mmol) in EtOH (100 mL) was refluxed for 24 hours. h. A small aliquot of the reaction mixture was taken for liquid chromatographic analysis, which indicated that the nearby 2- [(N-benzyl-4- [2-N-Boc-aminoethyl] anilino] -1-phenylethanol was formed as a minor product in parallel with another regio-isomer 2- [(N-benzyl-4- [2-N-Boc-aminoethyl) anilino] -2-phenyl-ethanol in a percentage of ~ l / 2. Evaporation of the solution gave pale, coarse yellow oil, the cell was purified by flash column chromatography on silica: 4/1 to 2/1 hexane / EtOAc. After repeated chromatography, 2- [(N-benzyl-4-N-Boc-aminoethyl) anilino] -1-phenyl-ethanol was obtained as a dye oil (4.01 g, 29%) (Rf = 0.76 in 2). Hexane / EtOAc). H1-? MR (CD3OD, 299.96 MHz): d (ppm); 7.4-7.1 (m, 10H), 7.1-7.6 (d, 2H), 6.68-6.65 (d, 2H), 5.0 (t, 1H), 4.52-4.46 (d, 1H), 4.26-4.22 (d, 1H) ), 3.76-3.68 (dd, 1H), 3.56-3.48 (dd, 1H), 3.22-3.12 (m, 2H), 2.68-2.56 (m, 2H), 1.41 (s, 9H); ESMS (C28H34? 203): caled. 446.6, obsd. 447.1 [M + H] +.

Stage 3 To a solution of 2- [(N-benzyl-4- [N-Boc-aminoethyl] anilino] -1-phenyl-ethanol (4.01 g, 8.99 mmolar) in CH2C12 (15 L) kept in an ice bath was added TFA (15 mL) under an atmosphere of nitrogen flow. After stirring at 0 ° C for 30 min., The reaction of the mixture was concentrated in vacuo to give a pale yellow oil. Purification by flash chromatography of silica: (1/2 hexane / EtOAc at 5% i-PrNH2 in hexane / EtOAc) gave 42 2- [(N-benzyl-4- [2-aminoethyl] anilino] -1-phenyl- ethanol as a pale yellow oil of such fractions with Rf of 0.2 (5% i-Pr? H2 in 1/2 hexane / EtOAc) in 74% yield (2.29 g). H ^? MR (CD30D, 299.96 MHz): d (ppm); 7.38-7.6 (m, 10H), 7.01-6.98 (d, 2H), 6.71-6.68 (d, 2H), 5.02-4.96 (dd, 1H), 4.54-4.48 (d, 1H), 4.29-4.23 (d , 1H), 3.76-3.67 (dd, 1H), 3.58-3.50 (dd, 1H), 2.82-2.74 (t, 2H), 2.64-2.59 (t, 2H); ESMS (C23H26? 20?): Caled. 346.5, obsd. 346.3 [M] +, Stage 4 A mixture of 42 2- [(N-benzyl-4- [2-aminoethyl] anilino] -1-phenyl-ethanol (2.28 g, 6.59 mmol), benzaldehyde (0.74 mL, 7.28 mmol), and 4 A sieves (4 g) in toluene (40 mL) was heated at 90 ° C. for 14 hours.The reaction of the mixture was cooled and filtered, and the sieves were rinsed with toluene.The combined filtrates were concentrated to give an oily residue which was washed with hexane, and dried The residue was dissolved in MeOH (40 mL) containing AcOH (0.4 mL) and the reaction of the mixture was cooled in an ice bath, NaCNBH3 (0.62 g, 9.87 mmol) was added and the reaction the mixture was stirred for 2 hr rt, and then concentrated.The oily residue was dissolved in 60% MeCN / H20, and purified by preparative reverse phase liquid chromatography (40 to 80% MeCN / H20, for 30 minutes: 30 mL / min to give 2- [(N-benzyl-4- [2-N-benzylaminoethyl] anilino] -1-phenylethanol as the TFA salt: The product was treated with alkaline saline, and extracted with ether (200 mL) The organic layer was dried with NaS0, and concentrated, to give 43 2- [(N-benzyl) 4- [2-N-benzylaminoethyl) anilino] -1-phenylethanol as a dye oil (1.36 g) HX-? MR (CD3OD, 299.96 MHz): d (ppm); 7.36-7.6 (m, 15H), 6.98-6.95 (d, 2H), 6.69-6.60 (d, 2H), 5.01-4.96 (t, 1H), 4.54-4.47 (d, 1H), 4.29-4.24 (d , 1H), 3.73 (s, 2H), 3.72-3.68 (dd, 1H), 3.59-3.54 (dd, 1H), 2.80-2.74 (m, 2H), 2.70-2.64 (m, 2H); ESMS (C30H32? 2O?): Caled. 336.6, obsd. 437.2 [M + H] ".

Stage 5 A concentrated solution of 2- [(N-benzyl-4- [2-N-benzylaminoethyl] anilino] -1-phenylethanol (1.36 g, 3.12 mmolar) and the compound 44 (S) -4-benzyloxy-3-methoxycarbonyl styrene oxide ( 0.887 g, 3.12 mmolar, ~ 95% ee) (prepared as described in R.Hett, R. Stare, P. Helquis, Tet.Lett., 35, 9375-9378, (1994)) in toluene (lmL9 warmed at 105 ° C for 72 hours under nitrogen atmosphere The reaction of the mixture was purified by flash column chromatography (2/1 hexane EtOAc for 3% MeOH in 1/1 hexane / EtOAc) to give 45 - { 2- [N-benzyl-N-2- (4-benzyloxy-3-methoxycarbonylphenyl) -2- (R) -hydroxy] ethylaminoethyl} -4- [N- (2-phenyl-2- (5) -hydroxy) ethylamino] benzene (Rf = 0.62 in 3% MeOH in 1/1 hexane / EtOAc) was obtained as a pale yellow foam (2.0 g, 89%).

H ^? MR (CD3OD, 299.96 MHz): d (ppm); 7.67-7.66 (d, 1H), 7.38-6.0 (, 20H), 6.88-6.85 (d, 2H), 6.65-6.62 (d, 2H), 5.15 (s, 2H), 5.05-4.98 (t, 1H) , 4.6-4.54 (t, 1H), 4.53-4.46 (d, 1H), 4.28-4.22 (d, 1H), 3.84 (s, 3H), 3.72-3.64 (m, 3H), 3.56-3.46 (dd, 1H), 2.74-2.56 (m, 6H); ESMS (C47H48? 205): caled. 720.9, obsd. 721.4 [M + H] +, 743.3 [M +? A] +.

Stage 6 To a suspension of LIAH4 (0.211 g, 5.56 mmolar) in THF (40 mL) cooled with an ice bath was added 45 l-. { 2 - [β-Benzyl-β-2- (4-benzyloxy-3-methoxycarbonylphenyl) -2- (R) -hydroxyethyl] aminoethyl} -4- [? - (2-phenyl-2- (S) -hydroxyethyl) amino] benzene (2.0 g, 2.78 mmol) in THF (10 mL) under nitrogen atmosphere. The reaction of the mixture was slowly warmed to rt and the stirring was continued for 5 hours. The reaction was cooled to 0 ° C, and 10% of αaOH (0.5 mL) was added. After 30 min., A thick gel formed. The gel was diluted with THF (300 mL), filtered, and the solid mass was rinsed with THF (50 mL).

The filtrates were combined, and concentrated in vacuo, yielding an oily residue. The residue was purified by flash column chromatography on silica (2/1) hexane / EtOAc at 3% MeOH in 1/1 hexane / EtOAc) to give 1-. { 2- [N-Benzyl-N-2- (4-benzyloxy-3-hydroxymethylphenyl) -2- (R) -hydroxyethyl] aminoethyl} -4- [N- (2-phenyl-2- (S) -hydroxyethyl) amino] benzene as a dye oil (1.28 g, 67%). HX-? MR (CD3OD, 299.96 MHz): d (ppm) 7.4-7.0 (m, 22H), 6.85-6.82 (m, 3H), 6.63-6.60 (d, 2H), 5.02-4.84 (m, 3H) , 4.66 (s, 2H), 4.59-4.54 (dd, 1H), 4.48-4.4 (d, 1H), 4.24-4.16 (d, 1H), 3.76-3.7 (d, 1H), 3.69-3.62 (dd, 1H), 3.58-3.52 (s, 1H), 3.50-3.44 (dd, 1H), 2.76-2.54 (m, 6H); ESMS (C46H48? 204): caled. 692.90, obs. 693.5 [M + H] +.

Stage 7 A solution of l- was hydrogen. { 2- [N-benzyl] -N-2- (4-benzyloxy-3-hydroxymethylphenyl) -2- (R) -hydroxyethyl] amino] ethyl} -4- [N-2-phenyl-2- (5) -hydroxyethyl) amino] -benzene (1.28 g, 1.85 mmol) in EtOH (80 mL) under H2 (1 atm) with 10% Pd / C (0.6 g ) for 36 hours. After filtration and rinsing the catalyst with EtOH (50 mL), the filtrates were combined, and evaporated in vacuo, yielding a pale yellow foam which was dissolved in 10% MeC? / H20, and purified by preparative liquid chromatography. of reverse phase (10 to 30% MeC? / H20 (containing 0.3% TFA) over 50 min; 30 mL / min; 254 nm) to give l-. { 2- [N-2- (4-hydroxy-3-hydroxymethyl-phenyl) -2- ^ (R) -hydroxyethyl] aminoethyl} -4- [N- (2-phenyl-2- (S) -hydroxyethyl) -amino] benzene as the TFA salt (0.6 g, 50%). Optical purity of 46 l-. { 2- [N-2- (4-hydroxy-3-hydroxymethylphenyl) -2- (R) -hydroxyethyl] aminoethyl} -4- [N- (2-phenyl-2- (S) -hydroxyethyl) amino] benzene which was analyzed with capillary electrophoresis by use of the chiral medium, and estimated to be ~ 93%.

H ^? MR (CD30D, 299.96 MHz): d (ppm) 7.42-7.28 (m, 8H), 7.26-7.22 (d, 2H), 7.18-7.14 (dd, 1H), 6.80-6.77 (d, 1H) , 4.88-4.82 (m, 2H), 4.65 (s, 2H), 3.5-3.43 (m, 2H), 3.29-3.26 (m, 2H), 3.19-4.14 (m, 2H), 3.06-3.0 (m, 2H), ESMS (C25H30? 2O4): caled. 422.5, obsd. 423.1 [M + H] +, 445.4 [M +? A] +.

Example 7 Synthesis of l-. { 6- [N- [2- (4-hydroxy-3-hydroxymethylphenyl) -2- [hydroxyethyl] -amino] hexyloxy} -4- . { 6- [N- [2- (4-hydroxy-3-hydroxyethylphenyl) -2-hydroxyethyl] amino] hexyloxypropyl} Benzene (Figure 11 below) Stage 1 A solution of 3- (4-hydroxyphenyl) -1-propanol (2.0 g, 13.1 mmol) in DMF (5 mL) was added to a solution of DMF (35 mL) containing NaH (1.31 g, 60% in mineral oil). ) at 0 ° C under nitrogen atmosphere. The reaction mixture was slowly warmed to 80 ° C. After stirring for one hour at 80 ° C, the reaction mixture was cooled to 0 ° C, and 6-bromohexanonitrile (5.78 g, 32.83 mmol) was added. The final mixture was re-heated to 80 ° C and stirred for 24 hours. The reaction mixture was rinsed with saturated NaCl solution (200 mL), and the product was extracted with EtOAC (300 mL). The organic layer was washed with saline, dried with Na 2 SO 4, and evaporated for drying, yielding a pale yellow solid. Purification of the crude product by flash column chromatography on silica: 4/1 to 1/1 hexane EtOAc provided 6-. { 3- [4- (5-cyanopentyloxy) phenyl] propoxy} hexanonitrile in 30% yields (1.33 g). Rf = 0.63 in 1/1 EtOAc / hexane. H ^ MR (CDC13, 299.96 MHz): d (ppm) 7.09-7.07 (d, 2H), 6.81-6.78 (d, 2H), 3.96-3.92 (t, 2H), 3.42-3.37 (m, 4H), 2.64-2.58 (t, 2H), 2.39-2.32 (m, 4H), 1.87-1.52 (m, 14 H).

Stage 2 A solution of 6- was added. { 3- [4- (5-pentyloxy) phenyl] propoxy} hexanonitrile (1.33 g, 3.88 mmol) in THF (10 mL) to a solution of LiAlH4 (0.442 g, 11.65 mmol) in THF (50 L) at 0 ° C under nitrogen atmosphere. The reaction mixture was slowly heated to reflux, and stirred for 2 hours. The reaction mixture was cooled to 0 ° C, and 10% NaOH solution (5 mL) was slowly added. After 30 min., The reaction mixture was filtered, and the collected solids were washed with THF (100 mL). The filtrate was concentrated to yield a pale yellow oil which was purified by flash column chromatography on silica: 5% MeOH / CH2Cl2 at 3% i-PrNH2 / 20% MeOH / CH2Cl2 to give 6-. { 3- [4- (6-aminohexyloxy) -phenyl] propoxy} -hexylamine as a dye oil (0.5 g, 37%) which was converted to the desired compound by the procedure described above in Example 1, step 2. The crude product was purified by reverse preparatory HPLC phase: 10 to 40% MeCN / H20 above 40 min; 20 mL / min; 254 nm. ESMS (C39H58N208): caled. 682.8, obsd. 683.6 [M + H] ", 797.5 [M + CF3C02H] +.

Example 8 Synthesis of bis. { 2-. { 2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxy] ethylamino} -2-hydroxyethoxy} Benzene (Figure 12 below) Stage 1 To a solution of saturated N2 acetonitrile (300 mL) containing 50 methyl 5-acetylsalicylate (20 g, 0.1 molar) and benzyl bromide (13.5 mL, 0.11 mmol) was added K2C03 (28.5 g, 0.21 mmol). The reaction mixture was stirred at 90 ° C for 5 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated, in vacuo, yielding a white solid which was suspended in hexane (300 mL), and collected in a Buchner funnel to give 51 Methyl O-benzyl. -5-acetylsalicylate as a dye for white crystals (28.1 g, 96%). Rf = 0.69 in 1/1 EtOAc / hexane. HX-NMR (CDCL3, 299.96 MHz): d (ppm) 7.8.43-8.42 (d, 1H), 8.1-8.04 (dd, 1H), 7.5-7.28 (m, 5H), 7.08-7.04 (d, 1H ), 5.27 (s, 2H), 3.93 (s, 3H), 2.58 (s, 3H).

Stage 2 To a solution of 51 Methyl O-benzyl-5-acetylsalicylate (14.15 g, 0.05 mmolar) in CHC13- (750 L) was added bromine (2.70 mL, 0.52 mmolar). The reaction of the mixture was stirred at rt. While stirring, the reaction of the mixture gradually turned red-brown for coloration. The mixture was stirred for 2 hours at rt, and rinsed by the addition of saline (300 mL). After stirring the mixture in a separatory funnel the organic layer was collected, washed with saline and dried under Na2SO4. The organic solution was concentrated in vacuo, yielding a white solid. This was washed with ether (200 mL). After air drying, 15 g (83%) of 52 methyl O-benzyl-5- (bromoacetyl) -salicylate were obtained. Rf = 0.76 in 1/1 EtOAc / hexane. HX-NMR (CDCL3, 299.96 MHz): d (ppm) 8.48-8.46 (d, 1H), 8.14-8.08 (dd, 1H), 7.51-7.3 (m, 5H), 7.12-7.09 (d, 1H), 5.29 (s, 2H), 4.42 (s, 2H), 3.94 (s, 3H).

Stage 3 To a solution of DMF (60 mL) containing 52 methyl 0-benzyl-5- (bromoacetyl) -salicylate (7.08 g, 0.019 molar) was added NaN3 (1.9 g, 0.029 molar). After stirring at rt for 24 hours in the dark, the mixture was diluted with EtOAc (200 mL), and washed with a saline solution (3 x 200 mL) in a separatory funnel. The organic phase was dried under MgSO 4 and concentrated to obtain a pale red solid. This was purified by flash column chromatography on silica: 10 to 50% EtOAc / hexane. The desired product 53 methyl O-benzyl-5- (acidoacetyl) salicylate was obtained as white crystals (4.7 g, 74%). Rf = 0.68 in 1/1 EtOAc / hexane. H NMR (CDCL3, 299.96 MHz): d (ppm) 8.38-8.36 (d, 1H), 8.08-8.04 (dd, 1H) 7.5-7.3 (m, 5H), 7.12-7.09 (d, 1H), 5.29 (s, 2H), 4.53 (s, 2H), 3.94 (s, 3H).

Stage 4 To a gray suspension of LiAlH4 (2.74 g, 0.072 mmol) in THF (400 mL) cooled in an ice bath was added 53 methyl O-benzyl-5- (acidoacetyl) salicylate (4.7 g, 0.014 mmol) under nitrogen atmosphere . The reaction mixture was stirred at 0 ° C for 1 hour, and gradually warmed to rt. After stirring for 16 h at rt, the mixture was heated at 75 ° C for 3 h. The reaction mixture was cooled in an ice bath and slowly rinsed by adding 10% NaOH (10 mL). After stirring for 1 hour, the precipitates were filtered, and rinsed with 5% MeOH in THF (200 mL). The filtrates were combined, and concentrated in vacuo, yielding a pale yellow oily residue. The crude product was purified by flash silica gel column chromatography: 10% MeOH / CH2Cl2 at 5% i-PrNH2 in 30% MeOH / CH2Cl2, to give 39 2- (4-benzyloxy-3-hydroxymethylphenyl) -2-hydroxyethylamine as a pale yellow solid (2.6 g, 66%). Rf = 0.63 in 5% i-PrNH2 in 30% MeOH / CH2Cl H ^ NMR (CD3OD, 299.96 MHz): d (ppm) 7.46-7.28 (m, 6H), 7.24-7.20 (dd, 1H), 7.0-6.96 (d, 1H), 5.11 (s, 2H), 4.70 (s, 2H), 44.65-4.60 (t, 1H), 2. 83-2. 81 (d, 2H); ESMS (C? 6H? 9N? 03): caled. 273 3, obsd. 274 7 [M + H] ", 547. 3 [2M + H] + Step 5 To a solution of EtOH (15 mL) of a compound 39 containing 2- (4-benzyloxy-3-hydroxymethylphenyl) -2-hydroxyethylamine (0.3 g, 1.1 mmol) was added resorcinol diglycidyl ether (0.122 g, 0.55 mmol). dissolved in EtOH (5 mL). The reaction mixture was refluxed for 20 hours. After cooling down rt, the reaction mixture was degassed with nitrogen and hydrogenated with 10% Pd / C (0.3 g, 10%) under H 2 atmosphere (1 atm) for 24 hours. After filtration of the catalyst, the filtrate was concentrated to dry, yielding an oily oil residue which was purified by reverse preparatory HPLC phase (10 to 50% Me CN / H20 = for 40 min, 20 mL / min, 254 nm) to give 54 bis. { 2-. { 2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxy] -etiamino} -2-hydroxyethoxy} benzene, ESMS (C3oH0N2O? o): caled. 588.6, obs. 589.4 [M + H] +, 610.7 [M + Na] +.

Example 9 Synthesis of l-. { 2- [N-2- (4-hydroxy-3-hydroxymethylphenyl) -2- hydroxy-ethyl] amino] ethyl} -4- [N- (2-naphth-l-yloxymethyl-2-hydroxyethyl) amino} Benzene (Figure 13 below) A solution of EtOH (50 L) quer contains 28 4- (N -Boc-2-aminoethyl) aniline (0.4 g, 1.69 mmolar) and 55 3- (l-naphthoxy) -1, 2-epoxypropane (0.33 g, 1.65 mmolar) was refluxed for 15 hours, and concentrated in vacuo for drying, yielding a pale yellow oil. This was dissolved in 10 mL of CH2C12, cooled in an ice bath, and treated with TFA (5 mL). After stirring for 2 hours at 0 ° C, the mixture was evaporated, yielding a pale red oil. This was dissolved in 30% aqueous acetonitrile and purified by preparative HPLC: 30% MeC? / H20 for 30 min; 20 mL / min; 254 nm. The product 56 was obtained as a coloring oil (260 mg, TFA salt). HX-? MR (CD3OD, 299.96 MHz): d (ppm) 8.88-8.25 (dd, 1H), 7.82-7.79 (dd, 1H), 7.51-7.42 (, 3H), 7.39- 7.38 (d, 1H), 7.33-7-30 (d, 2H), 7.25-7.23 (d, 2H) ), 6.91-6.89 (d, 1H), 4.37-4.31 (m, 1H), 4.22-4.19 (m, 2H), 3.69-3.63 (dd, 1H), 3.67-3.54 (dd, 1H), 3.67-3.54 (dd, 1H), 3.17-3.11 (t, 2H), 2.96-2.91 (t, 2H); ESMS (C2? H24? 202): caled. 336.4, obsd. 337.5 [M + H] ", 359.6 [M +? A] +, 673.4 [2M + H] +.

Stage 2 To a solution of compound 56 (0.13 g, 0.023 mmolar salt of TFA) in 5 mL of MeOH was added 1.0 M NaOH (1.0 M, 0.46 mL) after homogenizing the mixture, the solution was evaporated for drying. The residue was dissolved in THF (10 mL) followed by the addition of 12 glyoxal (52 mg, 0.023 mmol). The resulting suspension was stirred for 4 h at room temperature under nitrogen atmosphere. After cooling the resulting solution in an ice bath, an excess amount of 2 M BH3-Me2S in THF (3 mL, 6 mmol) was added to the previous reaction solution. The resulting mixture was slowly warmed to rt, and refluxed for 4 h under N2 stream. After cooling the hot solution, 5 mL of MOH was added to the cooled mixture to quench the reaction of the mixture under a nitrogen atmosphere. After stirring for 30 minutes at rt the final solution was evaporated in vacuo yielding a pale brown solid. This was washed with EtOAc / hexane (1/2, 20 mL), and dried. The crude product was dissolved in 50% MeCN / H20 containing 0.5% TFA and purified by pre-scale high performance liquid chromatography (HPLC) using a linear gradient (5% to 50% MeCN / H20 for 50 min. , 20 mL / min, detection at 254 nM). Fractions with UV absorption were analyzed by LC-MS to locate the desired product 57 l-. { 2- [N-2- (4-hydroxy-3-hydroxy-methylphenyl (-2-hydroxyethyl) amino] -ethyl.} -4- [N- (2-naphth-1-yloxymethyl-2-hydroxyethyl) ) amino] benzene.

ESMS (C3oH34N205): caled. 502 6, obsd. 503.2 [M + H] ", 525. 6 [M + Na] + Example 10 Synthesis of 1, 4, 7-tris { N- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethyl ] amino.} octane A solution of 4- (aminomethyl) -1,8-octadhodamine ( 115 mg, 0.66 mmol) in tetrahydrofuran (5 mL). The resulting suspension was stirred for 12 h at room temperature under nitrogen atmosphere. After cooling the resulting solution in an ice bath, an excess amount of 2 M BH3-Me2 in hexane (6 mL, 12 mmol) was added. The resulting mixture was slowly warmed to rt and refluxed for 6 h under nitrogen atmosphere. After cooling the reaction of the mixture was quenched with methanol (5 mL). The resolving solution was stirred at rt for 30 min, and then concentrated in vacuo to give a pale brown solid. The solid was washed with ethyl acetate: hexane mixture (1: 2) and then dried. The crude product was dissolved in 50% acetonitrile / water containing 0.5% TFA and purified by HPLC using a linear gradient (5% at 50% MeCN / H20 for 50 min., 20 mL / min., Detection at 254 nM. ). Fractions with UV absorption were analyzed by LC-MS to locate the desired product. ESMS (C36H53N3O9): Caled. 671.8; Obsd. 671.7.

Formulation Examples Example 1 Hard gelatine capsules containing the following ingredients were prepared: Ingredient Quantity (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium Stearate 5.0 The above ingredients were mixed and filled into hard gelatin capsules in amounts of 340 mg.

Example 2 A tablet formula was prepared using the ingredients below: Ingredient Quantity (mg / tablet) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are "folded and compressed to form tablets, each weighing 240 ng.

Example 3 An inhaled formulation of dry powder was prepared containing the following components: Ingredient Weight% Active ingredient 5 Lactose 95 The active ingredient was mixed with the lactose and the mixture was added to a dry powder of inhaled application.

Example 4 Tablets, each containing 30 mg of the active ingredient were prepared as follows: Ingredient Quantity (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a "10% solution in sterile water) 4.0 mg Carboxymethyl sodium starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120.0 mg The active ingredient, starch and cellulose were passed through a U.S. No. 20 mesh and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. No. 16 mesh. The granules produced are then dried at 50 ° C to 60 ° C and passed through a U.S. sieve. No. 16 mesh. The starch carboxymethyl sodium, magnesium stearate, and talc, previously passed through a U.S. No. 30 mesh, are then added to the granules which, after mixing, are compressed in a tablet machine to make tablets each weighing 120 mg.

Example 5 Capsules, each containing 40 mg of medication are made as follows: Ingredient Quantity (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 g Total 150.0 mg The active ingredient starch, and magnesium stearate are folded, passed through a U.S. No. 20, and filled into hard gelatin capsules in amounts of 150 mg.

Example 6 Suppositories, each containing 25 mg of the active ingredient are made as follows: Ingredient Quantity Active ingredient 25 mg For glycerides saturated fatty acids 2000 mg The active ingredient is passed through a U.S. sieve. No. 60 mesh and is suspended in glycerides saturated fatty acids previously melted using the minimum necessary heat. The mixture is then placed inside a suppository mold with a nominal capacity of 2.0 g and left to cool.

Example 7 Suspensions, each containing 50 mg of medication per 5.0 mL dose are made as follows: Ingredient Amount Active ingredient 50.0 mg Xanthan gum 40.0 mg Cellulose coryloxymethyl sodium (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Taste and color q.v. For purified water 5.0 mL The active ingredient, sucrose and xanthan gum are folded, passed through a U.S. No. 10 mesh, and then mixed with a solution previously made of microcrystalline cellulose and cellulose carboxymethyl sodium in water. The sodium benzoate, flavor, and color are diluted with some water and added with agitation. Then enough water is added to produce the required volume.

Example 8 A formulation can be prepared as follows: Ingredient Quantity (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, starch, and magnesium stearate are folded, passed through a U.S. No. 20 mesh sieve, and filled into hard gelatin capsules in amounts of 425.0 mg.

Example 9 A formulation can be prepared as follows: Ingredient Quantity Active ingredient 5.0 mg Corn oil 1.0 mL Example 10 A topical formulation can be prepared as follows: Ingredient Quantity Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft white paraffin 100 g The soft white paraffin is heated until melted. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersion. The mixture is then cooled to a solid.

Another preferred formulation employed in the methods of the present invention employ transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous and discontinuous infusion of the compounds of the present invention in controlled amounts: The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent 5,023,252, published on June 11, 1991, incorporated herein by reference in its entirety. Such patches can be constructed for continuous, pulsatile or demand release of pharmaceutical agents.

Other formulations suitable for use in the present invention can be found in Remington's Pharmaceutical Sciences, edited by E. Martín (Mack Publishing Company, 18th Edition, 1990).

Biological examples Example 1 Functional in vitro test of ß2 Adrenergic Receptors The functional activity of β2 adrenergic receptor compounds of the invention was tested as follows.

Sowing and cell growth: Smooth muscle primary bronchial cells from 21-year-old males (Clonetics, San Diego, CA) were seeded at 5,000 cells / well in 24-well tissue culture plates. The medium used was Clonetics SmBM-2 supplemented with hEGF, insulin, hFGF, and Bovine Fetal Serum. Cells were grown for two days at 37 ° C, 5% C02 until confluent monolayers were seen.

Cell agonist stimulation: The medium was aspirated from each well and replaced with 250 mL of fresh medium containing lmM IBMX, a phosphodiester inhibitor (Sigma, St Louis, MO). The cells were incubated for 15 minutes at 37 ° C, and then 250 mL of agonist was added at appropriate concentrations. The cells were then incubated for an additional 10 minutes. The medium was aspirated and 500 mL of 70% cold EtOH was added to the cells, and then removed to an empty plate of 96 deep wells after about 5 minutes. This Stage was then repeated. The deep well plate was then turned on an Epeed-vac until all the EtOH was drained, leaving the pellets dry. CAMP (pmol / well) was quantified using a cAMP ELISA kit from Stratagene (La Jolla, CA). EC50 curves were generated using the appropriate equation of parameter 4: y = (ad) / (l + (x / c) b) + d, were, y = cpm a = total union c = IC5o x = [compound] d = union NS b = inclination Fix the union NS and allow to float to all other parameters.

EXAMPLE 2 Radioligand binding assay in vi tro of Adrenergic β2 Receptor The ßl / 2 adrenergic receptor binding activity of the compounds of the invention can be tested as follows. SF9 cell membranes containing β1 or β2 adrenergic receptors (NEN, Boston, MA) were incubated with 0.07 nM of 125 I-iodocyanopeindolol (NEN, Boston, MA) in binding buffer containing 75 mM Tris-HCl (pH 7.4) , 12.5 mM MGC12 and 2 mM EDTA and varying concentrations of the test compound or buffer only in 96-well plates (control). The plates were incubated at room temperature with shaking for 1 hour. The radioligand bound to the receptor was harvested by filtration on 96-well filter plates GF / B (Packard, Meriden, CT) pre-blocked with 0.3% polyethylamine and washed twice with 200 μl of PBS using cell harvester. The filtrates were washed three times with 200 μl of PBS using cell harvester and then resuspended in 40 μl of scintillation cocktail. The radioactivity of the filter-binding was measured with a scintillation counter and IC50 curves were generated using the appropriate equation of parameter 4 described above.

The preceding invention has been described in some details by way of illustration and example, for purposes of clarity and understanding. It will be obvious to someone of skill in the state of the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is understood that the description above is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the foregoing description, but should rather be determined with reference to the following appended claims, in parallel with the total scope of equivalents for which such claims are accredited.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes in the same area as if each individual patent, patent application or publication were then individually denoted.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the contents of the following are declared as property:

Claims (49)

1. A multiple-bond compound of Formula (I): (L) p (X) q (I) characterized because: p is an integer from 2 to 10; q is an integer from 1 to 20; X is a linker; and L is a ligand where: one of the ligands, L, is selected from a compound of formula (a): (to) where: Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; W is a covalent bond linking the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa - (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -OP (O) O- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that minus one of Ar1, Ar2, R1, R2, or W binds the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): -Q-Ar3 (b) where: Ar 3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa - (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n- (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -0-P (0) 0-; Y pharmaceutically acceptable salts thereof provided that: (iv) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then both W and X are not alkylene or alkylene-O-; (ii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 is 4-hydroxy-2-methylphenyl, Ar2 is aryl, Ar3 is aryl or heterocyclyl, W is stylene, Q is a covalent bond, R1 is alkyl, then linker X is not linked to the group Ar3 through an atom of oxygen; Y (iii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1, Ar2, Ar3, R1, R2 are as defined above, W is alkylene, and Q is a covalent bond, then X is not -alkylene-O-.

2. The multiple-bond compound of claim 2 characterized in that q is less than p.

3. The multiple-binding compound of claim 2 characterized in that each linker, X, in the multiple-linking compound of the Formula (I) independently has the formula: -X to -Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C (O) -, -C (0) 0-, -OC (O) -, -C (0) NR-, -NRC (O) -, C (S), -C (S) 0-, -C (S) NR-, -NRC (S) -, or a covalent bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; each Ya to each separate occurrence is selected from the group consisting of -O-, -C (O) -, -OC (0) -, -C (0) 0-, -NR-, -S (0) n-, -C (0) NR'-, -NR'C (O) -, -NR 'C (O) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR'-, -NR'-C (= NR') -, -OC (0) -NR'-, -NR'-C (0) -0- -N = C (Xa) -NR'-, -NR'-C (Xa) = N-, -P (O) (OR ') -O-, -O- P (0) (OR') -, -S (0) nCR ' R "-, -S (0) n-NR'-, -NR'-S (0) n-, -SS-, and a covalent bond, where n is 0, lo 2; R, R 'and R' 'to each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, and Xa is as defined above.

4. a bivalent multiple-bond compound of Formula (II): (H) characterized because: Ar is: (a) a phenyl ring of formula (c) (c) where: R 4 is hydrogen, alkyl, halo, or alkoxy; R5 is hydrogen, hydroxy, halo, halo, amino, or -NHS02Ra where Ra is alkyl; R6 is hydrogen, halo, hydroxy, alkoxy, substituted alkyl, sulfonylamino, aminoacyl, or acylamino; W is a covalent bond linking the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group are optionally replaced by -0-; Ar2 is phenyl wherein the groups W and X are adhered at positions 1,2-, 1,3 and 1,4 of the phenyl ring; cyclohexyl optionally substituted with methyl and wherein groups W and X are adhered at the 1,3 and 1,4 positions of the cyclohexyl ring; or piperazine wherein the groups and X are adhered in the 1,4 positions of the piperazine ring; X is a linker; Q is a covalent bond, or a substituted alkylene group in which one or more of the carbon atoms in said substituted alkylene group is optionally replaced by a heteroatom such as -NRa- (where Ra is hydrogen, alkyl, or acyl, or a covalent bond linking the ligand to the linker), -0-, -S (0) n (where n is an integer from 0 to 20), -CO-, -PRb- (where R is alkyl), -P ( 0) 2- and -OP (0) 0- and binds the ligand to the linker; Y .Ar3 is or: (i) a phenyl ring of formula (c) as defined above; or (ii) a phenyl ring of formula (d): (d) where: R7 is hydrogen, alkyl, alkenyl, substituted alkyl, halo, alkoxy, substituted alkoxy, hydroxy, aminoacyl, or heteroaryl; and R8 is hydrogen, halo, alkoxy, substituted alkoxy, acylamino; or (iii) is naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5- (CH3C02CH20-) -1,2,3,4-tetrahydronaphthyl, lH-2-oxoindole, , 3,4-trihydrotianaphthalene, or 4-oxo-2,3-dihydrotianaphthalene; and pharmaceutically acceptable salts thereof provided that: when the multiple-linking compound of Formula (I) is a compound of Formula: where Ar1 and Ar3 are aryl, then as much as X are not alkylene or alkylene-O-;

5. The bivalent multiple-bond compound of claim 4, characterized in that: X is -O-, -O-alkylene, -O- (arylene) -NH- (substituted alkylene), -O- (alkylene) -O- (arylene) -O-alkylene-O- (alkylene) -NH- (substituted alkylene) -, -O- (alkylene) -0- (arylene) -, - (alkylene) - (cycloalkylene) -NH- (substituted alkylene); and Q is a covalent bond.

6. The bivalent multiple bond compound of claim 5, characterized in that: .Ar1 is: (a) a phenyl ring of formula (c): where: R 4 is hydrogen, methyl, fluoro, chloro, or methoxy; R5 is hydrogen, hydroxy, fluoro, chloro, amino, -NHS02CH3; R6 is hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, -CH2S02CH3, -NHS02CH3, -NHCHO, -CONH2, -NHCONH2; Ar2 is phenyl wherein the groups and X are adhered at the 1,4 position of the phenyl ring; and Ar3 is O: (i) a phenyl ring of formula (c) as defined above; or (ii) a phenyl ring of formula (d): (d) where : R7 is hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, -CH2C02Me, hydroxy, -CH2CONH2, -NHCOCH3, -NHCHO, or imidazol-1-yl, l-methyl-4-trifluoromethyl-imidazole-2 -il; Y R8 is hydrogen, fluoro, chloro, methoxy, -CH2C02Me, or -CONH2; or (iii) naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5- (CH3CO2CH2O-) -1,2,3,4-tetrahydronaphthyl, lH-2-oxoindole, 2, 3,4-trihydrotianaphthalene, or 4-oxo-2,3-dihydrotianaphthalene.

7. The bivalent multiple-bond compound of claim 6, characterized in that: .Ar1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3, 5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3- (HCONH-) phenyl, 4-hydroxy-3- (NH2C0-) phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4- (CH3S02NH-) -phenyl, 4-hydroxy-3- (CH3S02CH2-) phenyl, 4-hydroxy-3- (CH3S02NH-) phenyl, 4-hydroxy-3- ( NH2CONH-) phenyl, or 3,5-dichloro-4-aminophenyl; W is a bond, methylene, ethylene, propylene, - (CH2) 6-0- (CH2) 3 -, - (CH2) 6-0-, or -CH2CH (OH) CH2-0-; X is -0-; -0- (CH2) 4-; -O- (1, 4-phenylene) -NH-CH2-CH (OH) -; - 0- (CH2)? O-0- (1, 4-phenylene) - (CH2) 3-0- (CH2) 6-NH-CH2-CH (OH) -; -0- (CH2) 6-0- (1, 4-phenylene) - (CH2) 3-0- (CH2) 5-NH-CH2-CH (OH) -; -0- (CH2) 6-0- (1, 4-phenylene) -; - CH2- (1,4-cyclohexyl) -NH-CH2-CH (OH) -; Y Ar3 is; -na NHSOjMß

8. The bivalent multiple-bond compound of claim 4, characterized in that: X is a covalent bond; Y Q is a substituted alkylene group where one or more of the carbon atoms in said substituted alkylene group is optionally replaced by a heteroatom such as -NRa - (where Ra is hydrogen, alkyl, or acyl) or -0-.

9. The bivalent multiple-bond compound of claim 8, characterized in that: Ar1 is (b) a phenyl ring of formula (c) (c) where: R 4 is hydrogen, methyl, fluoro, chloro, or methoxy; R5 is hydrogen, hydroxy, fluoro, chloro, amino, -NHS02CH3; Y R6 is hydrogen, chloro, fluoro, hydroxy, methoxy, hydroxymethyl, -CH2S02CH3, -NHS02CH3, -NHCHO, -CONH2, -NHCONH2. Ar2 is phenyl wherein the groups and X are adhered at the 1,4 position of the phenyl ring; Y .Ar3 is or: (i) a phenyl ring of formula (c) as defined above; or (ii) a phenyl ring of formula (d): R7 Rß (d) where: R7 is hydrogen, methyl, propen-2-yl, fluoro, chloro, methoxy, -CH2C02Me, hydroxy, -CH2CONH2, -NHCOCH3, -NHCHO, imidazol-1-yl, or l-methyl-4-trifluoromethyl-imidazole-2 -il; Y R8 • is hydrogen, fluoro, chloro, methoxy, -CH2C02Me, -NHCHO, O-CONH2. (iii) naphthyl, pyridyl, benzimidazol-1-yl, indolyl, 2-cyanoindolyl, carbazolyl, 4-methylindanyl, 5- (CH3C02CH20-) - 1,2,3,4-tetrahydronaphthyl, lH-2-oxoindole, 2, 3,4- trihydrotianaphthalene, or 4-oxo-2,3-dihydrothianaphthalene.

10. The multivalent bivalent compound of claim 9, characterized in that: Ar 1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3, 5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3- (HCONH-) phenyl, 4-hydroxy-3- (NH2CO-) phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4- (CH3S02NH-) -phenyl, 4-hydroxy-3- (CH3S02CH2-) phenyl, 4-hydroxy-3- (CH3S02NH-) phenyl, 4-hydroxy-3- ( NH2CONH-) phenyl, or 3, 5-dichloro-4-aminophenyl; W is a bond, methylene, ethylene, propylene, - (CH2) 6-0- (CH2) 3 -, - (CH2) 6-0-, O -CH2CH (OH) CH2-0-; Q is -NH-CH2-CH (0H) -; - NH-CH (CH20H) -; - CH2-NH-CH2-CH (0H) -; - C (CH3) 2 -NH-CH2-CH (OH) -; - (CH2) 3-NH-CH2-CH (OH) -; - (CH2) 3-0- (CH2) 6-NH-CH2-CH (OH) -;-( CH2) 2-NH-CH2-CH (OH) -; or -0- (CH2) -CH (OH) -CH2-NH-CH2-CH (OH) -; Y Ar is:

11. The "multiple bond" compound of claim 10 characterized in that: Arxy Ar3 are phenyl; W is ethylene; Y Q is NH-CH2- * CH (OH) - (where * is stereochemically R or S);

12. The multivalent bivalent compound of claim 9, characterized in that: Ar 1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3,4-dichlorophenyl, 2-chloro-3,4-dihydroxyphenyl, 2-fluoro-3,4-dihydroxyphenyl, 2-chloro-3,5-dihydroxyphenyl, 2-fluoro-3, 5-dihydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-hydroxymethylphenyl, 4-hydroxy-3- (HCONH-) phenyl, 4-hydroxy-3- (NH2CO-) phenyl, 3-chlorophenyl, 2,5-dimethoxyphenyl, 4- (CH3SO2NH-) -phenyl, 4-hydroxy-3- (CH3S02CH2-) phenyl, 4-hydroxy-3- (CH3S02NH-) phenyl, 4-hydroxy-3- ( NH2CONH-) phenyl, or 3,5-dichloro-4-aminophenyl; is a bond, methylene, ethylene, propylene, - (CH2) 6-0- (CH2) 3 -, - (CH2) 6-0-, or -CH2CH (0H) CH2-0-; Q is -NH-CH2-CH (OH) -CH2-0-; Y Ar is; Y »(X-ClorF) (X-ClorF) -NHCONH2

13. A "pharmaceutical composition" characterized in that it comprises a pharmaceutically acceptable carrier and an effective amount of a multiple-linking compound of Formula (I): (L) p (X) q (I) where : p is an integer from 2 to 10; q is an integer from 1 to 20; X is a linker; and L is a ligand where: One of the ligands, L, is selected from a compound of formula (a): (to) where: Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; is a covalent bond joining the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa- ( where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n (where n is an integer from 0 to 2), -CO-, -PRb - (wherein Rb is alkyl), - P (0) 2-, and -OP (O) O- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that at least one of Ar1, Ar2, R1, R2, or W binds the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): -Q-Ar3 (b) where: Ar 3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa (where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n- (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -OP (O) O-; and pharmaceutically acceptable salts thereof provided that: (v) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then both W and X are not alkylene or alkylene-O-; (ii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 is 4-hydroxy-2-methylphenyl, Ar2 is aryl, Ar3 is aryl or heterocyclyl, W is stylene, Q is a covalent bond, R1 is alkyl, then linker X is not linked to the group Ar3 through an atom of oxygen; Y (iii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1, Ar2, Ar3, R1, R2 are as defined above, is alkylene, and Q is a covalent bond, then X is not -alkylene-O-.

14. The pharmaceutical composition of claim 13 characterized in that q is less than p.

15. The pharmaceutical composition of claim 14 characterized in that each linker independently has the formula: -X to -Z- (Ya-Z) m-Xa- where m is an integer from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -O-, -S-, -NR-, -C (O) -, -C (0) 0-, -OC (O) -, -C (0) NR-, -NRC (O) -, C (S), -C (S) 0-, -C (S) NR-, -NRC (S) -, or a covalent bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocycle, or a covalent bond; each Ya to each separate occurrence is selected from the group consisting of -O-, -C (O) -, -OC (O) -, -C (0) 0-, -NR-, -S (0) n-, -C (0) NR'-, -NR'C (O) -, -NR 'C (O) NR' -, -NR'C (S) NR'-, -C (= NR ') -NR' -, -NR'-C (= NR ') -, -OC (0) -NR'-, -NR'-C (0) -0- -N = C (Xa) -NR'-, -NR' -C (Xa) = N-, -P (O) (OR ') -O-, -0-P (O) (0R') -, -S (0) nCR'R "-, -S (0 ) n-NR'-, -NR'-S (0) n-, -SS and a covalent bond, where n is 0, so 2; R, R 'and R "at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, and Xa is as defined above.

16. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and an effective amount of the multiple binding compound of claim 7.

17. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and an effective amount of the multiple binding compound of claim 10.

18. A method for treating diseases mediated by a β2 adrenergic receptor in a mammal, said method characterized in that it comprises administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multiple-linking compound of Formula ( I): (L) p (X) ClX) characterized by: p is an integer from 2 to 10; q is an integer from 1 to 20; X is a linker; and L is a ligand where: One of the ligands, L, is selected from a compound of formula (a): (to) where : Ar1 and Ar2 are independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl wherein each of said substituents Ar1 and Ar2 optionally binds the ligand to a linker; R1 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl, or R1 is a covalent bond linking the ligand to a linker; R2 is selected from the group consisting of hydrogen, alkyl, aralkyl, acyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, or R2 is a covalent bond linking the ligand to a linker; is a covalent bond joining the group -NR2- to Ar2, alkylene or substituted alkylene where one or more of the carbon atoms in said alkylene or substituted alkylene group which is optionally replaced by a substituent selected from -NRa- ( where Ra is hydrogen, alkyl, acyl, or a covalent bond linking the ligand to a linker), -O-, -S (0) n (where n is an integer from 0 to 2), -CO-, -PRb - (where Rb is alkyl), -P (0) 2-, and -OP (O) O- and later where said alkylene or substituted alkylene group optionally binds the ligand to a linker provided that at least one of Ar1, Ar2, R1, R2, or joins the ligand to a linker; Y the other ligands are independently selected from a compound of formula (b): -Q-Ar3 (b) where: Ar3 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, and heterocyclyl; Q, which binds the other ligand to the linker, is selected from the group consisting of a covalent bond, alkylene, or a substituted alkylene group where one or more of the carbon atoms in said alkylene or substituted alkylene group is optionally replaced by a substituent selected from -NRa (where Ra is hydrogen, alkyl, acyl, or a covalent bond that binds the ligand to a linker), -O-, -S (0) n- (where n is an integer from 0 to 2), -CO-, -PRb- (where Rb is alkyl), -P (0) 2-, and -O-P (O) O-; Y pharmaceutically acceptable salts thereof provided that: (vi) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 and Ar3 are aryl, then both W and X are not alkylene or alkylene-O-; (ii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1 is 4-hydroxy-2-methylphenyl, Ar2 is aryl, Ar3 is aryl or heterocyclyl, W is stylene, Q is a covalent bond, R1 is alkyl, then linker X is not linked to the group Ar3 through an atom of oxygen; Y (iii) when the multiple-linking compound of Formula (I) is a compound of formula: where Ar1, Ar2, Ar3, R1, R2 are as defined above, W is alkylene, and Q is a covalent bond, then X is not -alkylene-O-.

19. A method for treatment of diseases mediated by a β2 adrenergic receptor in a mammal, said method characterized in that it comprises the administration to said mammal of a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multiple-binding compound of the claim 7

20. A method for the treatment of diseases mediated by a β2 adrenergic receptor in a mammal, said method characterized in that it comprises the administration to said mammal of a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a multiple-binding compound of the claim 10

21. The method of claim 20 characterized in that the disease is a respiratory disease.

22. The method of claim 21 characterized in that the disease is asthma.

23. A method for the identification of multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor characterized in that it comprises: (a) the identification of a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker of said library comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) preparing "a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the groups complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (d) the assay of multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor.

24. a method for identifying multimeric ligand compounds possessing multiple binding properties with the adrenergic β2 receptor characterized in that it comprises: (a) identification of a library of ligands wherein each ligand contains at least one reactive functionality; (b) the identification of a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the groups complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; Y (d) the assay of multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds that possess multiple binding properties with the adrenergic β2 receptor.

25. The method according to Claim 23 or 24, characterized in that the preparation of the library of multimeric ligand compounds is completed either by the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers. identified in (b).

26. The method according to claim 25 characterized in that the multimeric ligand compounds comprising the library of multimeric ligand compounds are dimeric.

27. The method according to claim 26 characterized in that the dimeric ligand compounds comprising the library of dimeric ligand compounds are heterodimeric.

28. The method according to claim 27 characterized in that the library of heterodimeric ligand compounds was prepared by sequential addition of a first and second ligand.

29. The method according to Claim 23 or Claim 24 characterized in that, prior to procedure (d), each member of the library of multimeric ligand compounds was isolated from the library.

30. The method according to claim 29, characterized in that each member of the library was isolated by preparative liquid chromatography (LCMS) mass spectrometry.

31. The method according to claim 23 or claim 24 characterized in that the binder or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acid linkers, basic linkers, linkers of different polarization and amphiphilic ligands.

32. The method according to claim 31, characterized in that it comprises linkers of different chain length and / or having different complementary reactive groups.

33. The method according to claim 32 characterized in that the linkers are selected to have different lengths of linker in the range of about 2 to 100 Á.

34. The method of Claim 23 or Claim 24 characterized in that the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.

35. The method according to claim 34 characterized in that said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides and precursors of these wherein the reactive functionality in the ligand is selected to be complementary to at least one of the reactive groups in the linker such that a covalent linkage can be formed between the linker and the ligand.

36. The method according to Claim 23 or Claim 24 characterized in that the library of multimeric ligand compounds comprises homomeric ligand compounds.

37. The method according to Claim 23 or Claim 24 characterized in that the library of multimeric ligand compounds comprises heteromeric ligand compounds.

38. a library of multimeric ligand compounds which may possess multivalent properties with the adrenergic β2 receptor whose library is prepared by the method characterized in that it comprises: (a) the identification of a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality; (b) identifying a library of linkers wherein each linker of said library comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) preparing a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the functional groups Complementaries react to form a covalent linkage between said linker and at least two of said ligands.

39. A library of multimeric ligand compounds which may possess multivalent properties with the β2 adrenergic receptor whose library is prepared by the method characterized in that it comprises: (a) identification of a library of ligands wherein each ligand contains at least one reactive functionality; (b) the identification of a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand; (c) the preparation of a library of multimeric ligand compounds by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the groups Complementary functional groups react to form a covalent bond between said linker and at least two of said ligands.

40. The library according to Claim 38 or Claim 39 characterized in that the linker or linkers employed are selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acid linkers, basic linkers, linkers of different polarization and linkers to fifílicos.

41. The library according to claim 40 characterized in that it comprises linkers of different chain length and / or having different complementary reactive groups.

42. The library according to claim 41 characterized in that the linkers are selected to have different lengths of linker in the range of about 2 to 100 Á.

43. The library of Claim 38 or Claim 39 characterized in that the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands.

44. The library according to claim 43 characterized in that said reactive functionality is selected from the group consisting of carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides and precursors of these wherein the reactive functionality in the ligand is selected to be complementary to at least one of the reactive groups in the linker such that a covalent linkage can be formed between the linker and the ligand.

45. The library according to Claim 38 or Claim 39 characterized in that the library of multimeric ligand compounds comprises homomeric ligand compounds.

46. The library according to Claim 38 or Claim 39 characterized in that the library of multimeric ligand compounds comprises heteromeric ligand compounds.

47. An iterative method for the identification of multimeric ligand compounds that possess multiple binding properties for the adrenergic β2 receptor characterized in that it comprises: (a) the preparation of a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which have affinity for a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity with at least one of the reactive functional groups of the ligand e wherein said contact is carried out under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; (b) testing said first collection or iteration of multimeric compounds to assess which of said multimeric compounds possess multiple binding properties with the adrenergic β2 receptor; (c) repeating the process of (a) and (b) above until it is found that at least one multimeric compound possesses multiple binding properties with the adrenergic β2 receptor; (d) the evaluation of which molecular coactions impart multiple binding properties with the adrenergic β2 receptor to the multimeric compound or compounds found in the first iteration recited in (a) - (c) above; (e) the creation of a second collection or iteration of multimeric compounds which are elaborated on the particular molecular constraints that impart multiple binding properties to the compound or multimeric compounds found in said first iteration; (f) the evaluation of which molecular constraints impart enhanced multiple binding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above; (g) the optional repetition of Steps (e) and (f) to elaborate further on said molecular constraints.

48. The method according to Claim 47 characterized in that Steps (e) and (f) are repeated from 2-50 times.

49. The method according to Claim 48 characterized in that Steps (e) and (f) are repeated from 5 to 50 times.