HK1128681A

HK1128681A - Amine derivatives

Info

Publication number: HK1128681A
Application number: HK09106791.9A
Authority: HK
Inventors: K．詹姆斯; L．H．琼斯; D．A．普赖斯
Original assignee: 辉瑞有限公司
Priority date: 2006-03-20
Filing date: 2007-03-07
Publication date: 2009-11-06

Description

Amine derivatives

The present invention relates to compounds of general formula (1):

wherein A and B have the meanings indicated below, and to processes and intermediates for preparing such derivatives, to compositions containing such derivatives and to the use of such derivatives.

β₂Adrenergic agonists and cholinergic muscarinic antagonists are recognized as therapeutic agents for the treatment of obstructive airways diseases such as COPD and asthma. Currently used suction type beta₂Agonists include short acting agents such as salbutamol (q.i.d.) and terbutaline (t.i.d.) and long acting agents such as salmeterol (salmeterol) and formoterol (formoterol) (b.i.d.), and produce bronchodilation via stimulation of adrenergic receptors on the smooth muscle of the trachea. Clinically used inhaled muscarine antagonists include short acting ipratropium bromide (q.i.d.), oxitropium bromide (q.i.d.), and long acting tiotropium (tiotropium) (q.d.). Muscarinic antagonists produce bronchodilation by inhibiting the cholinergic state of the trachea (cholinergictone) primarily through antagonism of the action of acetylcholine on muscarinic receptors present on the smooth muscle of the trachea. Several published studies have shown that inhaled beta is compared to patients receiving either single type of agent alone for patients with obstructive pulmonary disease₂Administration of agonists in combination with inhaled muscarine antagonists (whether short-acting or long-acting) results in superior improvements in lung function, symptoms and quality of life measurements. Studies to date have been limited to combination studies with a single pharmacological agent, however a combination of both pharmacological agents within a single molecule would be desirable as such a combination could result in enhanced bronchodilator efficacy with a similar therapeutic index to that of the single agent, or with a similar therapeutic index to that of the single agentHas similar efficacy with higher therapeutic index. In addition, combining two pharmacologies in a single molecule would make possible the combination with an anti-inflammatory agent, which in turn could provide triple therapy from a single inhaler.

The present invention relates to compounds of general formula (1):

wherein A is selected from:

wherein represents the point of attachment of a to the carbon atom bearing the hydroxyl group;

and B is selected from:

1)**-(CH₂)₂-(CH₂)_m-X¹-(CH₂)_n-¹Is O or S, m is an integer from 0 to 9, n is an integer from 0 to 9, and n + m is between 4 and 9 inclusive;

2) optionally via one or two C₁-C₄Alkyl substituted C₆-C₁₂An alkylene group;

3) a group of the formula:

wherein X²Is O or S, r is an integer from 2 to 7, S is an integer from 0 to 6, t is an integer from 0 to 6, S + t is between 1 and 6 inclusive, and r + S + t is between 3 and 8 inclusive;and

4) a group of the formula:

represents the point of attachment of B to the adjacent NH group, and represents the point of attachment of B to the adjacent phenyl group;

and quaternary ammonium salts thereof or, if appropriate, pharmaceutically acceptable salts thereof and/or isomers, tautomers, solvates or isotopic variations thereof.

The compounds of formula (1) are β 2 adrenergic receptor agonists and muscarinic receptor antagonists, which are particularly useful in the treatment of diseases or conditions in which such receptors are involved, by exhibiting excellent efficacy, particularly when administered via the inhaled route.

A compound of formula (1)

Can be prepared using conventional methods, such as by the following exemplary methods, wherein a and B are as previously defined for compounds of formula (1), unless otherwise specified.

Amine derivatives of formula (1) can be prepared by reacting an amine of formula (2):

(wherein Ra represents hydrogen or a suitable hydroxy protecting group, preferably benzyl) with a bromide of formula (3):

(wherein A is as defined above for the compound of formula (1)). The hydroxyl group of a is preferably protected using a suitable hydroxyl protecting group. Preferably the hydroxy protecting group is benzyl.

In a typical process, the amine of formula (2) is reacted with the bromide of formula (3) at a temperature between 80 ℃ and 120 ℃ for 12 to 48 hours, optionally in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, propionitrile, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate). The protecting Groups can then be removed using standard methods for cleaving oxygen protecting Groups, such as those found in textbook t.w.greene, Protective Groups in Organic Synthesis, a.wiley-Interscience Publication, 1981.

The bromides of formula (3) may be prepared according to the methods of WO2005/080324, US2005/222128, WO2004/032921, US2005/215590, WO 2005/092861.

The amine of formula (2) can be prepared from the corresponding protected amine of formula (4):

wherein R is_bAnd R_cAny suitable substituent is indicated so that the N atom can be readily reacted with R using standard methods for cleaving off nitrogen protecting groups, such as those found in textbook T.W.Greene, protective groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981_bA bond between N atom and R_cThe bond between them is broken to give the free amine of formula (2). For example, R_bAnd R_cCan be selected from allyl, benzyl, t-butyl carbamate or linked together to form phthalimide.R_bAnd R_cPreferably both are tert-butyl carbamate or R_bIs H and R_cIs tert-butyl carbamate.

An amine of formula (4) wherein Ra is benzyl and B is selected from (CH)₂)₂-(CH₂)_m-X¹-(CH₂)_n(wherein n is 0, and m and X¹As defined for the compound of formula (1) or a group of the formula:

(wherein t is 0 and r, s and X²As defined for the compound of formula (1),

which can be obtained by reacting a compound of the formula (5):

(wherein X³Is O or S) with a compound of formula (6):

(wherein B¹Is (CH)₂)₂-(CH₂)_mOr a group of the formula:

) By the reaction of (a).

In a typical process, the alcohol compound of formula (6) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethylsulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with a compound of formula (5) in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate) at a temperature between 60 ℃ and 120 ℃ for 4 to 48 hours.

Alternatively, the Mitsunobu procedure (e.g. diethyl azodicarboxylate/triphenylphosphine) may be employed in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, tetrahydrofuran) at a temperature between 25 ℃ and 60 ℃ for 2 to 4 hours.

A compound of formula (5) (wherein X³Is O) can be prepared from an aldehyde of formula (7):

in a typical process, aldehyde (7) is treated with an oxidizing agent (e.g., hydrogen peroxide; m-chloroperbenzoic acid) in the presence of a solvent or solvent mixture (e.g., methanol, water, acetonitrile) in the presence of an acid (e.g., sulfuric acid) at a temperature between 25 ℃ and 60 ℃ for 6 to 24 hours.

The aldehydes of the formula (7) can be prepared according to the process of WO 2005/012227.

A compound of formula (5) (wherein X³Is S) can be prepared from a halide of formula (13):

in a typical process, over a suitable palladium catalyst (e.g., of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) and a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate) in the presence of a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate). The reaction is preferably carried out at a temperature between 70 ℃ and 110 ℃ for 4 to 16 hours. The product silyl thioester is then deprotected using the method described in textbook T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981.

The aryl bromide of formula (13) may be prepared according to the method of WO 1994/11337.

The alcohol compounds of formula (6) can be prepared from commercially available amines using the methods found in the textbook T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-Interscience publication, 1981.

An amine of formula (4) wherein B is selected from:

-(CH₂)₂-(CH₂)_m-X¹-(CH₂)_nwherein X is¹Is O or S, m is an integer from 0 to 9, n is an integer from 3 to 9, and n + m is between 4 and 9;

optionally via one or two C₁-C₄Alkyl substituted C₆-C₁₂An alkylene group;

-a group of formula:

wherein X²Is O or S, r is an integer from 2 to 7, S is an integer from 0 to 6, and t is an integer from 3 to 6, and S + t is between 3 and 6, and r + S + t is between 5 and 8,

it can be prepared from an amine of formula (8):

wherein B is²is-CH₂-(CH₂)_m-X¹-(CH₂)_n1Wherein X is¹Is O or S, m is an integer from 0 to 9, n₁Is an integer of 1 to 7, and n₁+ m is between 2 and 7;

optionally via one or two C₁-C₄Alkyl substituted C₃-C₉An alkylene group;

-a group of formula:

wherein X²Is O or S, r₁Is an integer from 1 to 6, s is an integer from 0 to 6, and t₁Is an integer of 1 to 4, and s + t₁Between 1 and 4, and r₁+s+t₁Between 2 and 5.

In a typical process, the amine of formula (8) is hydrogenated using a metal catalyst (e.g., palladium on carbon; platinum oxide) in the presence of a hydrogen source (e.g., ammonium formate; formic acid, hydrogen gas) in a solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran) at a temperature between 20 ℃ and 90 ℃ for 1 to 6 hours.

The amine of formula (8) may be prepared from the reaction of an aldehyde of formula (7) with a phosphonium salt of formula (9) as previously described:

in a typical procedure, the phosphonium salt of formula (9) is treated with a suitable base (e.g., sodium hydride, triethylamine, n-butyllithium, bis (trimethylsilane) amine) and then reacted with the aldehyde of formula (8) in the presence of a solvent or solvent mixture (e.g., toluene, tetrahydrofuran, acetonitrile). The reaction is preferably carried out at a temperature between 50 ℃ and 110 ℃ for 4 to 24 hours.

The phosphorus salt (9) can be prepared by the reaction of triphenylphosphine with a bromide of formula (10):

in a typical process, the bromide of formula (10) is reacted with triphenylphosphine, optionally in the presence of a solvent or solvent mixture (e.g. toluene, tetrahydrofuran, acetonitrile). The reaction is preferably carried out at a temperature between 50 ℃ and 110 ℃ for 1 to 5 days.

The bromide of formula (10) may be formed by reaction of a suitable amine or amine equivalent with a dibromide of formula (11):

in a typical process, the dibromide of formula (11) is reacted with a suitable amine or amine equivalent (e.g., phthalimide, di-t-butyl iminodicarboxylate) in the presence of a solvent or solvent mixture (e.g., toluene, tetrahydrofuran, acetonitrile) and a suitable base (e.g., sodium hydride, triethylamine, n-butyllithium). The reaction is preferably carried out at a temperature between 25 ℃ and 110 ℃ for 4 to 24 hours.

The dibromide of formula (11) may be commercially available or may be derived from a diol of formula (12):

formed using standard methods (e.g., triphenylphosphine/carbon tetrabromide) in the presence of a solvent or solvent mixture (e.g., dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile).

The compounds of formula (12) are commercially available or can be readily prepared by those skilled in the art using commercially available materials and standard methods.

Alternatively, an amine of formula (4), wherein B is selected from:

-or a group of formula:

wherein X²Is O or S, r is an integer from 2 to 7, S is an integer from 0 to 6, and t is an integer from 3 to 6, and S + t is between 3 and 6, inclusive, and r + S + t is between 5 and 8, inclusive,

which can be prepared by reacting a bromide of formula (13):

with an olefin of formula (14):

(wherein B²As defined above).

In a typical process, over a suitable palladium catalyst (e.g., of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) in the presence of a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) to react the aryl halide of formula (13) with the olefin of formula (14). The reaction is preferably carried out at a temperature between 70 ℃ and 110 ℃ for 4 to 16 hours.

The amine of formula (14) can be prepared from a commercially available halide of formula (15):

wherein X is Cl, Br or I. In a typical process, a halide of formula (15) is reacted with a suitable amine or amine equivalent (e.g., phthalimide, di-tert-butyl iminodicarboxylate) in the presence of a solvent or solvent mixture (e.g., toluene, tetrahydrofuran, acetonitrile) and a suitable base (e.g., sodium hydride, triethylamine, n-butyllithium). The reaction is preferably carried out at a temperature between 25 ℃ and 110 ℃ for 4 to 24 hours.

Alternatively, if amine (14) has formula (16):

wherein X²Is O or S, and t₂Is an integer from 1 to 4, which can be obtained by reacting a compound of formula (17):

with a commercially available halide of formula (18):

(wherein X is Cl, Br or I).

In a typical process, a compound of formula (17) is treated with a halide (18) in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium hydride) at a temperature between 0 ℃ and 80 ℃ for 1 to 48 hours.

A compound of formula (17) (wherein X²Is O) can be prepared from commercially available 3- (2-aminoethyl) phenol or 4- (2-aminoethyl) phenol using the methods described in the textbook T.W.Greene, Protective Groups in organic Synthesis, A.Wiley-Interscience Publication, 1981.

A compound of formula (17) (wherein X²Is S) a halide of formula (17 a):

(wherein X is Cl, Br or I).

In a typical process, inSuitable palladium catalysts (e.g. of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) and a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate) in the presence of a base (17a) with triisopropylsilanethiol. The reaction is preferably carried out at a temperature between 70 ℃ and 110 ℃ for 4 to 16 hours. The product silyl thioester is then deprotected using the method described in textbook T.W.Greene, Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981.

The halide of formula (17a) may be obtained from commercially available halides of formula (17 b):

prepared using the method found in textbook t.w.greene, Protective Groups in organic synthesis, a.wiley-Interscience Publication, 1981.

Alternatively, if amine (4) has formula (19):

it may be formed by reaction of a compound of formula (17) with a compound of formula (20):

in a typical procedure, a compound of formula (20) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethyl sulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with a compound of formula (17) in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) at a temperature between 60 ℃ and 120 ℃ for 4 to 48 hours.

The compound of formula (20) may be derived from an alkene of formula (21):

formed by reaction with a borating agent (e.g., borane, 9-borabicyclo [3.3.1] nonane) in the presence of a suitable solvent (e.g., tetrahydrofuran) at a temperature between 60 ℃ and 100 ℃ for 4 to 24 hours. Followed by oxidation with hydrogen peroxide in a suitable solvent or solvent mixture (e.g., water, methanol, tetrahydrofuran) and a suitable base (e.g., sodium hydroxide).

The olefin of formula (21) may be formed from the aryl bromide (13) by reaction with a suitable vinyl compound (e.g., vinyltributylstannane; vinyltetrafluoroborate, 2, 4, 6-trivinylboroxine pyridine complex). In a typical process, over a suitable palladium catalyst (e.g., of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) in the presence of a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate)Potassium bicarbonate) with a vinyl compound. The reaction is preferably carried out at a temperature between 70 ℃ and 110 ℃ for 4 to 16 hours.

Alternatively, the compound of formula (20) may be derived from an ester of formula (37):

formed by reaction with a reducing agent (e.g. lithium aluminium hydride, lithium borohydride) in the presence of a suitable solvent (e.g. tetrahydrofuran) at a temperature between 0 ℃ and 100 ℃ for 4 to 24 hours.

The ester of formula (37) may be formed from an aryl bromide of formula (13) as hereinbefore described by reaction with a tert-butyl acetate anion under palladium catalysis. In a typical procedure, in the presence of a suitable palladium catalyst (e.g. palladium dibenzylidene acetate or compounds of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) and in the presence of a base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, lithium hexamethyldisilazane) the aryl halide (13) is reacted with an ester anion. The reaction is preferably carried out at a temperature between 0 ℃ and 110 ℃ for 4 to 16 hours.

Alternatively, the amine of formula (2) may be derived from the corresponding nitrile of formula (22):

(wherein B²As defined above).

In a typical process, a metal catalyst or combination of catalysts (e.g., palladium/carbon; platinum oxide, Raney-) The nitrile of formula (22) is hydrogenated by treatment with a hydrogen source (e.g. ammonium formate, formic acid, hydrogen gas) in the presence of a solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran) for 1 to 6 hours.

Nitriles of formula (22) can be prepared by the reaction of an aryl bromide (13) with an olefin of formula (23):

The olefin of formula (23) may be commercially available.

Alternatively, if olefin (23) has formula (24) as follows:

wherein X³Is O or S, and is a compound of,

B⁴is CH₂-(CH₂)_mWherein m is an integer of 0 to 9, and B⁵Is (CH)₂)_n1Wherein n is₁Is an integer of 1 to 7, and n₁+ m is between 2 and 7 (inclusive), or

B⁴Is a group of the formula:

wherein r is₁Is an integer from 1 to 6, s is an integer from 0 to 6, and B⁵Is (CH)₂)_t1Group, wherein t₁Is an integer of 1 to 4, and s + t₁Between 1 and 4 inclusive, and r₁+s+t₁Between 2 and 5 inclusive;

the compound of formula (24) may be prepared by reacting a compound of formula (25):

with a compound of formula (26):

is formed by the reaction of (a).

In a typical process, one of the compounds of formula (25) or (26) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethyl sulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with the other of the compounds of formula (25) or (26) in the presence of a solvent or solvent mixture (e.g. water, dimethyl sulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane) in the presence of a suitable base (e.g. sodium hydroxide, potassium tert-butoxide, sodium hydride), optionally in the presence of a phase transfer catalyst (e.g. tetraethylammonium bromide), at a temperature between 25 ℃ and 120 ℃ for 4 to 48 hours.

The compounds of formulae (25) and (26) are commercially available or can be readily prepared using well-known procedures.

Alternatively, the amine of formula (2) may be derived from the corresponding nitrile of formula (32):

(wherein B²As defined above).

In a typical process, a metal catalyst or combination of catalysts (e.g., palladium/carbon; platinum oxide, Raney-) The nitrile of formula (32) is hydrogenated by treatment with a hydrogen source (e.g. ammonium formate, formic acid, hydrogen gas) in the presence of a solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran) for 1 to 6 hours.

The nitrile of formula (32) may be formed by reacting an aryl bromide (13) with an alkyne of formula (33):

by the reaction of (a).

In a typical procedure, in the presence of a suitable palladium catalyst (e.g., tetrakis (triphenylphosphine) palladium or a compound of the formula Pd (OAc))₂/{P(o-Tol)₃}₂Palladium acetate/tri-o-tolylphosphine) in the presence of a solvent or solvent mixture (e.g. toluene, acetonitrile, hexane) in the presence of a base (e.g. triethylamine, piperidine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) an aryl halide of formula (13) is reacted with an alkyne of formula (33). The reaction is preferably carried out at a temperature between 70 ℃ and 110 ℃ for 4 to 16 hours.

The alkyne of formula (33) can be commercially available.

Alternatively, if alkyne (33) has formula (34) as follows:

wherein X³Is O or S, and is a compound of,

B⁴Is a group of the formula:

the compound of formula (34) may be prepared by reacting a compound of formula (25):

with a compound of formula (36):

is formed by the reaction of (a).

In a typical process, one of the compounds of formula (35) or (36) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethyl sulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with the other of the compounds of formula (35) or (36) in the presence of a solvent or solvent mixture (e.g. water, dimethyl sulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane) in the presence of a suitable base (e.g. sodium hydroxide, potassium tert-butoxide, sodium hydride), optionally in the presence of a phase transfer catalyst (e.g. tetraethylammonium bromide), at a temperature between 25 ℃ and 120 ℃ for 4 to 48 hours.

The compounds of formulae (35) and (36) are commercially available or can be readily prepared according to well-known methods.

A compound of formula (1) wherein B is selected from (CH)₂)₂-(CH₂)_m-X¹-(CH₂)_n(wherein n is 1) or a group of the formula

(wherein t is 1) by an amine of formula (27):

(wherein X³、B¹And Ra is as defined hereinabove) with a bromide of formula (3).

In a typical process, an amine of formula (27) is reacted with a bromide of formula (3) optionally in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, propionitrile, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate) at a temperature between 80 ℃ and 120 ℃ for 12 to 48 hours. The protecting Groups can then be removed using standard methods for cleaving oxygen protecting Groups, such as those found in textbook t.w.greene, Protective Groups in Organic Synthesis, a.wiley-Interscience Publication, 1981.

The amine of formula (27) may be prepared from the corresponding protected amine of formula (28):

wherein Rb and Rc are as defined above.

The amine (28) may be reacted with the alcohol (29):

with a compound of formula (30):

by the reaction of (a).

In a typical process, the alcohol of formula (29) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethyl sulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with a compound of formula (30) in the presence of a solvent or solvent mixture (e.g. water, dimethyl sulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane) in the presence of a suitable base (e.g. sodium hydroxide, potassium tert-butoxide, sodium hydride), optionally in the presence of a phase transfer catalyst (e.g. tetraethylammonium bromide), at a temperature between 25 ℃ and 120 ℃ for 4 to 48 hours.

The alcohol of formula (29) may be prepared from the aldehyde of formula (7). In a typical process, aldehyde (7) is treated with a reducing agent (e.g., sodium borohydride; lithium aluminum hydride) in the presence of a solvent (e.g., tetrahydrofuran, methanol, toluene) at a temperature between 0 ℃ and 40 ℃ for 1 to 24 hours.

The compound of formula (30) may be derived from a commercially available alcohol of formula (31):

Finally, if amine (4) has formula (38) as follows:

it can be prepared by reacting a compound of formula (39):

with a compound of formula (20):

is formed by the reaction of (a).

The compound of formula (39) above can be prepared according to the method described in WO 97/34905.

In a typical procedure, a compound of formula (20) is first converted to a halide (e.g., bromide, chloride, iodide) or sulfonate (e.g., methanesulfonate) using standard procedures (e.g., triphenylphosphine/iodine; triphenylphosphine/carbon tetrabromide; thionyl chloride; methanesulfonyl chloride/triethylamine) in the presence of a solvent or solvent mixture (e.g., dimethyl sulfoxide, dichloromethane, toluene, N-dimethylformamide, propionitrile, acetonitrile). This product is then reacted with a compound of formula (39) in the presence of a solvent or solvent mixture (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, acetonitrile, tetrahydrofuran), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) at a temperature between 60 ℃ and 120 ℃ for 4 to 48 hours.

The quaternary ammonium salts of the compounds of formula (1) include compounds of the formula:

wherein R is¹Selected from H, C₁-C₄Alkyl, benzyl or phenethyl, and X-is a suitable counterion, such as acetate, mesylate, xinafoate, tartrate, chloride, bromide, iodide, sulfate, phosphorusAn acid radical, a nitrate radical, a citrate radical, a methanesulfonate radical, a carboxylate radical having from 1 to 6 carbon atoms, a dicarboxylate radical having from 2 to 6 carbon atoms, a maleate radical, a fumarate radical and a benzoate radical. See int.j.pharm, 33, 201-217(1986) for other acceptable quaternary ammonium salts. X is preferably acetate, fumarate, methanesulfonate, bromide, chloride, sulfate, D-and L-tartrate or xinafoate (xinafoate). By reacting a compound of formula (4) with an alkylating agent R in the presence of a solvent or solvent mixture (e.g. dimethyl sulphoxide, toluene, N-dimethylformamide, propionitrile, acetonitrile, dichloromethane), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) at a temperature between 60 ℃ and 120 ℃¹-X (wherein R¹Is C₁-C₄Alkyl, benzyl or phenethyl, and X is a suitable leaving group (preferably R)¹the-X group is methyl iodide)) for 4 to 48 hours, such quaternary ammonium salts can be prepared. The resulting quaternary ammonium salt of the compound of formula (4) is then deprotected and reacted with a bromide of formula (3) as disclosed hereinabove to obtain the quaternary ammonium salt of the compound of formula (1).

For some steps in the preparation process of the compounds of formula (1) described hereinbefore, it may be necessary to protect potentially reactive functional groups which are not intended to react and it may therefore be necessary to cleave such protecting groups. In this case, any compatibility protecting group may be used. Specifically, methods of protection and deprotection such as those described by T.W.GREENE (Protective Groups in organic Synthesis, A.Wiley-Interscience Publication, 1981) or P.J.Kocienski (Protective Groups, Georg Thieme Verlag, 1994) may be used.

All the above reactions and preparations with respect to the novel starting materials used in the aforementioned processes are conventional and the reagents and reaction conditions suitable for their operation or preparation as well as the procedures suitable for isolating the desired products will be well known to the person skilled in the art from literature precedents and the examples and preparations related thereto.

Furthermore, the compounds of formula (1) and intermediates used in their preparation may be purified according to various well-known methods, such as crystallization or chromatography.

Preferred definitions of B are as shown below.

According to one embodiment, when B is optionally via one or two C₁-C₄Alkyl substituted C₆-C₁₂Alkylene group (CH)₂)₈、(CH₂)₉And (CH)₂)₁₀Is preferred.

According to another embodiment, when B has the formula · - (CH)₂)₂-(CH₂)_m-X¹-(CH₂)_n- (CH)₂)₆-O-(CH₂)₃、-(CH₂)₆-O-(CH₂)₄And- (CH)₂)₇O-is preferred.

According to another embodiment, when B has the formula:

the following groups are preferred:

the oxygen is preferably in the meta or para position. Oxygen is more preferably located in the para position.

According to another embodiment, when B has the formula:

oxygen in the para position is preferred.

Quaternary ammonium salts of the compounds of formula (1) are also preferred. Preferred quaternary ammonium salts are:

wherein X is an acetate radical, a fumarate radical, a mesylate radical, a bromide ion, a chloride ion, a sulfate radical, a D-and L-tartrate radical or a xinafoate radical.

According to another embodiment of the invention, quaternary ammonium salts of the formula:

(wherein X is a succinate group) is also preferred.

A is preferably a radical of the formula:

more preferably, A is a group of the formula:

particularly preferred compounds according to the invention are:

n- (5- { (1R) -2- [ (10- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } decyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide;

n- {5- [ (1R) -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide;

n- {5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide;

n- (5- { (1R) -2- [ (7- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenoxy } heptyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide;

n- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide;

n- {5- [ (1R) -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexyl ] amino } -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide;

n- {5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } carboxamide;

5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;

5- [ (1R) -1- { [ hydroxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol;

n- {5- [ (1R) -2- ({2- [3- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide;

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (2- {3- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } ethyl) phenol;

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] benzene-1, 3-diol;

n- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } carboxamide;

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (2- {4- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } ethyl) phenol;

n- (5- { (1R) -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide;

n- (5- { (1R) -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide;

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (4- {4- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } butyl) phenol;

n- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide succinate; and

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -11-dimethylethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one,

or (if appropriate) a pharmaceutically acceptable salt thereof and/or an isomer, tautomer, solvate or isotopic variant thereof.

The most preferred compounds according to the invention are:

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -11-dimethylethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;

Pharmaceutically acceptable salts of the compounds of formula (1) and their quaternary ammonium salts include acid addition salts and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, benzate (hibenzate), hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 1, 5-naphthalenedisulfonate, 2-naphthalenedisulfonate, nicotinate (nicotinate), nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, phosphate, dihydrogenphosphate, dihydrogensulfate, salicylate, acetate, salicylate, maleate, fumarate, salicylate, and salicylate, Sucrose acid salts, stearate salts, succinate salts, tartrate salts, tosylate salts and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycinate, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use' (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (1) and quaternary ammonium salts thereof may be prepared by one or more of the following three methods:

(i) by reacting a compound of formula (1) with a desired acid or base;

(ii) by removing acid-or base-sensitive protecting groups from suitable precursors of compounds of formula (1), or by ring-opening of suitable cyclic precursors (e.g. lactones or lactams), using the desired acid or base; or

(iii) One salt of the compound of formula (1) is converted to another salt by reaction with a suitable acid or base or by means of a suitable ion exchange column.

All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration, or may be recovered by solvent evaporation. The degree of ionization in the resulting salt can vary between complete ionization and little ionization.

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.

Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the aforementioned solvates. Also included are pharmaceutical compositions comprising two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized. For an overview of such complexes, see J Pharm Sci, 64(8), 1269-.

All references hereinafter to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (1) as defined above, including all polymorphs and crystal habit thereof, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomers) as defined below, and isotopically labeled compounds of formula (1).

As shown herein, so-called "prodrugs" of the compounds of formula (1) are also within the scope of the present invention. Thus, certain derivatives of the compounds of formula (1) which may themselves have little pharmacological activity may be converted, for example by hydrolytic cleavage, into compounds of formula (1) having the desired activity when administered to the body or body surface. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in the 'Pro-drugs as Novel Delivery Systems', Vol.14, ACSSymposium Series (T. Higuchi and W.Stella) and 'BioversibleCarriers in Drug Design', Pergamon Press, 1987 (compiled by E.B Roche, American Pharmaceutical Association).

For example, Prodrugs according to the invention may be made by replacing suitable functional groups present in compounds of formula (1) with certain moieties known to those skilled in the art as "front moieties" (for example as described in "Design of produgs" (Elsevier, 1985) by h.

Some examples of prodrugs according to the invention include:

(i) (in the case where the compound of formula (1) contains a methyl group) a hydroxymethyl derivative thereof (-CH)₃→-CH₂OH)；

(ii) (in the case where the compound of formula (1) contains an alkoxy group) a hydroxy derivative thereof (-OR → -OH);

(iii) (in the case where the compound of formula (1) contains a tertiary amino group) — secondary amino derivative thereof (-NR)¹R²→-NHR¹or-NHR²)；

(iv) (in the case where the compound of formula (1) contains a secondary amino group) a primary amino derivative thereof (-NHR)¹→-NH₂)；

(v) (in the case of compounds of formula (1) containing a phenyl moiety) the phenolic derivative thereof (-Ph → -PhOH); and

(vi) (in the case where the compound of formula (1) contains an amide group) a carboxylic acid derivative thereof (-CONH)₂→-COOH)。

Further examples of substituent groups according to the preceding examples and examples of other prodrug types can be found in the aforementioned citations.

Furthermore, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1).

Also included within the scope of the present invention are metabolites of the compounds of formula (1), i.e., compounds that are formed in vivo upon administration of a drug. Some examples of metabolites according to the invention include:

(i) (in the case where the compound of formula (1) contains a secondary amino group) a primary amino derivative thereof (-NHR)¹→-NH₂) (ii) a And

(ii) (in the case of compounds of formula (1) containing a phenyl moiety) the phenolic derivative thereof (-Ph → -PhOH).

All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1) are included within the scope of the invention, including compounds exhibiting multiple isomeric forms and mixtures of one or more such compounds. Also included are acid addition or base salts in which the counter ion is optically active, such as d-lactate or 1-lysine; or a racemate such as d 1-tartrate or d 1-arginine.

Cis/trans isomers may be isolated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol or an acid or base such as tartaric acid or 1-phenylethylamine in the case of compounds of formula (1) containing an acidic or basic moiety. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers converted to the corresponding pure enantiomers by methods well known to those skilled in the art.

Chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin through a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume, typically 2 to 20% by volume isopropanol, and 0 to 5% by volume of an alkylamine, typically 0.1% by volume diethylamine. Concentration of the eluate yields an enriched mixture.

Stereoisomeric agglomerates can be isolated by conventional techniques known to those skilled in the art-see, for example, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994) by E.L.

The invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (1) wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, such as²H and³h; isotopes of carbon, such as¹¹C、¹³C and¹⁴c; isotopes of chlorine, such as³⁶Cl; isotopes of fluorine, such as¹⁸F; isotopes of iodine, such as¹²³I and¹²⁵i; isotopes of nitrogen, such as¹³N and¹⁵n; isotopes of oxygen, such as¹⁵O、¹⁷O and¹⁸o; isotopes of phosphorus, such as³²P; and isotopes of sulfur, such as³⁵S。

Certain isotopically-labeled compounds of formula (1), for example those into which a radioisotope is incorporated, are useful in drug and/or stromal tissue distribution studies. Radioisotope tritium (i.e., tritium³H) And carbon-14 (i.e.¹⁴C) It is particularly suitable for this purpose in view of its ease of incorporation and ease of detection.

With compounds such as deuterium (i.e. deuterium)²H) Substitution with heavier isotopes of (a) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances.

With positron emitting isotopes (such as¹¹C、¹⁸F、¹⁵O and¹³n) can be used in Positron Emission Tomography (PET) studies for examination of stromal receptor occupancy.

Isotopically-labelled compounds of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying "examples" and "preparations", using a suitable isotopically-labelled reagent in place of the unlabelled reagent previously employed.

Pharmaceutically acceptable solvates according to the invention include those solvates in which the solvent of the crystallization may be isotopically substituted, for example D₂O、d₆-acetone, d₆-DMSO。

The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms are valuable pharmaceutically active compounds which are suitable for the treatment and prevention of numerous disorders, in which the agonism of the β 2 receptor and the antagonism of muscarine can lead to benefits, especially allergic and non-allergic tracheal diseases.

The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. For example, it may be obtained as a solid plug, powder or film by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporation-drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone, or in combination with one or more other compounds of the invention or with one or more other drugs (or as any combination thereof). Generally, it will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient will depend largely on factors such as: the effect of particular modes of administration, excipients on solubility and stability, and dosage form characteristics.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods of preparation can be found, for example, in ' Remington's Pharmaceutical Sciences ', 19 th edition (Mack publishing company, 1995).

The compounds of the invention may be administered orally. Oral administration may involve swallowing, in order to get the compound into the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound is taken directly from the mouth into the bloodstream.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing microparticles, liquids or powders, lozenges (including liquid-filled), chewables, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films, eggs, sprays and liquid formulations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by compounding solids, for example, from sachets.

The compounds of the present invention may also be used in the form of fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, (2001) by Liang and Chen.

For tablet dosage forms, depending on the dosage, the drug may comprise 1 to 80% by weight of the dosage form, more typically 5 to 60% by weight of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, cross-linked povidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl groups, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.

Binders are commonly used to impart cohesiveness to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrate and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate.

The tablets may also optionally contain surfactants (such as sodium lauryl sulfate and polysorbate 80) and glidants (such as silicon dioxide and talc). When present, the surfactant may comprise 0.2 to 5% by weight of the tablet, and the glidant may comprise 0.2 to 1% by weight of the tablet.

Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant typically comprises 0.25 to 10% by weight of the tablet, preferably 0.5 to 3% by weight.

Other possible ingredients include antioxidants, colorants, fragrances, preservatives, and taste masking agents.

Exemplary tablets contain up to about 80% drug, about 10 to about 90% binder, about 0 to about 85% diluent, about 2 to about 10% disintegrant, and about 0.25 to about 10% lubricant by weight.

The tablet blend may be compressed directly or by roller compression to form tablets. Alternatively, the tablet blend or partial blend may be wet granulated, dry granulated or melt granulated, melt congealed or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

In Pharmaceutical Dosage Forms of h.lieberman and l.lachman: formulation of Tablets is discussed in Tablets, volume 1, (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically flexible water-soluble or water-swellable film dosage forms that dissolve rapidly or are mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (1) may be water soluble or insoluble. The water soluble compound typically comprises from 1 wt% to 80 wt%, more typically from 20 wt% to 50 wt% solute. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (1) may be in the form of a multiplicity of beads.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids, and is typically present in the range of 0.01 to 99 wt%, more typically 30 to 80 wt%.

Other possible ingredients include antioxidants, colorants, fragrances and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste masking agents.

The film according to the invention is typically prepared by evaporation drying of an aqueous film coated on a peelable backing support or paper. This can be done in a drying oven or drying tunnel (typically a combination coater dryer), or by freeze drying or vacuum drying.

Solid formulations for oral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release formulations.

Modified release formulations suitable for the purposes of the present invention are described in U.S. Pat. No. 6,106,864. Details regarding other suitable delivery techniques, such as high energy dispersion and penetration and coating of particles, can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14, (2001). The use of a chewable tablet for achieving controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the bloodstream, muscle or organs in the body. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless injectors, and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers, preferably at a pH of from 3 to 9, but for some applications may be more suitably formulated as sterile non-aqueous solutions or in dry form to be used in combination with a suitable vehicle, such as sterile pyrogen-free water.

For example, parenteral formulations are prepared by freeze-drying under sterile conditions, which can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compound of formula (1) used to prepare the parenteral solution can be increased by using suitable formulation techniques, such as the incorporation of solubilizing agents.

Formulations for parenteral administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release formulations. Thus, the compounds of the present invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implantable drug reservoir, which may provide for modified release of the active compound. Examples of such formulations include drug-coated vascular stents and poly (d 1-lactic-co-glycolic acid) (PGLA) microspheres.

The compounds of the invention may also be applied topically, i.e. epicutaneously or transdermally, to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include ethanol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated-see, for example, J Pharm Sci, 88(10), 955-958 by Finnin and Morgan (10 months 1999).

Other methods of topical administration include delivery by electroporation, iontophoresis, sonophoresis and microneedles or needleless (e.g. Powderject)^TM、Bioject^TMEtc.) for injection.

Formulations for topical administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release formulations.

The compounds of the invention may also be conveniently administered in the form of a dry powder (alone, as a mixture, e.g., with lactose in a dry blend; or as a mixed component particle, e.g., with a phospholipid such as phosphatidylcholine) from a dry powder inhaler; or as an aerosol spray for intranasal administration or administration by inhalation from a pressurized container, pump, sprayer, nebulizer (preferably one that utilizes electrohydrodynamic force to produce a fine mist), or nebulizer with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, such as chitosan or cyclodextrin.

A pressurized container, pump, sprayer, nebulizer or spray contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or a suitable surrogate reagent for dispersion, solubilization, or delayed release of the active substance, a propellant as a solvent, and optionally a surfactant such as sorbitan trioleate, oleic acid, or oligomeric lactic acid.

Prior to use in dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a performance modifying agent such as 1-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable solution formulations for nebulizers that use electrohydrodynamic to generate fine mist may contain 1 μ g to 20mg of a compound of the invention per actuation, and the actuation volume may vary between 1 μ l to 100 μ l. Typical formulations may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents such as menthol and levomenthol (levomenthol) or sweetening agents such as saccharin or sodium saccharin may be added to those formulations of the invention intended for inhalation/intranasal administration.

Formulations for inhalation/intranasal administration may be formulated for immediate release and/or modified release using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release formulations.

In the case of dry powder inhalers and aerosols, the dosage units are determined by a valve delivering a metered amount. Units according to the invention are generally configured to administer a metered dose or "puff volume" (puff) containing from 0.001mg to 10mg of a compound of formula (1). The total daily dose will generally be in the range of from 0.001mg to 40mg, which may be administered in a single dose, or more usually in divided doses throughout the day.

The compounds of formula (1) are particularly suitable for administration by inhalation.

The compounds of the invention may be administered rectally, for example in the form of suppositories, pessaries or enemas, or vaginally. Cocoa butter is a traditional suppository base, but various alternatives may be used if appropriate.

Formulations for rectal/vaginal administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release formulations.

The compounds of the invention may also be administered directly to the eye or ear, usually in the form of micronized suspensions or drops of solutions in isotonic, pH adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate or vesicular systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., gum gums) may be incorporated with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/otic administration may be formulated for immediate release and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release or programmed release formulations.

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for any of the modes of administration described above.

For example, drug-cyclodextrin complexes are generally found to be suitable for use in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. For these purposes, alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin are most commonly used, examples of which can be found in international patent applications No. WO 91/11172, No. WO 94/02518 and No. WO 98/55148.

Since administration of a combination of active compounds may be desired, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, may suitably be combined in a kit suitable for co-administration of the compositions.

Thus, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) according to the invention, and means for separately retaining such compositions, such as a container, a separate bottle or a separate foil package. An example of such a kit is the common blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms (e.g. parenterally), for administering the separate compositions at different dosage intervals, or for titrating the separate compositions relative to each other. To aid compliance, the kit typically contains instructions for administration, and may be provided with so-called "memory aids".

For administration to human patients, the total daily dose of the compounds of the invention will generally be in the range of from 0.001mg to 5000mg, depending, of course, on the mode of administration. For example, an intravenous daily dose may only require 0.001mg to 40 mg. The total daily dose may be administered in a single dose or in divided doses and, at the discretion of the physician, may be outside the typical ranges given herein.

Such doses are based on a typical human subject having a body weight of about 65kg to 70 kg. A physician will readily be able to determine the dosage of subjects (such as infants and elderly) whose weights fall outside this range.

For the avoidance of doubt, reference herein to "treatment" includes reference to curative, palliative and prophylactic treatment.

According to another embodiment of the present invention, the compounds of formula (1) or pharmaceutically acceptable salts, derivative forms or compositions thereof may also be used in combination with one or more additional therapeutic agents for co-administration to a patient to achieve certain particularly desirable therapeutic end results, such as the treatment of pathophysiologically relevant disease processes, including, but not limited to, (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as asthma, cough. The second and other additional therapeutic agents may also be a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof, or one or more β 2 agonists, muscarinic antagonists or compounds known in the art to have activity as β 2 agonists and muscarinic antagonists. More typically, the second and further therapeutic agents will be selected from different classes of therapeutic agents.

As used herein, the terms "co-administration", "co-administration" and "combination" in relation to a compound of formula (1) and one or more other therapeutic agents are intended to mean and include the following meanings:

administering such a combination of a compound of formula (1) and a therapeutic agent simultaneously to a patient in need of treatment, which dosage form, when formulated together into a single dosage form, releases such components to the patient substantially simultaneously,

administering such a combination of a compound of formula (1) and a therapeutic agent substantially simultaneously to a patient in need of treatment, such dosage forms being administered substantially simultaneously by the patient when such components are formulated separately from each other into separate dosage forms, thereby releasing such components to the patient substantially simultaneously,

administering such combinations of a compound of formula (1) and a therapeutic agent sequentially to a patient in need of treatment, such dosage forms being taken by the patient sequentially with significant time intervals between administrations when such components are formulated separately from one another into separate dosage forms, whereby such components are released to the patient at substantially different times; and

such a combination of a compound of formula (1) and a therapeutic agent is administered sequentially to a patient in need of treatment, which dosage form releases such components in a controlled manner when formulated together into a single dosage form, whereby such components are administered to the patient simultaneously, consecutively and/or overlapping at the same and/or different times,

wherein each part may be administered by the same route or by different routes.

Suitable examples of other therapeutic agents that may be used in combination with a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof include (but are in no way limited to):

(a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist;

(b) leukotriene antagonists (LTRA) comprising LTB₄、LTC₄、LTD₄And LTE₄An antagonist of (1);

(c) histamine receptor antagonists including H1 and H3 antagonists;

(d) alpha for decongestant use₁-and a₂-an adrenoceptor agonist vasoconstrictive sympathomimetic agent;

(e) PDE inhibitors, such as PDE3, PDE4, and PDE5 inhibitors;

(f) theophylline (theophylline);

(g) cromoglyte (sodium cromoglycate);

(h) COX inhibitors, non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs);

(i) prostaglandin receptor antagonists and prostaglandin synthase inhibitors;

(j) oral and inhaled glucocorticoids;

(k) dissociated agonists of adrenocortical hormone receptors (DAGR);

(l) Monoclonal antibodies active against endogenous inflammatory entities;

(m) an anti-tumor necrosis factor (anti-TNF- α) agent;

(n) adhesion molecule inhibitors, including VLA-4 antagonists;

(o) kinin-B₁-and B₂-a receptor antagonist;

(p) immunosuppressive agents, including inhibitors of the IgE pathway and cyclosporine;

(q) inhibitors of Matrix Metalloproteinases (MMPs);

(r) tachykinin NK₁、NK₂And NK₃A receptor antagonist;

(s) protease inhibitors, such as elastase inhibitors;

(t) adenosine A2a receptor agonists and A2b antagonists;

(u) inhibitors of urokinase;

(v) compounds acting at dopamine receptors, such as D2 agonists;

(w) modulators of the NF κ β pathway, such as IKK inhibitors;

(x) Cytokine signaling pathway modulators, such as p38MAP kinase, PI3 kinase, JAK kinase, syk kinase, EGFR, or MK-2;

(y) agents that can be classified as mucolytic or anti-tussive;

(z) agents that enhance the response to inhaled corticosteroids;

(aa) antibiotics and antivirals effective against microorganisms that colonize the respiratory tract;

(bb) HDAC inhibitors;

(cc) CXCR2 antagonists;

(dd) integrin antagonists;

(ee) chemokines;

(ff) an epithelial sodium channel (ENaC) blocker or inhibitor;

(gg) P2Y2 agonists and other nucleotide receptor agonists;

(hh) thromboxane inhibitors;

(ii) nicotinic acid, and

(jj) adhesion factors including VLAM, ICAM and ELAM.

According to the invention, the combination of a compound of formula (1) with:

-an antagonist of H3, and,

-a PDE4 inhibitor which is,

-glucocorticoids of the oral and inhaled type,

-dissociated agonists of adrenocortical hormone receptors (DAGR);

-an adenosine A2a receptor agonist,

modulators of the cytokine signal transduction pathway, such as p38, MAP kinase, PI3 kinase, JAK kinase, syk kinase, EGFR or MK-2, or

Leukotriene antagonists (LTRA), which include LTB₄、LTC₄、LTD₄And LTE₄An antagonist of (1).

According to the present invention, the combination of the compound of formula (1) with glucocorticoids including prednisone (prednisone), flunisolide (flunisolide), triamcinolone acetonide (triamcinolone acetonide), beclomethasone dipropionate (beclomethasone dipropionate), budesonide (budesonide), fluticasone propionate (fluticasone propionate), ciclesonide (ciclesonide), mometasone furoate (mometasone furoate) and mometasone furoate (mometasone furoate) monohydrate is more preferred, and particularly inhaled glucocorticoids with reduced systemic side effects.

It will be understood that all references herein to treatment include references to curative, palliative and prophylactic treatment.

The compounds of formula (1) have the ability to interact with the β 2 receptor and the cholinergic muscarinic receptor, and thus have a wide range of therapeutic applications due to the important role played by the β 2 receptor and the muscarinic receptor in the physiological functions of all mammals, as described further below.

Accordingly, another aspect of the present invention is directed to compounds of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof for use in the treatment of diseases, disorders and conditions in which the β 2 receptor and/or the muscarine receptor is involved. More specifically, the present invention also relates to compounds of formula (1) or pharmaceutically acceptable salts, derivative forms or compositions thereof for the treatment of diseases, disorders and conditions selected from the group consisting of:

asthma of any type, etiology or pathology, in particular asthma of a member selected from the group consisting of: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma (essentialastrathrima), intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown etiology, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, asthma primordial, wheezy infant syndrome, and bronchiolitis;

chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction and emphysema;

obstructive or inflammatory airways diseases of any type, etiology or pathology, in particular selected from one member of the group consisting of: chronic eosinophilic pneumonia (chronic eosinophilic pulmonary onia), Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated or not associated with COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperresponsiveness following other drug treatment and airway disease associated with pulmonary hypertension;

bronchitis of any type, etiology or pathology, in particular bronchitis of a member selected from the group consisting of: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis (arachidic bronchitis), catarrhal bronchitis (catarrhal bronchitis), croupus bronchitis (croupus bronchitis), dry bronchitis, infectious asthmatic bronchitis (infectious bronchitis), proliferative bronchitis (productive bronchitis), staphylococcal or streptococcal bronchitis, and alveolar bronchitis;

acute lung injury;

bronchiectasis of any type, etiology or pathology, in particular bronchiectasis of a member selected from the group consisting of: columnar bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, cystic bronchiectasis (cystic broncheectasis), dry bronchiectasis, and follicular bronchiectasis (folliculularis).

Yet another aspect of the invention is directed to the use of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof for the manufacture of a medicament having β 2 agonist activity and M3 antagonist activity. In particular, the present invention relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof for the manufacture of a medicament for the treatment of diseases and/or conditions associated with the β 2 and M3 receptors, in particular the diseases and/or conditions listed above.

Accordingly, the present invention provides a particularly interesting method of treating mammals, including humans, with an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof. More specifically, the present invention provides a particularly interesting method for the treatment of β 2 mediated diseases and/or disorders associated with the β 2 and M3 receptors, in particular the diseases and/or disorders listed above, in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula (1), a pharmaceutically acceptable salt and/or derivative thereof.

The following examples illustrate the preparation of compounds of formula (1):

preparation 1

(9-Bromononyl) imidocarbonic acid di-tert-butyl ester

Sodium hydride (1.31g of a 60% dispersion in oil, 30.0mmol) was added in one portion to a stirred solution of di-tert-butyl iminodicarbamate (6.50g, 30.0mmol) in N, N-dimethylformamide (5ml) at 0 ℃ under nitrogen. The reaction was stirred at 0 ℃ for 5 minutes and then at room temperature for 30 minutes. The reaction was cooled to 0 ℃ and 1, 9-dibromononane (8.60g, 30.0mmol) was added dropwise, allowing the reaction to warm to room temperature and stir for 3 days. Ether (50ml) and water (20ml) were carefully added and the organic phase was separated, the aqueous layer was washed with ether (50ml) and the combined organic phases were dried (magnesium sulphate) and the solvent was removed in vacuo to give a clear oil. The oil was purified by column chromatography using diethyl ether: hexane (10/90 by volume) eluting through silica gel to give 5.80g of the title compound as a colourless oil.

¹H NMR(400MHz，CD₃OD)：δ＝1.30(10H，m)，1.50(20H，m)，1.83(2H，m)，3.42(2H，t)，3.58(2H，t)ppm。

Preparation 2

[10- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } dec-9-en-1-yl ] imidodicarbonate di-tert-butyl ester

Di-tert-butyl (9-bromononyl) imidocarbonate (preparation 1, 1.80g, 4.26mmol) and triphenylphosphine (2.00g, 7.63mmol) were dissolved in acetonitrile (40ml) and heated at reflux for 48 h. The reaction was cooled to room temperature and the solvent was reduced to 8ml in vacuo. The reaction was heated at reflux for 12 hours and allowed to cool to room temperature. The solvent was removed in vacuo to give the intermediate phosphonium salt as a gum. The gum (1.70g, 2.48mmol) was dissolved in tetrahydrofuran (15ml) under a nitrogen atmosphere and cooled to-78 ℃. N-butyllithium (0.90ml of a 2.5M solution in hexane, 2.25mmol) was added dropwise to give an orange solution, which was then warmed to 0 ℃ and stirred for 45 minutes. The reaction was cooled to-78 ℃ and a solution of 4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] benzaldehyde (prepared according to WO 2005/012227, 320mg, 0.75mmol) in tetrahydrofuran (5ml) was added dropwise and the reaction stirred at-78 ℃ for 10 min. The reaction was warmed to room temperature and stirred for 12 hours, and then poured onto ethyl acetate (30ml) and water (20 ml). The organic phase was separated, dried (magnesium sulfate) and the solvent removed in vacuo, and the residue purified by column chromatography using dichloromethane: methanol: 880 ammonia (90/10/1.0 by volume) eluting through silica gel to give 140mg of the title compound as a white gum.

LRMS：m/z 755.7[M+H]⁺。

Preparation 3

10- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } dec-9-en-1-amine

Hydrochloric acid (10.0ml of a 2M solution in ether) was added in one portion to a stirred solution of di-tert-butyl [10- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } dec-9-en-1-yl ] imidodicarbonate (preparation 2, 450mg, 0.59mmol) in dichloromethane (5ml) at room temperature under a nitrogen atmosphere. The reaction was stirred for 2 hours and the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30ml) and saturated aqueous sodium bicarbonate (20 ml). The organic phase was separated, washed with water (10ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (90/10/1.0 by volume) through silica gel to give 180mg of the title compound as a glass.

LRMS：m/z 556[M+H]⁺。

Preparation 4

N- {2- (benzyloxy) -5- [ (1R) -2- { [10- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } dec-9-en-1-yl ] amino } -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide

10- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } dec-9-en-1-amine (preparation 3, 170mg, 0.33mmol) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation according to WO2005/080324, 180mg, 0.33mmol) were heated in dimethyl sulfoxide (0.5ml) at 90 ℃ for 12 h. Ethyl acetate (20ml) and water (10ml) were added and the organic phase was separated, washed with water (10ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (80/20/2.0 by volume) through silica gel to give 90mg of the title compound as a glass.

LRMS：m/z 989[M+H]⁺。

Preparation 5

{2- [4- (allyloxy) phenyl ] ethyl } carbamic acid tert-butyl ester

Bromopropene (2.10ml, 24.8mmol) was added in one portion to a suspension of potassium carbonate (4.40g, 31.8mmol) and tert-butyl [2- (4-hydroxyphenyl) ethyl ] carbamate (prepared according to Journal of Organic Chemistry 1999, 64, 1074, 5.00g, 21.1mmol) in acetonitrile (50ml) at room temperature. The reaction was stirred for 12 hours and the solvent was removed in vacuo. Diethyl ether (50ml) and water (20ml) were added and the organic phase was separated, washed with water (20ml), dried (magnesium sulphate) and the solvent removed in vacuo to give a clear oil. The oil was purified by column chromatography eluting through silica gel with ethyl acetate pentane (25/75 by volume) to give 3.80g of the title compound as a white solid.

¹H NMR(400MHz，CDCl₃)：δ＝1.42(9H，s)，2.78(2H，m)，3.37(2H，m)，4.58(3H，m)，5.28(1H，dd)，5.40(1H，dd)，6.10(1H，m)，6.84(2H，d)，7.10(2H，d)ppm。

Preparation 6

[ tert-butyl [2- (4- { [ (2E) -3- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } prop-2-en-1-yl ] oxy } phenyl) ethyl ] carbamate

(3R) -3- [2- (benzyloxy) -5-bromophenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (prepared according to WO1994/11337, 800mg, 1.66mmol), {2- [4- (allyloxy) phenyl ] ethyl } carbamic acid tert-butyl ester (prepared 5, 924mg, 3.33mmol), palladium acetate (37mg, 0.16mmol), tris (o-tolyl) phosphine (101mg, 0.33mmol) and diisopropylethylamine (435. mu.l, 2.50mmol) were heated in acetonitrile (10ml) at 90 ℃ under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature and poured onto ethyl acetate (30ml) and water (20 ml). The organic phase was separated, washed with saturated aqueous sodium bicarbonate (20ml), water (20ml), brine (20ml), dried (magnesium sulfate) and the solvent removed in vacuo, and the residue purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (90/10/1.0 by volume) through silica gel to give 475mg of the title compound as a glass.

LRMS：m/z 677[M+H]⁺。

Preparation 7

{2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } carbamic acid tert-butyl ester

The reaction product of [2- (4- { [ (2E) -3- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl group]Phenyl-prop-2-en-1-yl]Oxy } phenyl) ethyl]Tert-butyl carbamate (preparation 6, 475mg, 0.70mmol) was dissolved in ethanol (20ml), and 10% palladium on carbon (50mg) was added. The reaction was heated to 40 ℃ under 50psi of hydrogen for 4 hours. The reaction was cooled to room temperature and passed through Arbocel^TMFiltration, collection of the filtrate and removal of the solvent in vacuo gave 400mg of the title compound as a glass.

LRMS：m/z 589[M+H]⁺。

Preparation 8

4- {3- [4- (2-aminoethyl) phenoxy ] propyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

Tert-butyl {2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } carbamate (preparation 7, 400mg, 0.68mmol) was dissolved in dichloromethane (15ml) and hydrochloric acid (10ml of a 2M solution in ether) was added to the stirred solution at 0 ℃. After 3 hours the solvent was removed in vacuo and ethyl acetate (20ml) and saturated aqueous sodium bicarbonate (10ml) were added and the organic phase was separated. The aqueous phase was washed with dichloromethane: methanol (90: 10 by volume, 2X 20ml) and the organic phase was combined, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (80/20/2.0 by volume) through silica gel to give 135mg of the title compound as a glass.

LRMS：m/z 489[M+H]⁺。

Preparation 9

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } amino) ethyl ] phenyl } methanesulfonamide

4- {3- [4- (2-aminoethyl) phenoxy ] propyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 8, 134mg, 0.27mmol) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation according to WO2005/080324, 145mg, 0.28mmol) were heated in dimethylsulfoxide (0.5ml) at 90 ℃ for 24 h. Ethyl acetate (20ml) and water (10ml) were added and the organic phase was separated. The aqueous phase was washed with ethyl acetate (20ml) and the combined organic phases were washed with brine (10ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (80/20/2.0 by volume) through silica gel to give 101mg of the title compound as a glass.

LRMS：m/z 923[M+H]⁺。

Preparation 10

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl)]-4-hydroxyphenyl } propoxy) phenyl]Ethyl } amino) ethyl]Phenyl } methanesulfonamide (preparation 9, 100mg, 0.11mmol) was dissolved in ethanol (10ml), and ammonium formate (68mg, 1.07mmol) and 10% palladium hydroxide on carbon (20mg) were added. The stirred reaction was heated at 90 ℃ for 2 hours, cooled to room temperature and passed through Arbocel^TMFiltration, collection of the filtrate and removal of the solvent in vacuo gave 98mg of the title compound as yellow glass.

LRMS：m/z 833[M+H]⁺。

Preparation 11

[ tert-butyl [2- (4- { [ (3E) -4- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } but-3-en-1-yl ] oxy } phenyl) ethyl ] carbamate

By reacting [2- (4-hydroxyphenyl) ethyl]Tert-butyl carbamate (prepared according to Journal of organic chemistry 1999, 64, 1074, 1g, 4.2mmol) was dissolved in dimethylformamide (8ml) and potassium carbonate (698mg, 5.1mmol) was added followed by 4-bromobut-1-ene (0.51ml, 5.1mmol) and the mixture was heated to 60 ℃. After 5 hours, it was cooled to room temperature, then another portion of potassium carbonate (698mg, 5.1mmol) and 4-bromobut-1-ene (0.51ml, 5.1mmol) was added and the mixture was reheated to 60 ℃. After 18 h, it was cooled to room temperature, then another portion of potassium carbonate (698mg, 5.1mmol) and 4-bromobut-1-ene (0.51ml, 5.1mmol) were added and the mixture was reheated to 60 ℃. After a further 5 hours cooling to room temperature was followed by addition of a further portion of potassium carbonate (350mg, 2.5mmol) and 4-bromobut-1-ene (0.25ml, 2.5mmol) and reheating of the mixture to 60 ℃. Stirring overnight, cooling to room temperature, adding water and extracting with ethyl acetate, drying(magnesium sulfate) and the solvent was removed in vacuo and the residue was purified by column chromatography eluting with pentane: ethyl acetate (80/20 by volume) through silica gel. The above reaction was repeated to give 1.1g of an intermediate, which was dissolved in acetonitrile (10ml), and (3R) -3- [2- (benzyloxy) -5-bromophenyl group was added]-N, N-diisopropyl-3-phenylpropan-1-amine (prepared according to WO9411337, 1.2g, 2.5mmol), tris (2-methylphenyl) phosphine (760mg, 2.5mmol) and diisopropylethylamine (0.87ml, 4.99mmol), and the mixture was degassed using a stream of argon. Palladium diacetate (280mg, 1.25mmol) was added and the mixture was heated to 90 ℃. After 5 hours, cool to room temperature and leave to stir overnight. Passing the mixture through Arbocel^TMFiltration and removal of the solvent in vacuo. Water was added and extracted with ethyl acetate, the organic layer was separated and dried (magnesium sulfate) and the solvent was removed in vacuo and the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 96/4/0.4 by volume) through silica gel to give 1.45g of the title compound as a colourless gum.

LRMS：m/z 691[M+H]⁺。

Preparation 12

{2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } carbamic acid tert-butyl ester

The reaction product of [2- (4- { [ (3E) -4- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl group]Phenyl } but-3-en-1-yl]Oxy } phenyl) ethyl]Tert-butyl carbamate (preparation 11, 725mg, 1.05mmol) was dissolved in ethanol (10ml), palladium hydroxide (20 wt% on carbon, 181mg, 0.25mmol) was added followed by ammonium formate (529mg, 8.39mmol) and heated to 80 ℃ for 5 min, followed by stirring at 75 ℃ for 1 h. The reaction was cooled to room temperature and the mixture was passed through Arbocel^TMFiltered and the solvent removed in vacuoAnd (3) preparing. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (97/3/0.3 to 94/6/0.6 by volume) through silica gel to give 460mg of the title compound as a white foam.

LRMS：m/z 603[M+H]⁺。

Preparation 13

4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol bis-hydrochloride

Tert-butyl {2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } carbamate (preparation 12, 450mg, 0.75mmol) was dissolved in dichloromethane (10ml), hydrogen chloride (2M in ether, 6ml, 12mmol) was added, followed by ethanol (1 ml). After 3 days, the solvent was removed in vacuo to give 420mg of the title compound as a yellow foam.

LRMS: m/z 503[ M (free base) + H]⁺。

Preparation 14

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] phenyl } methanesulfonamide

4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol bis-hydrochloride (preparation 13, 420mg, 0.73mmol), N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation according to WO2005/080324, 375mg, 0.73mmol), sodium bicarbonate (245mg, 2.92mmol) and potassium iodide (121mg, 0.73mmol) were added to acetonitrile (15ml) and heated to 90 ℃ for 30 min and left at room temperature for 48 h, water was added and extracted with ethyl acetate, dried (magnesium sulfate) and the solvent was removed in vacuo, the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (97/3/0.3 to 92/8/0.8 by volume) through silica gel to give 207mg of the title compound as a white foam.

LRMS：m/z 937[M+H]⁺。

Preparation 15

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl)]-4-hydroxyphenyl } butoxy) phenyl]Ethyl } amino) ethyl]Phenyl } methanesulfonamide (preparation 14, 200mg, 0.2mmol) and palladium hydroxide (20 wt% on carbon, 50mg, 0.07mmol) were dissolved in ethanol (5ml), followed by the addition of ammonium formate (74mg, 1.2mmol) and heating to 80 ℃ for 5 minutes, followed by stirring at 75 ℃ for 1 hour. The reaction was cooled to room temperature and the mixture was passed through Arbocel^TMFiltration and removal of the solvent in vacuo gave 190mg of the title compound as a white foam.

LRMS：m/z 847[M+H]⁺。

Preparation 16

4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] benzaldehyde (prepared according to WO2005012227, 1g, 2.32mmol) was dissolved in methanol (40ml), sulfuric acid (2M, 6ml) was added followed by hydrogen peroxide (30 wt% in water, 2ml) and the reaction mixture was allowed to stir overnight. The mixture was partitioned between water and diethyl ether, the organic layer was separated, washed with saturated sodium sulfite solution, dried (magnesium sulfate), filtered and the solvent removed in vacuo, and the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (24/1/0.1 to 23/2/0.2 by volume) through silica gel to give 560mg of the title compound as a pale yellow foam.

LRMS：m/z 418[M+H]⁺。

Preparation 17

Di-tert-butyl (7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenoxy } heptyl) imidodicarbonate

4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 16, 150mg, 0.36mmol) was dissolved in dimethylformamide (2ml), and cesium carbonate (140mg, 0.43mmol) was added and stirred at room temperature for 30 minutes. Tert-butyl (7-bromoheptyl) carbamate (prepared according to j.med.chem., 1994, 137, pages 2537 to 2551, 170mg, 0.43mmol) dissolved in dimethylformamide (1ml) was added and heated to 70 ℃. Cesium carbonate (70mg, 0.22mmol) was added after 2.5 hours and tert-butyl (7-bromoheptyl) carbamate (70mg, 0.18mmol) was added after another 10 minutes. Cesium carbonate (20mg, 0.06mmol) and tert-butyl (7-bromoheptyl) carbamate (35mg, 0.09mmol) are added after 1 hour, and after 1 hour at 70 ℃ the mixture is cooled to room temperature and stirred for 3 days, then water and brine are added, the mixture is extracted with ethyl acetate, dried (magnesium sulfate), filtered and the solvent is removed in vacuo, and the residue is purified by column chromatography using dichloromethane: methanol: 880 ammonia (98/2/0.2 to 95/5/0.5 by volume) eluting through silica gel to give 220mg of the title compound as a colourless gum.

LRMS：m/z 731[M+H]⁺。

Preparation 18

7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenoxy } hept-1-amine dihydrochloride

Di-tert-butyl (7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenoxy } heptyl) imidodicarbonate (preparation 17, 220mg, 0.30mmol) was dissolved in dichloromethane (6ml), followed by addition of hydrogen chloride (2M solution in ether, 6ml, 12mmol) and after 30 min addition of ethanol (1ml) and standing overnight. The solvent was removed in vacuo to give 190mg of the title compound as a light brown foam.

LRMS: m/z 531[ M (free base) + H]⁺。

Preparation 19

N- {2- (benzyloxy) -5- [ (1R) -2- [ (7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenoxy } heptyl) amino ] -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide

7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenoxy } hept-1-amine bis-hydrochloride (preparation 18, 190mg, 0.31mmol), N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation according to WO2005/080324, 161mg, 0.32mmol), sodium bicarbonate (106mg, 1.26mmol) and potassium iodide (52mg, 0.32mmol) were added to acetonitrile (5ml) and heated to 90 ℃ for 24 hours, then left overnight at room temperature, and brine and extracted with ethyl acetate, water was added, dried (magnesium sulfate) and the solvent was removed in vacuo, the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 92/8/0.8 by volume) through silica gel to give 100mg of the title compound as a colourless gum.

LRMS：m/z 965[M+H]⁺。

Preparation 20

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (7- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenoxy } heptyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -2- [ (7- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl group]Phenoxy } heptyl) amino]-1- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Phenyl } methanesulfonamide (preparation 19, 96mg, 0.10mmol) and palladium hydroxide (20 wt% on carbon, 25mg, 0.04mmol) were dissolved in ethanol (3ml), followed by addition of ammonium formate (69mg, 1.1mmol) and heating to 80 ℃ for 1 hour. The reaction was cooled to room temperature and the mixture was passed through Arbocel^TMFiltration and removal of the solvent in vacuo. The residue was dissolved in dichloromethane (containing traces of methanol) and washed with water (brine was added to aid separation), the organic layer was driedDry (magnesium sulfate), filter, and remove the solvent in vacuo to give 68mg of the title compound as a white foam.

LRMS：m/z 785[M+H]⁺。

Preparation 21

(3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine

2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethanol (prepared according to WO9843942, 390mg, 0.88mmol) was dissolved in tetrahydrofuran (6ml), triphenylphosphine (344mg, 1.31mmol) was added, followed by di-tert-butyl (265mg, 1.31mmol) of (E) -diazene-1, 2-dicarboxylate and the mixture was stirred for 20 min. Tert-butyl [2- (4-hydroxyphenyl) ethyl ] carbamate (prepared according to WO2004/020415, 311mg, 1.31mmol) was then added and the reaction stirred overnight. Hydrogen chloride (4M in ether, 5ml) was added and left to stir for 3 days, then hydrochloric acid (2M, 5ml) was added and after 1 hour the mixture was washed with ether, basified with 2N sodium hydroxide, extracted with ether, dried (magnesium sulfate), filtered and the solvent removed in vacuo and the residue purified by column chromatography using dichloromethane: methanol: 880 ammonia (242/8/0.8 to 95/5/0.5 by volume) eluting through silica gel to give 100mg of the title compound as a colourless oil.

LRMS：m/z 566[M+H]⁺。

Preparation 22

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide

(3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (preparation 21, 95mg, 0.17mmol), N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (WO2005/080324, 86mg, 0.17mmol), sodium bicarbonate (42mg, 0.51mmol) and potassium iodide (28mg, 0.17mmol) were added to acetonitrile (2.5ml) and heated to reflux for 24 hours, then cooled to room temperature and the solvent removed in vacuo, using dichloromethane: methanol: 880 ammonia (242/8/0.8 to 95/5/0.5 by column chromatography in volume: 242/8/0.8 to 95/5/0.5) The residue was purified by elution through silica gel to give 78mg of the title compound as a white foam.

LRMS：m/z 999[M+H]⁺。

Preparation 23

6- (but-3-en-1-yloxy) hexanenitrile

6-bromohexanenitrile (1.19ml, 9.00mmol) and 3-buten-1-ol (946. mu.l, 11.0mmol) were added to a stirred solution of potassium hydroxide (6.16g, 110mmol) and tetrabutylammonium bromide (434mg, 1.35mmol) in water (6ml) and dichloromethane (2 ml). The reaction was stirred at room temperature for 4 days and then washed with diethyl ether (2X 50 ml). The combined organic phases were washed with water (3 × 30ml), dried (magnesium sulfate) and the solvent removed in vacuo to give 1.48g of the title compound as a colourless oil.

LRMS：m/z 168[M+H]⁺。

Preparation 24

6- { [ (3E) -4- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } but-3-en-1-yl ] oxy } hexanenitrile

(3R) -3- [2- (benzyloxy) -5-bromophenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (WO9411337, 1.21g, 2.50mmol) was dissolved in acetonitrile (8ml), and 6- (but-3-en-1-yloxy) hexanenitrile (preparation 23, 708mg, 4.20mmol), diisopropylethylamine (0.64ml, 3.75mmol), palladium acetate (54mg, 0.25mmol) and tris (o-tolyl) phosphine (145mg, 0.25mmol) were added. The stirred reaction was heated at 90 ℃ under a nitrogen atmosphere for 12 hours, cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50ml) and washed with saturated aqueous sodium bicarbonate (50ml), brine (50ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/0.5 by volume) through silica gel to give 960mg of the title compound as an oil.

LRMS：m/z 567[M+H]⁺。

Preparation 25

6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexanenitrile

The reaction product of 6- { [ (3E) -4- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]Phenyl } but-3-en-1-yl]Oxy } hexanenitrile (preparation 24, 935mg, 1.65mmol) was dissolved in ethanol (20ml) and ammonium formate (1.90g, 30.0mmol) and 10% palladium hydroxide on carbon (190mg) were added. The reaction was heated at reflux for 1 hour, cooled to room temperature and the reaction was passed through Arbocel^TMFiltering, transferring in vacuumThe filtrate solvent was removed to give 783mg of the title compound as a colorless oil.

LRMS：m/z 479[M+H]⁺。

Preparation 26

4- {4- [ (6-aminohexyl) oxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

Reacting 6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]-4-hydroxyphenyl } butoxy) hexanenitrile (preparation 25, 783mg, 1.64mmol) was dissolved in ethanol (20ml) and Raney (Raney) nickel (100mg) was added. The reaction was hydrogenated at 40 ℃ and 60psi for 18 h, cooled to room temperature and passed through Arbocel^TMThe reaction was filtered and the filtrate solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (90/10/1.0 by volume) through silica gel to give 506mg of the title compound.

LRMS：m/z 481[M+H]⁺。

Preparation 27

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexyl ] amino } ethyl ] phenyl } methanesulfonamide

4- {4- [ (6-Aminohexyl) oxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 26, 153mg, 0.32mmol) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation 155mg, 0.32mmol according to WO 2005/080324), potassium iodide (10mg) and sodium bicarbonate (104mg, 1.23mmol) were heated in propionitrile (3ml) at 90 ℃ for 24 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30ml), washed with saturated aqueous sodium bicarbonate (30ml), water (30ml), brine (30ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the oil was purified by column chromatography using dichloromethane: methanol: 880 ammonia (85/15/1.5 by volume) eluting through silica gel to give 130mg of the title compound as a yellow oil.

LRMS (ES)：m/z 917[M+H]⁺。

Preparation 28

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexyl ] amino } ethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl]Oxy } -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]-4-hydroxyphenyl } butoxy) hexyl radical]Amino } ethyl group]Phenyl } methanesulfonamide (preparation 27, 530mg, 0.55mmol) was dissolved in ethanol, and ammonium formate (700mg, 10.9mmol) and 10% palladium hydroxide on carbon (100mg) were added. The reaction was heated at reflux for 12 h, cooled to room temperature and further ammonium formate (600mg, 9.37mmol) and 10% palladium hydroxide on carbon (60mg) were added. The reaction was heated at reflux for 3 hours, cooled to room temperature and 10% palladium hydroxide on carbon (60mg) was further added. The reaction was heated at reflux for 3 hours, cooled to room temperature and passed through Arbocel^TMAnd (5) filtering. The filtrate solvent was removed in vacuo and the oil was purified by column chromatography using dichloromethane: methanol: 880 ammonia (80/20/2.0 by volume) eluting through silica gel to give 420mg as a yellow oilThe title compound.

LRMS (ES)：m/z 827[M+H]⁺。

Preparation 29

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] phenyl } carboxamide

N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } carboxamide (prepared according to US2005/215590, 500mg, 1.1mmol), 4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol dihydrochloride (prepared 13, 745mg, 1.3mmol), sodium bicarbonate (550mg, 6.5mmol) and potassium iodide (50mg, 0.30mmol) were added to propionitrile (8ml) and heated to 90 ℃ and left to stir overnight. Then 4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 13, 50mg, 0.087mmol) was further added and the mixture was further stirred at 90 ℃ for 24 hours. After cooling, ethyl acetate and saturated aqueous sodium bicarbonate were added, the organic phase was separated and washed with more saturated aqueous sodium bicarbonate, then brine and then dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (96/4/0.4 to 92/8/0.8 by volume) through silica gel to give 400mg of the title compound as an oil.

LRMS：m/z 887[M+H]⁺。

Preparation 30

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } carboxamide

N- {2- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] phenyl } carboxamide (preparation 29, 400mg, 0.45mmol), ammonium formate (570mg, 9.0mmol) and 20% palladium hydroxide on carbon (60mg) were mixed in methanol (8ml) and stirred at 70 ℃ under nitrogen for 1 hour. Ammonium formate (500mg, 7.9mmol) and 20% palladium hydroxide on carbon (50mg) were then further added and heating continued for a further 1 hour at 70 ℃. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in methanol (8ml), and ammonium formate (500mg, 7.9mmol) and 20% palladium hydroxide on carbon (50mg) were added and stirred at 70 ℃ under nitrogen for 1 hour. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (25ml) and saturated aqueous sodium bicarbonate (25 ml). The organic phase was separated and washed with brine (15ml), dried (magnesium sulfate) and the solvent removed in vacuo to give 280mg of the title compound as a yellow solid.

LRMS：m/z 797[M+H]⁺。

Preparation 31

8- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] quinolin-2 (1H) -one

8- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one (prepared according to WO2005/092861, 530mg, 1.1mmol), 4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol dihydrochloride (prepared 13, 650mg, 1.3mmol), sodium bicarbonate (550mg, 6.5mmol) and potassium iodide (50mg, 0.30mmol) were added to propionitrile (8ml) and heated to 90 ℃ and left to stir overnight. After cooling, ethyl acetate and saturated aqueous sodium bicarbonate were added, the organic phase was separated and washed with more saturated aqueous sodium bicarbonate, then brine and then dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 94/6/0.6 by volume) through silica gel to give 406mg of the title compound as an oil.

LRMS：m/z 911[M+H]⁺。

Preparation 32

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -8-hydroxyquinolin-2 (1H) -one

8- (benzyloxy) -5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] quinolin-2 (1H) -one (preparation 31, 406mg, 0.45mmol), ammonium formate (560mg, 9.0mmol) and 20% palladium hydroxide on carbon (60mg) were mixed in methanol (8ml) and stirred at 70 ℃ under nitrogen for 1 hour. Ammonium formate (300mg, 4.8mmol) and 20% palladium hydroxide on carbon (30mg) were then further added and heating continued for a further 1 hour at 70 ℃. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in methanol (8ml), and ammonium formate (560mg, 8.9mmol) and 20% palladium hydroxide on carbon (60mg) were added and stirred at 70 ℃ under nitrogen for 1 hour. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (25ml) and saturated aqueous sodium bicarbonate (25 ml). The organic phase was separated and washed with brine (15ml), dried (magnesium sulfate) and the solvent removed in vacuo to give 305mg of the title compound as a yellow solid.

LRMS：m/z 821[M+H]⁺。

Preparation 33

4- {4- [4- (2- { [ (2R) -2- [3, 5-bis (benzyloxy) phenyl ] -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] amino } ethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

{ (1R) -1- [3, 5-bis (benzyloxy) phenyl ] -2-bromoethoxy } (tert-butyl) dimethylsilane (prepared according to US2005/222128, 570mg, 1.1mmol), 4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol bis-hydrochloride (prepared 13, 746mg, 1.3mmol), sodium bicarbonate (544mg, 6.48mmol) and potassium iodide (50mg, 0.30mmol) were added to propionitrile (8ml) and heated to 90 ℃ and left to stir overnight. After cooling, ethyl acetate and saturated aqueous sodium bicarbonate were added, the organic phase was separated and washed with more saturated aqueous sodium bicarbonate, then brine and then dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 94/6/0.6 by volume) through silica gel to give 720mg of the title compound as a yellow oil.

LRMS：m/z 950[M+H]⁺。

Preparation 34

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol

4- {4- [4- (2- { [ (2R) -2- [3, 5-bis (benzyloxy) phenyl ] -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] amino } ethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 33, 720mg, 0.76mmol), ammonium formate (960mg, 15.0mmol) and 20% palladium hydroxide/carbon (110mg) were mixed in methanol (8ml), and stirred at 70 ℃ under nitrogen for 1 hour. Ammonium formate (300mg, 4.75mmol) and 20% palladium hydroxide on carbon (30mg) were then further added and heating continued for a further 1 hour at 70 ℃. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in methanol (8ml), and ammonium formate (900mg, 14mmol) and 20% palladium hydroxide on carbon (100mg) were added and stirred at 70 ℃ under nitrogen for 1 hour. The reaction mixture was then cooled and filtered, the filtrate collected and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (25ml) and saturated aqueous sodium bicarbonate (25 ml). The organic phase was separated and washed with brine (15ml), dried (magnesium sulfate) and the solvent removed in vacuo to give 555mg of the title compound as an off-white foam.

LRMS：m/z 770[M+H]⁺。

Preparation 35

[2- (3-hydroxyphenyl) ethyl ] carbamic acid tert-butyl ester

3- (2-aminoethyl) phenolate (3g, 17.3mmol) and triethylamine (6.02ml, 43.2mmol) were dissolved in water (15ml) and 1, 4-dioxane (45ml) and di-tert-butyl dicarbonate (4.52g, 1.20mmol) were added. The mixture was stirred at room temperature for 2 days. Diethyl ether (100ml) and hydrogen chloride (2M in water, 100ml) were then added and the organic phase was separated and washed with saturated aqueous sodium bicarbonate (100ml), then brine (100ml), then dried (magnesium sulfate) and the solvent removed in vacuo to give 4.42g of the title compound as a clear gum.

LRMS：m/z 260[M+Na]⁺。

Preparation 36

Methanesulfonic acid 2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethyl ester

2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethanol (prepared according to WO1998/43942, 1.0g, 2.25mmol) was dissolved in dichloromethane (20ml) and N, N-diisopropylethylamine (1.8ml, 10mmol) was added. The solution was then cooled to 0 ℃ and methanesulfonyl chloride (0.42ml, 5.4mmol) was added. After stirring at 0 ℃ for 2 h the mixture was diluted with dichloromethane (20ml) and washed with water (50ml), brine (50ml) and then dried (magnesium sulphate) and the solvent removed in vacuo to give 1.56g of the title compound as a yellow oil.

LRMS：m/z 524[M+H]⁺。

Preparation 37

{2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -phenyl } ethoxy) phenyl ] ethyl } carbamic acid tert-butyl ester

Tert-butyl [2- (3-hydroxyphenyl) ethyl ] carbamate (preparation 35, 1.7g, 5.96mmol), potassium carbonate (1.65g, 11.9mmol), potassium iodide (5.0g, 0.03mmol) and 2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethyl methanesulfonate (preparation 36, 1.56g, 2.98mmol) were stirred in dimethylformamide (20ml) and stirred at 60 ℃ overnight. After cooling water (250ml) and ether (250ml) were added, the organic phase was separated and washed with water (100ml x 3), brine (150ml), then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 90/10/1.0 by volume) through silica gel to give 1.3g of the title compound as an oil.

LRMS：m/z 666[M+H]⁺。

Preparation 38

(3R) -3- [5- {2- [3- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine

Tert-butyl {2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -phenyl } ethoxy) phenyl ] ethyl } carbamate (preparation 37, 1.3g, 2.0mmol) was dissolved in dichloromethane (5ml) and hydrochloric acid (4M in dioxin) was added. The mixture was stirred at room temperature under nitrogen for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100ml) and aqueous sodium hydroxide (1M, 100ml), the aqueous phase was separated and extracted with dichloromethane (100 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo to give 880mg of the title compound as an oil.

LRMS：m/z 565[M+H]⁺。

Preparation 39

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide

(3R) -3- [5- {2- [3- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (preparation 38, 340mg, 0.52mmol), potassium iodide (86mg, 0.52mmol), sodium bicarbonate (175mg, 2.08mmol) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation 270mg, 0.52mmol according to WO 2005/080324) were added to propionitrile (5ml) and stirred at 100 ℃ under nitrogen overnight. The mixture was cooled and water (100ml) and ethyl acetate (100ml) were added. The organic phase was separated and washed with brine (100ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 85/15/1.5 by volume) through silica gel to give 257mg of the title compound as a glass.

LRMS：m/z 999[M+H]⁺。

Preparation 40

{2- (benzyloxy) -5- [ (1R) -2- ({2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol

(3R) -3- [5- {2- [3- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (preparation 38, 470mg, 0.72mmol), potassium iodide (120mg, 0.72mmol), sodium bicarbonate (240mg, 2.9mmol) and {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol (preparation 325mg, 0.72mmol according to WO 2004/032921) were stirred in propionitrile at 100 ℃ under nitrogen for 24 h. After cooling to room temperature, water (100ml) and ethyl acetate (100ml) were added, the organic phase was separated and washed with brine (100ml), dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 85/15/1.5 by volume) through silica gel to give 450mg of the title compound as a brown glass.

LRMS：m/z 935[M+H]⁺。

Preparation 41

{2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } carbamic acid tert-butyl ester

Tert-butyl [2- (4-hydroxyphenyl) ethyl ] carbamate (prepared according to WO1998/43942, 3.8g, 7.3mmol), potassium carbonate (2.6g, 8.0mmol), potassium iodide (1.1g, 7.3mmol) and 2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethyl methanesulfonate (prepared 36, 1.56g, 2.98mmol) were stirred in toluene (20ml) and stirred at 120 ℃ overnight. After cooling, water (80ml) and ethyl acetate (80ml) were added, the organic phase was separated and washed with saturated aqueous sodium bicarbonate (40ml), brine (40ml), then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (99/1/0.1 to 90/10/1.0 by volume) through silica gel to give 3.4g of the title compound as an oil.

LRMS：m/z 666[M+H]⁺。

Preparation 42

(3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine dihydrochloride

Tert-butyl {2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } carbamate (preparation 41, 3.4g, 5.1mmol) was dissolved in dioxane (20ml) and treated with hydrochloric acid (4M in dioxane, 26 ml). After stirring at room temperature for 4 hours, the solvent was removed in vacuo. The residue was azeotroped twice from dichloromethane to give the title compound as a brown solid, 3.

LRMS：m/z 565[M+H]⁺。

Preparation 43

(3R) -3- [2- (benzyloxy) -5- {2- [4- (2- { [ (2R) -2- [3, 5-bis (benzyloxy) phenyl ] -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] amino } ethyl) phenoxy ] ethyl } phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine

(3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine dihydrochloride (preparation 42, 600mg, 0.94mmol), { (1R) -1- [3, 5-bis (benzyloxy) phenyl ] -2-bromoethoxy } (tert-butyl) dimethylsilane (preparation 500mg, 0.94mmol according to US 2005/222128), potassium iodide (160mg, 0.94mmol), sodium bicarbonate (480mg, 5.65mmol) were added to propionitrile (10ml) and stirred at 100 ℃ under nitrogen overnight. The mixture was cooled and water (75ml) and ethyl acetate (75ml) were added. The organic phase was separated and washed with brine (25ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (99/1/0.1 to 90/10/1 by volume) over silica gel to give 346mg of the title compound as a gum.

LRMS：m/z 1012[M+H]⁺。

Preparation 44

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol

(3R) -3- [2- (benzyloxy) -5- {2- [4- (2- { [ (2R) -2- [3, 5-bis (benzyloxy) phenyl ] -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] amino } ethyl) phenoxy ] ethyl } phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (preparation 43, 346mg, 0.30mmol) was dissolved in methanol (30ml), and ammonium formate (380mg, 6.1mmol) and 20% palladium hydroxide on carbon (43mg) were added. The stirred reaction was then heated at 90 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered and the solvent was removed in vacuo. The residue was then dissolved in ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, washed with brine, then dried (magnesium sulfate) and the solvent removed in vacuo to give 174mg of the title compound as a yellow glass.

LRMS：m/z 742[M+H]⁺。

Preparation 45

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } carboxamide

N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } carboxamide (prepared according to US2005/215590, 440mg, 0.95mmol), (3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine dihydrochloride (prepared 42, 600mg, 0.94mmol), potassium iodide (160mg, 0.94mmol), sodium bicarbonate (480mg, 5.65mmol) were added to propionitrile (10ml) and stirred at 100 ℃ under nitrogen for 24 hours. The mixture was cooled and water (75ml) and ethyl acetate (75ml) were added. The organic phase was separated and washed with brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (99/1/0.1 to 90/10/1 by volume) over silica gel to give 174mg of the title compound as a gum.

LRMS：m/z 949[M+H]⁺。

Preparation 46

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } carboxamide

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } carboxamide (preparation 45, 174mg, 0.18mmol) was dissolved in methanol (20ml), and ammonium formate (230mg, 3.7mmol) and 20% palladium hydroxide on carbon (26mg) were added. The stirred reaction was then heated at 90 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered and the solvent was removed in vacuo. The residue was then dissolved in ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, washed with brine followed by drying (magnesium sulfate) and the solvent was removed in vacuo to give 180mg of the title compound as a yellow glass.

LRMS：m/z 769[M+H]⁺。

Preparation 47

8- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one

(3R) -3- [5- {2- [4- (2-aminoethyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine dihydrochloride (preparation 42, 800mg, 1.25mmol), 8- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one (preparation 615mg, 1.25mmol according to WO 2005/092861), potassium iodide (210mg, 1.25mmol), sodium bicarbonate (630mg, 7.5mmol) were added to propionitrile (15ml) and stirred at 100 ℃ under nitrogen overnight. The mixture was cooled and water (100ml) and ethyl acetate (100ml) were added. The organic phase was separated and washed with water (100ml) followed by brine (50ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 90/10/1 by volume) over silica gel to give 297mg of the title compound as a gum.

LRMS：m/z 973[M+H]⁺。

Preparation 48

{2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol

Tert-butyl {2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } carbamate (preparation 41, 830mg, 1.25mmol) was treated with hydrochloric acid (8ml of a 4M solution in 1, 4-dioxane) and stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was dissolved in acetonitrile (8ml) and {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol (Sali patent, 560mg, 1.24mmol) and sodium bicarbonate (368mg, 4.34mmol) were added. The mixture was heated to 85 ℃ and stirred overnight. The reaction was cooled to room temperature and ethyl acetate and water were added, the aqueous layer was separated and washed with ethyl acetate, and the combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (92.5/7.5/1 by volume) eluting through silica gel to give 280mg of the title compound as a gum.

LRMS：m/z 936[M+H]⁺。

Preparation 49

4- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] -2- (hydroxymethyl) phenol

{2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl)]Phenyl } ethoxy) phenyl]Ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Phenyl } methanol (preparation 48, 280mg, 0.30mmol) was dissolved in ethanol (6ml) and palladium hydroxide (20 wt% on carbon, 14mg, 0.02mmol) was added. The reaction was hydrogenated at room temperature and 40psi for 18 hours, cooled to room temperature and the reaction was passed through Celite^TMFiltration and removal of filtrate solvent in vacuo afforded the title compound as a gum, 235 mg.

LRMS：m/z 756[M+H]⁺。

Preparation 50

Oct-7-en-1-ylimidiniodidicarbonate di-t-butyl ester

To a stirred suspension of sodium hydride (840mg of a 60% dispersion in oil, 21.0mmol) in N, N-dimethylformamide (40ml) was added di-tert-butyl iminodicarbamate (4.56g, 21.0mmol) in one portion. After stirring for 40 min, 8-bromooct-1-ene (3.50ml, 21mmol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in water and ethyl acetate. The organic layer was separated and washed with water, followed by brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography using diethyl ether pentane (1/99 to 6/94 by volume) eluting through silica gel to give 5.51g of the title compound as a clear oil.

Preparation 51

[ (7E) -8- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } oct-7-en-1-yl ] imidodicarbonate di-tert-butyl ester

Di-tert-butyl oct-7-en-1-ylimidiniodidicarbonate (preparation 50, 649mg, 1.98mmol), (3R) -3- [2- (benzyloxy) -5-bromophenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine (preparation according to WO1994/11337, 560mg, 1.16mmol), palladium diacetate (27mg, 0.12mmol), tris (2-methylphenyl) phosphine (73mg, 0.24mmol) and N, N-diisopropylethylamine (0.304ml, 1.75mmol) were added to acetonitrile (6ml) and the mixture was heated to 90 ℃ and left under nitrogen for stirring overnight. The mixture was cooled and saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 96/4/0.4 by volume) through silica gel to give 530mg of the title compound as an oil.

LRMS：m/z 727[M+H]⁺。

Preparation 52

Di-tert-butyl (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) imidodicarbonate

Di-tert-butyl [ (7E) -8- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } oct-7-en-1-yl ] imidodicarbonate (preparation 51, 530mg, 0.73mmol), palladium hydroxide (20% by weight on carbon, 100mg, 0.14mmol) and ammonium formate (1.1g, 17mmol) were dissolved in ethanol (20ml) and heated to 70 ℃ for 3 hours. The reaction mixture was cooled and filtered, and the solvent was removed in vacuo to give 340mg of the title compound as a clear oil.

LRMS：m/z 640[M+H]⁺。

Preparation 53

4- (8-Aminooctyl) -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

Di-tert-butyl (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) imidodicarbonate (preparation 52, 340mg, 0.53mmol) was dissolved in dichloromethane (5ml) and hydrochloric acid (5.0ml of a 2M solution in ether) was added, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (magnesium sulfate) and the solvent removed in vacuo to give 170mg of the title compound as a yellow oil.

LRMS：m/z 439[M+H]⁺。

Preparation 54

N- [2- (benzyloxy) -5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] ethyl } phenyl ] methanesulfonamide

4- (8-Aminooctyl) -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol (preparation 53, 170mg, 0.39mmol) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation according to WO2005/080324, 191mg, 0.37mmol) were heated in dimethylsulfoxide (0.5ml) at 90 ℃ overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added and the organic phase was separated, washed with saturated aqueous sodium bicarbonate, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (99/1/0.1 to 95/5/0.5 by volume) eluting through silica gel to give 90mg of the title compound as a yellow oil.

LRMS：m/z 872[M+H]⁺。

Preparation 55

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide

N- [2- (benzyloxy) -5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] ethyl } phenyl ] methanesulfonamide (preparation 54, 90mg, 0.10mmol), ammonium formate (130mg, 2.0mmol) and 20% palladium hydroxide/carbon (20mg) were mixed in ethanol (3ml) and heated to 70 ℃ overnight. The reaction mixture was then cooled and filtered. The filtrate was collected and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 91/9/0.9 by volume) through silica gel to give the title compound as a gum to give 82mg of the title compound as a glass.

LRMS：m/z 783[M+H]⁺。

Preparation 56

{2- [4- (pent-4-en-1-yloxy) phenyl ] ethyl } carbamic acid tert-butyl ester

Tert-butyl [2- (4-hydroxyphenyl) ethyl ] carbamate (prepared according to Journal of organic chemistry 1999, 64, 1074, 1.0g, 4.21mmol) was dissolved in dimethylformamide (8ml) and potassium carbonate (1.2g, 8.4mmol) was added followed by 5-bromopent-1-ene (0.99ml, 8.4mmol) after 15 minutes and the mixture was stirred at 60 ℃ overnight.

After cooling to room temperature, water was added and extracted with ether, dried (magnesium sulfate) and the solvent was removed in vacuo to give 1.2g of the title compound as a white solid.

LRMS：m/z 328[M+Na]⁺。

Preparation 57

[ tert-butyl [2- (4- { [ (4E) -5- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } pent-4-en-1-yl ] oxy } phenyl) ethyl ] carbamate

Reacting {2- [4- (pent-4-en-1-yloxy) phenyl]Ethyl } carbamic acid tert-butyl ester (preparation 56, 1.2g, 3.9mmol), (3R) -3- [2- (benzyloxy) -5-bromophenyl phenyl]-N, N-diisopropyl-3-phenylpropan-1-amine (prepared according to WO9411337, 1.9g, 3.9mmol), palladium acetate (90mg, 0.4mmol), tri (o-tolyl) phosphine (200mg, 0.8mmol) and diisopropylethylamine (1.0ml, 5.9mmol) were mixed in acetonitrile (12ml), degassed with argon and heated to 90 ℃ for 5 hours. The reaction was cooled to room temperature, passed through Arbocel^TMFiltration and removal of the solvent in vacuo. The residue was dissolved in water and ethyl acetate, the organic phase was separated, dried (magnesium sulfate) and the solvent was removed in vacuo, by column chromatography using dichloro-benzeneMethane methanol 880 ammonia (98/2/0.2 to 95/5/0.5 by volume) the residue was purified by elution through silica gel to give 2.5g of the title compound as a pale yellow foam.

LRMS：m/z 705[M+H]⁺。

Preparation 58

(2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) carbamic acid tert-butyl ester

The reaction product of [2- (4- { [ (4E) -5- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl group]Phenyl } pent-4-en-1-yl]Oxy } phenyl) ethyl]Tert-butyl carbamate (preparation 57, 2.5g, 3.5mmol) was dissolved in ethanol (50ml) and palladium hydroxide (20 wt% on carbon, 600mg, 0.84mmol) and ammonium formate (2.0mg, 30mmol) were added and stirred at 90 ℃ for 1 hour. The reaction was cooled and passed through Arbocel^TMFiltration and removal of the solvent in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/0.5 to 90/10/1 by volume) through silica gel to give 1.66g of the title compound as a white foam.

LRMS：m/z 617[M+H]⁺。

Preparation 59

4- {5- [4- (2-aminoethyl) phenoxy ] pentyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol bis-hydrochloride

Tert-butyl (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) carbamate (preparation 58, 1.66g, 2.69mmol) was dissolved in dichloromethane (20ml) and ethanol (3ml), and hydrochloric acid (12ml of a 2M solution in ether) was added, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and the solvent was again removed in vacuo to give 1.6g of the title compound as a yellow foam.

LRMS：m/z 517[M+H]⁺。

Preparation 60

N- [2- (benzyloxy) -5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) amino ] ethyl } phenyl ] methanesulfonamide

4- {5- [4- (2-aminoethyl) phenoxy ] pentyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol dihydrochloride (preparation 59, 400mg, 0.68mmol) was dissolved in water and basified with saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was dissolved in dimethyl sulfoxide (0.3ml) and N- {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (prepared according to WO2005/080324, 400mg, 0.8mmol) was added and heated in a sealed vessel at 80 ℃ for 6 h. After cooling to room temperature, water was added, extracted with dichloromethane, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/0.5 by volume) through silica gel to give 370mg of the title compound.

LRMS：m/z 948[M+H]⁺。

Preparation 61

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide

N- [2- (benzyloxy) -5- { (1R) -1- { [ tert-butyl (dimethyl) silyl group]Oxy } -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] amino acid]-4-hydroxyphenyl } pentyl) oxy]Phenyl } ethyl) amino]Ethyl phenyl]Methanesulfonamide (preparation 60, 350mg, 0.37mmol) was dissolved in ethanol (10ml), and ammonium formate (1.0g, 16mmol) and 20% palladium hydroxide on carbon (250mg) were added and heated to 90 ℃ for 1 hour. The reaction mixture was then cooled and passed through Arbocel^TMFiltration and removal of the solvent in vacuo gave 250mg of the title compound as a colorless oil.

LRMS：m/z 858[M+H]⁺。

Preparation 62

4- {4- [4- (2- { [ (2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl ] -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] amino } ethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol

4- {4- [4- (2-aminoethyl) phenoxy ] butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenol tert-butyl {2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } carbamate dihydrochloride (preparation 13, 1.30g, 2.26mmol) was dissolved in a mixture of saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was dissolved in acetonitrile (10ml) and {2- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol (prepared according to WO2004/032921, 1.02g, 2.26mmol), sodium bicarbonate (570mg, 6.78mmol) were added and heated to 85 ℃ with stirring overnight. After cooling the solvent was removed in vacuo and the residue was dissolved in dichloromethane (30ml) and washed with water (2 × 20ml) followed by brine (20ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/1 to 90/10/1 by volume) through silica gel to give 388mg of the title compound as a gum.

LRMS：m/z 874[M+H]⁺。

Preparation 63

4- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2- (hydroxymethyl) phenol

4- {4- [4- (2- { [ (2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl]-2- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Amino } ethyl) phenoxy]Butyl } -2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]Phenol (preparation 62, 388mg, 0.44mmol) was dissolved in ethanol (5ml), and ammonium formate (280mg, 4.44mmol) and 20% palladium hydroxide on carbon (58mg) were added. The stirred reaction was heated at 85 ℃ for 18 hours. After cooling to room temperature, further ammonium formate (140mg, 2.22mmol) and 20% palladium hydroxide on carbon (20mg) were added and the mixture was stirred at 85 ℃ for 3 hours. The reaction mixture was then cooled and passed through Arbocel^TMFiltration, collection of filtrate and removal of solvent in vacuo gave 311mg of the title compound as a glass.

LRMS：m/z 784[M+H]⁺。

Preparation 64

{2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] -1, 1-dimethylethyl } carbamic acid tert-butyl ester

Tert-butyl [2- (4-hydroxyphenyl) -1, 1-dimethylethyl ] carbamate (prepared according to WO1997/34905, 1.5g, 5.6mmol), cesium carbonate (2.9g, 9.0mmol), sodium iodide (670mg, 4.5mmol) and 2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethyl methanesulfonate (prepared 36, 2.4g, 4.5mmol) were mixed in toluene (18ml) and stirred at 120 ℃ overnight. After cooling, water (100ml) and ethyl acetate (100ml) were added, then the aqueous layer was separated and extracted with additional ethyl acetate (100ml × 2). The combined organic phases were then dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting through silica gel with dichloromethane: methanol: 880 ammonia (95/5/1 by volume), the appropriate fractions were separated and the solvent was removed in vacuo. The residue was dissolved in a minimum volume of ethyl acetate and pentane (100ml) was added. The organic phase was then washed with aqueous NaOH (1N, 150ml × 2), followed by drying (magnesium sulfate) and removal of the solvent in vacuo to give 1.72g of the title compound as an oil.

LRMS：m/z 694[M+H]⁺。

Preparation 65

(3R) -3- [5- {2- [4- (2-amino-2-methylpropyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -N, N-diisopropyl-3-phenylpropan-1-amine dihydrochloride

Tert-butyl {2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -phenyl } ethoxy) phenyl ] -11-dimethylethyl } carbamate (preparation 64, 1.72g, 2.48mmol) was treated with hydrochloric acid (4M in dioxane, 15 ml). After stirring overnight at room temperature, the solvent was removed in vacuo to give 1.60g of the title compound as a colorless foam.

LRMS：m/z 594[M+H]⁺。

Preparation 66

8- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] -1, 1-dimethylethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one

(3R) -3- [5- {2- [4- (2-amino-2-methylpropyl) phenoxy ] ethyl } -2- (benzyloxy) phenyl ] -NN-diisopropyl-3-phenylpropan-1-amine dihydrochloride (preparation 65, 550mg, 0.83mmol), 8- (benzyloxy) -5- [ (1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one (preparation 405mg, 0.83mmol according to WO 2005/092861) and sodium bicarbonate (244mg, 2.9mmol) were added to acetonitrile (6ml) and stirred at 90 ℃ under nitrogen for 20 hours. The mixture was cooled and the solvent was removed in vacuo. The residue was then partitioned between water (40ml) and dichloromethane (40ml), the layers were separated and the aqueous layer was extracted with additional dichloromethane (40 ml). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/0.5 to 80/20/2 by volume) through silica gel to give 100mg of the title compound as a gum.

LRMS：m/z 999[M-H]^-。

Preparation 67

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -1, 1-dimethylethyl } amino) ethyl ] -8-hydroxyquinolin-2 (1H) -one

8- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl)]Phenyl } ethoxy) phenyl]-1, 1-Dimethylethyl } amino) -1- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Quinolin-2 (1H) -one (preparation 66, 370mg, 0.37mmol), ammonium formate (234mg, 3.7mmol) and 20% palladium hydroxide on carbon (100mg) were mixed in ethanol (5ml) and heated to 85 ℃ under a nitrogen atmosphere overnight. The reaction mixture was then cooled and passed through Celite^TMFiltration and removal of filtrate solvent in vacuo. The residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (97.5/2.5/0.25 to 95/5/0.5 by volume) eluting through silica gel to give 160mg of the title compound as a gum.

LRMS：m/z 821[M+H]⁺。

Example 1

N- (5- { (1R) -2- [ (10- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } decyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide

Palladium hydroxide (10% on carbon, 20mg) was added to stirred ammonium formate (344mg, 5.46mmol) and N- {2- (benzyloxy) -5- [ (1R) -2- { [10- {4- (benzyl) -4 at room temperatureOxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]Phenyl } dec-9-en-1-yl]Amino } -1- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Phenyl } methanesulfonamide (preparation 4, 90mg, 0.091mmol) was dissolved in methanol (10 ml). The reaction was heated at reflux for 1 hour, cooled to room temperature and passed through Arbocel^TMAnd (5) filtering. The filtrate was collected and the solvent was removed in vacuo to yield N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] as a mixture with the remaining ammonium formate]Oxy } -2- [ (10- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl group]-4-hydroxyphenyl } decyl) amino]Ethyl } -2-hydroxyphenyl) methanesulfonamide. LRMS: m/z 811[ M + H ]]⁺. The mixture was dissolved in tetrahydrofuran (4ml) and methanol (2ml), and triethylamine trihydrofluoride salt (88. mu.l, 0.54mmol) was added in one portion at room temperature. The reaction was stirred for 12 hours and the solvent was removed under reduced pressure, the residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (80/20/2.0 by volume) through silica gel to give 35mg of the title compound as a glass.

LRMS：m/z 697[M+H]⁺。

Example 2

N- {5- [ (1R) -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (3- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } propoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } methanesulfonamide (preparation 10, 98mg, 0.11mmol) was dissolved in tetrahydrofuran (4ml) and methanol (2ml), and triethylamine trihydrofluoride salt (95. mu.l, 0.58mmol) was added in one portion at room temperature. The reaction was stirred for 24 hours and the solvent was removed under reduced pressure, the residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure to give an off-white solid. The solid was dissolved in methanol (1ml) and precipitated with excess diisopropyl ether, which was collected by filtration to give 16mg of the title compound as a white solid.

LRMS：m/z 718[M+H]⁺。

Example 3

N- {5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } methanesulfonamide (preparation 15, 190mg, 0.22mmol) was dissolved in tetrahydrofuran (5ml), and N, N-diethylethanamine trihydrofluoride salt (0.2ml, 1mmol) was added dropwise. After 29 hours a mixture of tetrahydrofuran (5ml) and 880 ammonia (5ml) was added and brine was added after 15 minutes, the organic layer was separated, dried (magnesium sulfate), filtered, the solvent removed in vacuo and the residue purified by column chromatography eluting through silica gel with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 92/8/0.8 by volume) to give 90mg of the title compound as a white foam.

LRMS：m/z 732[M+H]⁺。

Example 4

N- (5- { (1R) -2- [ (7- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenoxy } heptyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (7- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenoxy } heptyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide (preparation 20, 68mg, 0.087mmol) was dissolved in tetrahydrofuran (3ml), and N, N-diethylethanamine trihydrofluoride salt (71. mu.l, 0.43mmol) was added dropwise. A mixture of methanol (4ml) and 880 ammonia (8ml) was added after 18 hours and the solvent was removed in vacuo after 15 minutes. The residue was dissolved in dichloromethane and the solvent was again removed in vacuo, and the residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (97/3/0.3 to 88/12/1.2 by volume) eluting through silica gel to give 30mg of the title compound as a white solid.

LRMS：m/z 670[M+H]⁺。

Example 5

N- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl)]Phenyl } ethoxy) phenyl]Ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl]Oxy } ethyl group]Phenyl } methanesulfonamide (preparation 22, 78mg, 0.078mmol) was dissolved in ethanol (2ml), ammonium formate (200mg, 3.17mmol) was added, heating was done to reflux, then palladium hydroxide (20 wt% on carbon, 50mg, 0.07mmol) was added, and after 30 minutes the reaction was cooled to room temperature and the mixture was passed through Arbocel^TMFilter andthe solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (2ml) and N, N-diethylethanamine trihydrofluoride salt (59 μ l, 0.37mmol) was added followed by 1 drop of methanol and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in 1: 1 methanol/880 ammonia, the solvent was removed in vacuo and the process was repeated 4 times. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (230/20/2 to 90/10/1 by volume) through silica gel to give 28mg of the title compound as a white solid.

LRMS：m/z 704[M+H]⁺。

Example 6

N- {5- [ (1R) -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexyl ] amino } -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { [6- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) hexyl ] amino } ethyl ] -2-hydroxyphenyl } methanesulfonamide (preparation 28, 420mg, 0.51mmol) was dissolved in tetrahydrofuran (6ml) and triethylamine trihydrofluoride salt (415. mu.l, 2.55mmol) was added. The reaction was stirred at room temperature for 4 hours and the solvent was removed in vacuo, the residue was dissolved in methanol (1ml) and 880 ammonia (1ml) and the solvent was removed in vacuo. The resulting oil was purified by column chromatography using dichloromethane: methanol: 880 ammonia (89/11/1.1 by volume) eluting through silica gel to give 26mg of the title compound as a yellow solid.

LRMS (ES)：m/z 712[M+H]⁺。

Example 7

N- {5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } carboxamide

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } carboxamide (preparation 30, 280mg, 0.35mmol) was dissolved in tetrahydrofuran (5ml) and triethylamine trihydrofluoride salt (0.29ml, 1.8mmol) was added and the mixture was stirred at room temperature overnight. Tetrahydrofuran (6ml) and 880 ammonia (6ml) were then added, the mixture stirred for 20 minutes, then the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (10ml), then brine (10ml), then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 88/12/1.2 by volume) through silica gel to give 74mg of the title compound as an off-white solid.

LRMS：m/z 683[M+H]⁺。

Example 8

5- [ (1R) -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -8-hydroxyquinolin-2 (1H) -one (preparation 32, 305mg, 0.37mmol) was dissolved in tetrahydrofuran (5ml) and triethylamine trihydrofluoride salt (0.30ml, 1.9mmol) was added and the mixture was stirred at room temperature overnight. Tetrahydrofuran (6ml) and 880 ammonia (6ml) were then added, the mixture stirred for 20 minutes, the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (10ml), then brine (10ml), then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 88/12/1.2 by volume) through silica gel to give 99mg of the title compound as a yellow solid.

LRMS：m/z 707[M+H]⁺。

Example 9

5- [ (1R) -1- { [ hydroxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol (preparation 34, 555mg, 0.72mmol) was dissolved in tetrahydrofuran (8ml) and triethylamine trihydrofluoride salt (0.59ml, 3.6mmol) was added and the mixture was stirred at room temperature overnight. Tetrahydrofuran (6ml) and 880 ammonia (6ml) were then added, the mixture stirred for 20 minutes, the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (10ml), then brine (10ml), then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (98/2/0.2 to 88/12/1.2 by volume) through silica gel to give 54mg of the title compound as a white solid.

LRMS：m/z 655[M+H]⁺。

Example 10

N- {5- [ (1R) -2- ({2- [3- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide

N- {2- (benzyloxy) -5- [ (1R) -2- ({2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanesulfonamide (preparation 39, 257mg, 0.26mmol) was dissolved in ethanol (20ml), and ammonium formate (325mg, 5.15mmol) and 20% palladium hydroxide on carbon (36mg) were added. The stirred reaction was heated at 90 ℃ and after 2 h further ammonium formate (325mg, 5.15mmol) and 20% palladium hydroxide on carbon (36mg) were added and the mixture was stirred at 90 ℃ for a further 2 h. After cooling to room temperature, the mixture was filtered and the solvent was removed in vacuo, then ethanol (20ml), ammonium formate (325mg, 5.15mmol) and 20% palladium hydroxide on carbon (36mg) were added and the mixture was heated to 90 ℃ for an additional 2 hours. After cooling, the mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in methanol (10ml) and tetrahydrofuran (20ml), and triethylamine trihydrofluoride salt (0.25ml, 1.5mmol) was added. The mixture was stirred overnight, followed by removal of the solvent in vacuo. The residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The procedure was repeated and the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (99/1/0.1 to 80/20/2.0 by volume) through silica gel to give (after trituration in diisopropyl ether) 52mg of the title compound as a white solid.

LRMS：m/z 704[M+H]⁺。

Example 11

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (2- {3- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } ethyl) phenol

{2- (benzyloxy) -5- [ (1R) -2- ({2- [3- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] phenyl } methanol (preparation 40, 450mg, 0.48mmol), ammonium formate (610mg, 9.6mmol) and 20% palladium hydroxide on carbon (68mg) were stirred in ethanol at 90 ℃ for 30 min. Ammonium formate (610mg, 9.6mmol) and 20% palladium hydroxide on carbon (70mg) were further added and the mixture was stirred at 90 ℃ for further 30 min. The mixture was cooled to room temperature and stirred overnight, followed by further addition of ammonium formate (610mg, 9.6mmol) and 20% palladium hydroxide on carbon (70mg), followed by stirring at 90 ℃ for 1 hour. After cooling, the mixture was filtered and the solvent was removed in vacuo. Methanol (10ml), tetrahydrofuran (20ml) and triethylamine trihydrofluoride salt (0.47ml, 2.9mmol) were added and the mixture was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The procedure was repeated and the residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (99/1/0.1 to 80/20/2.0 by volume) through silica gel to give (after trituration with diisopropyl ether) 95mg of the title compound as a white solid.

LRMS：m/z 641[M+H]⁺。

Example 12

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] benzene-1, 3-diol

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] benzene-1, 3-diol (preparation 44, 174mg, 0.23mmol) was dissolved in methanol (5ml) and tetrahydrofuran (10ml), and triethylamine trihydrofluoride salt (0.23ml, 1.4mmol) was added. The mixture was stirred overnight, and then the solvent was removed in vacuo. The residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The process was repeated and the residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (95/5/0.5 to 80/20/2.0 by volume) eluting through silica gel to give 83mg of the title compound as a foam.

LRMS：m/z 627[M+H]⁺。

Example 13

N- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } carboxamide

N- {5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] -2-hydroxyphenyl } carboxamide (preparation 46, 180mg, 0.18mmol) was dissolved in methanol (5ml) and tetrahydrofuran (10ml), and triethylamine trihydrofluoride salt (0.18ml, 1.1mmol) was added. The mixture was stirred overnight, and then the solvent was removed in vacuo. The residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The process was repeated and the residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (98/2/0.2 to 80/20/2.0 by volume) eluting through silica gel to give 69mg of the title compound as a gum.

LRMS：m/z 654[M+H]⁺。

Example 14

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one

8- (benzyloxy) -5- [ (1R) -2- ({2- [4- (2- {4- (benzyloxy) -3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] phenyl } ethoxy) phenyl ] ethyl } amino) -1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl ] quinolin-2 (1H) -one (preparation 47, 295mg, 0.30mmol) was dissolved in methanol (30ml), and ammonium formate (380mg, 6.1mmol) and 20% palladium hydroxide on carbon (43mg) were added. The stirred reaction was then heated at 90 ℃ for 2 hours. After cooling to room temperature, the mixture was filtered and the solvent was removed in vacuo. The residue was then dissolved in ethyl acetate (50ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, washed with brine, then dried (magnesium sulfate) and the solvent removed in vacuo. The residue was then dissolved in methanol (10ml) and tetrahydrofuran (20ml) and triethylamine trihydrofluoride salt (0.30ml, 1.8mmol) was added. The mixture was stirred overnight, and then the solvent was removed in vacuo. The residue was dissolved in methanol (20ml) and 880 ammonia (2ml) and the solvent was removed under reduced pressure. The procedure was repeated and the residue was purified by column chromatography using dichloromethane: methanol: 880 ammonia (98/2/0.2 to 80/20/2.0 by volume) eluting through silica gel to give 137mg of the title compound as a yellow foam.

LRMS：m/z 678[M+H]⁺。

Example 15

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (2- {4- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } ethyl) phenol

4- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) ethyl ] -2- (hydroxymethyl) phenol (preparation 49, 235mg, 0.30mmol) was dissolved in methanol (2.9ml) and water (1.4ml), and ammonium fluoride (112mg, 3.0mmol) was added. The reaction was heated to 40 ℃ and stirred overnight, cooled to room temperature and then saturated aqueous sodium bicarbonate (20ml) and ethyl acetate (20) were added. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (80/20/1.0 by volume) through silica gel to give 55mg of the title compound as a glass.

LRMS：m/z 641[M+H]⁺。

Example 16

N- (5- { (1R) -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (8- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } octyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide (preparation 55, 74mg, 0.095mmol) was dissolved in tetrahydrofuran (3ml), and triethylamine trihydrofluoride salt (90. mu.l, 0.54mmol) was added in one portion at room temperature. The reaction was stirred for 12 hours and the solvent was removed under reduced pressure, the residue was dissolved in methanol (10ml) and 880 ammonia (1ml) and the solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (97/3/0.3 to 85/15/1.5 by volume) through silica gel to give 34mg of the title compound as a yellow solid.

LRMS：m/z 668[M+H]⁺。

Example 17

N- (5- { (1R) -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) amino ] -1-hydroxyethyl } -2-hydroxyphenyl) methanesulfonamide

N- (5- { (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- [ (2- {4- [ (5- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } pentyl) oxy ] phenyl } ethyl) amino ] ethyl } -2-hydroxyphenyl) methanesulfonamide (preparation 61, 250mg, 0.29mmol) was dissolved in tetrahydrofuran (10ml) and methanol (0.5ml), and triethylamine trihydrofluoride salt (1.0ml, 6.1mmol) was added. The reaction was stirred for 3 days and the solvent was removed in vacuo. The residue was dissolved in 880 ammonia (1ml) and the solvent was removed under reduced pressure and the process was repeated 3 times. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (95/5/0.5 by volume) through silica gel to give 100mg of the title compound as a pale yellow foam.

LRMS：m/z 746[M+H]⁺。

Example 18

2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4- (4- {4- [2- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethyl } amino) ethyl ] phenoxy } butyl) phenol

4- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (4- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } butoxy) phenyl ] ethyl } amino) ethyl ] -2- (hydroxymethyl) phenol (preparation 63, 311mg, 0.356mmol) was dissolved in methanol (4ml) and water (0.5ml), and ammonium fluoride (132mg, 3.56mmol) was added. The reaction was heated to 40 ℃ and stirred overnight. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with dichloromethane: methanol: 880 ammonia (100/0/0 to 90/10/1.0 by volume) through silica gel to give 84mg of the title compound as a glass.

LRMS：m/z 669[M+H]⁺。

Example 19

N- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide succinate

N- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide (example 5, 2000mg, 2.84mmol) was dissolved in methanol (8ml), and water (2ml) and succinic acid (336mg, 2.84mmol) in methanol (2ml) were added to the stirred solution at room temperature in one portion. Further water was added until the salt appeared as a gum that seeded small crystals of the previously isolated salt. The mixture was left overnight and occasionally stirred to aid crystallization. After 5 days the solid was filtered and dried in vacuo to give 2336mg of the title compound as a white crystalline solid with a melting point of 148 to 150 ℃.

LRMS：m/z 704[M+H]⁺。

Example 20

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -1, 1-dimethylethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one

5- [ (1R) -1- { [ tert-butyl (dimethyl) silyl ] oxy } -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -11-dimethylethyl } amino) ethyl ] -8-hydroxyquinolin-2 (1H) -one (preparation 67, 160mg, 0.20mmol) was dissolved in methanol (20ml) and water (10ml), and ammonium fluoride (740mg, 3.6mmol) was added. The reaction was heated to 40 ℃ and stirred under a nitrogen atmosphere for 21 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was azeotroped from toluene followed by dichloromethane to give a white solid which was purified by column chromatography using dichloromethane: methanol: 880 ammonia (90/10/1 to 80/20/2 by volume) eluting through silica gel to give 19mg of the title compound as a glass.

LRMS：m/z 707[M+H]⁺。

In the expression of hM₃Functional assessment of antagonist activity was performed using a whole-cell beta-lactamase reporter gene assay in CHO cells of the receptor.

Cell culture

Will express the human muscarine M recombinantly₃CHO (Chinese hamster ovary) cells of the recipient were transfected with the NFAT-. beta. -Lac Zeo plasmid. Cells were recruited to have Glutamax-125mM HEPES (Life Technologies 32430-027) in DMEM containing 10% FCS (fetal calf serum; SigmaF-7524), 1nM sodium pyruvate (Sigma S-8636), NEAA (non-essential amino acids; Invitrogen 11140-035), and 200. mu.g/ml Zeocin (Invitrogen R250-01).

hM3 beta-Lac determination method

When the cells reached 80-90% coverage, enzyme-free cell Dissociation Solution (Life technologies 13151-014) was used with the cells at 37 ℃ in the presence of 5% CO₂For 5 minutes to collect the cells for assay. The separated cells were collected in warm medium and centrifuged at 2000rpm for 10 minutes, washed in PBS (phosphate buffered saline; Life Technologies 14190-. The cells were allowed to grow at 2X 10⁵The concentration of individual cells/ml is resuspended in culture medium (composition as described above). To each well of 384-well black clear plates (Greiner Bio One 781091-PFI) was added 20. mu.l of the cell suspension. The assay buffer used was PBS supplemented with 0.05% Pluronic F-127(Sigma 9003-11-6) and 2.5% DMSO. Using 80nM carbamoylcholine (Aldrich N240-9) with the cells at 37 deg.C/5% CO₂Incubation for 4 hours next to stimulate muscarine M₃Receptor signal, and was monitored at the end of the incubation period using a Tecan spectra fluor + plate reader (λ -excitation 405nm, emission 450nm and 503 nm). Test compounds were added to the assay at the beginning of the 4 hour incubation period and compound activity was measured as concentration-dependent inhibition of the carbachol-induced signal. Plotting inhibition curves and generating IC using 4-parameter sigmoidal fitting₅₀Values and K of carbamoylcholine using Cheng-Prusoff calibration and this assay_DValue pair IC₅₀Values were converted to Ki values.

In the expression of hB₂Functional assessment of agonist potency and efficacy was performed using a whole cell luciferase reporter assay in CHO cells of the receptor.

Cell culture

Will weigh heavilyGroup expression of human epinephrine B₂CHO (Chinese hamster ovary) cells transfected with the receptor and luciferase reporter gene were maintained in a culture medium consisting of F12 containing 10% fetal bovine serum (FBS: SigmaF03921), 10. mu.g/ml puromycin (Sigma N277698), 0.5mg/ml geneticin G418(Sigma G7034) and 2mM L-glutamine (Sigma G7513): DMEM (Sigma D6421). At 37 ℃ in a medium containing 5% CO₂The cells are stored under sterile conditions.

hB2 fluorescein determination procedure

When the cells reached 80-90% coverage, an enzyme-free cell dissociation solution (Life technologies 13151-014) was used with the cells at 37 ℃ in the presence of 5% CO₂For 5 minutes to collect the cells for assay. The isolated cells were collected in warm medium (composition described above) and resuspended in assay medium (F12: DMEM (Sigma D6421) containing 1% fetal bovine serum (FBS: Sigma F03921), 10. mu.g/ml puromycin (Sigma N277698), 0.5mg/ml geneticin G418(Sigma G7034) and 2mM L-glutamine (Sigma G7513)) to give 1X 10⁶Viable cell concentration per ml. To each well of a tissue culture treated low volume 384 well plate (Greiner 788073) was added 10. mu.l of the suspension and the plate was incubated at 37 ℃ in a medium containing 5% CO₂Was incubated for 2 hours in the atmosphere of (1). Test compounds were prepared in a series of concentrations in phosphate buffered saline containing 0.05% Pluronic-F127(Sigma P2443) and 2.5% DMSO. 2 μ l of each test concentration was added to the appropriate 384 well plate and returned to the incubator for an additional 4 hours. At the end of the incubation period, 4 μ l of Steady-Glo reagent (Steady-Glo fluorometric system (Promega E2520)) was added to each well and the plate was immediately read in a Leadeker plate reader (Amersham Bioscience) using a 660nm filter. Concentration effect curves were plotted and EC was generated using a 4-parameter sigmoidal fit (which uses an internal data analysis program)₅₀The value is obtained. Isoproterenol was used as a reference standard in each assay.

Examples 1 to 20 were tested according to the assay disclosed above and the following results were obtained:

example numbering	EC50-β2(nM)	Ki-M3(nM)
example numbering	EC50-β2(nM)	Ki-M3(nM)	1	0.88	3.4
2	0.32	1.1	1	0.88	3.4
2	0.32	1.1	3	0.14	1.4
4	1.3	0.28	3	0.14	1.4
4	1.3	0.28	5	0.2	0.3
6	0.19	2.4	5	0.2	0.3
6	0.19	2.4	7	0.049	2.1
8	0.035	0.31	7	0.049	2.1
8	0.035	0.31	9	4.8	1.1
10	0.26	1.10	9	4.8	1.1
10	0.26	1.10	11	2.2	1.5
12	13.8	0.26	11	2.2	1.5
12	13.8	0.26	13	0.078	0.38
14	0.054	0.76	13	0.078	0.38
14	0.054	0.76	15	0.25	0.060
16	1.3	2.0	15	0.25	0.060
16	1.3	2.0	17	0.57	3.0
18	0.22	0.77	17	0.57	3.0
18	0.22	0.77	19	0.2	0.3
20	0.028	0.39	19	0.2	0.3

Claims

1. A compound of the general formula (1):

wherein A is selected from:

and B is selected from:

2) optionally with one or two C₁-C₄Alkyl substituted C₆-C₁₂An alkylene group;

3) a group of the formula:

wherein X²Is O or S, r is an integer from 2 to 7, S is an integer from 0 to 6, t is an integer from 0 to 6, S + t is between 1 and 6 inclusive, and r + S + t is between 3 and 8 inclusive; and

4) a group of the formula:

as well as quaternary ammonium salts thereof or, where appropriate, pharmaceutically acceptable salts thereof and/or isomers, tautomers, solvates or isotopic variations thereof.

2. The compound according to claim 1, wherein B is C₆-C₁₂An alkylene group.

3. The compound according to claim 2, wherein B is selected from (CH)₂)₈、(CH₂)₉Or (CH)₂)₁₀。

4. The compound according to claim 1, wherein B is (CH)₂)₂-(CH₂)_m-X¹-(CH₂)_n。

5. A compound according to claim 4, wherein X¹Is O.

6. A compound according to claim 5, wherein B is selected from (CH)₂)₆-O-(CH₂)₃、(CH₂)₆-O-(CH₂)₄And (CH)₂)₇-O-。

7. A compound according to claim 1, wherein B is a group of the formula:

8. a compound according to claim 7, wherein X²Is O.

9. The compound according to claim 8, wherein B is selected from:

10. the compound according to claim 9, wherein B is selected from:

11. a compound according to claim 1, wherein B has the formula:

12. a compound according to claim 11, wherein B has the formula:

13. a compound according to any one of claims 1 to 12, wherein a has the formula:

14. a compound according to claim 1, selected from:

n- {5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] ethyl } amino) -1-hydroxyethyl ] -2-hydroxyphenyl } methanesulfonamide succinate;

5- [ (1R) -2- ({2- [4- (2- {3- [ (1R) -3- (diisopropylamino) -1-phenylpropyl ] -4-hydroxyphenyl } ethoxy) phenyl ] -1, 1-dimethylethyl } amino) -1-hydroxyethyl ] -8-hydroxyquinolin-2 (1H) -one;

15. A quaternary ammonium salt of a compound according to claim 1, said quaternary ammonium salt having the formula:

wherein X is acetate, fumarate, methanesulfonate, bromide, chloride, sulfate, D-and L-tartrate or xinafoate.

16. A quaternary ammonium salt of a compound according to claim 1, said quaternary ammonium salt having the formula:

wherein X is succinate.

17. A pharmaceutical composition comprising at least an effective amount of a compound of formula (1) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt or derivative form thereof.

18. The pharmaceutical composition according to claim 17, further comprising one or more pharmaceutically acceptable excipients and/or additives.

19. A compound of formula (1) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, derivative form or composition thereof, for use as a medicament.

20. A compound of formula (1) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, derivative form or composition thereof, for use in the treatment of diseases, disorders and conditions in which the β 2 and M3 receptors are involved.

21. A compound of formula (1) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, derivative form or composition thereof for use in the treatment of diseases, disorders and conditions selected from the group consisting of:

● asthma of any type, etiology or pathology, in particular asthma selected from one of the following: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, genuine asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown etiology, non-atopic asthma, bronchitic asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections, non-allergic asthma, asthma primordium, wheezy infant syndrome, and bronchiolitis;

● chronic or acute bronchoconstriction, chronic bronchitis, small trachea obstruction and emphysema;

● an obstructive or inflammatory airway disease of any type, etiology or pathology, in particular an obstructive or inflammatory airway disease selected from a member of the group consisting of: chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated or not with COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperresponsiveness following other drug treatment and airway disease associated with pulmonary hypertension;

bronchitis of any type, etiology or pathology, in particular bronchitis of a member selected from: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis;

● acute lung injury;

● bronchiectasis of any type, etiology or pathology, in particular bronchiectasis selected from one of the following: columnar bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

22. Use of a compound of formula (1) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, derivative form or composition thereof, for the manufacture of a medicament having both β 2 agonist activity and M3 antagonist activity.

23. Use of a compound of formula (1) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate or composition thereof for the manufacture of a medicament for the treatment of diseases, disorders and conditions selected from the group as described in claim 21.

24. A method of treatment of a mammal, including a human being, which comprises treating said mammal with an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof, as claimed in any one of claims 1 to 16.

25. The method according to claim 24, wherein the diseases, disorders and conditions are selected from the group as described in claim 21.

26. A compound according to any one of claims 1 to 16 in combination with a further therapeutic agent selected from:

(c) histamine receptor antagonists including H1 and H3 antagonists;

(e) PDE inhibitors, such as PDE3, PDE4, and PDE5 inhibitors;

(f) theophylline;

(g) sodium cromoglycate;

(i) prostaglandin receptor antagonists and prostaglandin synthase inhibitors;

(j) oral and inhaled glucocorticoids;

(k) dissociated agonists of adrenocortical hormone receptors (DAGR);

(l) Monoclonal antibodies active against endogenous inflammatory entities;

(m) an anti-tumor necrosis factor (anti-TNF- α) agent;

(n) adhesion molecule inhibitors, including VLA-4 antagonists;

(o) kinin-B₁-and B₂-a receptor antagonist;

(q) inhibitors of Matrix Metalloproteinases (MMPs);

(r) tachykinin NK₁、NK₂And NK₃A receptor antagonist;

(s) protease inhibitors, such as elastase inhibitors;

(t) adenosine A2a receptor agonists and A2b antagonists;

(u) inhibitors of urokinase;

(v) compounds acting at dopamine receptors, such as D2 agonists;

(w) modulators of the NF κ β pathway, such as IKK inhibitors;

(y) agents that can be classified as mucolytic or anti-tussive;

(z) agents that enhance the response to inhaled corticosteroids;

(bb) HDAC inhibitors;

(cc) CXCR2 antagonists;

(dd) integrin antagonists;

(ee) chemokines;

(ff) an epithelial sodium channel (ENaC) blocker or inhibitor;

(gg) P2Y2 agonists and other nucleotide receptor agonists;

(hh) thromboxane inhibitors;

(ii) nicotinic acid, and

(jj) adhesion factors including VLAM, ICAM and ELAM.

27. A compound of the formula:

wherein:

b is as defined in claim 1 and B is,

ra represents hydrogen or a suitable hydroxy protecting group,

rb and Rc represent any suitable substituent so that the bond between N and Rb and the bond between N and Rc can be easily cleaved to give the corresponding amine,

B²selected from:

-CH₂-(CH₂)_m-X¹-(CH₂)_n1wherein X is¹Is O or S, m is an integer from 0 to 9, n₁Is an integer of 1 to 7, and n₁+ m is between 2 and 7 inclusive;

optionally with one or two C₁-C₄Alkyl substituted C₃-C₉An alkylene group; or

-a group of formula:

wherein X²Is O or S, r₁Is an integer from 1 to 6, s is an integer from 0 to 6, and t₁Is an integer of 1 to 4, and s + t₁Between 1 and 4 inclusive, and r₁+s+t₁Between 2 and 5 inclusive.