ZA200605670B - Sulfonamide derivatives for the treatment of diseases - Google Patents

Description

SULFONAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES

This invention relates to B2 agonists of general formula:

OH

H

N

CH Ql

HO

0

NHSO,CH, in which R', R%, n and Q' have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of such derivatives.

Adrenoceptors are members of the large G-protein coupled receptor super-family. The adrenoceptor subfamily is itself divided into the a and B subfamilies with the p sub-family being composed of at feast 3 receptor sub- types: B1, p2 and B3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. p2 adrenergic (B2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas B3 adrenergic receptors are mainly expressed in fat tissues (therefore B3 agonists could potentially be useful in the treatment of obesity and diabetes) and (1 adrenergic receptors are mainly expressed in cardiac tissues (therefore B1 agonists are mainly used as cardiac stimulants).

The pathophysiology and treatments of airway diseases have been extensively reviewed in the literature (for reference see Barnes, P.J. Chest, 1997, 111:2, pp 17S5-26S and Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9:1, pp25-42) and therefore only a brief summary will be included here to provide some background information.

Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti- cholinergics and B2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled $2 agonists. Short acting, rapid onset 2 agonists are used for “rescue” bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.

Bronchodilation is mediated via agonism of the 2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, B2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because B2 receptors are so widely distributed in the airway, B2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that p2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how p2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, B2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.

In addition to the airways, it has also been established that (2 adrenoceptors are also expressed in other organs and tissues and thus B2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

However, numerous 2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at f2 adrenoreceptors expressed outside the airways

(muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class.

Accordingly, there is still a need for novel p2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, pharmacokinetics or duration of action. In this context, the present invention relates to novel p2 agonists.

Various Sulfonamide derivatives have already been disclosed. For example, W002066250 discloses compounds active as ps3 agonist, selective over p2, of formula :

OH

AN Rs

Zz TCL ale] SG 0) , (Oh wherein m may be 2, Ry may be H, OH or NRsSORs (Rs being H or C4+-Ce alkyl), Z may be a bond, Rz may be H or C4-Cs alkyl, Rq may be C4-Cs alkyl, B may be phenyl, Y is C4-Cs alkyl and A may be phenyl.

W002/000622 discloses selective $3 agonists of formula #4 X

R PS I oy: ER 1 ia Hg B {i wherein R' may be phenyl substituted with hydroxy and alkylsulfonylamino, X4 may be a bond, R? may be hydrogen, R® is hydrogen or hydroxyalkyl, Xo may be CH,, Xa is a bond, O or NH and R* is cyclic group.

Other sulfonamide derivatives are also disclosed in Uss,776,983 as B3 agonists They are more specifically of formula :

OH H RS pe

RS R3 R4

R2

NHSO,R! wherein R' may be CHs, R? may be OH, R® may be H, R® may be H or alkyl, R* may be H, alkyl, R’ may be H, R® may be C(O)NR’R™ wherein R® and R® may be H or lower alkyl.

However, none of the above sulfonamide derivatives have shown a B2 agonist activity and a pharmacological profile allowing them to be used as efficient drugs in the treatment of the p2-mediated diseases and/or conditions, in particular allergic and non-allergic airways diseases or other diseases such as those previously cited.

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

OH

H aes (CH,), Ql 1 R2 (1)

Bone R' R ~~

NHSO,CH, © wherein the (CH2)-C(=O)Q" group is in the meta or para position, R' and R? are independently selected from H and C4-C4 alkyl, nis 0, 1 or 2 and Q'is a group selected from:

R3 R¢ R

R8 R4 (CH), RS *—N \ RS .N RS Ré and a group * NRE-Q?-A, wherein p is 1 or 2, Q? is a C4-C4 alkylene optionally substituted with OH, R® is H or C4-C4 alkyl and A is pyridyl optionally substituted with OH, C3-C7 cycloalkyl optionally substituted with OH or a group

R3 R*

R3

RS

R4 5 RS or R7 R6 wherein R3, R*, R®, R® and R’ are the same or different and are selected from

H, C-Cs alkyl, OR®, SR’ halo, CN, CFs OCF, COOR?, SOMNR°RY,

CONR®R™, NR?R™, NHCOR'® and pheny! optionally substituted with 1 to 3 groups selected from OR®, halo and C4-C alkyl; wherein R® and R'® are the same or different and are selected from H or C4-Cs4 alkyl and the * represent the attachment point to the carbonyl group; wherein the group Q' is substituted at least with one hydroxy group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

The compounds of formula (1) are agonists of the P2 receptors, that are particularly useful for the treatment of p2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.

in the here above general formula (1), C+-C4 alkyl and C4-C4 alkylene denote a straight-chain or branched group containing 1, 2, 3 or 4 carbon atoms.

This also applies if they carry substituents or occur as substituents of other radicals, for example in 0-(C+-Cs)alkyl radicals, S-(C1-Ca)alkyl radicals etc... .

Examples of suitable (C+1-C4)alkyl radicals are methyl, ethyl, n-propyl, iso-propw, n-butyl, iso-butyl, sec-butyl, tert-butyl.... Examples of suitable (C1-Cs)alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butytoxy, sec-butyloxy and tert-butyloxy....

The Ca-C; cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Prefered C5-C7 cycloalkyl are substituted with OH.

Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro. in the following, the free bond on the phenyl group such as in the structure below, 1S; means that the phenyl can be substituted in the meta or para position.

The compounds of the formula (1)

OH H

Or (CH,) Q! 1 R2 " (1)

HO RTR Tr

NHSO,Me oO can be prepared using conventional procedures such as by the following illustrative methods in which R', R?, Q', and n are as previously defined for the compounds of the formula (1) unless otherwise stated.

The amide derivatives of the formula (1) may be prepared by coupling an acid of formula (2) or a salt thereof:

OH H

Cr (2) (CH), OH

NHSO,Me © with an amine of formula NHR®-Q*-A (3),

R3 R4 - R3 y a [Cx \ RS

HN

RS (3), 0r R® (3).

The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, N-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g.

N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.

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

The acid of formula (2) may be prepared from the corresponding ester of formula (4) :

OH

H

N 4) (CH,),_ ORa 1 o 50 T

NHSO,Me wherein Ra is a suitable acid protecting group, preferably a (C4-Ca)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, propionitrile, 1,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.

The ester of formula (4) may be prepared by reaction of an amine of formula (5) :

HN (6) x [ Jct, ORa

RR? 1 0 wherein Ra and n are as previously defined, with a bromide of formula (6):

OH

Br (6)

HO

NHSO,Me

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

The bromide of formula (6) may be prepared according to the method of

WO 02/06258 (pg. 36, example 14a).

Alternatively, the ester of formula (4) where n=1 may be prepared from the bromide of formula (7)

OH

H

N

Ce (7) 1

HO R!' R2

NHSO Me

In a typical procedure the bromide (7) is treated with a suitable palladium catalyst (e.g. [1,1"-bis(diphenylphophino)ferroceneldichioro palladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (up to 100psi) to give the ester of formula (4).

The amine of formula (5), where Ry is Me and Ry is H, may be prepared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (8) :

N 8

Rb” Fo he (8)

R! R2 2 Oe wherein Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRBbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be a-methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic

Synthesis , A. Wiley-interscience Publication, 1981.

The amine of formula (8) may be prepared as a single diastereomer by reaction of an amine of formula HNRDbRG with a ketone of formuia (9):

Cr (9)

CH

0 ( 2h 5 0

Oo wherein Ra, Rb, Rcand n are as previously defined.

In a typical procedure, the reaction of the ketone of formula (9) with the amine of formula HNRbRc leads to a chiral intermediate which is in tum reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula

NaCNBHj; or sodium triacetoxyborohydride of formula Na(OAc)3BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate} and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (8) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (8) as a single diastereomer.

The ketone of formula (9) where n=1 may be prepared by palladium mediated coupling of an ary! halide of formula (10):

Hal

Ur (10) 0 wherein Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate -or enolate equivalent.

In a typical procedure, the aryl halide of formula (10) is reacted with a tin enolate generated in-situ by treatment of isoprenyl acetate with tri-n-butyitin methoxide of formula Buz;SnOMe in the presence of a suitable palladium catalyst (palladium acetate! tri-ortho-tolylphosphine of formula Pd(OAc)./P(o-

Tol)s) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80°C and 110°C for 6 to 16 hours.

The aryl halide of formula (10) may be obtained by esterification of the corresponding acid of formula (11):

Hal

Ory © 0) wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule. in a typical procedure, the acid of formula (11) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours.

The acid of formuta (11) is a commercial product.

The amine of formula (5), where Ry = R, = alkyl, may be prepared according to the following scheme:

Scheme 1

HO 7

O

RaO PR KO re OH 3 (CH,),” “OH R' R? 13 (12) (13)

H,N 7 2

R! R? (5) wherein R', R? and Ra are as previously defined.

In a typical procedure, the ester of formula (12) is reacted with an “activated” alkyl (organometallic alkyl such as R3MgBr, R2MgCl or R®Li) to give the corresponding tertiary alcohol of formula (13) using the method described above.

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

Alternatively, the amine of formula (5), where R! = R? = C4-C, alkyl and n=0, may be prepared according to the following scheme:

Scheme 2

RaO HO

Br —— Br — (14) (15)

Br _—

R! R?

Rt R? ORa (16) 5) wherein R'. R? and Ra are as previously defined.

In a typical procedure, the ester of formula (14) is reacted with an wactivated” alkyl (organometallic alkyl such as R®MgBr, R?MgCi or RL) to give the corresponding tertiary alcohol of formula (15) using the method described above.

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

The resulting bromo amine (16) is treated with a suitable palladium catalyst (e.g. [1.1"-bis(diphenylphophino)ferrocene]dichloropaliadium(il) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).

The ketone of formula (9) where n=2 may be prepared by reduction of an alkene of formula (17):

H,C 0 (17)

TU ew

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

The alkene of formula (17) may be prepared by a palladium mediated coupling of an activated olefin with an ary! halide of formula (18):

H,C

IRE (18) eo]

In a typical procedure, the aryl halide (18) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.0. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPhs)s, palladium acetate/tri-ortho-tolylphosphine of formula Pd(OAc)/P(o-tol)a or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCi2) in a sutiable solvent (e.g. acetonitrile, N, N-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40°C and 110°C for 8 to 24 hours.

The ketone of formula (18) is a commercial product.

The amine of formula (5), where R' and R® are both H, may be prepared according to the following scheme:

Scheme 3 o 0

HO JS HO JL OR

TC Fe ORa ___ > (CHp), “8 0 (19) (20) 0]

Ea JX (CH,), OR wherein R', R? and Ra are as previously defined.

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

Said primary alcohol of formula (20) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile. The preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenyiphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the atkyl group to furnish the amine. in a typical procedure, the compounds of formula (1) wherein R' and R? are both methyl and n is 1, may be prepared by reacting a compound of formula (21)

H

N

HO

NHSO,Me 21)

where X is H, K, Na, Li and potentially an organic amine base or other metal salt,, with a suitable amine of formula NHRE-Q?-A (3)

R3 4

R3 R Re Re (CH,), RS N

HN Re

R6 (3), or Rs 3") in the presence of a conventional coupling agent such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine dimethylformamide and dimethylacetamide optionally in the presence of an * organic base (such as Hunig's base) and an additive (such as 1- hydroxybenzotriazole) in order to obtain a compound of formula (1):

OH

H

SG

(CH), Qt 1 R2 (1) ~ or pi ~

NHSO,CH © 2 3 : wherein R' and R? are methyl and n is 1.

Said compound of formula (21) may be obtained by hydrogenation of a compound of formula (22)

OH

H .

N

2308 00, X

NHSO,M i (22) wherein X is H, Na, Li or K and an potentially an organic amine or other metal salts, in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.

Said compound of formula (22) may be obtained by reacting a compound of formula (23)

H

N

FO) eoreroen

Sh

NHSO,Me (23) with M-OH wherein M is selected from Na, K or Li, optionally in the presence of '5 a suitable solvent such as propionitrile, tetrahydrofunan or dioxane, preferably propionitrile.

Said compound of formula (23) may be obtained by deprotecting a compound of formula (24)

QTBDMS

H

N

<r CO,-C;-Caalkyl

Cr fon

NHSO,M .

Ze (24) using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trihydrofluoride in the presence of a suitable solvent such as propionitrile.

Said compound of formula (24) may be obtained by reacting a compound of formula

HN 0—C,-C alkyl with a compound of formula

OTBDMS

Br re

Hg OF o © in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO, and optionally in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, Hunig's base or triethylamine, at a temperature between 50°C and 150°C for 12 to 36 hours.

For some of the steps of the here above described process of preparation of the compounds of formula (1), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by

T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience

Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme

Verlag, 1994), can be used.

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

Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

Preferably Q° is -CHp-, =(CHz)-, ~(CHz)s, -(C(CHa)) -(CHa)s or - (CH(CH.0H))-

Preferably, Q'is

R3 R#

RS

*—N

Re , wherein one of Rs, Rs, Rs and Rg is OH and the others are H.

Preferably Q' is

RS

R4 +—N

H

RS

R® . wherein one of Rs, Rs, Rs and Re is OH and the others are H.

Preferably Q' is a group *-NR®-Q”A, wherein R® is H, CHa or CH2CHs, Q° is a

C+-Cq alkylene and A is naphty! substituted by one hydroxy.

Preferably, Q' is a group *-NR®Q?-A, wherein R® is H, CHs or CH,CH3, Qis a

C4-Cs alkylene and A is a group

R3 R4 ~ -

R7 R8 wherein one of R%, RY, R®, R® and R” is OH and the others are the same or different and are selected from H, C4-C4 alkyl, OR®, SR®, ‘halo, CF3, OCF3,

SO.NRR™, CONRPR™, NR°R", NHCOR®, provided af least 2 of R® to R” are equal to H;

wherein R® and R' are the same or different and are selected from H or C4-Ca alkyl.

More preferably, Q' is a group + .NH-Q%A, wherein Q% is a -CHz-, -(CHz)z-, - (CHa)4-, ~CH2-C(CHa))- preferably -CHa-, and A is a group

R3 R*

He

R7 R6 wherein one of R®, R*, R®, R® and R’ is OH and the others are the same or different and are selected from H, OH, CHa, OCH,-CHj, SCH, halo, CFs, - OCF3, provided at least 2 of R3 to R” are equal to H.

Preferably, Q' is a group *NR®-Q’-A, wherein R® is H, CHa or CHzCHg, Q is a

C4-Cs4 alkylene and A is a group

R3 R4

R7 RS wherein one of R%, R* R%, R® and R’ is phenyl substituted by OH and the others are H. :

In the above groups of compounds, the following substituents are particularly preferred:

R' is H or C4-C4 alkyl and R2? is C4-C, alkyl. More preferably, R'is H or CH; and 'R%is CHa. nis 0 or 1. More preferably n is 1.

R'is H and R?is CHz and n is 1.

© R'is CHa, R2is CHgand nis 1.

Particularly preferred are the compounds of the formula (1) as described in the Examples section hereafter, i.e. : 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3- {{methylsulfonyhaminojphenyljethybamino]-2-methylpropyliphenyl)-N-(4 hydroxy-3-methoxybenzyl)acetamide;

N[(4Hydroxybiphenyl-4-yimethyll-2-(3-2-[(2R)-2-hydroxy-2-{4-hydroxy-3- {(methylsulfonyljaminolphenyljethyljamino]-2-methylpropyljphenyl)acetamide:

N-(4-Chloro-2-hydroxybenzyl)-2-(3-2-[((2R)-2-hydroxy-2-{4-hydroxy-5- ((methylsulfonyhaminolphenyllethyljamino]-2-methylpropylyphenylacatamide;

N-(4-Hydroxy-3 5-dimethylbenzyl)-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- (methylsulfony)aminolphenyljethyl)amino]-2-methylpropy}phenyl)acetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- (methylsulfony)aminolphenyljethyhamino]-2-methylpropyphenyl)-N-{(2- hydroxy-1 -naphthyl)methyljacetamide; 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminolphenylethyhamino]-2-methylpropyliphenyl;-N-[6- hydroxy-2-naphthyl)methyllacetamide;

N-{(4-Hydroxybiphenyl-3-yhmethyl}-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsutfonyhaminalphenyljethyl)aminol-2-methylpropyijphenyl)acstamide;

N-[(3-Hydroxybiphenyl-3-yi)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminolphenyljethyl)aminol-2-methylpropyliphenyljacetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- f(methylsulfonyliaminalphenyljethyl)amino]-2-methylpropyliphenyl}-N-[2-(4- hydroxyphenyl)-2-methylpropyljacetamide;

N-(3,5-Dichloro-2-hydroxybenzyl)-N-athyl-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy- 3.{(methylsulfonyl)amina]phenyijethyl)aminol-2-methylpropyliphenyl)acetamide; 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethyl)amino}-2-methylpropyliphenyl)-N-{(6- hydroxy-1-naphthyl)methyl]-N-methylacetamide;

N-[(2"-Hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethyl)amino}-2-methylpropyljphenyl)acetamide;

N-(2-Hydroxy-54(1R)-1-hyd roxy-2-[(2-{3-[2-(6-hydroxy-3 4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyilphenyl}-1,1- dimethylethyl)aminojethyl}phenyl)methanesulfonamide; 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3- f(methylsulfonyljaminojphenylethyhaminol-2-methylpropyljphenyl)-N-{4-(4- hydroxyphenyl)butyllacetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- ((methylsulfonyl)amino]phenylethy)amino}-2-methylpropyliphenyl)-N-{2-(4- hydroxyphenyl)ethyljacetamide;

N-(2-Chloro-4-hydroxybenzyl)-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminolphenyljethyl)amino]-2-methylpropyljphenyl)acstamide

N-(3,5-Dichloro-4-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminojphenyljethyamino]-2-methylpropyljphenyl)acetamide;

N-(2,3-Dichloro-4-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyliaminojphenyljethyamino}-2-methylpropyliphenyhacetamide ; 2-(3-{2-((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminophenyl}ethyl)amina]-2-methyipropyliphenyl)-N-{(4- hydroxy-1 -naphthyl)methyllacetamide ; : 2.(3-{2-[((2R)-2-Hhydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethyl)amino]-2-methylpropyf}phenyl)-N-[3- hydroxy-5-(trifluoromethyl)benzyljacetamide;

N-(2-Chloro-4-hydroxybenzyl)-N-ethyl-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethyl)amino}-2-methylpropyljphenyljacetamide;

N-(2-Chloro-4-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyljaminojphenyljethyl)amino]-2-methylpropyliphenyl)-N- methylacetamide;

N-(3-Fluoro-5-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminc]phenyljethyl)amino]-2-methylpropyliphenyl)-N- methylacetamide;

N-{(2'-Hydroxybiphenyl-2-yl)methyi]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonylarmina]phenyilethyl)amino]-2-methylpropyl}phenyl)acetamide;

N-[(3'-Hyd roxybiphenyl-2-yhmethyl}-2-(3-{2-{((2R)-2-hydroxy-2-{4-hyd roxy-3- [(methylsulfonyl)amino]phenyllethy! Jamino]-2-methylpropyl}phenyl)acetamide;

N-(4-Hyd (oxy-2,6-dimethylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- ((methylsulfonyl)aminclphenyljethyhaminol-2-methylpropyliphenyl)acetamide;

N-(2-Hydroxy-5-{(1R)-1-hyd roxy-2-[(2-{3-[2-(7-hydroxy-3 ,A-dihydroisoquinolin- 2(1 H)-yl)-2-oxoethyllphenyi}-1 A- dimethylethyl)aminclethyl}phenyl)methanesulfo namide;

N-(2-Hydroxy-5-{(1R)-1-hyd roxy-2-[(2-{3-[2-(5-hyd roxy-3,4-dihydraisoquinolin- 2(1 H)-yl)-2-oxoethyllphenyi}-1,1- dimethylethyl)aminclethyl}phenyl)methanesulfonamide; 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsutfonyl)aminolphenyljethyamino]-2-methylpropyltphenyl)-N-{(1 R)-2- hydroxy-1 -phenylethyfjacetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3- [(methylsulfony)aminolphenyljethyaminol-2-methylpropyliphenyi)-N-i(1 S)-2- hydroxy-1 -phenylethyllacetamide;

N-[(3'-Hyd roxybiphenyl-4-yl)methyi}-2-(3-{2-{((2 R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminojphenyljethylamino]-2-methylpropyliphenyljacetamide;

N-[(2'-Hydroxybiphenyi-4-yt ymethyl]-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3- [(methylsulfonyl)aminojphenyljethyhamino}-2-methylpropyliphenyljacetamide;

N-[(4"-Hydroxybiphenyl-4-yl)methyl]-3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3- [(methylsulfonyiaminojphenyijethyl)amino]-2-methylpropyltbenzamide; 3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminojphenyljethyl)amina]-2-methyipropyl}-N-[2-(4- hydroxyphenyl)-2-methylpropyllbenzamide;

N-{(4'-Hyd roxybiphenyl-3-yl)methyl]-3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3- [(methylsulfonyl)aminolphenyl}ethyl)amino]-2-methylpropyljbenzamide;

N-[2-(4-Hydroxy-2,5-dimethyiphenyl)ethyl]-3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3- [(methylsulfonyl)amina]phenyl}ethyl)amino]-2-methylpropyl}benzamide;

N-[2-(4-Hydroxy-2,3-dimethylphenyt)ethyl-3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)aminojphenyi}ethyl)amino}-2-methylpropyl}benzamide; and,

3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- ((methylsulfonyhaminolphenyljethyljamino]-2-methylpropyl}-N-{2-{4-nydroxy-5- methylphenyt)ethyljbenzamide.

According to one aspect of the present invention, the compounds of formula 0) . wherein the (CH)-C(=0)Q’ group is in the meta position are generally preferred.

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

Suitable acid addition salts are formed from acids which form non-toxic salts.

Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate and xinafoate salts.

Suitable base salts are formed from bases which form non-toxic salts.

Examples include the aluminium, arginine, benzathine, calcium, choline, 95 diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:

Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim,

Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods: (i) by reacting the compound of formula (1) with the desired acid or base; (ii) by removing an acid- of base-labile protecting group from a suitable precursor of the compound of formula (1) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (ii) by converting one salt of the compound of formula (1) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

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

The compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-Jabeled compounds of formula (1)-

As indicated, so-called ‘pro-drugs’ of the compounds of formula (1) are also within the scope of the invention. Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage.

Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS

Symposium Series (T. Higuchi and W. Stella) and ‘Bioreversible Carriers in

Drug Design’, Pergamon Press, 1987 (ed. E. B Roche, American

Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

(@) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaced by (C1-Cs)alkyl; (ii) where the compound of formula (1) contains an alcoho! functionality (-

OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1) is replaced by (C1+-Ce)alkanoyloxymethyl; and (ii) where the compound of formula (1) contains a primary or secondary amino functionality (-NH or -NHR where R #H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) is/are replaced by (C4-Cro)atkanovl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

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

Also included within the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed in vivo upon administration of the drug.

Some examples of metabolites in accordance with the invention include 0) where the compound of formula (1) contains a methyl group, an hydroxymethyl derivative thereof (-CH3 — -CH20H): (ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR — -OH);

(iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR'R*> > NHR" or -NHR?); (iv) where the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR' = -NH>); (v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph — -PhOH); and (vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONHz — COOH).

Compounds of formula (1) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric cis/trans (or ZJE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, of so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or Hysine, or racemic, for example, di-tartrate or dl-arginine.

Cislirans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparationfisolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically

HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic

Compounds” by E. L. Eliel (Wiley, New York, 1994).

According to one aspect of the present invention, the (R,R)-sterecisomer of the formula below, wherein R' is hydrogen and R? is C4-Cq alkyl, preferably methyl, and n and Q' are as defined above, is generally preferred:

OH

H

N or OU em el

HO R1 R2 ~

NHSO,CH, ©

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

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as “H and 3H, carbon, such as 'C, °C and 4G. chlorine, such as *Cl, fluorine, such as 8 iodine, such as 2 and "I, nitrogen, such as ™°N and N, oxygen, such as 150, 70 and *®0, phosphorus, such as 22P, and sulphur, such as *S.

Certain isotopically-labelled compounds of formula (1 ), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. °H, and carbon-14, i.e. 4G are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as Yc, BF, 50 and PN, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Claims (38)

1. A compound of general formula (1): OH H N CH a HO Oo NHSO,CH, wherein the (CH2)-C(=0)Q" group is in the meta or para position, R' and R? are independently selected from H and C4-C4 alkyl, nis 0, 1 or 2and Q'is a group selected from: R3 R* RS R® R4 . os *—N \ RS AN RS Re and a group * NR®-Q%A, wherein p is 1 or 2, Q? is a C4-C4 alkylene optionally substituted with one hydroxy group, R® is H or C4-C4 alkyl and A is pyridyl optionally substituted with OH, C3-C7 cycloalkyl optionally substituted with OH, or a group R3 R4 . R3 R4 RS or FR Re wherein R%, R*, R%, R® and R’ are the same or different and are selected from H, Ci-Cs alkyl, OR’, SR’, halo, CN, CFs, OCFa, COOR’, SO.NR’R", CONR°R™, NR°R', NHCOR'™ and phenyl optionally substituted with 1 to 3 groups selected from OR®, halo and C4-C, alkyl,

wherein R® and R' are the same or different and are selected from H or C4-Cs alkyl and the * represent the attachment point to the carbonyl group; wherein the group Q' is substituted at least with one hydroxy group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

2. A compound according to claim 1 wherein Q' is a group * NRS.Q%-A, wherein R® is H, CHj or CH,CH; and and A is naphtyl substituted by one hydroxy.

3. A compound according to claim 1 wherein Q' is a group * NR®-Q?-A, wherein R® is H, CH3 or CH,CH3; and A is a group R3 R4 R7 RS wherein one of R®, R*, R%, R® and R’ is OH and the others are the same or different and are selected from H, C4-C4 alkyl, OR®, SR? halo, CF;, OCF, SO,NRR™, CONR®RY, NR°R"®, NHCOR™ provided at least 2 of R® to R’ are equal to H; wherein R® and R" are the same or different and are selected from H or C+-C4 alkyl.

4. A compound according to claim 3 wherein Q' is a group *.NH-Q%A and A is a group R3 R¢ 3 4 pe R7 - R® wherein one of R%, RY, R%, R® and R” is OH and the others are the same or different and are selected from H, OH, CHj, OCH-CHs, SCH3, halo, CF3, OCF,, provided at least 2 of R® to R are equal to H.

5. A compound according to claim 1 wherein Q' is a group * NRE-Q?%-A, wherein R®is H, CHz or CH,CH; and A is a group R3 R4 He RT Re wherein one of R?, R*, R®, R® and R’ is phenyl substituted by OH and the others are H.

6. A compound according to any one of claims 1 to 5 wherein Q° is -CHy-, - (CHa)z, -(CH2)3-, (C(CHa))- (CHz)s- or -(CH(CH20H))-.

7. A compound according to claim 6 wherein Q? is -CHz-.

8. A compound according to claim 1 wherein Q'is R3 eed *—N H RS : Re , wherein one of Rs, Rs, Rs and Rs is OH and the others are H.

9. A compound according to claim 1 wherein Q'is

R3 R¢ RS *—N R® , wherein one of Ra, Rs, Rs and Rs is OH and the

. others are H.

10. A compound according to any one of claims 1 to 10 wherein R'is H or C4- Cs alkyl and R? is C4-C4 alkyl.

11. A compound according to claim 11 wherein R'is H or CH; and R? is CH.

12. A compound according to claim 12 wherein nis 1.

13. The (R,R)-stereoisomer of a compound according to any one of claims 1 to

12.

14. A compound according to any one of claim 1 to 13 wherein the (CH2)n- c(=0)Q’ group is in the meta position.

15. A compound according to claim 1 selected from the group consisting of 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methyisulfonyl)amino]phenyl}ethyl)aminol-2-methylpropyl}phenyl)-N-(4- hydroxy-3-methoxybenzyl)acetamide; N-[{(4'-Hydroxybiphenyl-4-yl)methyl}-2~(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide; N-(4-Chloro-2-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyli}ethyl)amino}-2-methylpropyl}phenyl)acetamide; N-(4-Hydroxy-3,5-dimethylbenzyl)-2~(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyliphenyi)acetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)}-N-[(2- hydroxy-1-naphthyl)ymethyl]lacetamide;

2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyjaminolphenyljethyl)amino}-2-methylpropyl}phenyl)-N-[(6- hydroxy-2-naphthyl)methyilacetamide; N-{(4'-Hydroxybiphenyl-3-yhmethyl}-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-

[(methyisulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide; N-[(3"-Hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyi}ethyl)amino]-2-methylpropyl}phenyl)acetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)-N-[2-(4-

hydroxyphenyl)-2-methylpropyilacetamide; N-(3,5-Dichloro-2-hydroxybenzyl)-N-ethyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy- 3-[(methylsulfonyi)amino]phenyljethyl)amino]-2-methylpropyl}phenyl)acetamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino}-2-methyipropyl}phenyl)-N-[(6-

hydroxy-1-naphthyl)methyl]-N-methylacetamide; N-[(2'-Hydroxybiphenyl-3-yl)methyl}-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide; N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-{(2-{3-[2-(6-hydroxy-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyllphenyl}-1,1-

dimethylethyt)aminolethyl}phenyl)methanesulfonamide; 2-(3~{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methyipropyl}phenyl)-N-{4-(4- hydroxyphenyl)butyljacetamide; 2-(3-{2-{((2R)-2-Hydroxy-2-{4-hydroxy-3-

[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)-N-[2-(4- hydroxyphenyl)ethyllacetamide; N-(2-Chloro-4-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide N-(3,5-Dichloro-4-hydroxybenzyl)-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3-

[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide; N-(2,3-Dichloro-4-hydroxybenzyi)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide ;

2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsutfonyt)amino]phenyllethyl)amino]-2-methylpropyliphenyl)-N-[(4- hydroxy-1-naphthyl)methyijacetamide ; 2-(3-{2-[((2R)-2-Hhydroxy-2-{4-hydroxy-3-

[(methylsulfonyl)amina]phenytjethyl)amino}-2-methylpropyl}phenyl)-N-[3- hydroxy-5-(trifluoromethyl)benzylJacetamide; N-(2-Chloro-4-hydroxybenzyl)-N-ethyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethyl)amino]-2-methylpropyl}phenyl)acetamide; N-(2-Chloro-4-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- )

[(methylsulfonyl)amino]phenyfjethyl)amino]-2-methylpropyi}phenyl)-N- methylacetamide; N-(3-Fluoro-5-hydroxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)aminc]-2-methylpropyl}phenyt)-N- methylacetamide;

N-[(2"-Hydroxybiphenyl-2-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methyisulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide; N-[(3'-Hydroxybiphenyl-2-y)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino}phenyl}ethyl)amino]-2-methyipropyl}phenyl)acetamide; N-(4-Hydroxy-2,6-dimethylbenzyl)-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3-

[(methylsulfonyl)amino]phenyljethyl)amino]-2-methylpropyi}phenyl)acetamide; N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-{(2-{3-[2-(7-hydroxy-3,4-dihydroisoquinolin- 2(1H)-yl)-2-oxoethyl]phenyl}-1,1- dimethylethyhamino]ethyl}phenyl)methanesulfonamide; N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[(2-{3-[2-(5-hydroxy-3,4-dihydroisoquinolin-

2(1H)-yl)-2-oxoethyl}phenyl}-1,1- dimethylethyl)amino]ethyl}phenyl)methanesulfonamide; 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-

: [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)-N-[(1 R)-2- hydroxy-1-phenylethyljacetamide;

2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyi}phenyl)-N-{(1 S)-2- hydroxy-1-phenylethyl]acetamide;

N-[(3"-Hydroxybiphenyl-4-yl)methyll-2~(3{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyljethylyamino]-2-methylpropyl}phenyl)acetamide; N-[(2-Hydroxybiphenyl-4-yl)methyl}-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyt)amina]phenyljethyt)amino}-2-methylpropyi}phenyl)acetamide; N-[(4'-Hydroxybiphenyl-4-y))methyi}-3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- : [(methytsulfonyl)amino]phenyl}ethyl)amino}-2-methylpropyl}benzamide; 3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}-N-[2-(4- hydroxyphenyl)-2-methylpropyilbenzamide; N-[(4'-Hydroxybiphenyl-3-yl)methyl]-3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methyisulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}benzamide; N-[2-(4-Hydroxy-2,5-dimethyiphenyl)ethyl]-3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyi)amino]-2-methylpropyl}benzamide; N-[2-(4-Hydroxy-2,3-dimethylphenyl)ethyl]-34{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino}-2-methylpropyi}benzamide; and, 3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino J-2-methylpropyl}-N-[2-(4-hydroxy-3-methylphenyl)ethyllbenzamide.

16. N-[(4"-Hydroxybiphenyl-4-yl)methyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide.

17. N-[(4'-Hydroxybiphenyl-3-y)methyl]-2-(3-{2-{((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino}-2-methylpropyl} phenyl)acetamide.

18. 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-{(methylsulfonyl)amino] phenyl}ethyl)amino]-2-methylpropyl}phenyl)-N-[2-(4-hydroxyphenyl)-2- methylpropyl]acetamide

19. N-[(3'-Hydroxybiphenyl-3-yl)methyi}-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3- [(methylsulfonyl)amino}phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetamide

20. N-(3,5-Dichloro-2-hydroxybenzyl)-N-ethyl-2-(3-{2-{((2R)-2-hydroxy-2-{4- hydroxy-3-[(methylsuifonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}phenyl)acetamide

21. A pharmaceutical composition including a compound of the formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt or derived form thereof, together with customary pharmaceutically innocuous excipients and/or additives.

22. A compound of the formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament.

23. A compound of the formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions in which the p2 receptor is involved.

24. A compound of the formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : « asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis, « chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, « obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic

PCT/IB2005/000086 @® 126 e eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension, e bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, e acute lung injury, e bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric ~~ bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

25. The use of a compound of the formula (1) as described in any one of claims 1 to 20 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having a B2 agonist activity.

26. The use of a compound of the formula (1) as described in any one of claims 1 to 20 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions selected from the group as described in claim 24. AMENDED SHEET

PCT/IB2005/000086 @® 127

27. A process for the preparation of a compound of formula (1) according to any one of claims 1 to 20, said process comprising the following steps: (a) coupling an acid of formula (2): OH H N (2) / Fc, OH RI R, hig HO 0 NHSO, Me wherein R', R? and n are as defined in claim 1, with an amine of formula NR®-Q?-A (3), R3 2 R1 R Re Re *—N R3 HN R® RE (3), or Re (3"), wherein R®to R®, R®, Q2 and A are as defined in claim 1, (b) isolating said compound of formula (1).

28. A process for the preparation of a compound of formula (1) according to claim 1 wherein R' and R? are methyl and n is 1, said process comprising the following steps (a) reacting a compound of formula (21) OH N HO NHSO,Me 21) AMENDED SHEET

PCT/IB2005/000086 @® 128 where X is H, K, Na, Li and potentially an organic amine base or other metal salt, with a suitable amine of formula NHR3-Q?-A (3), 3 rR? RS R Re R4 (CH), Re N \ RS

HN . R® (3) or Re (3") in the presence of a conventional coupling agent such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine dimethylformamide and dimethylacetamide optionally in the presence of an ’ organic base and an additive in order to obtain said compound of formula (1). (b) islolating said compound of formula (1).

29. A process according to claim 28 where said compound of formula (21) is obtained by hydrogenation of a compound of formula (22) OH H N 208 c0,X NHSO_M i (22) wherein X is H, Na, Li or K and an potentially an organic amine or other metal salts, in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.

30. A process according to claim 29 where said compound of formula (22) is obtained by by reacting a compound of formula (23) AMENDED SHEET

PCT/1B2005/000086 9 129 OH H N PO) oon J NHSO Me 2 (23) with M-OH wherein M is selected from Na or LiK, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofunan or dioxane.

31. A process according to claim 30 wherein said compound of formula (23) is obtained by deprotecting a compound of formula (24) OTBDMS H N De og NHSO,M = (24) using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trihydrofluoride in the presence of a suitable solvent such as propionitrile.

32. A process according to claim 31 wherein said compound of formula (24) is by reacting a compound of formula HN 0—C,-C alkyl al TT with a compound of formula AMENDED SHEET

PCT/IB2005/000086 C 130 OTBDMS or 0) SN HN CH; Jo in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO, and optionally in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, Hunig's base or triethylamine, at a temperature between 50°C and 150°C for 12 to 36 hours.

33. Combination of a ccmpound according to any one of claims 1 to 20 with other therapeutic agent(s) selected from: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC, LTD4, and LTE,, (c) Histamine receptor antagonists including H1 and H3 antagonists, (d) a4- and az-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents, (f) PDE inhibitors, e.g. PDE3, PDE4 and PDES inhibitors, (g) Theophylline, (h) Sodium cromoglycate, (i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (I) Anti-tumor necrosis factor (anti-TNF-a) agents, AMENDED SHEET

PCT/IB2005/000086 ® 131 (m)Adhesion molecule inhibitors including VLA-4 antagonists, (n) Kinin-B, - and B; -receptor antagonists, (0) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK4, NK, and NK; receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists, (v) Modulators of the NFkB pathway, e.g. IKK inhibitors, (w)modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor (x) Agents that can be classed as mucolytics or anti-tussive, and (y) Antibiotics.

34. A compound according to any one of claims 1 to 20 or 22 to 24, substantially as herein described with reference to and as illustrated in any of the examples.

35. A composition according to claim 21, substantially as herein described with reference to and as illustrated in any of the examples.

36. Use according to claim 25 or claim 26, substantially as herein described with reference to and as illustrated in any of the examples.

37. A process according to any one of claims 27 to 32, substantially as herein described with reference to and as illustrated in any of the examples.

38. A combination according to claim 33, substantially as herein described with reference to and as illustrated in any of the examples AMENDED SHEET