ZA200607882B - Formamide derivatives useful as adrenoceptor - Google Patents

Description

FORMAMIDE DERIVATIVES USEFUL AS ADRENOCEPTOR )

This invention relates to B2 agonists of general formula:

OH H

N

Bea NAS re a

HN Y

Pa 0) 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 « and B subfamilies with the § sub-family being composed of at least 3 receptor sub- types: B1, p2 and p3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. $2 adrenergic (2) 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 p1 adrenergic receptors are mainly expressed in cardiac tissues (therefore p1- 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 17S26S 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.

Glucocorticosterolds, anti-leukotrienes, theophylline,. cromones, anti- cholinergics and p2 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 B2 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 p2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, $2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because p2 receptors are so widely distributed in the airway, p2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that B2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how (2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, 2 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 p2 adrenoceptors are also expressed in other organs and tissues and thus p2 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 B2 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 p2 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 B2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action. In this context, the present invention relates to novel p2 agonists.

Various formamide derivatives have already been disclosed. For example, US2004/0006112 discloses compounds active as 2 agonist, of formula:

OH H

HO R2 ~K

R! ®) R¢ RS

US2003/0229058 discloses selective $2 agonists of formula :

R13

R' oH

H R® R12

R? H (Ro),

Un .

R6 R7 Rs R10 R

Rs RS

R "

However, none of the above formamide derivative have shown a pharmacological profile allowing them to be used as efficient drugs in the treatment of p2-mediated diseases and/or conditions, such as allergic and non- allergic airways diseases; in particular by the inhalation route.

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

OH

H

N

CH Qt } or aeE IN 1)

H 0)

H

Oo wherein the (CH2)-C(=0)Q" group is in the meta or para position, -R! and R? are independently selected from H and C4-C, alkyl; -nis0,1o0r2; -Q' is a group selected from,

R3 Re ene

N=ch), ‘re wherein p is 1 or 2 and q is 1 or 2, said group being optionally bridged by one carbon atom,

R3

Rs R4

CI -

RS Ly

Re and a group *-NR®-Q%-A, wherein Q° is a C+-Cs alkylene, R® is H or C4-Cy alkyl and A is pyridyl, C3-C4o cycloalkyl, said cycloalkyl being optionally bridged by one or more, preferably 1, 2, 3 or 4, carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyrany or a group

Rs Ré

R3

R5

R4

RE o FR Re -R® R* RS R® and R’ are the same or different and are selected from H, C4-Cs alkyl, OR®, SR®, SOR’, SO,R’, halo, CN, CO;R®, CFs, OCFs, SONR°R",

CONR®R, NR°R'®, NHCOR' and phenyl optionally substituted with 1 to 3 5 groups selected from OR’, halo and C4-C, alkyl - R? and R" are the same or different and are selected from H or C4-C, alkyl and the * represent the attachment point to the carbonyl 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 2 receptors, that are particularly useful for the treatment of B2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.

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

This also applies if they carry substituents or occur as substituents of other radicals, for example in O-(C4-C4)alkyl radicals, S-(C4-Cs)alkyl radicals etc... .

Examples of suitable (Ci<Cq)alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butvi, iso-butyl, sec-butyl, tert-butyl... Examples of suitable O-(C4-Cs)alkyl radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy....

The Ca-C1o cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo[3.1.1]heptane,

bicyclo[2.2.1]heptane, bicyclo2.2.2]octane. Preferred cycloalkyl .groups are. cyclohexyl and adamantyl.

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, means that the phenyl can be substituted in the meta or para position.

The compounds of the formula (1)

OH

H pass (CH), Q' q

HO or N ~

HN o > o] can be prepared using conventional procedures such as by the following illustrative methods in which Q', @Q% R', R?, A 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):

H

H

Cr “ (CH), OH

R! R2

HO Tr

NHCHO with an amine of formula NHR®-Q%-A (3),

(CHy), RS CCT a o >

CH, "RE (3), 0r Re 3") 3").

The coupling is generally carried out in an excpss of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride , N, N-dicyclohexylcarbodiimide or O-(1H- benzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate), 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-methyimorpholine, 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), (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):

PN hit Nee ~~ | (4)

Xs -N~ ™

AN Jew ORa

NHCHO © wherein Ra is a suitable acid protecting group, preferably a benzyl group or a (C4-C4) alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen. chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1,4- dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours. Alternatively, if the ester is a benzyl group, the ester may be hydrogenated in the presence of a suitable catalyst (e.g. palladium-on-carbon, or palladium hydroxide-on-carbon) in a suitable solvent such (methanol, ethanol, 2M ammonia in methanol) at a temperature comprised between 20 °C and 50 °C for 1-48 h at 1-4 atmospheres of hydrogen.

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

HN (5)

TS ern, one oO wherein Ra and n are as previously defined, with a bromide of formula (6)

OH

Br

HO (6)

NHCHO

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

The bromide of formula (6) may be prepared according to the method disclosed in “Organic Process Research and Development 1998, 2, 96-99". .

The amine of formula (5), where R' is Me and R? is H, may be prepared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (7):

Re

Ll (7) 7 Fen oe 0) wherein Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRbRc Is a chiral amine (for example, Rb may be hydrogen and Rc may be 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 Protective Groups in Organic Synthesis Third

Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1999.

The amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):

H,C (8)

Trem om @) wherein Ra, Rb, Rc and n are as previously defined.

In a typical procedure, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula

NaCNBHj; or sodium triacetoxyborohydride of formula Na(QAc);BH) optionally 20 . 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 (7) 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 or nitrate salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethyl acetate,

ethanol, methanol, diisopropyl! ether or diisopropyl ether/methanol) to give (7) as a single diastereomer.

The ketone of formula (8) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (9):

Hal hom © oO 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 (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula BusSnOMe 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 (9) may be obtained by esterification of the corresponding acid of formula (10):

Hal . N ha oO 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 (10) 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. Altematively, the acid of formula (10) is reacted with a base (for example cesium or potassium. carbonate) and treated with an alkyl halide (for example methyl iodide, benzyl bromide) in an appropriate solvent such as N, N-diemthylformamide at a temperature between 10 °C and 40 °C (room temperature) for 1 to 20 h.

The acid of formula (10) is a commercial product.

The amine of formula (5), where R' and R? are both C+-C4 alkyl, may be prepared according to the following scheme:

Scheme 1

HO it

RaO 1 POT oon o (CHp),” "OH R' R?2 (11) (12)

HN R

-_— Fo Fen ORa

R' R2 (5) wherein R', R? and Ra are as previously defined.

In a typical procedure, the ester of formula (11) is reacted with an “activated” alkyl (organometallic alkyl such as R?MgBr, R®MgCl or R2Li) to give the corresponding tertiary alcohol of formula (12) using the method described above.

Said tertiary alcohol of formula (12) Is then treated with an alkyl nitrile (e.g. acelonitrile, chloroacetonitrile) in the presence of an acid (c.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 20 . mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5).

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

Scheme 2

Ra0O HO (13) (14) ag TUCK

Br —_—

R! R?

RT R? ORa (15) (6) wherein R', R? and Ra are as previously defined.

In a typical procedure, the ester of formula (13) is reacted with an “activated” alkyl (organometallic alkyl such as R°MgBr, R?MgCli or R2Li) to give the corresponding tertiary alcohol of formula (14) using the method described above.

Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile (e.g. acetonitrile, chioroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks to give the bromo amine (15). ) -

The resulting bromo amine (15) is treated with a suitable palladium catalyst” (e.g. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(il), palladiu m(il) acetate 1,1’-bis(diphenylphosphino)ferrocene], tris(dibenzylideneacetone)dipalladium(0), 2,2"-bis(diphenylphosphino)-1,1'- binaphthyldichloropalladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH, benzyl alcohol), or alternatively using a co-solvent such as DMF, at elevated temperature (100°C) and pressure (100psi) to give the ester of formula (5).

The ketone of formula (8) where n=2 may be prepared by reduction of an alkene of formula (16) :

H,C o (16)

TO

In a typical procedure, a solution of the olefin of formula (16) 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 (16) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (17):

H,C 0]

In a typical procedure, the aryl halide (17) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPhs)s, palladium - acetate/tri-ortho-tolylphosphine of formula Pd(OAc)/P{o-Tol)z or - (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCl2) in a suitable 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 (17) is a commercial product.

Alternatively a compound of formula (1) may be prepared by reaction of a bromide of formula (6) and an amine of formula (18):

HN

ASE Cha (18) 0 where R!, R2, Q'and n are as previously defined for the compounds of the formula (1) unless otherwise stated.

In a typical procedure, the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylisulfoxide, toluene, N, N-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.

The amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1:

H p AN (19)

CH

RR? ( yr

Oo with an amine of formula NHR®-Q?-A (3), 3

R3 R4 R

R8 R4

PIS

(Ci), \- , ~R3 H a \ RS HN - HN~

CHa Re (3), Re (3"), 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'-dicyclohexyicarbodiimide), 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, N,N-dimethyfformamide, 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'), (3") and (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 (19) may be prepared from the corresponding ester of formula (5).

The acid of formula (19), where R' and R? are both C4-C4 alkyl, may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:

H,N (5) 2 [Jon ora 0) wherein Ra is a suitable acid protecting group, preferably a (C4-Cs)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours. " The amine of formula (5), where R' and R? are both H, may be prepared according to the following scheme:

Scheme 3

0 : 9

HO 1 HO J (CH,).”” “ORa (CH,), ORa ©) (20) (21) 0) a 1

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

In a typical procedure, the acid of formula (20) is preferentially reduced to the corresponding alcohol (21) 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 (21) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with an appropriate amine nucleophile. The preferred nucleophile is an azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to fumish the amine. - 0) eo} .

SC Xomo \ 7

Jehu eo p 1

Z. g o CH (22) (23) : [o) — o HN Jig

N

© (28)

Alternatively, the amide of formula 22, can be prepared as outlined earlier using. standard amide bond forming reactions. The compound of formula 22 can then be reacted with a protected vinylamine (e.g. N-vinyiphthalimide) in the presence of a suitable catalyst (e.g. palladium(li)acetate) and a phosphine (e.g. triphenylphosphine, tri-ortho-tolylphosphine) in the presence of a base (e.g. N,

N-diisopropylethylamine) in a solvent (e.g. N,N-dimethylformamide, acetonitrile) at a temperature comprised between 20 °C and 120 °C and for 1 to 48 hours.

The alkene of formula 23 can then be reduced to an alkane of formula 24 using standard hydrogenation conditions and the protecting phthalimide group removed using standard protecting group removal. The amine of formula 25 can be reacted with a bromide of formula 6 to give a compound of formula 1 using conditions outlined earlier.

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 and P. G. M. Wuts (Protective Groups in Organic Synthesis,

John Wiley and Sons Inc., 1999) 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 pracedures 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.

Subgroups of compounds of formula (1) containing the following substituents. are preferred:

Preferably Q' is a group *.NH-Q?-A, wherein A is cyclohexyl or adamantyl.

Preferably, Q' is

R: .R* Re

R4 ~RS —N *—N RS +—N >

R® Ré or wherein R®, R*, R® and R® are H.

Preferably Q'is

R3 R¢ Re

R4 re “TN *N RS

Re | RS wherein one of R® to R® is

OH and the others are H.

Preferably, Q' is a group *-NH-QA, wherein A is a group

RT Re . } RS

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

H, C1-Cs alkyl, ORS, SR’, SOR’, SOR’, halo, CN, CO:R’, CFs, OCF;

SONR'R™, CONRPR'™®, NR°R'™®, NHCOR" and phenyl optionally substituted with 1 to 3 groups selected from OR®, halo and C1-C4 alkyl provided at Beast 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-C, alkyl.

More preferably, Q" is a group *-NH-Q-A, wherein A is a group

R4 Re — —

RY Ré wherein RS, R*, R®, R® and R’ are the same or different and are selected from

H, OH, CH3, OCHs, OCF3, OCH2-CHa, SCH3, N(CH3)2, N(C=0)CHa, C(=O)NHz,

COOCHS;, SO,CH3, SO,NH,, halo, CN, CF3 and phenyl optionally subsstituted with OH provided at least 2 of R® to R’ are equal to H.

In a preferred embodiment, A is a group

R3 R4

R7 RS - } _ wherein one of R3to R’ is OH or phenyl substituted with OH.

In a preferred embodiment, A is a group

R3 R4 . CE . . .

Cr

R7 Re6 wherein one of R® to R” is OH or phenyl substituted with OH and the other are selected from H, Cl or CHa provided at least 2 of R® to R’ are H.

Preferably A is naphthyl optionally substituted with OH.

Preferably, A is naphthyl substituted with OH.

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

Q? is -CH2-, ~(CH2)z-, {(CHz)s=, -CH2-C(CHa)2- or -C(CHa).-, preferably -CHz- or - (CH2)2.

R'is Hor C+-C alkyl and R? is C4-C4 alkyl. More preferably, R'is H or CH3 and

R?is H or CHa. nis Oorft.

R'is Hand R?is CH; and nis O or 1.

R'is CHa, R%is CHzand nis O or 1. ~

Particularly preferred are the compounds of the formula (1) as described - in the Examples section hereafter, i.e. :

N-Benzyl-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}phenyl)acetamide;

N-(3,4-Dimethylbenzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino}-2-methyipropyl}phenyl)acetamide;

N-[2-(4-Chlorophenylethyil-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino}-2-methylpropyi}benzamide; )

N-[2-(2-Chlorophenyl)ethyi]-3-{2-[(2R)-2~(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyi}benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(2-naphthalen-1-yiethyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-N-[2-(4-methylphenyl)ethyl]benzamide;

N-[2-(2,6-Dimethylphenyl)ethyl]-3-{2-{(2R)-2-(3-formylamino-4-hydroxyphenyl}- 2-hydroxyethylamino}-2-methylpropyl}benzamide;

N-[2-(2,3-Dimethylphenyl)ethyi]-3-{2-[(2R)-2~(3-formylamino-4-hydroxypheny!)- 2-hydroxyethylamino}-2-methylpropylbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-N-[2-(4-hydroxy-2,3-dimethylphenyl)ethyllbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxypheny)-2-hydroxyethylamino]-2- methylpropyi}-N-[2-(4-methoxyphenyl)ethyllbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methyipropyl}-N-phenethyi-benzamide;

N-Cyclohexylmethyl-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino}-2-methylpropyl}benzamide;

N-[5-((1R)-2-{1,1-Dimethyl-2-[3-(piperidine-1-carbonyl)phenyl]ethylamino}-1- hydroxyethyi)-2-hydroxyphenyilfformamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-[2-(3-triflucromethylphenyl)ethyllbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyi}-N-(3-phenylpropyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-N-indan-2-ylbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(2-pyridin-2-ylethyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- . methylpropyl}-N-[2-(4-sulfamoyiphenyt)ethyi]benzamide;

N-(4-Dimethylaminobenzyl)-2+(3-{(2R)-2-{(2R)-2-(3-formylamino-4- } hydroxyphenyl)-2-hydroxyethylamino]propyliphenyl)acetamide;

N-[5-(2-{(1R)-2-{3-(3,4-Dihydro-1 H-isoquinoline-2-carbonyl)-phenyi}-1,1- dimethyl-ethylamino}-1-hydroxyethyl}-2-hydroxyphenyllformamide; 3-{2-[(2R)-2~(3-Formylamino-4-hydroxypheny!)-2-hydroxyethylamino}-2- methyipropyl-N-(4"-hydroxybiphenyl-3-yimethyl)benzamide 3-{2-[(2R)-2~(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-[2-(4-hydroxy-2,5-dimethylphenyl)ethyl]benzamide; 3-{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-N-[2-(4-hydroxy-3-methylphenyi)ethyllbenzamide;

N-(4-Acetylaminobenzyl)-2-(3+{(2R)-2-[(2R)-2-(3-formylamino-4-hydroxyphenyl}- 2-hydroxyethylamino]propyi}phenyl)acetamide; 4-{[2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyi}-2- hydroxyethylamino]propyi}phenyl)acetylamino}methyi}benzamide;

N-Adamantan-1-yl-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyi}-N-(2-hydroxy-naphthalen-1-yimethyl)benzamide; 3-{2-[(2R)-2-(3-Formytamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(4-hydroxy-3,5-dimethylbenzyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyi}-2-hydroxyethylamino}-2- methylpropyl}-N-(6-hydroxy-naphthaleN-2-yimethyl)benzamide;

N-(3,6-Dichloro-2-hydroxybenzyl)-3-{2-{(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methyipropyl}benzamide; -

N-(3 4-Dimethylbenzyl)-2-(3-{2-{(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]ethyl}phenyl)acetamide; 3-{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-[2-(4-hydroxyphenyl)-2-methylpropyflbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(4'-hydroxybiphenyl-4-yimethyl)benzamide;

N-Adamantan-1-yl-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-hydroxyphenyf)-2- hydroxyethylamino]propyl}phenyl)acetamide;

N-{5-(2-{2-3-(10-Aza-tricyclo[6.3.1 .0%2,7*ldodeca-2(7),3,5-triene-10- . . carbonyl)phenyl]-1,1-dimethyl ethylamino}-1 -hydroxyethyl)-2-hydroxyphenyl}- formamide; 2-(3H{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(4'-hydroxybiphenyl-3-yimethyl)acetamide; 4-4]2-(342-[(2R)-2-(3-Formylamino-4-hydroxyphenyt)-2-hydroxyethylamino}-2- methyipropyl}phenyl)-acetylamino]methyl}benzoic acid methyl ester; 2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}phenyl)}-N-4-trifluoromethoxy-benzyl)acetamide;

N-(2-Chloro-4-hydroxybenzyl)-N-ethyl-2-(3-{(2R)-2-{(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyi}phenyl)-cetamide;

N-(2-Chloro-4-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino}-2-methylpropyl}-phenyl)acetamide; 2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- 16 hydroxyethylamino}propyl}phenyl)-N-(4-hydroxy-3,5-dimethylbenzylJacetamide; 2-(3{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N~(2-hydroxynaphthalen-1- ylmethyl)acetamide;

N-(5-Chioro-2-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylaminolpropyl}phenyl)acetamide;

N-(3,5-Dichloro-2-hydroxybenzyl)-2-(3-{(2R)-2-{(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylaminojpropyl}phenyl)acetamide; 2-(3-{(2R)-2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(6-hydroxynaphthalen-2- ylmethyl)acetamide; 2-(3{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(4"-hydroxybiphenyl-4-yimethyl)acetamide;

N-(4-Cyano-benzyl)-2-(3-{2-{(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}-phenyi)-acetamide; oo 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-phenyl)-N-(4-methanesulfonyl-benzyl)-acetamide; :

2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-phenyl)-N-(4-methylsulfanyl-benzyl)-acetamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-phenyl)-N-(4-trifiucromethyl-benzyt)-acetamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}phenyl)-N-(4'-hydroxy-biphenyl-4-yimethyl)acetamide;

N-[2-(5-Chloro-2-hydroxyphenyl)-ethyl}-3-{2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}-benzamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}phenyl)-N-(4"-hydroxybiphenyl-3-yimethyl)-acetamide; 3-{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxysthylamino}-propyi}-N- [2-(4-hydroxyphenyl)-2-methylpropyl]-benzamide;

N-(2-Chloro-4-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-(2R)-2-(3-formylamino-4- hydroxypheny!)-2-hydroxyethylamino]propyl}phenyl)acetamide; N-[2-(5-Chloro-2-hydroxyphenyl)-ethyl]-3-{2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropytibenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-propyl}-N- [2-(4-hydroxyphenyl)-2-methylpropyilbenzamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyi}phenyl)-N-(tetrahydro-thiopyran-4-ylJacetamide;

N-(5-Chloro-2-hydroxybenzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)- 2-hydroxyethylamino]-2-methylpropyl}phenyl)acetamide; and,

N-{5-[(1R)-2-((1R)-2-{3-[3~(3,4-Dihydro-1H-isoquinolin-2-yl}-3- oxopropyilphenyl}-1-methylethylamino}-1-hydroxyethyl]-2- hydroxyphenyliformamide.

According to one aspect of the present invention, the compounds of formula (1) wherein the (CH2)-C(=0)Q"' group is in the meta position are generally preferred. oo

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

Claims (28)

1. A compound of general formula (1), "OH H N CH Qt ) or KO Nr (1) HN 0 HH 0 wherein the (CH2)-C(=0)Q" group is in the meta or para position, -R'and R? are independently selected from H and C4-Cs alkyl; -nis0,1o0r2; -Q' is a group selected from, R3 R* N=(cHy), RS wherein p is 1 or 2 and q is 1 or 2, said group being optionally bridged by one carbon atom, So R3 Rg R4 - *—N RS «—N > RS and a group *NR?-Q%A wherein Q% is a C4-Cs alkylene, R® is H or C4-C, alkyl and A is pyridyl, Cs-C1o cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl. or a group RS Ré R3 RS R4 RS or R7 Re -RY, R* R®, RP and R are the same or different and are selected from H, C1+Cs alkyl, OR®, SR®, SOR®, SO,R®, halo, CO;R® CF3, CN, OCF3;, SO.NR’R™, CONRR', NR°R™, NHCOR'? and phenyl optionally substituted with 1 to 3 groups selected from OR®, halo and C4-C, alkyl; - R? and R' are the same or different and are selected from H or C-Cs alkyl and the * represent the attachment point to the carbonyl 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 *-NH-Q?A, wherein A is cyclohexyl or adamantyl.

3. A compound according to claim 1 wherein Q' is a group *-NH-Q’-A, wherein Ais a group R? R4 a es R7 Re wherein R®, R*, R®, R® and R” are the same or different and are selected from H, Ci-Cs alkyl, OR?, SR’, SOR’, SOR’, halo, CN, COR®, CF; OCF,

SO.NR’R™, CONR’R™, NR°R', NHCOR™ and phenyl optionally substituted with 1 to 3 groups selected from OR’, halo and C1-Ca alkyl 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 C1-Cs alkyl.

4. A compound according to claim 3 wherein Q' is a group *_NH-Q?-A, wherein Ais a group R3 R* R7 R6 wherein R?, R*, R%, R® and R’ are the same or different and are selected from H, OH, CHs, OCHs, OCF3, OCH2-CHa, SCH3, N(CHs)z, N(C=0)CHs, C(=O)NHz, COOCH,, SO.CHa, SO:NH,, CN, halo, CF3, and phenyl optionally substituted with OH.

5. A compound according to claim 1 wherein A is a group R3 R4 : - R7 RS wherein one of R*to R is OH or phenyl substituted with OH.

6. A compound according to claim 1 wherein A is naphthyl optionally . susbstituted with OH. .

7. A compound according to any one of claims 1 to 6 wherein Q* is -CHz-, - (CHz)z-, -(CHz)a, -CH2-C(CHa)2- or -C(CHs)z-. : :

8. A compound according to claim 7 wherein Q? is -CHo-.

9. A compound according to claim 1 wherein Q' is Lo : : R3 R* Re R#4 Re TN *—N RS RS R6 : wherein Rj, Rq, Rs and Rg are H.

10. A compound according to any one of claims 1 to 9 wherein R' is H or C4-C4 alkyl and R? is C4-C, alkyl.

11. A compound according to claim 10 wherein R' is H or CHs and R? is H or

CHa.

12. A compound according to claim 1 to 11 wherein nis O or 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 (CHz)- C(=0)Q’ group is in the meta position.

15. A compound according to claim 1 selected from the group consisting of N-Benzyl-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyi)-2- hydroxyethylamino]-2-methylpropyl}phenyl)acetamide; : N=(3,4-Dimethylbenzyl)-2-(3-{2-{(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}phenyl)acetamide; N-[2-(4-Chlorophenyl)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}benzamide; N-[2-(2-Chlorophenyi)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino}-2-methylpropyl}benzamide; 3-{2-[(2R)-2~(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(2-naphthalen-1-ylethyl)benzamide;

3-{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- : methylpropyi}-N-[2-(4-methylphenyl)ethyllbenzamide; ) N-[2-(2,6-Dimethylphenyl)ethyi]-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)- 2-hydroxyethylamino]-2-methylpropyl}benzamide;

N-[2-(2,3-Dimethylphenyi)ethyi}-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl}- 2-hydroxyethylamina]-2-methylpropylbenzamide; 3-{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyl}-N-[2-(4-hydroxy-2,3-dimethyiphenyl)ethyllbenzamide; 342-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamina] 2 methylpropyl}-N-[2-(4-methoxyphenyl)ethyllbenzamide; 34{2-{(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino }-2- methylpropyl}-N-phenethyl-benzamide; N-Cyclohexyimethyl-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyl}benzamide;

N-[5-((1R)-2-{1,1-Dimethyl-2-[3-(piperidine-1-carbonyl)phenyllethylarmino}-1- hydroxyethyl)-2-hydroxyphenyllformamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino J-2- methylpropyl}-N-{2-(3-trifluoromethylphenyl)ethyilbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)}-2-hydroxyethylamino}-2-

methylpropyl}-N-(3-phenyipropyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)}-2-hydroxyethylamino]-2- methylpropyl}-N-indan-2-ylbenzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyi)-2-hydroxyethylamino }-2- methylpropyl}-N-(2-pyridin-2-ylethyl)benzamide; -

3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylaminoJ-2- oC methylpropyl}-N-[2-(4-sulfamoylphenyl)ethyl]benzamide; N-(4-Dimethylaminobenzyl}-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylaminojpropyi}phenyl)acetamide; N-[5-(2-(1 R)-2-[3-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-phenyl}-1 1-

dimethyl-ethylamino}-1-hydroxyethyl)-2-hydroxyphenyilformamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- : methylpropyl}-N-(4'-hydroxybiphenyi-3-yimethyl)benzamide

3-4{2-{(2R)-2~(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-[2-(4-hydroxy-2,5-dimethylphenyfjethyllbenzamide; ) 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}]-2- methylpropyl}-N-[2-(4-hydroxy-3-methylphenyl)ethyl]benzamide;

N-(4-Acetylaminobenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-hyd roxyphenyl)- 2-hydroxyethytamino]propyl}phenyl)acetamide; 4-{[2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl}-2- hydroxyethylamino]propyl}phenyl)acetylaminolmethyl}benzamide; N-AdamantaN-1-yl-3-{2-[(2R)-2-(3-formylaminc-4"hydroxyphenyl) 2-

hydroxyethylamino]-2-methyipropyl}benzamide; 3-{2-[(2R)-2(3-Formylamino-4-hydroxyphenyli)-2-hydroxyethylamino]-2- methylpropyl}-N-(2-hydroxy-naphthaleN-1-yimethyl)benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyi}-N-(4-hydroxy-3,5-dimethylbenzyl)bgnzamide;

3~{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl}-2-hydroxyethylamino}-2- methylpropyl}-N-(6-hydroxy-naphthaleN-2-ylmethyl)benzamide; N-(3,6-Dichloro-2-hydroxybenzyl)-3-{2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino}-2-methylpropyi}benzamide; N-(3,4-Dimethyibenzyl)-2-(3-{2-{(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-

hydroxyethylamino]ethyl}phenyi)acetamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methylpropyi}-N-[2-(4-hydroxyphenyi)-2-methylpropyi]benzamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}-N-(4'-hydroxybiphenyl-4-ylmethyl)benzamide; -

N-Adamantan-1 -yl-2-(3-{(2R)-2-{(2R)-2-(3-formylamino-4-hydroxyph enyl)-2- oC hydroxyethylamino]propyl}phenyl)acetamide; N-[5-(2-{2-[3-(10-Aza-tricyclo[6.3.1 .0*2,7*]dodeca-2(7),3,5-triene-10- carbonyl)phenyl}-1,1-dimethylethylamino}-1-hydroxyethyl)-2-hydroxy phenyl]- formamide; oo

2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(4'-hydroxybiphenyl-3-yimethyl)acetamide;

4-{[2-(34{2-[(2R)-2~(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- . methyipropyl}phenyl)-acetylamino]methyl}benzoic acid methyl ester; - 2-(3-{(2R)-2-[(2R)-2~(3-Formylamino-4-hydroxyphenyl}-2-hydroxyethylamino}-2- methylpropyijphenyl)-N-{4-trifluoromethoxy-benzyl)acetamide;

N-(2-Chloro-4-hydroxybenzyl)-N-ethyl-2-(3-{(2R)-2-{(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methyipropyl}phenyl)-cetamide; N-(2-Chloro-4-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)}-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino}-2-methylpropyl}-phenyl)acetamide; 2-(3-{(2R)-2-[(2R)-2-(3-F ormylamino-4-hydroxyphenyl)-2-

hydroxyethylamino]propyl}phenyl)-N-(4-hydroxy-3,5-dimethylbenzyl)acetamide; 2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(2-hydroxynaphthalen-1- yimethyl)acetamide; N-(5-Chioro-2-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4-

hydroxyphenyl)-2-hydroxyethylamino]propyl}phenyl)acetamide; N-(3,5-Dichloro-2-hydroxybenzyl)-2~(3-{(2R)-2-{(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]propyl}phenyl)acetamide; 2-(3-{(2R)-2-{(2R)-2-(3-Formylamino-4-hydroxyphenyi)-2- hydroxyethylamino]propyl}phenyt)}-N-(6-hydroxynaphthalen-2-

ylmethyl)acetamide; 2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N~(4"-hydroxybiphenyi-4-yimethyl)acetamide; N-(4-Cyano-benzyl)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyt)-2- hydroxyethylamino}-2-methylpropyi}-phenyl}-acetamide; -

2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyi)-2-hydroxyethylamino)-2- oo methyipropyl}-pheriyl)-N-(4-methanesulfonyl-benzyl)-acetamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2- methyipropyl}-phenyl)-N-(4-methylsulfanyl-benzyl)-acetamide; 2-(3{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-

methylpropyl}-phenyl)-N-(4-trifluoromethyl-benzyi)-acetamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- - methyipropyl}phenyl)-N-(4'-hydroxy-biphenyl-4-yimethyl)acetamide;

N-[2-(5-Chloro-2-hydroxyphenyl)-ethyl]-3-{2-[(2R)-2-(3-formylamino4- : hydroxyphenyl)-2-hydroxyethylamino}-2-methyipropyl}-benzamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-2- methylpropyl}phenyl)-N-(4'-hydroxybiphenyl-3-yimethyl)-acetamide; 3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylarmino}-propyl}-N- [2-(4-hydroxyphenyl)-2-methyipropyl}-benzamide; N-(2-Chloro-4-hydroxybenzyl)-2-(3-{(2R)-2-{(2R)}-(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxysthylamino]propyl}phenyl)acetamide; N-2-(5-Chloro-2-hydroxyphenyl)-ethyl]-3-{2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyi}benzamid e; 34{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino}-propyl}-N- [2-(4-hydroxyphenyl)-2-methyipropyl}-benzamide; 2-(3-{2-[(2R)-2-(3-Formylamino-4-hydroxyphenyi)-2-hydroxyethylamino)-2- methylpropyl}phenyl)-N-(tetrahydro-thiopyran-4-yl)acetamide; N-(5-Chloro-2-hydroxybenzyt)-2-(3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyl)- 2-hydroxyethylamino]-2-methylpropyl}phenyl)acetamide; and, N-{5-[(1R)-2-((1R)-2-{3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl}-3- oxopropyllphenyl}-1 -methylethylamino)-1-hydroxyethyi}-2- hydroxyphenyl}formamide.

16. A pharmaceutical composition comprising at least an effective amount of a compound of the formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt or derived form thereof.

17. A compound of the formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt, derived form or composition thereof, for use asa medicament.

18. The use of a compound of the formula (1) as described in any one of claims “1'to 15 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug for 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, e chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, o obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper- reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension, : Ce 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, Co catarrhal bronchitis, croupus bronchitis, dry bronchitis, - infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, Co e acute lung injury,

143 PCT/IB2005/000619 ® « bronchiectasis of whatever type. etiology, or pathogenesis, in particular, Bronchieclasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchietasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

19. Combination of a compound according to any one of claims 1 to 15 with other therapeutic agent (s) selected from: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists. (b) Leukotriene antagonists (L1RAs) including antagonists of LTBs, L1Ca LTD, and LTE,, (¢) Histamine receptor antagonist including H1 and H3 antagonists, (d) u1- and «2 —adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (c) Muscarinic M3 receptor anlagonists or anticholinergic agents; (N PDE inhgibitors, 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 glucocorticosleroids, (k) Monoclonal antibodies active against endogenous inflammatory entities, (1) Anti-tumor necrosis factor (anti-TNF-u) agents, (m) Adhesion molecule inhibitors including VLA-4 antagonist, (n) Kinin-B;- and B,- receptor antagonists, (0) Immunusuppresive ayenls, (p) Inhibitors of matrix metalioproteases (MMPs), (q) Tachykinin NKjy,K; and NK; receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receplor antagonists, (1) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g.D2 agonists, (v) Modulators of the NF«f pathway,e.g. IKK inhibitors, (w) Modulators of cylokine signalling pathways such as p38 MAP kinase or syk kinase, AMENDED SHEET

> RA 144 PCT/IB2005/000619 ® (x) Agents that can be classed as mucolytics or anti-tussive, {(y) Antibiotics, (z) HDAC inhibitors, and, (aa)P13 kinase inhibitors.

20. N-(5-Chloro-2-hydroxybenzyl)-2-(3-{(2R)-2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]propyl}phenyl)acetamide or a pharmaceutically acceptable salt or solvale thereof.

21. 2-(3-{2R)-2-[2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino] propyl}phenyl)-N-(4-hydroxyl-3,5-dimethylbenzyl)acetamide or a pharmaceutically acceptable salt or solvate.

. 22. 2-(3-{(2R)-2-[(2R)-2-(3-Formyiamino-4-hydroxyphenyij-2- hydroxyethylamino]propyl}phenyl)-N-(6-hydroxynaphthalen-2-yimethy)acetamide or a pharmaceutically acceptable salt or solvate thereof.

23. 2-(3-{(2R)-2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-N-(4'-hydroxybiphenyl-4-ylmethyl)acetamide ora pharmaceutically acceptable salt or solvate thereof.

24. N-[2-(4-Chlorophenyl)ethyl]-3-{2-[(2R)-2-(3-formylamino-4-hydroxyphenyt)-2- hydroxyethylamino]-2-methylpropyl}benzamide or a pharmaceutically acceptable salt or solvate thereof.

25. A compound according lo any one of claims 1 to 15, or 20 to 24, substantially as herein described with reference to and as illustrated in any of the examples.

26. A composition according to claim 16 or claims 17, substantially as herein described with reference to and as illustrated in any of the examples.

27. Use according to claim 18, substantially as herein described with reference to and as illustrated in any of the examples.

28. A combination according to claim 19, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET