HK1193811B - Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity - Google Patents

Description

Compounds having muscarinic receptor antagonist and beta 2 adrenergic receptor agonist activity

Technical Field

The present invention relates to compounds of general formula (I) acting both as muscarinic receptor antagonists and as β 2 adrenergic receptor agonists, to processes for their preparation, to compositions comprising them, to therapeutic uses and combinations with other pharmaceutically active ingredients.

Background

Generally, bronchodilators are used to treat pulmonary diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). Well-known classes of bronchodilators include beta-2 adrenergic receptor agonists, such as albuterol, fenoterol, formoterol and salmeterol. These compounds are typically administered by inhalation.

Yet another well-known class of bronchodilators includes muscarinic receptor antagonists (anticholinergic compounds), such as ipratropium and tiotropium bromide. These compounds are also typically administered by inhalation.

Inhaled formulations of beta-2 agonists and muscarinic receptor antagonists are both valuable agents in the treatment of asthma and COPD, both of which provide symptomatic relief due to their ability to relax tight airways. The observation that the bronchodilator effects of both classes of agents can add up has prompted the study of combinations of both agents. In 1975, it was shown that the combination of two ingredients such as fenoterol and ipratropium bromide in a single aerosol formulation could achieve beneficial effects. This prompted the development of a fixed dose combination of ipratropium bromide, first with fenoterol (Berodual, introduced in 1980) and then with salbutamol (combivant, introduced in 1994).

Recently, the availability of both long-acting muscarinic antagonists and long-acting β -2 agonists has prompted the development of combinations of these agents. For example, WO00/69468 discloses pharmaceutical compositions containing a muscarinic receptor antagonist such as tiotropium bromide, and a β -2 adrenergic receptor agonist such as formoterol fumarate or salmeterol, while WO2005/115467 discloses a combination comprising a β -2 agonist and a salt of an antagonist of the M3 muscarinic receptor, i.e. 3(R) - (2-hydroxy-2, 2-dithien-2-ylacetoxy) -1- (3-phenoxypropyl) -1-azoniabicyclo [2.2.2] octane.

An alternative approach to the development of fixed dose combinations is to identify molecules that combine muscarinic antagonism and β -2 agonistic activity. Indeed, compounds having both β -2 adrenergic receptor agonist and muscarinic receptor antagonist activity are highly desirable because such bifunctional compounds provide bronchodilation through two separate mechanisms of action, while possessing a single molecular pharmacokinetics.

Such compounds are described in several patent applications, such as WO2004/074246, WO2004/074812, WO2005/051946, WO2006/023457, WO2006/023460, WO2010/123766 and WO 2011/048409.

It has now been found that certain specific ester or thioester (thioesterer) derivatives, in addition to having both β -2 adrenergic receptor agonist and muscarinic receptor antagonist activity, also have increased affinity for the M3 muscarinic receptors and long-lasting bronchodilatory activity.

Disclosure of Invention

The present invention relates to compounds of general formula (I) which act as muscarinic receptor antagonists and β 2 adrenergic receptor agonists, processes for their preparation, compositions containing them, therapeutic uses and combinations with other pharmaceutically active ingredients such as those currently used in the treatment of respiratory disorders, e.g. corticosteroids, P38MAP kinase inhibitors, IKK2, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.

Detailed Description

In particular, the invention relates to compounds of the general formula (I)

Wherein

Q is a group of formula Q1, Q2, Q3, Q4, Q5 or Q6

Z is H or OH;

y is- (CH)₂)_n-, where n is an integer from 1 to 12 or is a divalent radical of the formula Y1

Wherein

A1 and A2 are each independently absent or selected from (C)₁-C₆) Alkylene group, (C)₃-C₈) Cycloalkylene and (C)₃-C₈) Heterocycloalkylene;

b is absent or selected from (C)₃-C₈) Cycloalkylene radical (C)₃-C₈) Heterocycloalkylene, arylene and heteroarylene or a radical of the formula B1

C is absent or selected from-O-, -OCO-, -C (O) O-, -S-, -S (O) -, -S (O)₂-and-N (R)₄) Or is one of the following groups C1-C10:

wherein R is₄Is H or is selected from (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Heterocycloalkyl, aryl and heteroaryl;

d is selected from (C)₁-C₁₂) Alkylene group, (C)₂-C₁₂) Alkenylene and (C)₂-C₆) Alkynylene, optionally substituted with one or more (C)₁-C₆) Alkyl substitution;

r is-H or (C)₁-C₄) An alkyl group;

x is-O-or-S-;

R₁is H or is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl, optionally substituted by one or more (C)₁-C₄) Alkoxy substitution;

R₂is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl radicals and(C₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl optionally substituted by one or more halogen atoms or (C)₁-C₄) Alkoxy substitution;

R₃is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆)；

R₅And R₆Independently is H or (C)₁-C₆) An alkyl group;

and pharmaceutically acceptable salts or solvates thereof.

Expression "(C)₁-C₆) Alkyl "refers to a straight or branched chain alkyl group in which the number of carbon atoms is1 to 6. Examples of radicals are methyl, ethyl, n-propyl, isopropyl, tert-butyl, pentyl, hexyl and the like.

Similarly, the expression "(C)₁-C_x) Alkylene "refers to a divalent group in which the number of carbon atoms is1 to x, such as methylene, ethylene, n-propylene, isopropylene, tert-butylene, pentylene, hexylene, octylene, nonylene, decylene, undecylene, dodecylene, and the like.

The expression "hydroxy (C)₁-C₆) Alkyl "refers to-alkyl-substituted with hydroxy-.

Expression "(C)₂-C₆) Alkenyl "refers to a straight or branched carbon chain having one or more double bonds, wherein the number of carbon atoms is from 2 to 6. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

Similarly, the expression "(C)₂-C_x) The "alkenylene group" means a divalent group in which the number of carbon atoms is 2 to x, such as vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, decenylene, undecenylene, dodecenylene and the like.

Expression "(C)₂-C₆) Alkynyl "refers to a straight or branched carbon chain having one or more triple bonds wherein the number of carbon atoms is from 2 to 6. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

Similarly, the expression "(C)₂-C_x) The "alkynylene group" means a divalent group in which the number of carbon atoms is 2 to x, such as ethynylene, propynyl, butynyl, pentynyl, hexynyl, and the like.

Expression "(C)₁-C₆) Alkoxy "refers to an alkyl-oxy (e.g., alkoxy) group, the alkyl portion being as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

Expression "(C)₃-C₈) Cycloalkyl "refers to a mono-or di-cycloaliphatic hydrocarbon group having from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1 ]]Hept-2-yl, and the like.

Expression "(C)₃-C₈) Heterocycloalkyl "means (C)₃-C₈) Cycloalkyl in which at least one ring carbon atom is replaced by a heteroatom or heteroaromatic group (e.g., N, NH, S or O). Examples include quinuclidinyl, pyrrolidinyl, piperidinyl and the like.

Similarly, the expression "(C)₃-C₈) Cycloalkylene "and" (C)₃-C₈) Heterocycloalkylene "means a divalent radical such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, bicyclo [2.2.1 ] ene]Hept-2-yl and quinuclidinylene, pyrrolidinylene, piperidinyl, azabicyclo [3.2.1]Octane-3-yl and azoniabicyclo [2.2.2]Octyl (azoniabicyclo [ 2.2.2)]octanylene）。

The term "aryl" refers to a mono-, bi-or tricyclic ring system having 5 to 20, preferably 5 to 15 ring atoms, and wherein at least one ring is aromatic.

The expression "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 20 ring atoms, preferably 5 to 15 ring atoms, wherein at least one ring is aromatic and wherein at least one carbon ring atom is a heteroatom or a heteroaromatic group (e.g. N, NH, S or O).

Examples of suitable aryl or heteroaryl monocyclic systems include, for example, thiophene, benzene, pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, imidazolidine, furan residues and the like.

Examples of suitable aryl or heteroaryl bicyclic ring systems include naphthalene, biphenylene, purine, pteridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzodioxine, dihydrobenzodioxepine, benzoxazine residues and the like.

Examples of suitable aryl or heteroaryl tricyclic ring systems include fluorene residues as well as benzo-fused derivatives of the aforementioned heteroaryl bicyclic ring systems.

Similarly, the terms "arylene" and "heteroarylene" refer to divalent radicals such as phenylene and thienylene.

The expression "aryl (C)₁-C₆) Alkyl "," heteroaryl (C)₁-C₆) Alkyl "and" (C)₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl "means an aryl, heteroaryl or (C) group, each independently, substituted by one or more groups as hereinbefore defined₃-C₈) Cycloalkyl-substituted "(C)₁-C₆) Alkyl groups ".

Aryl radical (C)₁-C₆) Examples of alkyl groups include benzyl, triphenylmethyl, and the like.

In the case of a basic amino group in the compounds of the formula (I), a physiologically acceptable anion selected from the group consisting of chloride, bromide, fluoride, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate may be present. Similarly, in the presence of acidic groups such as COOH groups, corresponding salts of physiological cations may be present, including, for example, alkali metal, alkaline earth metal ions or ammonium salts.

It is evident that the compounds of formula (I) may contain asymmetric centers. Thus, the present invention also includes any optical stereoisomers, diastereomers and mixtures thereof in any proportion.

In particular, to R₁，R₂And R₃The carbon atom of the radical, depending on R among those reported previously₁，R₂And R₃The meanings provided may represent chiral centers.

In a first preferred embodiment, the absolute configuration of the chiral center may be (R).

In a further embodiment, the preferred configuration is (S).

In a preferred embodiment, the compounds of general formula (I) described in the present invention are present as a mixture of diastereomers.

In yet another embodiment, where Z is-OH in the compound of formula (I), the carbon atoms attached to Q and Z represent chiral centers, with (R) being the preferred configuration.

A first preferred group of compounds are of the general formula (I), wherein R₁Is H or is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl and aryl (C)₁-C₆) An alkyl group; r₂Is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) An alkyl group; r₃Is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆) (ii) a X is-O-or-S-; r is-H or (C)₁-C₄) An alkyl group; y, Z and Q are as defined above.

More preferred within this class are compounds of formula (I) wherein R is₁Is H or is selected from cyclobutyl, cyclopentyl, phenyl, benzyl, cycloheptyl, thienyl and cyclohexyl; r₂Selected from phenyl, thienyl, cyclohexyl, triphenylmethyl, chlorophenyl, methoxyphenyl, and fluorophenyl; r₃Is H or is selected from-OH, -NH₂，-CH₂OH，-NHCOCH₃(ii) a X is-O-; r is H or-CH₃。

A second preferred group of compounds of the general formula (I) is that wherein R₁，R₂，R₃X and R are as previously defined; y is- (CH)₂)_n-, where n is an integer from 1 to 12 or is a radical of the formula Y1

Wherein

A1 and A2 are each independently absent or selected from (C)₁-C₆) Alkylene group, (C)₃-C₈) Cycloalkylene and (C)₃-C₈) Heterocycloalkylene;

b is absent or selected from (C)₃-C₈) Cycloalkylene radical (C)₃-C₈) Heterocycloalkylene, arylene and heteroarylene or are a radical of the formula B1,

c is absent or selected from-O-, -OCO-, -C (O) O-, -S-, -N (R)₄) -or one of the following C1-C10 groups,

wherein R is₄Is H or is selected from (C)₁-C₈) Alkyl radical (C)₃-C₈) Cycloalkyl group, (C)₃-C₈) Heterocycloalkyl, aryl and heteroaryl; d is selected from (C)₁-C₁₂) Alkylene group, (C)₂-C₁₂) Alkenylene and (C)₂-C₆) Alkynylene, optionally substituted with one or more (C)₁-C₆) Alkyl substitution;

z is-H or-OH and Q is a group of formula Q1, Q2, Q3, Q4, Q5 or Q6

More preferred within this class are compounds of formula (I) wherein Y is- (CH)₂)_nZ is OH and Q is a group of the formula Q1

Having the general formula (IA)

Even more preferred are compounds of formula (IA) wherein n is 4, 5, 6, 7 or 8.

A further preferred class of compounds of formula (I) is that wherein Y is a divalent radical of formula Y1,

wherein A1 is (C)₃-C₈) Cycloalkylene, B and C are absent, D is (C)₁-C₁₂) Alkylene, Z is OH and Q is a group of formula Q1,

having the general formula (IB), wherein (C)₃-C₈) Cycloalkylene is represented by "cy",

even more preferred are compounds of formula (I) wherein Y is a divalent group of formula Y1 wherein A1 is piperidinyl, D is hexylidene, Z is OH and Q is a group of formula Q1,

a further preferred class are compounds of the general formula (I) wherein Y is- (CH)₂)_nZ is H and Q is a group of formula Q3,

having the general formula (IC)

Even more preferred are compounds of formula (IC) wherein n is 8.

It is understood that all preferred groups or embodiments described above for the compounds of the formula (I) can be combined with one another and, where appropriate, also apply to the compounds of the formulae (IA), (IB) and (IC).

The invention also provides pharmaceutical compositions of the compounds of formula (I) alone or in combination or admixture with one or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides the use of a compound of formula (I) for the manufacture of a medicament.

In a further aspect, the present invention provides the use of a compound of formula (I) for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

In a further aspect, the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD).

The invention also provides a method for the prevention and/or treatment of any broncho-obstructive or inflammatory disease, preferably asthma or chronic bronchitis or Chronic Obstructive Pulmonary Disease (COPD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of general formula (I).

The invention also provides pharmaceutical compositions suitable for administration by inhalation.

Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations.

The invention also relates to devices which may be single-or multi-dose dry powder inhalers, metered dose inhalers and soft mist nebulizers comprising a compound of formula (I).

The invention also relates to a kit comprising a pharmaceutical composition of a compound of formula (I), alone or in combination or admixture with one or more pharmaceutically acceptable carriers and/or excipients, and a device which may be a single or multi dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer containing a compound of formula (I).

The invention also relates to a process for the preparation of the compounds of general formula (I) comprising the reaction of the intermediate 7

With compounds of the formula 6

Wherein R is₁，R₂And R₃Having the meaning reported above.

The invention also relates to a process for the preparation of a compound of formula (I) which comprises alkylating a compound of formula 7 with a compound of formula 8,

wherein LG is a leaving group suitable for reacting with an amine.

According to a specific embodiment, the present invention provides compounds that report:

the compounds of the present invention can be readily prepared from available starting materials by using the following known general methods and procedures or by using other readily available methods known in the art. While specific embodiments of the invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the invention can be made using the methods described herein or using other known methods, reagents, and starting materials. It will also be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are provided, other process conditions can also be used unless otherwise specified. Although the optimal reaction conditions may vary depending on the particular reactants or solvents used, the conditions can be readily determined by one skilled in the art by routine optimization procedures.

The compounds of general formula (I) can be prepared according to the following synthetic scheme, wherein Bn represents a benzyl group.

General procedure for the preparation of Compounds of formula (I)

The compounds of formula (I) can be prepared in several different ways, some of which are reported in the schemes and are suitable, for example, for preparing compounds of formula (I) wherein Y is a group of formula Y1 and wherein A1 is (C)₁-C₆) Alkylene, A2, B and C being absent and D being (C)₁-C₆) An alkylene group. This is merely a non-limiting example. Similar routes can be used for the preparation of compounds of general formula (I) wherein a1, a2, B, C and D have the meanings reported above, using well known methods described in the literature for the introduction of specific moieties in organic compounds.

Compounds of the formula VII are defined as compounds in which A1 is substituted by oxo (C)₁-C₆) Alkylene, cycloalkylene orHeterocycloalkylene, forming an aldehyde or ketone protected as a cyclic acetal. The cyclic acetal protecting group can be removed to obtain the compound of formula VIII. In the case where A1 is absent and B is cycloalkylene, heterocycloalkylene or a group of formula B1, the carbonyl moiety as such or protected must be considered to be on the group B.

The synthesis of compounds of general formula (I) may require the protection of potentially reactive functional groups in addition to those already described. In the above case, examples of compatible protecting Groups and their specific protection and deprotection methods are described in "Protective Groups in Organic Synthesis" by T.W.Green and P.Wutz (Wiley-Interscience publication, 1999).

A compound of the general formula (I) wherein Y is- (CH)₂)₉-, can be prepared by: reacting an intermediate of formula IX with an aldehyde of formula VIII (wherein R, R₁，R₂，R₃A1, A2B, C, D, Z and Q have the meanings reported above). The reaction can be carried out in a solvent such as methanol, ethanol, Tetrahydrofuran (THF) or Dichloromethane (DCM). The reaction scheme depends on the reducing agent used. For example NaBH₄NaBCNH with pH ≈ 5 requiring the preliminary formation of the imine₃Or NaAc, or₃BH can be used in one pot reaction. In all cases, the time to complete the reaction at Room Temperature (RT) was 1 to 12 hours.

Intermediates of formula VIII can be readily prepared by alkylation of intermediates of formula VI with suitably protected aldehydes followed by deprotection. The alkylation reaction takes place in a polar aprotic solvent such as acetonitrile or Dimethylformamide (DMF), at a temperature ranging from RT to 100 ℃ and is completed in 1 to 24 hours. The reaction can be activated by conventional thermal heating or microwave heating.

Alternatively, the compound of formula (I) can be obtained via alkylation of an intermediate of formula IX with a compound of formula XI, wherein the Leaving Group (LG) can be chloro, bromo, methanesulfonyl, toluenesulfonyl or other known leaving groups suitable for reaction with an amine. The reaction takes place at RT or higher in a solvent such as DCM, THF, acetonitrile or DMF and is completed in the presence of an organic or inorganic base over a period of time from 0.5 to 12 hours.

Intermediates of formula XI can be obtained from compounds of formula VIII via reduction of the aldehyde, followed by tosyl chloride, methanesulfonyl chloride, CBr₄And PPh₃Or SOCl₂The alcohol obtained is converted into the compound of formula XI. All reactions must be carried out in aprotic solvents such as DCM or THF. Intermediates of formula XI can be obtained by alkylating compounds of formula VI with a bifunctional reagent of formula X, such as 1, 9-dibromononane, under the same reaction conditions described for the alkylation of compounds of formula VI with VII.

The ester intermediates of formula VI can be readily prepared: starting from acid IV and alcohol II, followed by deprotection to obtain compounds of formula V, conventional ester Synthesis is performed (see Green's Protective Groups in Organic Synthesis fourth, Wiley-Interscience Publication). The ester formation reaction can be carried out under several different conditions: in the presence of an acid activating agent such as Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [ 3-dimethylaminopropyl]Carbodiimide hydrochloride (EDC), 2- (1H-benzotriazol-1-yl) -1,1,3,3, -tetramethyluronium Hexafluorophosphate (HBTU), or alternatively first with SOCl₂Or oxalyl chloride converts the acid to the corresponding acid chloride. Alternatively, the alcohol II hydroxyl group can be converted to LG as described above for the preparation of intermediate XI from VIII, and then reacted with acid VI in a polar aprotic solvent (e.g. acetonitrile or DMF) in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate.

An alternative route to the compounds of formula (I) is alkylation of the amino intermediate VI with XIV followed by removal of the protecting group previously introduced. This alkylation reaction can be effected under the classical reaction conditions already described for the preparation of intermediate VIII from VI.

The preparation of compounds of formula XIV can be achieved by reacting intermediate XIII with a bifunctional reagent such as 1, 9-dibromononane for this example (as described above for the preparation of intermediate VIII from VI) and can be readily extended to the preparation of other analogues.

The intermediate of formula XIII can be prepared: the epoxide of the formula XII is treated with benzylamine. The reaction can be carried out neat (neat) or in a high boiling solvent such as toluene, dioxane or butanol. The reaction is carried out smoothly by thermal heating or microwave heating, and is completed at 80 to 120 ℃ over a period of 1 to 24 hours. Alternatively, the intermediate can be prepared by: the intermediate XVI is alkylated under the conditions already described for the alkylation of amines with alkyl bromides.

The synthesis of intermediates of the general formulae XI and XVI, wherein Q is a group of the formula Q1 and PG1 is a benzyl group protecting the phenolic hydroxy moiety, is described in US 2004224982.

Intermediates of general formula XII, wherein Q is a group of formula Q1 and PG1 is a benzyl group protecting the phenolic hydroxyl moiety, can be readily prepared from intermediate XI, as described in WO 2008/104781.

The preparation of intermediate IX, wherein Q is a group of formula Q1 and Z is OH, can be achieved starting from intermediate XVI by: reaction with basic azide salts in polar solvents such as DMF or DMSO at 80 ℃ or higher, followed by catalytic hydrogenation conditions or by using other reducing agents such as PPh₃Well known azide reductions are performed and the introduced protecting group is removed.

Compounds of the general formula IV are commercially available, or are available at R₁And R₂Has the meaning indicated above and R₃Where they are hydroxy, they can be prepared by reacting a suitable α -ketoester of formula XX with an appropriate Grignard reagent of formula XXI in an aprotic solvent such as THF at-20 deg.C or less to give an acid of general formula IV wherein R is₁And R₂Has the meaning described hereinbefore and R₃Is a hydroxyl group.

The synthesis of intermediates of the general formulae XI and XVI, wherein Q is a group of the formula Q1 and PG1 is a benzyl group protecting the phenolic hydroxyl moiety, is described in US 2004224982.

Intermediates of general formula XII, wherein Q is of formula Q1 and the group PG1 is a benzyl group protecting the phenolic hydroxyl moiety, can be readily prepared from intermediate XI, as described in WO 2008/104781.

The preparation of intermediate IX, wherein Q is a group of formula Q1 and Z is OH, can be achieved starting from intermediate XVI by: reaction with basic azide salts in polar solvents such as DMF or DMSO at 80 ℃ or higher, followed by catalytic hydrogenation or with other reducing agents such as PPh₃Well known reduction of azides is performed to remove the introduced protecting group.

Compounds of the general formula IV are commercially available, or are available at R₁And R₂Has the meaning indicated above and R₃In the case of hydroxy, they can be prepared by reacting the appropriate α -keto ester of formula XX with the appropriate Grignard reagent of formula XXI, the reaction is carried out in an aprotic solvent such as THF at-20 deg.C or less, and the acid of formula IV is obtained, where R is₁And R₂Have the meanings described above and R₃Is a hydroxyl group.

LCMS methods a and B for characterizing compounds of the invention are described below:

method A (IS10cm _ ESCI _ formic acid _ MeCN)

HPLC setup

Solvent: acetonitrile (far UV grade) containing 0.1% (V/V) formic acid

Water (high purity, via PureLab Option apparatus) with 0.1% formic acid

Column: phenomenex Luna5 μ C18(2), 100X 4.6 mm. (Plus guard post)

Ionization was performed by Electrospray (ESI) or Atmospheric Pressure Chemical Ionization (APCI).

UV detection was via HP or Waters DAD.

Start Range (nm)210 end Range (nm)400 Range Interval (nm)4.0

MS detection

Micromass ZQ, single quadrupole device.

Scanning range (m/z) of MS data

Start (m/z)100

End (m/z)650 or 1000, if necessary

With + ve/-ve conversion

Method B (IS15cm _ formic acid _ ASCENTIS _ HPLC _ CH)₃CN)

HPLC setup

Solvent: acetonitrile (far UV grade) containing 0.1% (V/V) formic acid

Water (high purity, via PureLab Ultra equipment) with 0.1% formic acid

Column: the amount of the Supelco is,express C18 or Hichrom Halo C18, 2.7 μmC18, 150 × 4.6.6 mm.

Equipment: agilent1100, binary pump, Agilent sampler and Agilent DAD detector.

Diode array detection: (300nm, 200nm bandwidth; ref 450nm, 100nm bandwidth).

The invention also provides Pharmaceutical compositions of a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII ed.

The compounds of the present invention may be administered to the patient in need thereof, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally, and by infusion), by inhalation, rectally, vaginally, topically, regionally, transdermally, and by eye.

Various solid oral dosage forms that can be used to administer the compounds of the present invention include solid forms such as tablets, soft gelatin capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time-release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used to administer the compounds of the present invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. The dosage form can also contain suitable known inert diluents such as water, suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other agents may also be included.

Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compounds with suitable excipients such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration can be in the form of creams, gels, pastes, foams or spray formulations which, in addition to the active ingredient, contain known suitable carriers.

For topical administration, the pharmaceutical compositions can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays and drops suitable for application to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via a device such as a transdermal patch.

For the treatment of respiratory diseases, the compounds according to the invention are preferably administered by inhalation.

Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable formulations.

For administration as an anhydrous powder, single or multiple dose inhalers known in the art may be used. In this case, the powder may be filled into gelatin, plastic or other capsules, cartridges or blister packs or into reservoirs.

A diluent or carrier, which is generally non-toxic and chemically inert to the compound of the invention, such as lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compound of the invention.

Inhalation aerosols containing a propellant gas such as a hydrofluoroalkane may contain the compounds of the invention in solution or in dispersed form. The propellant-driven formulation may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

Propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in water, alcohol or water/alcohol media, and they may be prepared by spray atomizers or ultrasonic atomizers known from the prior art or by soft-mist atomizers such asAnd (4) delivering.

The compounds of the invention may be administered as the sole active agent or in combination with other pharmaceutically active ingredients including those currently used in the treatment of respiratory disorders, such as corticosteroids, P38MAP kinase inhibitors, IKK2, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.

The dosage of the compounds of the invention will depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage intervals, the particular compound employed, the potency, toxicological profile and pharmacokinetic profile of the compound.

Advantageously, the compound of formula (I) can be administered, for example, at a dose of 0.001 to 1000 mg/day, preferably 0.1 to 500 mg/day.

In the case where the compounds of formula (I) are administered by the inhaled route, they are preferably provided in a dose of from 0.001 to 500 mg/day, preferably from 0.1 to 200 mg/day.

The compound of formula (I) may be administered for the prevention and/or treatment of broncho-obstructive or inflammatory diseases such as asthma, chronic bronchitis, Chronic Obstructive Pulmonary Disease (COPD), bronchial hyperreactivity, cough, emphysema or rhinitis; urological disorders such as urinary incontinence, urinary frequency, bladder spasms, chronic cystitis and overactive bladder (OAB); gastrointestinal disorders such as bowel syndrome, spastic colitis, diverticulitis, peptic ulcer, gastrointestinal motility or gastric acid secretion; drying the mouth; mydriasis, tachycardia; ocular interventional cardiovascular disorders such as vagally induced sinus bradycardia.

The invention will now be further described by way of the following examples.

The intermediate compounds used for the synthesis of the final compounds of general formula (I) are obtained by the preparation methods described hereinafter.

Preparation of intermediate 1

9-Bromononanal

Pyridinium chlorochromate (38.7g, 180mmol) suspended in methylene chloride (250mL) and silica 60A (39g, particle size 35-70 microns) were stirred at RT for 45 minutes. 9-Bromononanol (26.7g, 120mmol) was added in one portion and the suspension was stirred at RT for 18 h. The reaction mixture was filtered through a celite cartridge, and the resulting filtrate was concentrated under reduced pressure to provide the title compound (28.0g, > 100%).

This material was used in the next step without further purification.

¹H NMR(400MHz，CHCl₃-d)：9.77(s，1H)，3.41(t，2H)，2.43(t，2H)，1.90-1.80(m，2H)，1.63(s，2H)，1.43(s，2H)，1.32(s，6H)。

Preparation of intermediate 2

2- (8-bromooctyl) -1, 3-dioxolane

9-Bromononanal (28.0g, setting 120mmol), ethylene glycol (33.6mL, 600mmol) and p-toluenesulfonic acid (2.7g, 13mmol) in toluene (210mL) were heated under reflux for 20 h. The reaction was cooled to RT and quenched with saturated aqueous sodium bicarbonate (300 mL). The resulting mixture was extracted with diethyl ether (. times.2). The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water and brine (100 mL). The organic phase was dried (magnesium sulfate), filtered and evaporated under reduced pressure to give the title compound (25.2g, 79%).

¹H NMR(400MHz，CHCl₃-d)：4.84(t，1H)，3.95-3.78(m，4H)，3.43-3.37(m，2H)，1.90-1.79(m，2H)，1.69-1.54(m，2H)，1.42(s，3H)，1.32(s，7H)。

All other 1, 3-dioxolanes (i.e., 2- (7-bromoheptyl) -1, 3-dioxolane; 2- (6-bromohexyl) -1, 3-dioxolane; 2- (5-bromopentyl) -1, 3-dioxolane and 2- (4-bromobutyl) -1, 3-dioxolane) were also prepared by the same method.

Preparation of intermediate 3

8- (benzyloxy) -5- (2-bromoacetyl) quinolin-2 (1H) -one

To a solution of 5-acetyl-8- (benzyloxy) quinolin-2 (1H) -one (19.4g, 66.4mmol) in anhydrous THF (240mL) and anhydrous methanol (165mL) was added dropwise a solution of tetra-n-butylammonium tribromide (54.5g, 113.0mmol) in anhydrous THF (130mL) over 1.5H. The resulting solution was stirred at RT overnight and then concentrated under reduced pressure without heating. The residue was redissolved in methanol (200 mL). Saturated aqueous ammonium chloride (390mL) was added under ice cooling. The resulting suspension was filtered, the solid washed with water and dried under reduced pressure. The solid was suspended in dichloromethane and methanol (1:1v/v, 100mL) for 90 minutes. The solid was collected by filtration, washed with dichloromethane and air dried to provide the title compound (18.0g, 73%).

¹H NMR(400MHz，CDCl₃-d)：9.23(br s，1H)，8.78(d，1H)，7.67(d，1H)，7.40(s，5H)，7.03(d，1H)，6.75(d，1H)，5.25(s，2H)，4.42(s，2H)。

Preparation of intermediate 4

(R) -8- (benzyloxy) -5- (2-bromo-1-hydroxyethyl) quinolin-2 (1H) -one

8- (benzyloxy) -5- (2-bromoacetyl) quinolin-2 (1H) -one (26.0g, 69.9mmol) and (R) -3, 3-diphenyl-1-methyltetrahydro-3H-pyrrolo [1,2-c ] [1,3,2] oxazaborole (oxazaborole) (21.3g, 76.8mmol) were azeotroped with toluene (. times.3) and suspended in anhydrous THF (400mL) under a nitrogen atmosphere. The suspension was cooled to-20 ℃ (external temperature) and borane dimethyl sulfide complex solution (45.4mL, 90.8mmol, 2.0M THF solution) was added over 3 hours by syringe pump. After the addition was complete, the reaction mixture was stirred for 1 hour, then quenched with methanol (25 mL). The reaction was warmed to RT over 20 min. The mixture was concentrated in vacuo and the residue was suspended in aqueous hydrochloric acid (500mL, 1M solution) and stirred at RT for 18 h. After this time, the solid was collected by filtration and washed with water (× 3). The solid portion was dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to give the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate, heated at reflux for 2 hours, and then filtered to provide a filtrate containing pure product. This process was repeated four more times. The combined solids were recrystallized from ethyl acetate and petroleum ether to provide the title compound (20.0g, 76%).

¹H NMR(400MHz，DMSO)：10.68(s，1H)，8.19(d，J=9.9Hz，1H)，7.58(d，J=7.5Hz，2H)，7.41-7.36(m，2H)，7.34-7.29(m，1H)，7.23-7.19(m，2H)，6.57(d，J=9.8Hz，1H)，5.94(d，J=4.7Hz，1H)，5.31(s，2H)，5.25-5.19(m，1H)，3.71-3.58(m，2H)。

Preparation of intermediate 5

(R) -8- (benzyloxy) -5- (2-bromo-1- (tert-butyldimethylsilyloxy) ethyl) -quinolin-2 (1H) -one

2, 6-lutidine (6.9mL, 59.5mmol) was added to a solution of (R) -8- (benzyloxy) -5- (2-bromo-1-hydroxyethyl) quinolin-2 (1H) -one (10.1g, 27.0mmol) in dichloromethane (100mL) at 0 deg.C. The reaction mixture was stirred for 5 minutes, then tert-butyldimethylsilyl triflate (13.0mL, 56.8mmol) was added dropwise over 15 minutes. The mixture was stirred at 0 ℃ for 30 minutes, then at RT overnight. After this time, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (× 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Isohexane (500mL) was added to the crude material and the resulting solid was collected by filtration. The solid was recrystallized from ethyl acetate and petroleum ether (40:60) to provide the title compound (11.3g, 85%).

¹H NMR(400MHz，CDCl₃-d)：9.19(s，1H)，8.23(dd，J=9.9，4.4Hz，1H)，7.43(d，J=4.6Hz，5H)，7.17(dd，J=8.3，4.5Hz，1H)，7.03(dd，J=8.2，4.4Hz，1H)，6.71(dd，J=9.9，3.7Hz，1H)，5.18(d，J=4.5Hz，3H)，3.63-3.56(m，1H)，3.49(dd，J=10.4，4.8Hz，1H)，0.88(t，J=4.4Hz，9H)，0.14(d，J=4.4Hz，3H)，-0.11(d，J=4.4Hz，3H)。

Preparation of intermediate 6

(R) -5- (2-azido-1- (tert-butyldimethylsilyloxy) ethyl) -8- (benzyloxy) -quinolin-2 (1H) -one

(R) -8- (benzyloxy) -5- (2-bromo-1- (tert-butyldimethylsilyloxy) ethyl) -quinolin-2 (1H) -one (5.0g, 10.2mmol) was dissolved in dimethylformamide (90mL) and water (10 mL). Sodium iodide (1.7g, 11.3mmol) and sodium azide (0.7g, 11.3mmol) were added sequentially. The reaction mixture was stirred at RT until all solids formed a solution. The solution was heated at 80 ℃ for 40 h, then cooled to RT and diluted with water (300 mL). The aqueous layer was extracted with dichloromethane and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was recrystallized from ethyl acetate and iso-hexane to provide the desired compound, (3.6g, 78%) and used in the next step without further purification.

¹H NMR(400MHz，CDCl₃-d)：9.19(s，1H)，8.18(d，J=9.9Hz，1H)，7.45-7.36(m，4H)，7.20(d，J=8.3Hz，1H)，7.04(d，J=8.3Hz，1H)，6.70(dd，J=9.9，2.2Hz，1H)，5.19-5.13(m，3H)，3.48(dd，J=12.7，8.1Hz，1H)，3.26(dd，J=12.7，3.8Hz，1H)，0.89(s，9H)，0.14(s，3H)，-0.11(s，3H)。

Preparation of intermediate 7

(R) -5- (2-amino-1- (tert-butyldimethylsilyloxy) ethyl) -8-hydroxyquinolin-2 (1H) -one formate salt

Palladium on activated carbon (0.4g, 10% w/w) was added to a suspension of (R) -5- (2-azido-1- (tert-butyldimethylsilyloxy) ethyl) -8- (benzyloxy) quinolin-2 (1H) -one (2.05g, 4.60mmol) and ammonium formate (2.87g, 63mmol) in methanol (50 mL). The reaction mixture was heated at 80 ℃ for 1 hour, then filtered through celite, washed with water. The reaction mixture was concentrated under reduced pressure. The resulting solid was washed with water, triturated with ethyl acetate and collected by filtration to provide the title compound (1.32g, 86%).

¹H NMR(400MHz，DMSO)：8.34(s，1H)，8.31-8.22(m，1H)，7.03(d，J=8.1Hz，1H)，6.98-6.90(m，1H)，6.53(d，J=9.9Hz，1H)，5.13(t，J=6.0Hz，1H)，3.18(s，1H)，2.84-2.73(m，2H)，0.83(s，9H)，0.06(s，3H)，-0.17(s，3H)。

(R) -5- (2-amino-1- (tert-butyldimethylsilyloxy) ethyl) -8-hydroxyquinolin-2 (1H) -one

To an ice-cooled suspension of palladium on activated carbon (4.50g, 10% w/w) and (R) -5- (2-azido-1- (tert-butyldimethylsilyloxy) ethyl) -8- (benzyloxy) quinolin-2 (1H) -one (4.50g, 10.0mmol) in ethanol (50mL) was added dropwise 1-methyl-1, 4-cyclohexadiene (11.0mL, 97.9 mmol). The coolant was removed and the suspension was stirred at ambient temperature for 10 minutes and then heated to 50 ℃ for one hour. The reaction mixture was allowed to cool and the suspension was filtered through celite. The filter cake was washed with further ethanol and the combined filtrates were concentrated under reduced pressure. The residue was triturated with acetonitrile to give the title compound (3.03g, 90%).

Preparation of intermediate 8

(R) -5- (2-amino-1-hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one hydrochloride

(R) -5- (2-amino-1- (tert-butyldimethylsilyloxy) ethyl) -8-hydroxyquinolin-2 (1H) -one formate (0.23g, 0.61mmol) was dissolved in hydrochloric acid (5mL, 4M dioxane solution) and methanol (5 mL). The reaction mixture was stirred at RT for 16 h, then concentrated in vacuo. The resulting residue was washed with ethyl acetate and dried in a vacuum oven for 18 hours to provide the title compound (0.15g, 99%).

¹H NMR(400MHz，CD₃OD)：7.71(d，J=9.8Hz，1H)，6.57(d，J=8.2Hz，1H)，6.31(d，J=8.2Hz，1H)，6.02(dd，J=9.8，6.5Hz，1H)，4.58(dd，J=9.6，3.5Hz，1H)，2.47-2.31(m，2H)。

Preparation of intermediate 9

2-hydroxy-2-phenyl-2- (thien-3-yl) acetic acid ethyl ester

To a stirred solution of ethyl benzoylformate (1.30g, 7.30mmol) in THF (5mL) at-78 deg.C under nitrogen was added 3-thienylmagnesium iodide (29.2mL, 8.76mmol) over 10 minutes. After stirring at-78 ℃ for 1 hour, the reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (× 3). The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 0-10% ethyl acetate/isohexane to provide the title compound (1.06g, 55%).

¹H NMR(400MHz，CDCl₃-d)：7.45-7.39(m，2H)，7.37-7.28(m，5H)，7.12-7.09(m，1H)，4.38-4.28(m，2H)，4.30-4.25(m，1H)，1.32-1.24(m，3H)。

Preparation of intermediate 10

2-hydroxy-2-phenyl-2- (thien-3-yl) acetic acid

To a stirring solution of ethyl 2-hydroxy-2-phenyl-2- (thiophen-3-yl) acetate (1.06g, 4.02mmol) in THF (10mL) was added sodium hydroxide (10mL, 2.0M aqueous solution). The reaction was heated at 60 ℃ for 24 hours. The reaction was allowed to cool to RT and THF was removed under reduced pressure. The resulting residue was washed with diethyl ether (. times.3). The aqueous layer was acidified to pH1 with 2.0M aqueous hydrochloric acid and extracted with ethyl acetate (. times.3). The combined ethyl acetate layers were washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo to provide the title compound (0.75g, 79%).

¹H NMR(400MHz，CDCl₃-d)：13.20(br s，1H)，7.52(d，J=2Hz，1H)，7.49-7.28(m，6H)，7.05(d，J=2Hz，1H)，6.56(br s，1H)

The final compound is prepared as described below using the appropriate acid (1) and the appropriate bromo-1, 3-dioxolane.

Preparation of intermediate 11

4- (tosyloxymethyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (5.0g, 23.2mmol) in anhydrous pyridine (18.5mL) was added p-toluenesulfonyl chloride (4.87g, 25.55mmol) in one portion at 0 ℃ under nitrogen. The reaction was stirred at 0 ℃ for 100 minutes and then warmed to RT. After 18 h, the reaction mixture was poured into water (100mL) and extracted with ethyl acetate (3X 50 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2 × 100mL, 1.0M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo to give the title compound (7.87g, 91%).

¹H NMR(400MHz，CDCl₃-d)：7.77-7.70(m，2H)，7.31(d，J=8.0Hz，2H)，3.80(d，J=6.5Hz，2H)，2.61(d，J=13.1Hz，2H)，2.41(s，3H)，1.84-1.72(m，1H)，1.60(d，J=13.1Hz，2H)，1.46-1.36(m，9H)，1.05(ddd，J=24.9，12.5，4.4Hz，2H)，-0.05(t，J=3.3Hz，2H)。

Preparation of intermediate 12

4- ((2-cyclohexyl-2-hydroxy-2-phenylacetyloxy) methyl) -piperidine-1-carboxylic acid tert-butyl ester

Cyclohexylmandelic acid (885mg, 3.78mmol) was added to tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (957mg, 3.44mmol) and potassium carbonate (713mg) in dimethylformamide (10mL) with stirring at RT. After 72 hours, the reaction was diluted with ethyl acetate and water. The organic extracts were washed with saturated sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography eluting with 0-30% ethyl acetate/isohexane to provide the title compound (1.10g, 75%).

¹H NMR(400MHz，CDCl₃-d)：7.64-7.59(m，2H)，7.37-7.30(m，2H)，7.31-7.25(m，1H)，4.15-4.04(m，2H)，4.05-3.97(m，2H)，3.68(s，1H)，2.73-2.60(m，2H)，2.28-2.17(m，1H)，1.83-1.76(m，2H)，1.70-1.53(m，4H)，1.46(s，9H)，1.42(dd，J=8.3，3.4Hz，2H)，1.32-1.03(m，7H)。

Preparation of intermediate 13

Piperidin-4-ylmethyl 2-cyclohexyl-2-hydroxy-2-phenylacetic acid ester hydrochloride

Tert-butyl 4- ((2-cyclohexyl-2-hydroxy-2-phenylacetoxy) methyl) -piperidine-1-carboxylate (1.10g, 2.55mmol) was dissolved in hydrochloric acid (5mL, 4M dioxane solution) and dichloromethane (5 mL). The reaction mixture was stirred at RT for 3h and concentrated under reduced pressure to afford the title compound (970mg, >100%) which was used in the next step without further purification.

¹H NMR(400MHz，CDCl₃-d)：9.79-9.64(bs，1H)，9.58-9.40(bs，1H)，7.63-7.59(m，2H)，7.37-7.30(m，2H)，7.29-7.25(m，1H)，4.10(dd，J=11.0，6.3Hz，1H)，4.03-3.97(m，1H)，3.65(s，1H)，3.47(d，J=13.0Hz，2H)，2.79(s，2H)，2.29-2.22(m，1H)，1.92-1.61(m，8H)，1.51-1.23(m，4H)，1.21-1.05(m，3H)。

Preparation of intermediate 14

(1- (9- (1, 3-dioxolan-2-yl) nonyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetic acid ester

2- (8-Bromooctyl) -1, 3-dioxolane (218mg, 0.82mmol) followed by diisopropylethylamine (361. mu.L, 2.07mmol) was added to a solution of piperidin-4-ylmethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate hydrochloride (252mg, 0.69mmol) in acetonitrile (4 mL). The reaction mixture was heated at 60 ℃ for 17 hours. After this time, the reaction was cooled to RT and diluted with dichloromethane. The organic extracts were washed with water, filtered through a hydrophobic frit (frat) and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 100% dichloromethane to 40:1 dichloromethane: methanol to provide the title compound, which was used in the next step without further purification.

¹H NMR(400MHz，CDCl₃-d)：7.63(d，J=7.8Hz，2H)，7.33(t，J=7.7Hz，2H)，4.84(t，J=4.8Hz，1H)，4.03-3.93(m，3H)，3.87-3.82(m，2H)，3.69(s，1H)，2.94(s，2H)，2.37-2.20(m，3H)，1.96-1.72(m，3H)，1.70-1.06(m，32H)。

Preparation of intermediate 15

(1- (10-oxodecyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate

(1- (9- (1, 3-dioxolan-2-yl) nonyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (200mg, 0.39mmol) was dissolved in THF (2mL) and hydrochloric acid (4mL, 2M aq.) with stirring at RT. After 3 hours, the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate solution. The layers were separated and the organic extract was allowed to flow over the hydrophobic frit. The solvent was removed in vacuo. The title compound was isolated (> 100%) and used in the next step without further purification.

Preparation of intermediate 16

4- ((2-hydroxy-2-phenyl-2- (thien-3-yl) acetoxy) -methyl) piperidine-1-carboxylic acid tert-butyl ester

To a stirring solution of 2-hydroxy-2-phenyl-2- (thiophen-3-yl) acetic acid (0.75g, 3.197mmol) in toluene (4mL) and dimethylformamide (0.4mL) was added tert-butyl 4- (tosyloxymethyl) piperidine-1-carboxylate (0.909g, 2.459mmol) in 1, 8-diazabicyclo [5.4.0] undec-7-ene (735 μ L, 4.919mmol) followed by toluene (3.5mL) and dimethylformamide (0.35 mL). The reaction mixture was heated at 100 ℃ overnight. After this time, the reaction mixture was cooled to RT and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using isohexane: gradient elution with ethyl acetate (1:0 to 3:1) provided the title compound (0.84g, 79%).

¹H NMR(400MHz，CDCl₃-d)：7.44-7.38(m，2H)，7.37-7.28(m，5H)，7.08(dd，J=5.0，1.4Hz，1H)，4.24(s，1H)，4.13-4.05(m，2H)，2.76-2.44(m，3H)，1.82-1.69(m，1H)，1.64-1.26(m，12H)；1.11-0.98(m，2H)。

Preparation of intermediate 17

Piperidin-4-ylmethyl 2-cyclohexyl-2-hydroxy-2-phenylacetic acid tosylate

To a stirred solution of tert-butyl 4- ((2-hydroxy-2-phenyl-2- (thiophen-3-yl) acetoxy) methyl) piperidine-1-carboxylate (0.84g, 1.94mmol) in acetonitrile (10mL) was added p-toluenesulfonic acid monohydrate (0.55g, 2.91 mmol). The reaction was stirred at 30 ℃ overnight and then concentrated under reduced pressure to provide the title compound (1.17g, >100%) which was used in the next step without further purification.

Preparation of intermediate 18

4- ((3-hydroxy-2, 2-diphenylpropanoyloxy) methyl) -piperidine-1-carboxylic acid tert-butyl ester, used for the preparation of example 20

Tert-butyl 4- ((2, 2-diphenylacetoxy) methyl) piperidine-1-carboxylate (as in the preparation of intermediate 12, substituting cyclohexylmandelic acid with 2, 2-diphenylacetic acid) (0.40g, 0.98mmol) in THF (5mL) was treated with lithium hexamethyldisilazide (1.17mL, 1.17mmol, 1.0M in THF) followed by formaldehyde (0.20g, 50% w/w). The reaction mixture was stirred at RT for 16 h and then quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 30-60% ethyl acetate/petroleum ether (40:60) to provide the title compound (0.10g, 23%).

¹H NMR(400MHz，CDCl₃-d)：7.35-7.24(m，10H)，4.34(d，J=7.2Hz，2H)，4.12-3.96(m，3H)，2.75-2.66(m，1H)，2.59(s，2H)，1.78-1.65(m，1H)，1.50-1.41(m，11H)，1.03(ddd，J=24.9，12.4，4.4Hz，2H)。

Preparation of intermediate 19

4- ((2-Acetylamino-2, 2-diphenylacetoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester, used in Synthesis example 23

To a solution of tert-butyl 4- ((2-amino-2, 2-diphenylacetoxy) -methyl) piperidine-1-carboxylate (as prepared for intermediate 12, cyclohexylmandelic acid was replaced with diphenylglycine) (0.50g, 1.18mmol) in DCM (1.5mL) was added a solution of acetic anhydride (0.122mL, 1.30mmol) in DCM (0.5 mL). The reaction mixture was heated at 40 ℃ for 18 hours. The reaction mixture was allowed to cool to RT and further acetic anhydride (0.06mL, 0.65mmol) was added. The reaction mixture was heated at 40 ℃ for a further 18 hours. The reaction mixture was allowed to cool to RT, quenched with water, and the mixture stirred at RT for 1 hour. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate and DCM. The organic phase was removed and the aqueous phase was extracted with further SCM. The combined DCM extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was isolated (> 100%) as 0.541 g. The crude product was used in the next step without further purification.

Preparation of intermediate 20

(1- (6- (4-Oxopiperidin-1-yl) hexyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate used in Synthesis example 28

To a stirred solution of methyl (1- (6-oxohexyl) piperidin-4-yl) 2-cyclohexyl-2-hydroxy-2-phenylacetate (as prepared for intermediate 15, but using a solution of (1- (5- (1, 3-dioxolan-2-yl) pentyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (0.20g, 0.47mmol) and 1, 4-dioxa-8-azaspiro [4.5] decane (0.133g, 0.93mmol)) in THF (5mL) was added sodium triacetoxyborohydride (0.294g, 1.39 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic phase was removed and the aqueous phase was extracted with further DCM. The combined organics were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was dissolved in THF (2mL) and 2M aqueous HCl and heated at 60 ℃ for 18 h. The reaction mixture was allowed to cool to RT and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted twice with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product was isolated (0.193g, 80%).

Example 1

(1- (9- ((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethylamino) nonyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (Compound 1)

Triethylamine (90. mu.L, 0.65mmol) was added to a solution of (1- (10-oxodecyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (182mg, 0.39mmol) and (R) -5- (2-amino-1-hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one hydrochloride (100mg, 0.39mmol) in methanol (4 mL). The reaction mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (154mg, 0.73mmol) followed by acetic acid (74. mu.L, 1.29mmol) was added and the reaction mixture was stirred at RT for 72 h. The reaction was quenched by addition of water (500. mu.L) and evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and subjected to reverse phase preparative HPLC for final purification. The title compound (42.3mg, 16%) was obtained by isolation.

¹H NMR(400MHz，CD₃OD)：8.58(s，2H)，8.40(d，J=9.8Hz，1H)，7.66-7.61(m，2H)，7.37-7.22(m，4H)，7.03(d，J=8.1Hz，1H)，6.69(d，J=9.8Hz，1H)，5.43-5.35(m，1H)，4.02(d，J=6.2Hz，2H)，3.28-3.13(m，4H)，3.06-2.97(m，2H)，2.73-2.65(m，2H)，2.49-2.36(m，2H)，2.38-2.28(m，1H)，1.87-1.59(m，10H)，1.54-1.03(m，20H)。

The following compounds of the general formula (IA)

And compounds 28 to 31, prepared using the procedure described for the preparation of compound 1 (report R below)₁In the meaning, "c" represents cyclic):

example 28

Example 28 was prepared using the procedure described for the preparation of compound 1, substituting (1- (10-oxodecyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate with (1- (6- (4-oxopiperidin-1-yl) hexyl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, the synthesis of which was described in preparation 20.

Example 29

Example 29 prepared using the methodology described for the preparation of compound 1 in example 1, the (R) -5- (2-amino-1-hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one hydrochloride was replaced with 7- (2-aminoethyl) -4-hydroxybenzo [ d ] thiazol-2 (3H) -one hydrobromide (prepared as described in Organic Process Research & Development2004, 8, 628-one 642).

Example 30

(1- ((E) -5- (3- (((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl) amino) propoxy) -4-methylpent-3-en-1-yl) piperidin-4-yl) methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate

Preparation of example 30 required the synthesis of (E) -5-bromo-1- (3, 3-diethoxypropoxy) -2-methylpent-2-ene instead of 2- (8-bromooctyl) -1, 3-dioxolane as in step 4 of example 1.

Step 1; 3- (3, 3-diethoxypropoxy) -2-methylpropan-1-ene

To a stirred solution of 3, 3-diethoxy-1-propanol (3.0g, 22.2mmol) in anhydrous THF (50mL) was added sodium hydride (60% dispersion in mineral oil, 1.07g, 26.6 mmol). The reaction mixture was stirred for 30 minutes, then 3-bromo-2-methyl-1-propene (3.63g, 24.5mmol) was added. The reaction mixture was then stirred for a further 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (× 3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give an oil (2.25g, 50%). This material was used in the next step without further purification.

Step 2; (E) -5-bromo-1- (3, 3-diethoxypropoxy) -2-methylpent-2-ene

To pre-denitrified gas DCM (18mL) was added a second generation Grubbs catalyst (0.225g, 0.30mmol) followed by 3-bromobutene (2.03g, 15.0mmol) and 3- (3, 3-diethoxypropoxy) -2-methylpropan-1-ene (1.52g, 7.52 mmol). The reaction mixture was further degassed for 5 minutes and then heated at reflux for 2 hours. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with 0-100% ethyl acetate/isohexane, to give the title compound (0.208g, 9%).

¹H NMR(400MHz，CDCl₃)：5.47-5.32(m，1H)；4.69-4.62(m，1H)；3.85(s，2H)；3.72-3.61(m，2H)；3.58-3.32(m，6H)；2.63(dd，J=14.3，7.2Hz，2H)；1.94-1.85(m，2H)；1.66(s，3H)；1.28-1.15(m，6H)。

Example 31

(R) - (1- (4- ((6- ((2-hydroxy-2- (8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl) ethyl) amino) hexyl) oxy) benzyl) piperidin-4-yl) methyl 2-hydroxy-2, 2-diphenylacetate (Compound 31)

Preparation of Compound 31 entails the synthesis of (1- (4- ((5- (1, 3-dioxolan-2-yl) pentyl) oxy) benzyl) piperidin-4-yl) methyl 2-hydroxy-2, 2-diphenylacetate

Step 1; 4- ((5- (1, 3-dioxolan-2-yl) pentyl) oxy) benzaldehyde

To a stirring solution of 2- (5-bromopentyl) -1, 3-dioxolane (4.38g, 19.6mmol) in dimethylformamide (30mL) were added 4-hydroxybenzaldehyde (3.00g, 24.4mmol) and potassium carbonate (4.52g, 32.8 mmol). The reaction mixture was stirred at 50 ℃ for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (× 3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to afford an oil. The crude material was purified by column chromatography on silica gel eluting with 0-100% ethyl acetate/isohexane to provide the title compound (1.92g, 36%).

¹H NMR(400MHz，CDCl₃)：9.92-9.86(m，1H)；7.85-7.80(m，2H)；7.03-6.95(m，2H)；4.87(t，J=4.7Hz，1H)；4.07-3.80(m，6H)；1.89-1.79(m，2H)；1.75-1.67(m，2H)，1.58-1.46(m，4H)。

Step 2; (1- (4- ((5- (1, 3-dioxolan-2-yl) pentyl) oxy) benzyl) piperidin-4-yl) methyl 2-hydroxy-2, 2-diphenylacetate

To a stirring solution of piperidin-4-ylmethyl 2-hydroxy-2, 2-diphenylacetate (0.4g, 1.23mmol) and 4- ((5- (1, 3-dioxolan-2-yl) pentyl) oxy) benzaldehyde (0.38g, 1.44mmol) in DCM (5mL) was added sodium triacetoxyborohydride (0.388g, 1.83 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1 to 10% methanol/ethyl acetate to provide the title compound as a colorless oil (0.50g, 26%).

¹H NMR(400MHz，CDCl₃)：7.43-7.37(m，5H)；7.35-7.29(m，5H)；7.23-7.08(m，2H)；6.92-6.78(m，2H)；4.86(t，J=4.8Hz，1H)；4.25(s，1H)；4.13-3.79(m，10H)；3.44-3.30(m，2H)；2.80(d，J=11.3Hz，2H)；1.92-1.65(m，7H)；1.57-1.42(m，4H)；1.28-1.11(m，2H)。

Compounds 32 to 37 were prepared in the same manner as compound 31, using the appropriate bromides (2- (5-bromopentyl) -1, 3-dioxolane and 2- (4-bromobutyl) -1, 3-dioxolane) in step 1 and the appropriate amine (piperidin-4-ylmethyl 2-hydroxy-2, 2-diphenylacetate or piperidin-4-ylmethyl 2-cyclohexyl-2-hydroxy-2-phenylacetate) in step 2.

The analytical characterization of compounds 1 to 37 is reported in the table below.

For in CDOD₃The NMR data in (1) were all the exchanged protons unobservable.

HPLC data

The method comprises the following steps:

a is10cm _ ESCI _ formic acid _ MeCN

B is15cm _ formic acid _ ASCENTIS _ HPLC _ CH₃CN

Illustration of the drawings

*NMR

s = single peak

d = doublet peak

t = triplet peak

q = quartet

dd = doublet

m = multiplet

br = width

Biological characterization

Example 38

M3 receptor radioligand binding assay

Human M3 acceptor membranes (15. mu.g/well) from Perkin Elmer were incubated: with 0.52nM Scopolamine Methyl Chloride, [ N-Methyl-3H ], with or without test compound; alternatively, atropine (5. mu.M) was used at saturating concentrations to determine non-specific binding. The assay was performed in a 250. mu.l volume in 96-well polypropylene plates. The test buffer used was 50mM Tris-HCl, 154mM NaCl (pH 7.4). The final assay concentration of DMSO was 0.5% (v/v). The plates were sealed and incubated for 2h at room temperature on an orbital shaker (slow speed). Membranes were harvested on 96-well unifilter GF/C filter plates pretreated with 0.5% polyethyleneimine (v/v) using a filter manifold and washed 4 times with 200. mu.l of test buffer. Plates were dried, then 50 μ l scintillation fluid microscint-0 was added, sealed, and then read in a Trilux Microbeta scintillation counter. IC50 values were determined from the competition curves using a non-linear curve fitting program. Ki values were calculated from IC50 values by the Cheng and Prusoff equations.

The test compounds had Ki values of less than 10 nM.

Example 39

Beta 2 adrenoceptor radioligand binding assay

Human β 2 adrenoceptor membranes from Perkin Elmer (7.5 μ g/well) were incubated: test compounds were added or not with 0.3nM 125-iodocyanopindolol; alternatively, s-propranolol (2. mu.M) was used at saturating concentrations to determine non-specific binding. The assay was performed in a volume of 200. mu.l in 96-well polypropylene plates. The test buffer used was 25mM HEPES, 0.5% BSA (w/v), 1mM EDTA, 0.02% ascorbic acid (v/v), (pH 7.4). The final assay concentration of DMSO was 0.5% (v/v). The plates were sealed and incubated for 1h at room temperature on an orbital shaker (slow speed). Using a filter manifold, each membrane was harvested onto a 96-well unifilter GF/C filter plate pretreated with 0.5% polyethyleneimine (v/v) and washed 6 times with 200. mu.l of wash buffer containing 10mM HEPES and 500mM NaCl. Plates were dried, then 50 μ l scintillation fluid microscint-0 was added, sealed, and then read in a Trilux Microbeta scintillation counter. IC50 values were determined from the competition curves using a non-linear curve fitting program. Ki values were calculated from IC50 values using the Cheng and Prusoff equations.

The test compounds have Ki values of less than 10 Nm.

Claims (22)

1. A compound of the general formula (I)

Wherein Q is a group of formula Q1 or Q3

Z is H or OH;

y is-(CH₂)_n-, where n is an integer from 1 to 12 or is a divalent radical of the formula Y1

Wherein

A₁And A₂Each independently is absent or selected from (C)₁-C₆) Alkylene group, (C)₃-C₈) Cycloalkylene and (C)₃-C₈) Heterocycloalkylene;

b is absent or selected from (C)₃-C₈) Cycloalkylene radical (C)₃-C₈) Heterocycloalkylene, arylene and heteroarylene;

c is absent or-O-;

d is selected from (C)₁-C₁₂) Alkylene group, (C)₂-C₁₂) Alkenylene and (C)₂-C₆) Alkynylene, optionally substituted with one or more (C)₁-C₆) Alkyl substitution;

r is-H or (C)₁-C₄) An alkyl group;

x is-O-or-S-;

R₁is H or is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) An alkyl group;

R₂is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl optionally substituted by one or more halogen atoms or (C)₁-C₄) Alkoxy substitution;

R₃is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆)；

R₅And R₆Independently is H or (C)₁-C₆) An alkyl group;

wherein said aryl means a mono-, bi-or tricyclic ring system having 5 to 15 ring atoms and wherein at least one ring is aromatic, wherein said heteroaryl means a mono-, bi-or tricyclic ring system having 5 to 15 ring atoms, wherein at least one ring is aromatic and wherein at least one ring atom is a heteroatom selected from N, S or O, wherein said arylene and heteroarylene means a divalent group selected from phenylene and thienylene;

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R₂Is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) An alkyl group; r₃Is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆) (ii) a X is-O-or-S-; r is-H or (C)₁-C₄) An alkyl group; y, Z and Q are as defined in claim 1.

3. A compound according to claim 1, wherein R₁Is H or is selected from cyclobutyl, cyclopentyl, phenyl, benzyl, cycloheptyl, thienyl and cyclohexyl; r₂Selected from phenyl, thienyl, cyclohexyl, triphenylmethyl, chlorophenyl, methoxyphenyl, and fluorophenyl; r₃Is H or is selected from-OH, -NH₂，-CH₂OH，-NHCOCH₃(ii) a X is-O-; r is H or-CH₃。

4. A compound of the general formula (IA),

r is-H or (C)₁-C₄) An alkyl group;

R₁is H or is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl radical；

R₂Is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl optionally substituted by one or more halogen atoms or (C)₁-C₄) Alkoxy substitution;

R₃is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆)；

R₅And R₆Independently is H or (C)₁-C₆) An alkyl group;

n is 4, 5, 6, 7 or 8;

wherein said aryl group refers to a mono-, bi-, or tricyclic ring system having 5 to 15 ring atoms and wherein at least one ring is aromatic, wherein said heteroaryl group refers to a mono-, bi-, or tricyclic ring system having 5 to 15 ring atoms, wherein at least one ring is aromatic and wherein at least one ring atom is a heteroatom selected from N, S, or O;

and pharmaceutically acceptable salts thereof.

5. A compound according to claim 1, wherein Y is a divalent group of formula Y1

Wherein A is₁Is (C)₃-C₈) Cycloalkylene, B and C are absent, Z is OH and Q is a group of formula Q1

Having the general formula (IB), wherein (C)₃-C₈) Cycloalkylene is represented by "cy

6. A compound according to claim 1, wherein Y is a divalent group of formula Y1

Wherein A is₁Is piperidinyl, D is hexylene, Z is OH and Q is a group of formula Q1

7. A compound of the general formula (IC),

wherein

R₁Is H or is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) An alkyl group;

R₂is selected from (C)₃-C₈) Cycloalkyl, aryl, heteroaryl, aryl (C)₁-C₆) Alkyl, heteroaryl (C)₁-C₆) Alkyl and (C)₃-C₈) Cycloalkyl (C)₁-C₆) Alkyl optionally substituted by one or more halogen atoms or (C)₁-C₄) Alkoxy substitution;

R₃is H or is selected from-OH, hydroxy (C)₁-C₆) Alkyl, -N (R)₅R₆) and-N (R)₅)CO(R₆)；

R₅And R₆Independently is H or (C)₁-C₆) An alkyl group;

n is 8;

wherein said aryl group refers to a mono-, bi-, or tricyclic ring system having 5 to 15 ring atoms and wherein at least one ring is aromatic, wherein said heteroaryl group refers to a mono-, bi-, or tricyclic ring system having 5 to 15 ring atoms, wherein at least one ring is aromatic and wherein at least one ring atom is a heteroatom selected from N, S, or O;

and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 3 and 5 to 6, together with one or more pharmaceutically acceptable carriers and/or excipients.

9. A pharmaceutical composition comprising a compound of formula (IA) as defined in claim 4, together with one or more pharmaceutically acceptable carriers and/or excipients.

10. A pharmaceutical composition comprising a compound of formula (IC) as defined in claim 7, together with one or more pharmaceutically acceptable carriers and/or excipients.

11. Use of a compound of formula (I) according to any one of claims 1 to 3 and 5 to 6 for the preparation of a medicament for the prevention and/or treatment of broncho-obstructive or inflammatory diseases.

12. Use of a compound of formula (IA) according to claim 4 for the preparation of a medicament for the prevention and/or treatment of broncho-obstructive or inflammatory diseases.

13. Use of a compound of formula (IC) according to claim 7 for the preparation of a medicament for the prevention and/or treatment of broncho-obstructive or inflammatory diseases.

14. Use of a compound of formula (I) according to any one of claims 1-3 and 5-6 for the preparation of a medicament for the prevention and/or treatment of asthma, chronic bronchitis or chronic obstructive pulmonary disease.

15. Use of a compound of formula (IA) according to claim 4 for the preparation of a medicament for the prevention and/or treatment of asthma, chronic bronchitis or chronic obstructive pulmonary disease.

16. Use of a compound of formula (IC) according to claim 7 for the preparation of a medicament for the prevention and/or treatment of asthma, chronic bronchitis or chronic obstructive pulmonary disease.

17. A pharmaceutical composition of a compound of formula (I) as defined in any one of claims 1 to 3 and 5 to 6 with one or more active ingredients selected from the group consisting of: corticosteroids, P38MAP kinase inhibitors, IKK2 inhibitors, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.

18. A pharmaceutical composition of a compound of formula (IA) as defined in claim 4 together with one or more active ingredients selected from the group consisting of: corticosteroids, P38MAP kinase inhibitors, IKK2 inhibitors, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.

19. A pharmaceutical composition of a compound of formula (IC) as defined in claim 7 together with one or more active ingredients selected from the group consisting of: corticosteroids, P38MAP kinase inhibitors, IKK2 inhibitors, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDs and mucus regulators.

20. A pharmaceutical composition according to any one of claims 17 to 19 for administration by inhalation.

21. A pharmaceutical composition according to any one of claims 17 to 19 for administration by inhalation of a powder, a propellant-containing metered aerosol or a propellant-free inhalable formulation.

22. A device comprising a pharmaceutical composition according to claim 20 or 21, which may be a single-or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer.