NL1028599C2 - Compounds for the treatment of diseases. - Google Patents

Description

* * 5 Compounds for the treatment of diseases The present invention relates to β2-agonists of the general formula: / -JC "20 ifT ^ XY + -W, \ / 0 '(1) HO ^ fN R" R2 γ

CH 2 OH

Wherein R1, R2, n and Q1 have the meanings indicated below, and on methods for the preparation of compositions containing such derivatives, and the uses of such derivatives.

Adrenoceptors are members of the large G-protein receptor coupled super family. The adrenoceptor subfamily is itself divided into the α and β subfamilies where the β ~ subfamily consists of at least 3 receptor subtypes: βΐ, β2 and β3. These receptors exhibit different expression patterns in tissues of different systems and organs of mammals, β2-adrenergic (β2) receptors are primarily expressed in smooth muscle cells (e.g., vascular, bronchial, uterine or intestinal) 1028599

"I

2 smooth muscles), whereas P3 adrenergic receptors are primarily expressed in adipose tissues (therefore p3 agonists may be useful in the treatment of obesity and diabetes) and βΐ-5 adrenergic receptors are primarily expressed in tissues of the heart (therefore, βΐ-agonists are mainly used as cardiac stimulants).

Extensive overviews of pathophysiology and treatments of respiratory diseases have been given in the literature (for reference, see Barnes, P.J. Chest, 1997, 111: 2, pp. 17S-26S and Bryan, S.A. et al., Expert

Opinion on investigational drugs, 2000, 9: 1, p. 25-42) and therefore only a brief summary will be included here to provide some background information.

Glucocorticosteroids, anti-leukotrienes, theophyllin, cromones, anti-cholinergic substances and β2-agonists form classes of drugs currently used to treat respiratory diseases that may or may not be due to allergies such as asthma and chronic obstructive disease. respiratory tract (COPD). Treatment guidelines for these diseases include both short-acting and long-acting inhaled β2 agonists. Short-acting β2 agonists that start quickly are used for "reddirigs" bronchodilation, while long-acting forms provide long-term relief and are used as maintenance therapy.

Bronchodilation is mediated via β2 adrenoceptor agonism expressed on airway smooth muscle cells, resulting in relaxation and bronchodilation from there. Thus, as functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because β2-35 receptors are so widespread in the airways, β2 agonists can also influence other types of cells that play a role in asthma. It has been mentioned, for example, that 1028599 3 1-p 2 agonists can stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be that β2 agonists block the bronchoconstriction induced by allergens, movement and cold air. In addition, P2 agonists inhibit cholinergic neurotransmission in the human airways, which may result in reduced cholinergic reflex bronchoconstriction.

In addition to the respiratory tract, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and thus P2 agonists, such as those described in the present invention, may be useful in the treatment of other diseases such as, but not limited to those of the central nervous system, premature labor, congestive heart failure, depression, inflammatory disease and skin diseases due to allergy, psoriasis, proliferative skin diseases, glaucoma, and in conditions where there is an advantage in lowering the gastric acidity, in particular with gastric and peptic ulcers.

Numerous p2 agonists, however, are limited in their use due to their low selectivity or adverse side effects that are driven by high systemic exposure and are primarily mediated by activity in p2 adrenoceptors expressed outside the airways (muscle tremor, tachycardia, palpitations, restlessness). That is why there is a need for improved resources in this class.

Thus, there is still a need for new β2 agonists that would have a suitable pharmacological profile, for example in terms of strength, selectivity, pharmacokinetics or duration of action. In this context, the present invention relates to novel P2 agonists.

The invention relates to the compounds of general formula (1): 1028599 4

OH

ί \ ^ ΝΧΎ ^ (0Η2) η. q.

HoR 1 R 2 γ (1) ch 2 OH 0 wherein the (CH 2) n-C (= 0) Q x group is in the meta or para position 10, R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl; n is 0, 1 or 2; Q1 is a group selected from R3 R4 f * 3 W f /1.R4, x> r '- Q5 (CH2) q NR6 R R6 R11

*> I

/ "^ / \ / - \

* —N R12 * —N N — R12 * - N f \ | —R12 * - N O

\ "J \ / \ / \ / 25"

• -OO

and a group * -NR8-Q2-A or * -NR8-Q3, wherein> 30 - p is 1 or 2 and q is 1 or 2; - Q 2 is a single bond or a C 1 -C 4 alkylene optionally substituted with OH; R8 is H or C1 -C4 alkyl; Q 3 is C 1 -C 6 alkyl optionally substituted with NR 9 R 10, OR 9 or phenoxy; A is selected from: 1028599 15 C 3 -C 10 cycloalkyl, which cycloalkyl is optionally bridged by one or more carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, and is optionally substituted with one hydroxy group; o. a 5- to 6-membered heterocyclic group, optionally aromatic, containing one or two hot roatoms selected from 0, N or S, optionally substituted with one or two substituents selected from C 1 -C 4 alkyl, zyl and cyclopropylmethyl or: R3, R4, R5, R7, R6, or, quinolyl or isoquinolyl; R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, C 1 -C 4 alkyl, OR 9, SR 9, SOR 9, SO 2 R 9, halogen, CN, CF 3, OCF 3, SO 2 NR 9 R 10, COOR 9, CONR 9 R 10, NR 9 R 10, NHCOR10 and phenyl, optionally substituted with OH; R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl, R 11 is selected from H or OH, and, R 12 and R 13 are the same or different and are selected from H, C 1 -C 4 alkyl, optionally substituted with OR 9, C (= O) NH 2, C (= O) CH 3, N (CH 3) C (= O) CH 3 / C (= O) 0 R 9, phenyl, optionally substituted with halogen, pyridyl, optionally substituted with CN and oxadiazolyl, optionally substituted with C 1 -C 4 alkyl, and * represents the point of attachment to the carbonyl group; Or, if applicable, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotope variations thereof.

1028598 to 6

The compounds of formula (1) are agonists of the P2 receptors, which are particularly useful for the treatment of β2-mediated diseases and / or disorders, by exhibiting excellent potency, in particular when administered via the inhalation route.

In the foregoing general formula (1), C 1 -C 4 alkyl and C 1 -C 4 alkylene denote a straight or branched-chain group containing 1, 2, 3 or 4 carbon atoms. C 1 -C 6 alkyl denotes a straight or branched chain group containing 1, 2, 3, 4, 5 or 6 carbon atoms. This also applies if they carry substituents or exist as substituents of other groups, for example in O- (C 1 -C 4) alkyl groups, S- (C 1 -C 4) alkyl groups, etc. ... Examples of suitable (C 1 -C 4) alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl .... Examples of suitable O- (C 1 -C 4) alkyl groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and t-butyloxy ....

The C 3 -C 10 cycloalkyl in which 2 carbon atoms or more are optionally bridged by one or more carbon atoms is, inter alia, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicylo [3.1.1] heptane, bicylo [2.2. 1] heptane, bicylo [2.2.2] octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.

Non-limiting examples of a "heterocyclic group with 5 or 6 atoms, optionally aromatic, containing one or two heteroatoms selected from O, N or S" are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl.

Preferably, said heterocyclic group contains one nitrogen, two nitrogen substances or one nitrogen and one oxygen atom.

1028599 7

Preferred aromatic 5 or 6 membered heterocyclic groups are pyrazolyl and pyridyl.

Preferred non-aromatic 5 or 6 membered heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl and piperazinyl.

Finally, halogen denotes a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

In the following, the free bond to the phenyl group as in the following structure means that the phenyl may be substituted at the meta or para position.

The compounds of the formula (1)

OH

IV-X'Y ^ CHA-x.Q "(1) 25 ho ^ Yn r" r2 ^. ch 2 OH may be prepared using conventional processes such as the following illustrative processes wherein Q 1, Q 2, R 1, R 2, A and n are as previously defined for the compounds of formula (1) unless otherwise stated.

The amide derivatives of the formula (1) can be prepared by an acid of the formula (2): 1028599 8

OH

I H

5 HO 2 fN R 1 R 2 O 2 ch 2 OH with an amine of formula NHR 8 -Q 2 -A, NHR 8 -Q 3.

R3, 10, R8, R4

) == (n / YY

ΗΝ - (ΥΚο R "jf V

HN / ^ - R12 H11 / R12 HN N - R12 H1 /?). ^ /, ^ - ', or "OO.

Coupling is generally carried out in an excess of that amine as an acid receptor, with a conventional coupling agent (e.g. 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride or N, N'-dicyclo-hexylcarbodiimide), 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 can be carried out in a suitable solvent, such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate, and at a temperature between 10 ° C and 40 ° C (room temperature), for a period of 1-24 hours.

1 Θ 2 S 5 9 I

* I

9

Those amines are commercially available or can be prepared by conventional methods well known to those skilled in the art (e.g. reduction, oxidation, alkylation, transition metal mediated coupling, protection, removal of protecting groups, etc.), from commercially available material.

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

10 ΟΠ H

"-V" - "y" · ch 2 OH wherein R a is a suitable acid protecting group, preferably a (C 1 -C 4) alkyl group containing, but not limited to, methyl and ethyl, according to any method employed in the it is well known to those skilled in the art to prepare an acid from an ester without altering the rest of the molecule, for example, the ester can be hydrolyzed by treatment with an acid or aqueous base (e.g., hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide) ), optionally in the presence of a solvent or mixture of solvents (for example water, 1,4-dioxane, tetrahydrofuran / water), at a temperature between 20 ° C and 100 ° C, for a period of 1 to 72 hours .

The ester of formula (4) can be prepared by reacting an amine of formula (5): • D> (CH 2 VOR a 35 ° wherein Ra and n are as previously described, with an epoxide of formula (6): 1028599 (6) 10 (<ν </ · η ° γ 5 ch2oh

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

The epoxide of formula (6) can be prepared according to the method described in US-4031108.

The amine of formula (5) wherein R1 is Me and R2 is H can be prepared as the (R) or (S) enantiomer from the corresponding protected amine of formula (7):

Rc

Rb "NX ^ V ^ L (7) 25 HJHCH *>" Y ° Ra o where Ra and n are as previously defined, and Rb and Rc represent any suitable substituents such that HN-30 RbRc is a chiral amine (Rb can for example hydrogen and Rc can be α-methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily split to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups , such as those found in the Handbook Protective Groups in Organic Syn-

1028599 I

11 thesis, third edition of T.W. Greene and P.G.M. Wuts, John Wiley and Sons Ine., 1999.

The amine of formula (7) can be prepared as a single diastereomer by reacting an amine of formula HNRbRc with a ketone of formula (8): H 3 CV ^ V ^ 1 (8) o

O

Wherein Ra, Rb, Rc and n are as previously described.

In a conventional process, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which in turn is reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride with formula Na (OAC) 3 BH), optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid), yielding the amine of formula (7) as a mixture of diastereomers. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature ranging between 20 ° C and 80 ° C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallized from a suitable solvent or mixture of solvents (e.g., isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) to yield (7) as a single diastereomer.

The ketone of formula (8) where n = 1 can be prepared by palladium-mediated coupling of an aryl halide of formula (9): 1028591 12 Χ> γ “· Bl

5 O

wherein Ra is as previously defined, and Hal represents a halogen atom that includes, but is not limited to, bromine and iodine, with an enolate or enolaate equivalent.

In a conventional process, the aryl halide of formula (9) is reacted with a tin enolate generated in situ by treatment of isopropenyl acetate with tri-n-butyl tin methoxide of formula

Bu3 SnOMe, in the presence of a suitable palladium catalyst (palladium acetate / tri-ortho-tolyl phosphine of formula Pd (Oac) 2 / P (o-Tol) 3) in a non-polar solvent (e.g. toluene, benzene, hexane). The reaction is preferably carried out at a temperature between 80 ° C and 110 ° C for 6 to 16 hours.

The aryl halide of formula (9) can be obtained by esterification of the corresponding acid of formula (10): (in) 25 - OH (} ^ 1 30 where Hal is as previously defined, according to any process well known to those skilled in the art to prepare an ester from an acid without altering the rest of the molecule.

In a conventional process, the acid of formula (10) is reacted with an alcohol-containing solvent of formula RaOH, where Ra is as previously defined, in the presence of an acid, such as hydrochloric acid, at a temperature between 10 ° C and 40 ° C (room temperature) for 8 to 16 hours.

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

The amine of formula (5), wherein R 1 and R 2 are both C 1-5 alkyl, can be prepared according to the following scheme:

Scheme 1 f ° H ~ R "R =: n (11) (12) 1" R1 is R2 (5) wherein R1, R2 and Ra are as previously described.

In a conventional process, the ester of formula (11) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCl or R 2 Li) yielding the corresponding tertiary alcohol of formula (12) using the process described above.

That tertiary alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to yield a protected intermediate which in turn is split using standard methodology for splitting off a nitrogen protecting group such as those mentioned in manuals. The resulting amino acid is then esterified using the method described herein to yield the amine of formula (5).

1028599 14

Alternatively, the amine of formula (5), wherein R 1 and R 2 are both C 1 -C 4 alkyl and n = 0, can be prepared according to the following scheme: Scheme 2 Η ° 'Χ / ^ ΐίΧ ^ _Β o \ ^ Br ~ R 'R2 ^^ "Br ~ 10 (13) (14) R' R2 \ ^" ΒΓ R 'R2 ^^ "o Ra (15) (5) wherein R1, R2 and Ra are as previously described.

In a conventional process, the ester of formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCl or R 2 Li) yielding the corresponding tertiary alcohol of formula (14) using the process described above.

The tertiary alcohol of formula (14) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to yield a protected intermediate which in turn is split with use of standard methodology for splitting off a nitrogen protecting group such as those mentioned in manuals, yielding the bromoamine (15).

The resulting bromamine (15) is treated with a suitable palladium catalyst (e.g., [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) under an atmosphere of carbon monoxide using RaOH as solution 1028111

* I

Release agent (e.g. MeOH, EtOH) at an elevated temperature (100 ° C) and pressure (100 psi) to yield the ester of formula (5).

The ketone of formula (8) wherein n = 2 can be prepared by reduction of an olefin of formula (16): τ T - '(16) 0 ORa

In a conventional process, 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 carbon) and stirred under an atmosphere of hydrogen, optionally at an elevated pressure (e.g. 60 psi), at a temperature between room temperature and 60 ° C for 8-24 hours.

The olefin of formula (16) can be prepared by a palladium-mediated coupling of an activated olefin with an aryl halide of formula (17):

In a conventional process, 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 (O) of formula Pd (Pfen3) 4, palladium acetate / tri- ortho-tolylphosphine of formula Pd (Oac) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocenylpalladium chloride of formula dppfPd-35 CI 2 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 8-24 hours.

The ketone of formula (17) is a commercial product.

Alternatively, a compound of formula (1) can be prepared by reacting a bromide of formula (6) and an amine of formula (18): 10 (18> o where R 1, R 2, Q 1 and n are as previously described is for the compounds of the formula (1), unless stated otherwise.

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

The amide of formula (18) can be prepared by an acid of formula (19) that a suitable amine protecting group PI: 3 ° (19)

"A I - (chj" OH

R ’R * γ

O

35, to be coupled with an amine of the formula NHR8-Q2-A, NHR8-Q3, 1028599 17

* * R. ^ s φΟ. »QC

HN-fc R6 R11 T Λ (CH2) q R6 R6 R119>

HN R «HN N — R« HN ^^ N — R «HN ^ ^ O

10 'w' \ _ / \ - / \ _ / V 9 I. , or

HN 'X

Coupling is generally carried out in an excess of that amine as an acid receptor, with a conventional coupling agent (e.g. 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride or Ν, Ν'-dicyclo-hexylcarbodiimide ), 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 can be carried out in a suitable solvent, such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at a temperature between 10 ° C and 40 ° C (room temperature) for a period of time from 1-24 hours.

That amine is commercially available or can be prepared by conventional methods well known to those skilled in the art (e.g. reduction, oxidation, alkylation, transition metal mediated coupling, protection, removal of protecting groups, etc.), from commercially available material.

The acid of formula (19) can be prepared from the corresponding ester of formula (5).

1028599 18

The acid of formula (19), wherein R1 and R2 are both C1 -C1 alkyl, can be prepared from the ester (5) containing a suitable amine protecting group P1, before or after the acid formation: (5)

• I: - (CH2) 0 Ra R1 R2 YY. Y

O

Wherein R a is a suitable acid protecting group, preferably a (C 1 -C 4) alkyl group that contains, but is not limited to, methyl and ethyl, according to any method well known to those skilled in the art to acidify from an ester without changing the rest of the molecule. The ester can be hydrolyzed, for example, by treatment with an acid or aqueous base (e.g., hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g., water, 1,4-dioxane, tetrahydrofuran / water ), at a temperature between 20 ° C and 100 ° C, for a period of 1 to 40 hours.

The amine of formula (7), wherein R1 and R2 are both H, can be prepared according to the following scheme:

Schedule 3

H0V ^ S X ΗΟχ / χτΤ ^ ι X

5 ([<≤ c, -NN ORa O O ^ ^ -CHA ORa (20) (21) - 1028599 19 wherein R1, R2 and Ra are as previously defined.

In a conventional process, the acid of formula (20) is preferentially reduced to the corresponding alcohol (21) in the presence of the ester. This can be done by forming the acylimidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.

That primary alcohol of formula (21) is then converted to a leaving group, such as mesylate, tosylate, bromide or iodide, and displaced by a suitable amine nucleophile. The preferred nucleophile is the azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Other nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to provide the amine.

For a number of steps of the above-described method of preparing the compounds of formula (I), it may be necessary to protect potentially reactive functional groups that are not desired to react, and to subsequently cleave off those protecting groups. In such a case, any suitable protecting group can be used. In particular, methods for protecting and removing protecting groups such as those described by T.W. Greene and P.G.M. Wuts (Protective Groups in Organic Synthesis, John Wiley and Sons Ine., 1999) or by P.J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.

All of the above-described reactions and the preparation of new starting materials used in the foregoing processes are conventional and suitable reagents and reaction conditions for their implementation or preparation as well as methods for isolating the desired products will be well known to those skilled in the art. 1028599 I 20 are known with regard to literature precedents and the examples and preparations relating thereto.

The compounds of formula (1) as well as intermediates for their preparation can also be purified by various well-known methods, such as, for example, crystallization or chromatography.

In a preferred embodiment of the invention, Q 2 is a single bond.

In a preferred embodiment of the invention, A is selected from morpholinyl, pyrrolidinyl, piperidyl, piperazinyl or pyrazolyl optionally substituted with a methyl group.

In a preferred embodiment of the invention, A is selected from pyrazolyl optionally substituted with one or two C 1 -C 4 alkyl groups.

In a preferred embodiment of the invention, Q1 * is -NR8-Q3.

In a preferred embodiment of the invention, Q 1 is a group selected from 7 V 2 R 2.

*. N \ - <R'3 —I \ / N-R'2 25 R11 t, * —sl — R12 * "" N ^ * \ • »30

The following group of compounds of formula (1) is more preferred: 21

OH

R1 R2 'Ί' · 'Ah ° where the (CH2) n ~ C (= 0) Qx group is at the meta or para position,

10 - R1 and R2 are independently selected from H

and C 1 -C 4 alkyl; n is 0, 1 or 2; Q1 is a group selected from r3 γ f3 K Kid R6 R6 and a group * -NR8-Q2-A, where p is 1 or 2, Q2 is a C 1 -C 4 alkylene, R 8 is H or C 1 C 4 alkyl and A is pyridyl, C 3 -C 10 cycloalkyl, wherein said cycloalkyl is optionally bridged by 1, 2, 3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydothiopyranyl or a group R 3 R 4 R3) - (R5 or R7 is Re, 35 - R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1 -C4 alkyl, OR9, SR9, SOR9, SO2R9, 1028599 4 22 halogen, CN, CF 3, OCF 3, SO 2 NR 9 R 10, COOR 9, CONR 9 R 10, NR 9 R 10, NHCOR 10 and phenyl optionally substituted with OH; R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl and, - * the attachment point to the carbonyl group, or, if appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotope variations thereof.

The compounds of formula (1) containing the following 10 substituents are preferred.

Preferably, Q1 is a group * -NH-Q2-A wherein A is cyclohexyl or adamantyl.

Preferably, Q1, R3, R4, * 3 are V- / XR1, R6 where R3, R4, R5 and R6 are H.

Preferably, Q 1 is a group * -NH-Q 2 -A wherein A is a group V / H L V r 'R 6 wherein R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, C 1 -C 4 alkyl, OR 9, SR 9, SOR 9, SO 2 R 9, halogen, CF 3, OCF 3, SO 2 NR 9 R x O, CONR 9 R 10, NR 9 R 10, NHCOR 10 and phenyl, provided that at least 2 of R 3 to R 7 are equal to 35 H; wherein R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl.

1028599 23

More preferably, Q1 is a group * -NH-Q2-A where A is a group R3, R4, 5 -R5

W RB

10 wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, OH, CH3, OCH3, ÖCH2-CH3, SCH3, halogen, preferably Cl or F, CF3, provided that at least 2 of R3 until R 7 is H.

In the foregoing groups of compounds, the following substituents are particularly preferred: Q 2 is -CH 2 -, - (CH 2) 2 -, - (CH 2) 3 - or -C (CH 3) 2 - at preferably -ch2-.

R 1 is H or C 1 -C 4 alkyl and R 2 is C 1 -C 4 alkyl. More preferably, R1 is H20 or CH3 and R2 is CH3. n is 1.

R1 is H and R2 is CH3 and n is 1.

R1 is CH3, R2 is CH3 and n is 1.

The following compounds, which can be prepared according to the methods described herein, are preferred: N-benzyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6]) - (hydroxy-methyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -30-acetamide; N-cyclopropyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxy-methyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} - acetamide; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -35-pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [( IR, 2S) -2- (hydroxymethyl) cyclohexyl] acetamide; 1028599 24 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl-N- (3 morpholin-4-yl-propyl-acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl-N- (pyridine-2-) ylmethyl) acetamide; 2- {3- [2- ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl) -N- (2-morpholine) 4-ylethyl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl-N-isopropylacetamide; N- (4-chlorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] - Phenyl} acetamide; N- [2- (dimethylamino) ethyl] -2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} acetamide; N- [2- (diethylamino) ethyl] -2- {3- [2 - ((2-hydroxy-2- [5-20 hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl}) amino) -2-methylpropyl] phenyl} acetamide; N- [3- (dimethylamino) propyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine]) 2-yl] ethyl-amino) -2-methylpropyl] phenyl} acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) } amino) -2-methylpropyl] phenylJ-N-pentylacetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) ) -2-methylpropyl] phenyl} -N- (2-30 pyrrolidin-1-ylethyl) acetamide; N- (2,4-dichlorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [ 5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl-amino) -2-methylpropyl] -phenyl} acetamide; N- (3,4-dichlorobenzyl) -2- {3— [2 - ({2-hydroxy) -2- [5-hydroxy-6-35 (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl acetamide, 1028599 2- {3 - [2 - ((2-hydroxy-2) - [5- hydroxy-6- (hydroxymethyl) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (4-methoxybenzyl) acetamide; N- (2-hydroxyethyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6-5 (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-propylacetamide; 2 - {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- (3 methoxypropyl acetamide; N-cyclobutyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl] acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} -N - [(IR) - 1- (1-naphthyl) ethyl] acetamide; N-2,3-dihydro-1H-inden-1-yl-2- {3- [2 - ({2-hydroxy-2- [5-20 hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) } amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [2- (1-methylpyrolidin-2-yl) ethyl] acetamide; N- (4-fluorobenzyl) -2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl } acetamide; 2 - {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl-amino) -2-methylpropyl] phenyl} -N- (4 -30 phenylbutyl) acetamide, 2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} -N - (3-methoxybenzyl) acetamide, N- (3-ethoxypropyl) -2- (3- (2 - ((2-hydroxy-2- [5-hydroxy-6-35 (hydroxymethyl) pyridin-2-yl] ethyl-amino) ) -2-methylpropyl] phenyl} acetamide, 1028599 26 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) - 2-methylpropyl] phenyl} -N- (3,4,5-trimethoxybenzyl) acetamide; 2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -5-pyridine) 2-yl] ethyl-amino) -2-methylpropyl] phenyl) -N- [4- (trifluoromethyl) benzyl] acetamide; 2- (3- [2 - ({2-hydroxy-2- [5-hydroxy-6- ( hydroxymethyl) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) -N- [2- (trifluoromethyl) benzyl] acetamide; 10 N- (3,5-dimethoxybenzyl) -2- {3- [ 2 - (( 2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} acetamide; .

2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (2- Phenoxyethyl) acetamide 2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} - N - [(IS) -2-hydroxy-1-methyl-ethyl] acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -20-pyridin-2-yl] ] ethyl} amino) -2-methylpropyl] phenyl) -N - [(IS) - 1- (hydroxymethyl) -2-methylpropyl] acetamide, 2- (3- [2 - ((2-hydroxy-2- [5 -hydroxy-6- (hydroxymethyl) -pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- [(IS, 2S) -1- (hydroxymethyl) -2-methylbutyl] acetamide; 25 N - [(IR) -1-benzyl-2-hydroxyethyl] -2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) ) -2-methylpropyl] phenyl} -acetamide; 2 - {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2 - methylpropyl] phenyl} - N - [(IR) - 30 - 1- (hydroxymethyl) propyl] acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) - pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl) -N - [(IS ) 1- (hydroxymethyl) -2,2-dimethylpropyl] acetamide; N - [(IS) -2-cyclohexyl-1- (hydroxymethyl) ethyl] -2- (3- (2 - ((2-35 hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine-2- yl] -ethyl) amino) -2-methylpropyl] phenyl} acetamide, 1028599 27 N - [(1S, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -2- (3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2- ( {2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (2-propoxyethyl) acetamide; N- (4 -hydroxycyclohexyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3- propoxypropyl) acetamide, N-ethyl-N- (2-hydroxyethyl) -2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl]) amino) -2-15 methylpropyl] phenyl} acetamide; 1- ((3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino)) -2-methylpropyl] phenyl} acetyl) piperidine-4-carbox amide; 6- (2 - ((2- (3- (2- (4-acetyl-piperazin-1-yl) -2-oxoethyl] -20-phenyl] -1,1-dimethylethyl) amino] -1-hydroxyethyl} -2-) (hydroxymethyl) pyridine-3-ol; 6- (2 - ((2- (3- [2- (3,4-dihydroisoquinoline-2 (1 H) -yl) -2-oxoethyl] phenyl} -1, 1- dimethylethyl) amino] -1-hydroxyethyl} 2- (hydroxymethyl) pyridine-3-ol; N-benzyl-2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- ( hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-methylacetamide; 6- (1-hydroxy-2 - {[2- (3- (2- (4- (2-hydroxyethyl) ) piperazin-1-yl] -2-oxoethyl] phenyl) -1,1-dimethylethyl] amino} ethyl) -2-30 (hydroxymethyl) pyridine-3-ol; 6- (2 - {[2- (3- (2- (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl] -2-oxoethyl] phenyl) -1,1-dimethylethyl] amino] -1-hydroxyethyl) -2- (hydroxymethyl) pyridine-3 -ol; 6- (2 - ((1'-dimethyl-2- (3- [2- (4-methylpiperazin-1-yl) -2-35 oxoethyl] phenyl) ethyl) amino] -1-hydroxyethyl} -2 - (hydroxymethyl) pyridine-3-ol, 1028599 28

1 · I

2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-methyl-N - (2-phenylethyl) acetamide; 6 - {2 - [(1,1-dimethyl-2- {3- [2-oxo-2- (4-pyridin-2-yl-pipera-5-zin-1-yl) ethyl] phenyl} ethyl) amino] - 1-hydroxyethyl} -2- (hydroxymethyl) pyridine-3-ol; N- [3- (dimethylamino) propyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2- methylpropyl] phenyl} -N-methylacetamide; N- (2-hydroxyethyl) -2- {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] -phenyl] -N-propylacetamide; N- [2- (diethylamino) ethyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-15 methylpropyl ] phenyl] -N-methylacetamide; 6- {2 - [(1,1-dimethyl-2- {3- [2- (4-methyl-1,4-diazepan-1-yl) -2-oxoethyl] phenyl] ethyl) amino] -1- hydroxyethyl} -2- (hydroxymethyl) pyridine-3-ol; 6- (2 - [{1,1-dimethyl-2- [3- (2-morpholin-4-yl-2-oxoethyl) -20 phenyl] ethyl] amino) -1-hydroxyethyl] -2- (hydroxymethyl) pyridine-3-ol; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-methyl-N - [(IS) -1-phenylethyl] acetamide; 6 - (2 - ((1,1-dimethyl-2- [3- (2-oxo-2-piperidin-1-ylethyl) phenyl] ethyl] amino) -1-hydroxyethyl] -2- (hydroxymethyl) -pyridine-3-ol; 6- (1-hydroxy-2 - {[2- (3 - {2 - [(3R) -3-hydroxy-pyrrolidin-1-yl] -2-oxoethyl] phenyl) -1.1 -dimethylethyl] amino] ethyl) -2-30 (hydroxymethyl) pyridine-3-ol; 6- (1-hydroxy-2 - {[2- (3- (2 - [(3R) -3-hydroxypiperidine-1-) yl] -2-oxoethyl] phenyl) -1,1-dimethylethyl] amino] ethyl) -2- (hydroxymethyl) pyridine-3-ol; 6- (2- [(2- {3- [2- (4- acetyl-1,4-diazepan-1-yl) -2-oxoethyl] -35 phenyl} -1,1-dimethylethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) pyridine-3-ol; 102 8 S 9§ 29 6- (1-hydroxy-2 - {[2- (3 - {2 - [4- (hydroxymethyl) piperidin-1-yl] -2-oxoethyl} phenyl) -1,1-dimethylethyl] amino} ethyl) -2- (hydroxymethyl) pyridine-3-ol; N- [1 - ({3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -5-pyridine-2-) yl] ethyl} amino) -2-methylpropyl] phenylacetyl) pyrrolidin-3-yl] -N-methylacetamide 2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) ) -pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- (2-methoxyethyl) -N-propylace N-ethyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (2-methoxyethyl) acetamide; N- [3- (dimethylamino) -2,2-dimethylpropyl] -2- {3- [2 - ((2-hydroxy-2- (5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] -15 ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- [3-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6]) - (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) - Pyridin-2-yl] ethyl-amino) -2-methylpropyl] phenyl} -N - [(IS) - 1- (hydroxymethyl) -3-methylbutyl] acetamide; 2- {3- [2 - ((2-hydroxy-) 2- [5-hydroxy-6- (hydroxymethyl) -pyridin-2-yl] -ethyl-amino] -2-methyl-propyl] -phenyl} -N - [(IS) -2-hydroxy-1-phenylethyl] -acetamide; 25 N / N -diethyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; - {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N-1H-pyrazole -5-ylacetamide; 2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} - N- (5-methyl-1 H -pyrazol-3-yl) acetamide; N- (cyclohexylmethyl) -2- {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6-35 (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl acetamide; 1028599 * * ethyl-4 - ({3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyljacetyl piperazine 1-carboxylate; N- (5-chloropyridin-2-yl) -2- {3— [2 - ({2-hydroxy-2- [5-5 hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2- methylpropyl] phenyl} acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- (6- methylpyridin-2-yl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3 -methylpyridin-2-yl) acetamide; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methyl-propyl] phenyl} -N-15 isoquinoline-1- ylacetamide; N- (4,6-dimethylpyridin-2-yl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2- ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -20-pyridin-2-yl] ethyl] amino) -2-methyl-propyl] phenyl} -N- (2-methoxybenzyl) acetamide; N - [(IS) -1-benzyl-2-hydroxyethyl] -2- {3— [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl}) amino) -2-methylpropyl] phenyl} acetamide; N- (1-ethyl-1H-pyrazol-5-yl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl-amino) -2-methylpropyl] phenyl} acetamide; N- (1,3-dimethyl-1H-pyrazol-5-yl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl]) ethyljamino) -2-30 methylpropyl] phenyljacetamide; N- (3-fluorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} acetamide; 1 - ({3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -35-pyridin-2-yl] ethyl] amino) -2-methyl-propyl] phenyl-acetyl) -L-proline amide; 1028599 • * 31 6 - {2 - [(2 - {3 - [2- (5-amino-3-t-butyl-1H-pyrazol-1-yl) -2-oxoethyl] phenyl} -1, 1- dimethylethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) pyridine-3-ol; 2 - {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N - [( IS) - 1-phenylethyl] acetamide, N- (3,4-dimethylbenzyl) -2- (3 - {2 - [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] - 2-methylpropyl} - phenyl) acetamide, 10 N- [2- (4-chlorophenyl) ethyl] -2- (3- (2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridine-2-) yl) ethylamino] -2-methyl-propyl} phenyl) acetamide, 6- (2- [(2 - {3 - [2 - (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) - 2-oxoethyl] phenyl} -1,1-dimethylethyl) amino] -1-hydroxyethyl} -15 2- (hydroxymethyl) pyridine-3-ol; and N- (2-hydroxybenzyl) -2- (3 - {2 -) [(2R) -2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide, N-benzyl 2- (3 - {(2R) -2- [ 2-hydroxy-2- (5-hydroxy-6-hydroxy-methylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide, N- (3,4-dimethylbenzyl) -2- (3 - ((2R) - 2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} -phenyl) acetamide; N- (2,5-dimethylbenzyl) -2- (3 - {(2R)) -2- [2-hydroxy-2- (5-25 hr ydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide; 2- (3 - ((2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethyl-pyridin-2-yl) ethylamino] propyl} phenyl) -N- (2-methoxy-benzyl) N- (2-ethoxybenzyl) -2- (3 - ((2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) - N- (3,4-dichlorobenzyl) -2- (3 - {(2 R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-35 yl) ethylamino] propyl} phenyl ) acetamide, and 1028599 32 N- (2-chloro-6-fluorobenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl acetamide.

According to one aspect of the present invention, the compounds of formula (1) are generally preferred wherein the (CH 2) n -C (= O) Q 1 group is in the meta position.

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

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, beosylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, ash -ylate, formate, fumarate, glucepate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate , D- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, phosphate / phosphate dihydrogen, pyroglutamate, saccharate, stearate, succinate, tannate, D and L tartrate, 1-hydroxy-2-naphthoate, tosylate and xinafoate salts.

Suitable basic salts are formed from bases that form non-toxic salts. Examples include the aluminum, argihine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tro- . methamine and zinc salts.

1028599 33

Hemi salts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

For an overview of suitable salts, see "Handbook 5 of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

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

All three reactions are generally carried out in a solution. The resulting salt can precipitate and be collected by filtration or can be obtained by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex that contains the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used if that solvent is water.

Within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug that contain two or more organic and / or inorganic components that can be in stoichiometric or non-stoichiometric amounts. The complexes obtained may be ionized, partially ionized or non-ionized. For an overview of such complexes, see J. Pharm. Sci., 64 (8), 1269-1288 from Haleblian (August 1975).

20

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

25

The compounds of the invention include compounds of formula (1) as described above, including all polymorphs and crystal formations thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as described below, and compounds labeled with isotopes of formula (1).

As indicated, so-called "prescription drugs" also fall within the scope of the invention. Thus, certain derivatives of compounds of formula (1), which themselves may have little or no pharmacological activity, when administered to or on the body, may be converted into compounds of formula (1) which have the desired activity, for example by hydrolysis. technical split. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E.B. Ro-10 che, American Pharmaceutical Association).

Prodrugs according to the invention can be prepared, for example, by replacing suitable functional groups in the compounds of formula (1) with certain residues known to those skilled in the art as "fore residues", as described, for example, in "Design or Prodrugs "by H. Bundgaard (Elsevier, 1985),

Some examples of prodrugs according to the invention include: (i) when the compound of formula (1) contains a functional carboxylic acid group (-COOH), an ester thereof, for example a compound wherein the hydrogen of the functional carboxylic acid group of the compound of formula (1) is replaced by (C 1 -C 6) alkyl; (ii) when the compound of formula (1) contains a functional alcohol group (-OH), an ether thereof, for example a compound in which the hydrogen of the functional alcohol group of the compound of formula (1) is replaced by ( C 1 -C 6 alkanoyloxymethyl; and (iii) when the compound of formula (1) has a functional

35 primary or secondary amino group (-NH 2 or -NHR)

wherein R Φ contains H), an amide thereof, for example a compound in which, as may be the case, one or both of 1028599 36 hydrogens of the functional amino group of the compound of formula (1) have been replaced by (C 1 -C 10) alkanoyl.

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

In addition, some compounds of formula (1) may function themselves as prodrugs of other compounds of formula (1).

Also included in the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include (i) when the compound of formula (1) contains a methyl group, a hydroxymethyl derivative thereof (-CH 3 -> -CH 2 OH); (ii) when the compound of formula (1) contains an alkoxy group, a hydroxy derivative thereof (-OR - »-OH); (Iii) when the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR1 R2 -NHR1 or -NHR2); (Iv) when the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2); (v) when the compound of formula (1) contains a phenyl radical, a phenol derivative thereof (-Ph -PhOH); and

10 2 8 SS

(Vi) when the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH 2, -COOH).

Compounds of formula (1) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. When a compound of formula (1) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. When structural isomers can be converted into each other via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can be in the form of proton automerism in compounds of formula (1) which contain, for example, an imino, keto or oxime group, or so-called valentiet-carrie in compounds which contain an aromatic radical. It follows that a single compound can exhibit more than one type of isomerism.

The scope of the present invention includes all stereoisomers, geometric isomers, and tautomeric forms of the compounds of formula (1), including compounds that exhibit more than one type of isomer, and mixtures of one or more thereof. Also included are acid addition or basic salts where the counter ion is optically active, for example d-lactate or I-lysine, or is racemic, for example dl tartrate or dl arginine.

Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or separation into enantiomers of the racemate (or the race 1028599

I I

38 measure of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

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

15

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

25

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

30

In one aspect of the present invention, the (R, R) stereoisomer of the following formula is generally preferred wherein R 1 is hydrogen and R 2 is C 1 -C 4 alkyl, preferably methyl, and 35 n and Q1 are as described above: 1028599 39

OH

ï Η 5 Γτ <cha \ / Q ’ηο ^ υν ri rj ^ γ ch2oh 0

The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of formula (1) wherein one or more atoms have been replaced by atoms having the same atomic number, but an atomic mass that is different from the atomic mass or mass that is in nature has the upper hand '.

15

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as UC, 13 C and 14 C, chlorine such as 36 Cl, fluorine such as 10 F, iodine such as 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 150, 170 and 1 BO, phosphorus such as 32 P, and sulfur such as 35 S.

Some isotope-labeled compounds of formula (1), for example those containing a radioactive isotope, are useful in investigating drug and / or substrate distribution in tissue. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of recording and convenient detection means.

Substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic benefits that result from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence 1 to 2 '8 5 9 940 may be preferred in some circumstances.

Replacement with isotopes emitting positrons, such as UC, 18F, 150 and 13N, may be useful in positron emission topography (PET) studies to investigate receptor occupancy with substrate.

Isotope-labeled compounds of formula (1) may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, using a suitable isotope-labeled reagent instead of the non-labeled reagent previously used.

Pharmaceutically acceptable solvates according to the invention include those in which the solvent for crystallization may be substituted with isotopes, for example D20, d6-acetone, dg-DMSO.

The compounds of formula (1), their pharmaceutically acceptable salts and / or forms obtained therefrom are valuable pharmaceutically active compounds which are suitable for the treatment and preventive treatment of numerous disorders in which the P2 receptor is involved or in which agonism of this receptor can occur. lead to benefits, in particular respiratory diseases that may or may not be due to allergies, but also in the treatment of other diseases such as, but not limited to, those of the central nervous system, premature labor pains, congestive heart failure , depression, inflammatory skin diseases and skin diseases due to allergy, psoriasis, proliferative skin diseases, glaucoma, and in conditions where there is an advantage in reducing gastric acidity, particularly in gastric and peptic ulcers.

Compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. For example, they can be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Drying with microwaves or radio wave lengths can be used for this purpose.

They may be administered separately or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as an optional combination thereof). In general, they will be administered as a preparation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any component that differs from the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

25

Pharmaceutical compositions suitable for the release of compounds of the present invention, and methods of their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention can be administered orally. Oral administration may mean swallowing, so that the compound enters the gastrointestinal tract, or buccal 1028599 42 or sublingual administration may be used whereby the compound enters the bloodstream directly from the mouth.

Preparations suitable for oral administration include solid preparations such as tablets, capsules containing particulate matter, liquids or powders, lozenges (including liquid-filled), sweets, multi and nano-particulate matter, gels, solid solution, liposome, films, eggs, sprays, and liquid preparations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions can be used as fillers in soft or hard capsules and generally contain a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. . Liquid preparations can also be prepared by the reconstitution of a solid, for example from a sachet.

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

For tablet dosage forms, depending on the dose, the drug may comprise 1% to 80% by weight of the dosage form, more usually 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted starch, hydroxypropyl cellulose starch, starch-propyl cellulose . In general, it will disintegrate. from 1 wt% to 25 wt%, more preferably 5 wt% to 20 wt% of the dosage form.

5

Binders are generally used to impart binding properties to a tablet preparation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pre-gelled starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrosse, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may optionally also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. If present, surfactants can make up 0.2% to 5% by weight of the tablet and lubricants can make up 0.2% to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably 0.5% to 30% by weight of the tablet.

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

35

Typical tablets contain up to about 80% drug, about 10% to about 90% by weight 1028599 44 binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight disintegrant and about 0.25 wt% to about 10 wt% lubricant.

5

Mixtures of tablets can be compressed directly or with a roller to form tablets. Mixtures of tablets or parts of mixtures can alternatively be wet, dry or melt granulated, melted or extruded prior to tableting. The final preparation may contain one or more layers and may or may not be coated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, vol. 1, from H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Edible oral films for human or veterinary use are generally bendable water-soluble or water-swellable dosage forms of a thin film that rapidly dissolve or adhere to the mucosa and generally a compound of formula (1), a film-forming polymer, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the preparation can perform more than one function.

The compound of formula (1) can be water soluble or insoluble. A water-soluble compound generally forms from 1% by weight to 80% by weight, more generally from 20% to 50% by weight of the dissolved substances. Less soluble compounds may constitute a larger proportion of the composition, generally up to 88% by weight of the dissolved substances. Alternatively, the compound of formula (1) may be in the form of beads of multiple particles.

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

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

Films according to the invention are generally prepared by drying by evaporation thin aqueous films which are coated on a carrier or paper with a removable backing layer. This can be done in a drying oven or drying tunnel, generally a combined device for coating and drying, or by freeze drying or vacuum suction.

Solid compositions for oral administration can be formulated for immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, regulated, targeted, and programmed release.

30

Suitable modified release preparations for the purpose of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable delivery technologies such as high energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-line, 25 (2), 1-14, from Verma et al.

1028599 46 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly into the bloodstream, into a muscle or into an internal organ. Suitable agents for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-urethral, intrasternal, intracranial, in-tramuscular, and subcutaneous agents. Suitable devices for parenteral administration include injectors with a needle (including a micro needle), needle-free injectors and infusion techniques.

Parenteral compositions are generally aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably up to a pH of 3 to 9), but for some applications, they may more conveniently be formulated as a ste-20. sterile non-aqueous solution or as a dried form to be used together with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

! The solubility of compounds of formula (1) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents.

35

Preparations for parenteral administration can be formulated for immediate release and / or modified release. Modified-release preparations include delayed, long-lasting, pulsed, regulated,. targeted and programmed delivery. Thus, compounds of the invention can be formulated as a solid, semi-solid or thixotropic fluid for administration as an implanted depot that provides modified release of the active compound. Examples of such compositions include drug-coated stents and microspheres of poly (dl-milk-coglycol) acid (PGLA).

The compounds of the invention may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressing materials, foams, films, skin patches, waffles, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white vaseline, glycerin, polyethylene glycol, and propylene glycol. Agents that increase penetration can be included - see, for example, J. Pharm. Sci., 88 (10), 955-958 from Finnin and Morgan (October 1999).

25

Other means for topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and injection via a micro needle or without a needle (e.g., Powderject ™, Bioject ™, etc.).

30

Preparations for topical administration may be formulated for immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, regulated, targeted, and programmed release.

1028599 48

The compounds of the invention can also be administered intranally or by inhalation, generally in the form of a dry powder (individually, as a mixture, for example in a dry mixture with lactose, or as a particle of mixed components, for example mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, aerosol, atomizer (preferably an atomizer using electrohydrodynamica to produce a fine mist), or syringe, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane. or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a biological adhesive, for example chitosan or cyclodextrin.

The container under pressure, pump, spray can, spray or spray contains a solution or suspension of the compound (s) of the invention that, for example, solubilize, dissolve or enlarge ethanol, an aqueous ethanol solution or a suitable alternative means for dispersing of the release of the active agent, a propellant gas (propellant gases) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligamic acid.

Before use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (generally less than 5 microns). This can be accomplished by any suitable method of fine grinding, such as spiral-jet grinding, fluid-bed jet grinding, supercritical fluid-forming liquid to form nanoparticles, high-pressure homogenization, or spray-drying.

1028599 49

Capsules (made for example from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to form a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch, and an agent performance, such as 1-leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable formulation of a solution for use in an atomizer using electrohydrodynamica to produce a fine mist may contain 1 µg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μΐ to 100 μΐ. A conventional preparation may contain a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

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

30 ..

Preparations for administration by inhalation / intranasal administration may be formulated for immediate release and / or modified release using, for example, PGLA. Modified-release preparations include delayed, sustained, pulsed, regulated, targeted, and programmed release.

10285S9 50

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a measured amount. Units of the invention are generally controlled to administer a measured dose or "puff" containing 0.001 mg to 10 mg of the compound of formula (1). The total daily dose will generally be in the range of 0.001 mg to 40 mg, which can be administered in a single dose or, more usually, as divided doses over the day.

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

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

20

Preparations for rectal / vaginal administration can be formulated for immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, regulated, targeted, and programmed release.

The compounds of the invention can also be administered directly to the eye or ear, generally in the form of drops of a micronized suspension or solution in an isotonic, pH-adjusted, sterile saline solution. Other preparations suitable for eye and ear administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, waffles, lenses, and particle-shaped or vesicle-forming systems, such as niosomes or liposomes. A polymer, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, can be incorporated together with a preservative, such as benzalkonium chloride. Such compositions may also be delivered by iontophoresis.

Preparations for administration to eye and ear can be formulated for immediate release and / or modified release. Modified-release preparations include delayed, sustained, pulsed, regulated, targeted, or programmed release.

The compounds of the invention can be combined with soluble macromolecular units, such as cyclodextrin and suitable derivatives thereof or polyethyleneglycol-containing polymers, to improve their solubility, rate of dissolution, masking of taste, biological availability and / or stability. improve for use in one of the aforementioned modes of administration.

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizing agent. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in international patent applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

35

To the extent that it may be desirable to administer a combination of active compounds, for example, to treat a specific disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which is a compound according to the invention, can be suitably assembled in the form of a kit suitable for administration together with the compositions.

Thus the kit of the invention contains two or more separate pharmaceutical preparations, at least one of which contains a compound of formula (1) according to the invention, and means for separately storing those preparations, such as a container, divided bottle or shared fo-run package. An example of such a kit is the known blister package that is used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example parenterally, for administering the individual compositions at different dosage intervals, or for titrating the individual compositions against each other. To promote flexibility, the kit generally contains instructions for administration and can be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention is generally in the range of 0.001 mg to 5000 mg depending, of course, on the mode of administration. For example, an intravenous daily dose may require only 0.001 mg to 40 mg. The total daily dose can be administered in a single dose or divided doses and may, in the physician's opinion, fall outside the usual range given herein.

1028599 53

These dosages are based on an average human patient weighing around 65 to 70 kg.

. The doctor will be able to easily determine doses for patients whose weight falls outside this range, such as children and the elderly.

For the avoidance of doubt, references herein to "treatment" include references to healing, analgesic, and preventative treatment.

10

According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, forms therefrom or mixtures thereof can also be used as a combination with one or more additional therapeutic agents to be administered together to a patient to obtain a specific desired therapeutic end result, such as the treatment of pathophysiologically relevant disease processes including, but not limited to, (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, signs and symptoms such as shortness of breath, cough. The second and more additional therapeutic agents may also be a compound of formula (1), or a pharmaceutically acceptable salt, forms thereof, or mixtures thereof, or one or more P2 agonists known in the art. More generally, the second and more therapeutic agents will be selected from a different class of therapeutic agents.

30. As used herein, the terms "administration together with", "administered together with" and "in combination with" are intended to refer to the compounds of formula (1) and one or more other therapeutic agents , which mean and relate to and which include: • simultaneous administration of such a combination of a compound (s) of formula 1028599 54 (1) and a therapeutic agent (s) to a patient in need of treatment , if such components are formulated together in a single dosage form that delivers those 5 components to that patient at substantially the same time, • substantially simultaneous administration of such a combination of a compound (s) of formula (1) and a therapeutic agent (therapist). Means) to a patient in need of treatment, when such components are formulated separately from each other in separate dosage forms taken by that patient at substantially the same time, after which said components are delivered to that patient at substantially the same time, • sequential administration of such a combination of a compound (s) of formula (1) and a therapeutic agent (s) to a patient in need of treatment, when such components are formulated separately from each other in separate dosage forms taken by that patient at successive times with a significant interval between each administration, after which that components are delivered to that patient at essentially different times; and • sequential administration of such a combination of a compound (s) of formula (I) and a therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that those components delivers in a controlled manner, after which they are administered to that patient simultaneously, sequentially and / or overlapping at the same time and / or different times, wherein each part can be administered by the same or a different route.

Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of formula (1), or pharmaceutically acceptable salts thereof, forms obtained therefrom or mixtures thereof, include, but are not in any way limited to: (a) 5-lipoxygenase inhibitors (5-LO inhibitors) or antagonists of 5-lipoxygenase activating protein (FLAP), (b) leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4 and LTE4, (c) histamine receptor antagonists including H1 and H3 antagonists, (d) αχ and ct2 adrenoceptor agonist vasoconstrictor sympathomimetic agents for use as deconge stivum, (e) muscarinic M3 receptor antagonists or anticholinergic agents, (f ) PDE inhibitors, for example PDE3, PDE4 and PDE5 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 glucocorticosteroid n, such as DAGR (dissociated corticoid receptor agonists), (k) monoclonal antibodies active against endogenous inflammatory entities, (1) anti-tumor necrosis factor agents (anti-TNF-α agents), (m) adhesion molecule inhibitors including VLA -4 antagonists, (n) quinine and B2 receptor antagonists, (o) immunosuppressive agents, (p) inhibitors of matrix metalloproteases (MMPs), 1028599 56 (q) tachykinin NK1, NK2 and NK3 receptor antagonists, (r) elastase inhibitors, (s) adenosine A 2a receptor agonists, (t) inhibitors of urokinase, 5 (u) compounds that act on dopamine receptors, for example D2 agonists, (v) modulators of the NFxp route, for example IKK inhibitors , (w) modulators of the cytokine signaling pathways, such as p38 MAP kinase, syk kinase or JAK kinase inhibitor, (x) agents that can be classified as mucolytic agents or antitussives, (y) antibiotics, (z ) HDAC inhibitors, and, (aa) PI3 kinase inhibitors.

According to the present invention, preference is given to a combination of the compounds of formula (1) with: 20 - H3 antagonists, muscarinic M3 receptor antagonists, PDE4 inhibitors, glucocorticosteroids, adenosine A2a receptor agonists, - modulators of cytokine signaling pathways, such as p38 MAP kinase or syk kinase, or, leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4 and LTE4.

According to the present invention, furthermore, preference is given to a combination of the compounds of formula (1) with: glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, predn-isolon, flunisolide, triamcinolone acetonide, and 1028599 57 clomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate, or muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitepine salts, pepsinepepine salts, and p.

It is to be understood that all references herein to treatment include healing, analgesic and preventive treatment. The description that follows relates to the therapeutic applications to which the compounds of formula (1) can be subjected.

The compounds of formula (1) have the ability to react with the p2 receptor and therefore have a wide range of therapeutic applications, as described below, due to the essential role that the P2 receptor plays in the physiology of all mammals .

20

Therefore, a further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, forms thereof or mixtures thereof, for use in the treatment of diseases, disorders and conditions wherein the P2 receptor involved. More specifically, the present invention also relates to the compounds of formula (1), or pharmaceutically acceptable salts, forms therefrom or mixtures thereof, for use in the treatment of diseases, disorders and conditions selected from the group consisting of • asthma of any type, aetiology or pathogenesis, in particular asthma being a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, real asthma, intrinsic asthma caused by pathophysiological disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or unclear cause, non-atopic asthma, bronchitic asthma, emphysematous ast-5 ma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, b eroepsasthma, asthma due to infection caused by bacterial infection, fungal infection, protozoan or viral infection, non-allergic asthma, early asthma, shortness of breath in children and broncholytis, • chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema, obstructive respiratory or inflammatory diseases of the respiratory tract of any type, aetiology or pathogenesis, in particular an obstructive respiratory or inflammatory respiratory disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea, whether or not associated with COPD, COPD characterized by irreversible, progressive airway obstruction, respiratory distress syndrome in adults (ARDS), aggravation of hyperreactivity of the airways due to v n other drug treatment and respiratory disease associated with pulmonary hypertension, • bronchitis of any type, aetiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, bronchitis crouposa, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal bronchitis or streptococci and vesicular bronchitis, acute lung injury, 1028599 59 therefore, in particular bronchiectasia that is a member selected from the group consisting of cylindrical bronchiectasia, bag-shaped bronchiectasia, fusiform bronchiectasia, capillary bronchiectasia, cystic bronchiectasia, dry bronchiectasia and follicular bronchiectasia.

A still further aspect of the present invention also relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, forms obtained therefrom or mixtures thereof, for the preparation of a medicament which has the activity of a β2-15 agonist. In particular, the present invention relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, forms thereof or mixtures thereof, for the preparation of a medicament for the treatment of β2-mediated diseases and / or disorders , in particular the diseases and / or conditions mentioned above.

As a result, the present invention provides a particularly interesting method of treating a mammal, including a human, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, form thereof or mixture thereof. More precisely, the present invention provides a particularly interesting method for the treatment of β2 mediated diseases and / or disorders in a mammal, including a human, in particular the diseases and / or disorders mentioned above, which administer to comprising mammal of an effective amount of a compound of formula (1), the pharmaceutically acceptable salts thereof and / or forms obtained therefrom.

1028599 * 60

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

Preparation 1: ethyl ester of (3-ethoxycarbonylmethyl-phenyl) acetic acid 10

Acetyl chloride (12.5 ml, 175 mmol) was added to a suspension of 2.2 (1,3-phenylene) diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml) and the resulting solution was kept for 16 hours heated to reflux temperature. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between saturated sodium hydrogen carbonate (300 ml) and ethyl acetate (500 ml). The organic phase was washed with water (200 ml), saturated sodium chloride (300 ml), dried (Na 2 SO 4) and the solvent was removed in vacuo to give the title compound as a light yellow oil (63.5 g).

a HNMR (CDCl 3, 400 MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, q), 7.24-7.36 (4H, m).

MS (electron spray): m / z 251 [M + H] + 10285§§

»P

61

Preparation 2: (3-ethoxycarbonylmethylphenyl) acetic acid TOT "

A solution of preparation 1 (44.3 g, 177 mmol) and 2,2 '- (1,3-phenylene) diacetic acid (59.2 g, 308 mmol) in ethanol 10 (24 ml) and dioxane (290 ml) was treated dropwise with hydrochloric acid (12 M, 4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux temperature for 18 hours before allowed to cool, and concentrated to a small volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was taken up in water and basified with sodium hydrogen carbonate until the pH was neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with a solution of sodium hydrogen carbonate (5 x 30 ml) and a saturated aqueous sodium chloride solution (50 ml). The combined aqueous extracts were acidified to pH 3 with 6 M hydrochloric acid and extracted with ether (3 x 30 ml). The organic extracts were combined, dried (MgSO 4) and concentrated in vacuo. The residue was triturated with pentane to give the title compound as a colorless solid (10.8 g).

XHNMR (CD3OD, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, q), 7.18- 7.32 (4 H, m).

MS (electron spray): m / z 245 [MNa] + 1028599 62

Preparation 3: [3- (2-hydroxy-2-methylpropyl) phenyl] acetic acid ΎΤΧτΓ

A solution of preparation 2 (6.85 g, 32 mmol) in diethyl ether (100 ml) was cooled to 0 ° C and treated with a solution of methyl magnesium bromide in ether (3 M, 23.5 ml, 70, 0 mmol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours, the reaction was quenched by the addition of a saturated solution of ammonium chloride (200 ml). The organic phase was separated and washed with brine (100 ml), dried (Mg-SO 4) and concentrated in vacuo. Purification by column chromatography (40-100% dichloromethane in pentane) gave the title compound as a colorless oil (6.23 g).

1 NMR (CDCl 3, 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m) .

MS (electron spray): m / z 209 [M + H] +

Preparation 4: {3- [2- (2-chloroacetylamino) -2-methyl-propyl] phenyl} acetic acid 25% ac 2 * Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of preparation 3 (16.0 g, 70 mmol) in acetic acid (33 ml) The resulting solution was cooled to 0 ° C, treated with concentrated sulfuric acid (33 ml) and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was poured on ice for 1 hour and made basic with sodium carbonate, the solution was extracted with ethyl acetate (2 x 500 ml) and 1028599 63 the combined organic extracts were dried (Mg-SO 4) and concentrated in vacuo to give the title compound as a colorless solid (19.0 g).

XHNMR (CDCl3, 400 MHz) 6: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 ( 1 H, m), 7.06-7.31 (4 H, m).

MS (electron spray): m / z 282 [M-H] "

Preparation 5: methyl ester of [3- (2-amino-2-methylpropyl) phenyl] acetic acid. A solution of preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated to reflux for 16 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in methanol (150 ml), saturated with hydrochloric acid gas, and the resulting solution was heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 ml) and 5% sodium carbonate solution (200 ml). The organic phase was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified with a strong cation exchange resin (methanol and then a 2 M solution of ammonia in methanol).

The eluent was concentrated in vacuo to give the title compound as a yellow oil (2.68 g). 1 HNMR (CDCl 3, 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7.08-7 , 16 (3 H, m), 7.23-7.27 (1 H, m).

MS (electron spray): m / z 222 [M + H] + 1028599 * 64

Preparation 6: methyl ester of (3 - {2 - [2 - (2,2-dimethyl-4 H- [1,3] dioxino [5,4-b] pyridin-6-yl) -2-hydroxyethylamino] -2- methylpropyl} phenyl) acetic acid 5 2,2-Dimethyl-6-oxiranyl-4H- [1,3] dioxino [5,4-b] pyridine (2.24 g, 10.82 mmol) and preparation 5 (2, 39 g, 10.82 mmol) in dimethyl sulfoxide (20 mL) were heated to 90 ° C for 24 hours. The reaction mixture was taken up in ethyl acetate (200 ml), washed with saturated brine (4 x 50 ml) and dried (MgSO 4). The crude material was purified by chromatography (0-10% methanol in dichloromethane + 1% ammonia) to give a brown oil (1.96 g).

1 HNMR (CD3OD, 400 MHz) δ: 1.12 (6H, s), 1.55 (6H, s), 2.76 (2H, d), 2.82-2.89 (1H, m), 3 , 10 (1H, d), 3.60 (2H, s), 3.67 (3H, s), 4.72-4.79 (1H, bs), 7.05-7.10 (4H, m), 7.21-7.29 (2H, m).

MS (APCI): m / z 429 [M + H] +

Preparation 7: (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethyl-pyridin-2-yl) -ethylamino] -2-methyl-propyl) -phenyl) -acetic acid-bis-hydrochloride iT ^ For HO 30 or 0

Preparation 6 (2.16 g, 5.05 mmol) in tetrahydrofuran (30 ml) was treated with lithium hydroxide (1 M, 10.1 ml, 10.09 mmol) and stirred for 20 hours at room temperature. Hydrochloric acid (1 35 M, 20 ml, 20.0 mmol) was added and stirring was continued for 2 hours and then for 1 hour at 60 ° C. The solvent was removed in vacuo and the 102 8 5 99 <<65 material was added to an SCX column (methanol to 2 M NH 3 in methanol) and then purified by chromatography (0-20% methanol in dichloromethane + 1%) ammonia) to give a yellow oil which was taken up in tetrahydrofuran (5 ml), treated with lithium hydroxide (1 M, 2.72 ml, 2.72 mmol) and stirred for 3 days at room temperature. The reaction mixture was neutralized with hydrochloric acid (1 M, 2.72 ml, 2.72 mmol) and the solvents were removed. Lithium hydroxide (1 M, 2.72 ml, 2.72 10 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was neutralized with hydrochloric acid (4 M in dioxane, 1 ml, 4 mmol) and the solvents were removed to yield a yellow glass (629 mg).

1 HNMR (CD3OD, 400 MHz) δ: 1.85 (6H, s), 3.05 (2H, s), 3.35 (1H, dd), 3.60 (1H, dd), 3.63 ( 2 H, s), 4.77 (2 H, s), 5.01 - 5.05 (1 H, m), 7.14-7.26 (3 H, m), 7.29-7.38 (2 H, m), 7.45-7.50 (1 H, m).

MS (APCI): m / z 375 [M + H] + 20

Preparation 8: Methyl (3-bromophenyl) acetate "γγγ0Ό", 25 0

Acetyl chloride (0.7 ml, 9.3 mmol) was slowly added to a solution of (3-bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 ° C under nitrogen. gradually warm the reaction mixture to room temperature over a period of 5 hours. The solvent was removed in vacuo and the remaining oil redissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colorless oil (20.6 g) - 1028598 66 1 HNMR (400 MHz , CDCl 3) δ: 3.59 (2H, s), 3.70 (3H, s), 7.17-7.24 (2H, m), 7.37-7.45 (2H, m).

LRMS ESI: m / z 253 [M + Na] +.

Preparation 9: Methyl [3- (2-oxopropyl) phenyl] acetate "

Tributyl tin methoxide (28.3 ml, 98 mmol), the product of preparation 8 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), palladium (II) acetate (750 mg, 3.30 mmol) and tri-ortho-tolylphosphine (2.0 g, 6.5 mmol) were stirred together in toluene (75 mL) for 5 hours at 100 ° C. After cooling, the reaction mixture was diluted with ethyl acetate (150 ml) and a 4 M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through Arbocel® and the organic phase was separated and concentrated in vacuo. The residue was then purified by column chromatography on silica gel, eluting with diethyl ether: pentane, 0: 100 to 25:75, followed by dichloromethane to give the title compound as a pale yellow oil in a yield of 94% (12.6 g) ).

1 HNMR (400 MHz, CDCl 3) 6: 2.15 (3 H, s), 3.61 (2 H, s), 3.69 (5 H, s), 7.10-7.13 (2 H, m), 7 , 19 (1H, d), 7.30 (1H, t).

LRMS ESI: m / z 229 [M + Na] \ Preparation 10: Methyl- [3- ((2R) -2- {[(IR) -1-phenylethyl] amino] propyl) phenyl] acetate hydrochloride Η ™ ^ ΥγνγγΝ

J5 is CH, CH, O

1028599 67

A solution of the product of preparation 9 (8.5 g, 41.2 in mol), (R) -α-methylbenzylamine (4.8 ml, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) ) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) were stirred at room temperature for 48 hours. The reaction mixture was quenched by the addition of a saturated solution of sodium hydrogen carbonate (200 ml) and allowed to stir until bubbling ceased. The aqueous phase was separated and extracted with dichloromethane (100 ml). The combined organic solution was then dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane: methanol: ammonia, 99: 1: 0.1 to 95: 5: 0.5, gave a 4: 1 mixture of diastereomers (R, R as the largest) as a light yellow oil (8.71 g). Treatment with hydrogen chloride (40 ml of a 1 M solution in methanol, 40 mmol), followed by three successive crystallizations (diisopropyl ether / methanol) gave the title compound as a white crystalline solid in a yield of 50%, 5.68 g .

1 HNMR (400 MHz, CD3 OD) δ: 1.18 (3 H, d), 1.68 (3 H, d), 2.60 - 2.66 (1 H, m), 3.15-3.26 (1 H, m), 3.25-3.30 (1 H, m), 3.31 (3 H, s), 3.62 (2 H, s), 4.59 (1 H, q), 6.99-7.02 (2H, m), 7.17 (1H, m), 7.25-7.28 (1H, m), 7.48-7.52 (5H, m).

LRMS ESI: m / z 312 [M + H] +.

Preparation 11: Methyl {3- [(2 R) -2-aminopropyl] phenyl} acetate 30 L II X CH 3 CH 3. O

A solution of the product of preparation 10 (7.69 g, 22 35 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75 ° C in the presence of 20% palladium hydroxide-on-carbon (2.00 g ). After 90 minutes, the reaction mixture was cooled to room temperature, filtered through Arbocel®, and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 0.88% ammonia (100 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a colorless oil in quantitative yield (4.78 g).

10 HNMR (400 MHz, CD3OD) δ: 1.06 (3H, d), 2.57-2.67 (2H, m), 3.05-3.12 (1H, m), 3.63 (2H , s), 3.67 (3 H, s), 7.09-7.13 (3 H, m), 7.23-7.27 (1 H, t).

LRMS ESI: m / z 208 [M + H] \ Preparation 12: methyl ester of (3 - {(2R) -2- [2- (2,2-dimethyl-4H- [1,3] dioxino [ 5,4-b] pyridin-6-yl) -2-hydroxyethyl-amino] propyl} phenyl) acetic acid

OH

The title compound was prepared from the product of preparation 11 and 2,2-dimethyl-6-oxiranyl-4H- [1,3] dioxino [5,4-b] pyridine, using a method similar to that of is with that of preparation 6, as a brown oil (1.35 g, 42%).

1 HNMR (CD3OD, 400 MHz) δ: 1.06 (3H, d), 1.52 (6H, s), 2.56-2.75 (3H, m), 2.83-3.04 (2H , m), 3.61 / 3.67 (3H, 2 xs), 4.66-4.71 (1H, m), 4.74 / 4.78 (2H, 2 xs), 7.04-7 , 30 (6H, m).

LRMS APCI: m / z 415 [M + H] +.

35 1028598 69

Preparation 13: (3 - {(2 R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) acetic acid hydrochloride

OH

s Th N 1 tss. J 0

HO

HCT

10

Preparation 12 (1.35 g, 3.26 mmol) in tetrahydrofuran (20 mL) was treated with lithium hydroxide (1 M, 6.52 mL, 6.52 mmol) and stirred for 40 hours at room temperature. Hydrochloric acid (1 M, 20 ml, 20.0 mmol) was added and stirring was continued for 2 hours at 60 ° C. The solvent was removed in vacuo to yield a brown glass (2.94 g,> 100%).

1 HNMR (CD 3 OD, 400 MHz) 6: 1.28 (3H, 2 xd), 2.75-2.84 (1H, m), 3.26-3, 34 (1H, m), 3.53-3 , 67 (5H, m), 4.97 (2H, s), 5.36 (1H, dt), 7.17-7.24 (3H, m), 7.80 (1H, dt), 7 88-7.95 (2 H, m).

LRMS APCI: m / z 361 [M + H] +.

Example 1: N- (3,4-dichlorobenzyl) -2- (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-methylpropyl} phenyl ) acetamide XH η nc '

Ci ^ NyCrTisAAa 30 Η0Λ ^ ν U o H 0 ^

Preparation 7 (150 mg, 342 pmol, crude), 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (65 mg, 342 pmol), hydroxybenzotriazole hydrate (53 mg, 342 pmol) and triethylamine (93 μΐ, 684 pmol) were stirred for 10 min in 1028599 70 N, N-dimethylformamide (5 ml), then 3,4-dichlorobenzylamine (60 mg, 342 μιηοΐ) was added and the resulting solution was stirred at room temperature for 20 hours. The solvent was removed and the product was taken up in dichloromethane (20 ml), washed with saturated sodium hydrogen carbonate (20 ml), brine (2 x 30 ml) and dried (MgSO 4). The product was purified twice by chromatography (0-10% methanol in dichloromethane + 1% ammonia) to yield a yellow glass (15 mg).

10 HNMR (CD3OD, 400 MHz) δ: 1.04 (3H, s), 1.05 (3H, s), 2.68 (2H, dd), 2.91 (1H, dd), 3.00 ( 1 H, dd), 3.47 (2 H, s), 4.25 (2 H, s), 4.63 (2 H, s), 4.67 (1 H, dd), 7.00-7.34 (9 H , m).

MS (APCI): m / z 532/533/534 [M + H] +.

Example 2: N- (3,4-dimethylbenzyl) -2- (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-methylpropyl} phenyl acetamide

H Η H f'Y

J

hot

Was prepared using the method summarized in Example 25 1, using 3,4-dimethylbenzylamine, yielding a pale yellow foam.

^ NMR (CD3OD, 400 MHz) δ: 1.07 (3H, s), 1.08 (3H, s), 2.18 (3H, s), 2.19 (3H, s), 2.70 ( 2H, dd), 2.91 (1H, dd), 2.99 (1H, dd), 3.52 (2H, s), 4.27 (2H, s), 4.69 (2H, s), 4.71 (1H, dd), 6.89-7.25 (9H, m).

MS (APCI): m / z 492 [M + H] +.

1028599

Example 3: N-cyclohexylmethyl 2- (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-methyl-propyl} phenyl) acetamide 71? H Η Η Λ0Λ ^ ΧΧΓΤ ^ HCl was prepared using the process summarized in Example 1, using cyclohexylmethylamine, yielding a pale yellow foam.

1 HNMR (CD3 OD, 400 MHz) 6: 0.81-0.94 (2H, m), 1.09 (3H, s), 1.11 (3H, s), 1.14-1.27 (4Ή, m), 1.84-1, 86 (1H, m), 1.59-1.72 (4H, m), 2.71 (2H, dd), 2.91-3.05 (4H, m) ), 3.47 (2H, s), 4.70 (2H, s), 4.72 (1H, dd), 7.05 (1H, d), 7.12-7.26 (5H, m) .

MS (APCI): m / z 470 [M + H] +.

Example 4: N- [2- (4-chlorophenyl) ethyl] -2- (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2- methylpropyl} phenyl) acetamide OH;

Was prepared using the method summarized in Example 30 1, using 4-chlorophenylethylamine, yielding a pale yellow foam.

^ NMR (CD3OD, 400 MHz) δ: 1.09 (3H, s), 1.11 (3H, s), 2.69 -2.80 {4H, m), 2.91 (1H, dd) , 3.00 (1H, dd), 3.39 (2H, t), 3.43 (2H, s), 4.70 (2H, s), 4.72 (1H, dd), 7.05- 7.14 (6H, 35 m), 7.17-7.26 (4H, m).

MS (APCI): m / z 512/513/514 [M + H] +.

102®5 | §

Example 5: N- (2-hydroxybenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethyl amino] propyl} phenyl acetamide 72 HO 2 The title compound was prepared from the product of preparation 13 and 2-aminomethylphenol, using a method of. comparable to that of example 1, as a pale yellow foam (28 mg).

1 HNMR (CD3OD, 400 MHz) δ: 1.06 / 1.07 (3H, 2 xd), 2.56-2.66 (1H, m), 2.72-2.81 (1H, m), 2.86-3.09 (3 H, m), 3.52 / 3.53 (2 H, 2 x s), 4.32 / 4.33 (2 H, 2 x s), 4.69 / 4.70 (2 H (2 xs), 4.70-4.74 (1 H, m), 6.70-6.78 (2 H, m), 7.01-7.25 (8 H, m).

MS (APCI): m / z 466 [M + H] +.

Example 6: N-benzyl-2- (3 - {(2 R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl) -phenyl) acetamide

The title compound was prepared from the product of preparation 13 and benzylamine, using a method similar to that of Example 1.

JHNMR (CD3OD, 400 MHz) δ: 1.05 / 1.06 (3H, 2 xd), 2.56-2.66 (1H, m), 2.70-2.80 (1H, m), 2 , 84-3.10 (3 H, m), 3.52 / 3.53 (2 H, 2 x s), 4.35 / 4.36 (2 H, 2 x s), 4.68 / 4.69 (2 H, 2 xs), 35 4.70-4.73 (1 H, m), 7.02-7.28 (11 H, m).

MS (APCI): m / z 450 [M + H] +.

1028599

Example 7: N- (3,4-Dimethylbenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethyl-amino) propyl} phenyl acetamide t 73

5 r h „fY

HO ^ 10 The title compound was prepared from the product of preparation 13 and 3,4-dimethylbenzylamine, using a method similar to that of Example 1. 1 HNMR (CD 3 OD, 400 MHz) δ: 1.06 / 1.07 (3 H, 2 x d), 2.19 / 2.20 (6 H, 2 x s), 2.55-2, 66 (1 H, m), 2.70-2.80 (1 H, m), 2.84 - 3.10 (3 H, m), 3.50 / 3.51 (2 H, 2 x s), 4.28 / 4.29 (2 H, 2 x s), 4.67 / 4.68 (2 H, 2 xs), 4.70-4.73 (1 H, m), 6.88-7.28 (9 H, m).

MS (APCI): m / z 478 [M + H] \ Example 8: N- (2,5-dimethylbenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2-) (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethyl-aminopropyl} phenyl) acetamide 25. The title compound was prepared from the product of preparation 13 and 2,5-dimethylbenzylamine, using one. method similar to that of Example 1. ^ HNMR (CD3OD, 400 MHz) δ: 1.06 / 1.07 (3H, 2 xd), 2.18 (3H, 2 xs), 2.21 (3H, 2 xs), 2.56-2.66 (1H, m), 2.70-2.80 (1H, m), 2.82-3.08 (3H, m), 3.51 / 3, 52 (2H, 2 xs), 4.30 / 4.31 (2H, 2 xs), 4.68 / 4.69 (2H, 2 xs), 4.70-4.73 (1H, m), 6 , 90-7.26 (9H, m).

1028599 74 MS (APCI): m / z 478 [M + H] +.

Example 9: 2- (3 - {(2 R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) -N- (2-5 methoxybenzyl) ) acetamide "^ Vxnr ^?

10 J

HO

The title compound was prepared from the product of preparation 13 and 2-methoxy-benzyl amine, using a method similar to that of Example 1.

1 HNMR (CD3OD, 400 MHz) δ: 1.05 / 1.06 (3H, 2 xd), 2.56-2.66 (1H, m), 2.70-2.80 (1H, m), 2 , 81-3.10 (3 H, m), 3.51 / 3.52 (2 H, 2 x s), 3.78 (3 H, s), 4.36 / 4.37 (2 H, 2 x s), 4 , 68 / 4.69 (2H, 2 xs), 4.69-4.74 (1H, m), 6.79-6.84 (1H, 20t), 6.90 (1H, d), 7 , 02-7.27 (8 H, m).

MS (APCI): m / z 480 [M + H] +.

Example 10: N- (2-ethoxybenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-propyl} phenyl) acetamide nxr 30 H0

The title compound was prepared from the product of preparation 13 and 2-ethoxybenzylamine, using a method similar to that of Example 1.

35 HNMR (CD3OD, 400 MHz) 5: 1.06 / 1.07 (3H, 2 xd), 1.34 (3H, t), 2.56-2.66 (1H, m), 2.70- 2.80 (1H, m), 2.81-3.10 (3H, m), 3.52 / 3.53 (2H, 2 xs), 4.02 (2H, q), 4.34 / 4 35 (2H, 2 10 2 8 S § § 75 xs), 4.70 / 4.71 (2H, 2 xs), 4.70-4.74 (1H, m), 6.81 (1H, t ), 6.88 (1 H, d), 7.01-7.24 (8 H, m).

MS (APCI); m / z 494 [M + H] +.

Example 11: N- (3,4-dichlorobenzyl) -2- (3 - {(2 R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethyl-amino] propyl} phenyl) acetamide 15 The title compound was prepared from the product of preparation 13 and 3,4-dichlorobenzylamine, using a method similar to that of Example 1. 1HNMR (CD30D, 400 MHz) δ: 1.06 / 1.07 (3H, 2 xd), 2.56-2.66 (1H, m), 2.70-2.80 (1H, m), 2.82-3.10 (3H, m), 3 , 54 / 3.55 (2H, 2 xs), 4.34 / 4.35 (2H, 2 xs), 4.70 / 4.71 (2H, 2 xs), 4.70-4.74 ( 1 H, m), 7.03-7.22 (7 H, m), 7.36 (1 H, d), 7.451 (1 H, d).

MS (APCI): m / z 518 [M + H] +.

Example 12: N- (2-chloro-6-fluorobenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethyl-amino] propyl} phenyl) acetamide

HO Y.

HO ^

The title compound was prepared from the product of preparation 13 and 2-chloro-6-fluorobenzylamine, using a method similar to that of Example 1.

1028599 76 1 HNMR (CD3OD, 400 MHz) δ: 1.06 / 1.07 (3H, 2 xd), 2.55-2.63 (1H, m), 2.70-2.80 (1H, m) , 2.82-3.10 (3 H, m), 3.47 / 3.48 (2 H, 2 x s), 4.54 / 4.55 (2 H, 2 x s), 4.69 / 4.70 ( 2 H, 2 x s), 4.70-4.73 (1 H, m), 7.00-7.34 (9 H, m).

MS (APCI): m / z 502 [M + H] +.

The ability of the compounds of formula (1) to function as potent P2 agonists that therefore mediate smooth muscle relaxation can be determined by measuring the effect of beta-2-adrenergic receptor stimulation on the an electric field stimulated contraction of strips of guinea pig trachea.

Guinea pig trachea Male, Dunkin-Hartley guinea pigs (475-525 g) are killed by CO2 asphyxiation and blood drainage from the femur and the trachea is isolated. Four preparations are obtained from each animal, the decomposition starting immediately after the larynx and a length of 2.5 cm of trachea is removed. The trachea piece is opened by notching the cartilage opposite the tracheal muscle and then transversal sections, 3-4 cartilage leg rings wide, are cut. The resulting strip preparations are suspended in 5 ml organ baths using cotton threads fastened by the upper and lower cartilage bands. The strips are equilibrated for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μΜ indo-methacine (Sigma 17378), 10 μΜ guanethidine (Sigma G8520) 30 and 10 μΜ atenolol (Sigma A7655) heated treated at 37 ° C and with gas consisting of 95% 02/5% CO2, before an initial voltage of 1 g is applied. The compositions are allowed to equilibrate for an additional 30-45 minutes, during which time they are re-tensioned (at 1 g) twice at 15 minute intervals. Voltage changes are recorded and monitored via standard isometric transducers linked to a 1028599 77 data collection system (designed to order at Pfizer). After equilibrating the voltage, the tissues are subjected to stimulation with an electric field (EFS) using the. The following parameters: 10 sec series every 2 minutes, pulse width 0.1 ms, 10 Hz and constant exactly maximum voltage (25 volts) for the entire duration of the experiment. EFS from cholinergic nerves after the ganglia in the trachea results in smooth muscle contractions from one phase and the peak of the cramps is recorded. In the organ baths, the Krebs Ringer buffer described above is continuously infused by means of a peristaltic pumping system (pump flow rate 7.5 ml / minute) throughout the experiment, except when a beta-2 agonist according to the If the present invention is added, the pump is stopped during the time of giving a cumulative dose to the bath and restarted after the maximum response for the washout period is achieved.

20

Experimental protocol for determining the strength and effectiveness

After equilibration on EFS, the peristaltic pump is stopped and the preparations are "processed" with a single dose of 300 nM isoprenaline (Sigma 15627) to determine a maximum response in terms of inhibition of the astringent EFS response. The isoprenaline is then washed out over a 40-minute period. After processing and restoration of washout, a standard isoprenaline curve is established for all tissues (isoprenaline curve 1) by means of cumulative bolus addition to the bath using half-log increases. The concentration range used is le "9 to le / 3rd" 6 M. At the end of the isoprenalin curve the preparations are washed again for 40 minutes before setting up a second curve, or for isoprenaline (as internal control) ) or for a 1028599 78 beta-2 agonist of the present invention. Beta-2 agonist responses are expressed as the percent inhibition of the EFS response, data for the beta-2 agonist are normalized by expressing the inhibition as 5 is a percentage of the maximum inhibition induced by isoprenaline in curve 1. The EC 50 value for the beta-2 agonist of the present invention relates to the concentration of compound required to cause the half-maximal effect. beta 2-10 agonists of the present invention are then expressed as the relative potency for isoprenaline defined by the ratio (EC50 beta 2 agonist) / (EC50 is oprenaline).

Confirmation of functional activity mediated by beta-2

The beta-2 agonist activity of test compounds is confirmed using the protocol described above, however, before constructing the curve for the beta-2 agonist of the present invention, the compositions are pre-incubated (for at least 45 minutes) with 300 nM ICI 118551 (a selective β2 agonist), which in the case of a beta-2 mediated effect results in a shift to the right of the dose-response curve of the test compound.

According to another alternative, the p2 receptor agonist of the compounds of the formula (1) can also be determined by measuring the concentration of compound of the present invention that is needed to achieve the half-maximal effect (EC50) for the β2 receptor.

1028599 79

Preparation of the compound 10 mM / 100% DMSO (dimethyl sulfoxide) stock of the compound is diluted to the required top dose in 4% DMSO. This top dose is used to construct a semi-log dilution curve of 10 points, all in 4% DMSO. Isoprenaline (Sigma, 1-5627) was used as standard in every experiment and for control wells on each plate. The data were expressed as a% isoprenaline response.

10

Cultures of cells CHO cells (Chinese hamster ovary cells) recombinantly expressing the human p2-adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhP2), were grown in Dulbecco's MEM / NUT MIX F12 (Gibco, 21331-020) supplemented with 10% fetal bovine serum (Sigma, F4135, lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 pg / ml geneticin (Sigma, G7034) and 10 pg / ml puromycin (Sigma, P8833). The cells were expanded to give approximately 90% confluence before testing.

Analysis method 25 μΐ / well of each dose of compound was transferred to a cAMP-Flashplate® (NEN, SMP004B), with 1% DMSO as basic controls and 100 nM isoprenaline as max controls. This was diluted 1: 2 by the addition of 25 μΐ / well PBS. The cells were treated with trypsin (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B), yielding 1 x 106 cells / ml CHOhB2. The compounds were incubated with 50 μΐ / well of cells for 1 hour. The cells were then lysed by the addition of 100 μΐ / well detection buffer (NEN, SMP004B) containing 0.18 pCi / ml 125 I-cAMP (NEN, NEX-130), and the plates were left for an additional 2 hours at room temperature 1028599 80 incubated. The amount of 125 I-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. The dose response data were expressed as% isoprenaline activity and the best fitting curve was set up using an S-shaped adjustment of four parameters.

Thus, it has been found that the compounds of formula (1) according to the present invention illustrated in Examples 1 to 12 exhibit a β2-οΑΜΡ EC50 that is lower than 5 nM.

1028599

Claims (31)

5 - CONCLUSIONS 1. Compound of formula (1) OH 10 ΓΓ ^ Υ ^ ΝΧ ^ Υ ^ ι Η0 ^ γΝ R 'R2' ΗΑνγ '° 1 <1), ch2oh 0 15 where the (CH2) n ~ C (= 0) Q1 group is in the meta or para position, R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl, n is 0, 1 or 2 and 20. Q1 is a group selected from R3 Rv / R4 Re 1 ^ R <\ = YOU \ / R12 (CHA-V ^ V-'R ^ * NV_ ^ r'3 R "r6. R" · » R12 - / N - R12 * -Nx / ° 1 = -0: 0, * -NR8-Q2-A or * -NR8-Q3, where 35. p 1 or 2 and q is 1 or 2, Q is a single bond or a C 1 -C 4 alkylene optionally substituted with OH, 1028599 R 8 is H or C 1 -C 4 alkyl and Q 3 is C 1 -C 6 alkyl optionally substituted with NR9 R10, OR9 or phenoxy, A is selected from: 5. C 3 -C 10 cycloalkyl, which cycloalkyl is optionally bridged by 1 or 2, 3 or 4 carbon atoms and is optionally substituted with one hydroxy group, a 5 to 6-membered heterocyclic group, optionally aromatic, which is one or two heteroatoms selected from O, N or S, optionally substituted with one or two substituents selected from C 1 -C 4 alkyl, benzyl and cyclopropylmethyl or 15 a group R 3 R 4 - or R 5 R 7 R 6, or quinolyl or isoquinolyl, R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1 -C4 alkyl, OR9, SR9, SOR9, SO2R9 / halogen, CN, CF3, OCF3, SO2 NR9R10, COOR9, CONR9 R10, NR9 R10, NHCOR10 and phenyl, optionally substituted with OH; R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl, 30. R 11 is selected from H or OH, and R 12 and R 13 are the same or different and are selected from H, C 1 -C 4 alkyl, optionally substituted with OR 9, C (= 0) NH 2, C (= 0) CH 3, N (CH 3) C (= O) CH 3, C (= O) 0 R 9, phenyl, optionally substituted with halogen, pyridyl, optionally substituted with CN, and oxadiazolyl, optionally substituted with C 1 -C 4 alkyl, and * the attachment point to represents the carbonyl group; 1028599 or, where applicable, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotope variations thereof. The compound of claim 1, wherein Q 2 is a single bond. 3. A compound according to claim 1, wherein A is selected from morpholinyl, pyrrolidinyl, piperidyl, piperagazine or pyrazolyl, which groups are optionally substituted with a methyl. The compound of claim 1, wherein A is selected from pyrazolyl optionally substituted with one or two C 1 -C 4 alkyl. The compound of claim 1, wherein Q1 * is -NR8-Q3. The compound of claim 1, wherein the (CH 2) n - C (= 0) Q 1 group is in the meta or para position, R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl, n Is 0, 1 or 2 25. Q1 is a group selected from, R3 KN, R8 30 m ^ R5 * -n- <XXR5, R6 R6 and a group * -NR8-Q2-A, where p is 1 or 2, Q2 is a C1- C 4 alkylene, R 8 is H or C 1 -C 4 alkyl and A is pyridyl, C 3 -C 10 cycloalkyl, which cycloalkyl is optionally bridged by 1, 2, 3 or 4 carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or a group 1028599 R3 R4 is R5 or R7 is R6, R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1 -C4 alkyl, OR9, SR9, SOR9, SO2R9, halogen, CN, CF3, OCF 3, SO 2 NR 9 R 10, COOR 9, CONR 9 R 10, NR 9 R 10, NHCOR 10 and phenyl, optionally substituted with OH; R 9 and R 10 are the same or different and are selected from H or C 1 -C 4 alkyl and it * represents the point of attachment to the carbonyl group; or, where applicable, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotope variations thereof. A compound according to claim 6, wherein Q 1 is a group * -NH-Q 2 -A wherein A is cyclohexyl or adamantyl. 8. A compound according to claim 6, wherein Q1 is a group * -NH-Q2-A, wherein A is a group R3 R4 hQ-- R <V is where R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, C 1 -C 4 alkyl, OR 9, SR 9, SOR 9, SO 2 R 9, halogen, CF 3, OCF 3, SO 2 NR 9 R 10, CONR 9 R 10 , NR 9 R 10, NHCOR 10 and phenyl, provided that at least 2 of R 3 to R 7 are H; 1028599 wherein R9 and R10 are the same or different and are selected from H or C1 -C4 alkyl. A compound according to any one of claims 6 to 8, wherein Q 2 is -CH 2 -, - (CH 2) 2 -, - (CH 2) 3 - or -C, (CH 3) 2 -. 10. A compound according to claim 6, wherein Q1 is R3, R6, R6, wherein R3, R4, R5 and R6 are H. A compound according to any of claims 1 to 10, wherein R 1 is H or CH 3 and R 2 is CH 3. The compound of any one of claims 1 to 11, wherein n is 0 or 1. 13. (R, R) stereoisomer of a compound according to any of claims 1 to 12. 25 The compound of any one of claims 1 to 13, wherein the. (CH 2) n ~ C (= 0) Q 1 group at the meta position. The compound of claim 1, which is selected. is from the group consisting of N-benzyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxy-methyl) pyridin-2-yl] ethyl} amino) - 2-methylpropyl] phenyl} acetamide; N-cyclopropyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxy-35-methyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) -acetamide; 1028599 <»2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [{IR, 2S) -2- (hydroxymethyl) cyclohexyl] acetamide; 2— (3— [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3 - Morpholin-4-yl-propyl) -acetamide; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl ] phenyl} -N- (pyridin-2-ylmethyl) acetamide; 2- 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) } amino) -2-methylpropyl] phenyl} -N- (2-morpholine-4-ylethyl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl)) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -W-15 isopropylacetamide; N- (4-chlorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5 -hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] -phenyl} acetamide; N- [2- (dimethylamino) ethyl] -2- {3- [2 - {{2 -hydroxy-2- [5-20 hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl acetamide; N- [2- (diethylamino) ethyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2- methylpropyl] phenyl} acetamide; N- [3- (dimethylamino) propyl] -2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2 -methylpropyl] phenyl} acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl } -N-30 pentylacetamide; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} - JV- (2-pyrrolidin-1-ylethyl) acetamide; N- (2,4-dichlorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6-35 (hydroxymethyl)) pyridin-2-yl] ethyl-amino) -2-methylpropyl] -phenyl} acetamide, 1028599 <* N- (3,4-dichlorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5- hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] -phenyl} acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl} ethyl} amino) -2-methylpropyl] phenyl} -N- (4-methoxybenzyl) acetamide; N- (2-hydroxyethyl) -2- {3— [2 - ({ 2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) acetamide; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl) phenyl} -N-propylacetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl) -N- (3-15 methoxypropyl) acetamide; N-cyclobutyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} acetamide; 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -20 pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- [{ 1R) -1- (1-naphthyl) ethyl] acetamide; N-2,3-dihydro-11-inden-1-yl-2- {3- [2- ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl) acetamide; 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- [2 - (1-methylpyrolidin-2-yl) ethyl] acetamide, N- (4-fluorobenzyl) -2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine] 2-yl] ethyl} amino) -2-methylpropyl] -30 phenyl) acetamide 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -pyridine-2- yl] ethyl) amino) -2-methylpropyl] phenyl) -N- (4-phenylbutyl) acetamide; 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -) Pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- (3-methoxybenzyl) acetamide, 1028599 N- (3-ethoxypropyl) -2 - {3 - [2 - ({2-hydroxy -2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methyl-propyl] phenyl) acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -J- (3,4,5-trimethoxybenzyl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl) phenyl) -N- [4- (trifluoromethyl) benzyl] acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [2 - (trifluoromethyl) benzyl) acetamide; N- (3,5-dimethoxybenzyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methyl -15 propyl] phenyl acetamide; 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) -1- ( 2-phenoxyethyl) acetamide, 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -2-pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [(IS) -2-hydroxy-1-methylethyl] acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -pyridine-2 -yl] ethyl) amino) -2-methylpropyl] phenyl} -N- [(IS) - 1- (hydroxymethyl) -2-methylpropyl] acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -W - [( IS, 2S) -1- (hydroxymethyl) -2-methylbutyl] acetamide; N- [(IJ?) -1-benzyl-2-hydroxyethyl] -2- {3— [2- ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl) ) amino) -2-30 methylpropyl] phenyl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl) -N- [(IJ ?) -1- (hydroxymethyl) propyl] acetamide; 2 - {3 - [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -35-pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- [( IS) 1- 1- (hydroxymethyl) -2,2-dimethylpropyl] acetamide; 1028599 N - [(IS) -2-cyclohexyl-1- (hydroxymethyl) ethyl] -2- {3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine-2 yl] -ethyl-amino) -2-methyl-propyl] phenyl-acetamide, N - [(IS, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -2- {3- [2-5 ( {2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2- {3- [2 - ({2-hydroxy- 2- [5-hydroxy-6- (hydroxymethyl) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) -N- (2-propoxyethyl) acetamide; N- {4-hydroxycyclohexyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl) acetamide; 2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} -N- (3-15 propoxypropyl) acetamide; N-ethyl-N- (2-hydroxyethyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl ] phenyl} acetamide; 1- ({3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -20-pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetyl) piperidine -4-carboxamide; 6- {2 - [(2 - (3 - [2 - (4-acetylpiperazin-1-yl) -2-oxoethyl] phenyl) -1,1-dimethylethyl) amino] -1-hydroxyethyl } -2- (hydroxymethyl) pyridine-3-ol; 6 - {2 - [(2 - {3 - [2- (3,4-dihydroisoquinoline-2 (1 H) -yl) -2-oxoethyl] phenyl} -1,1-dimethylethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) pyridine-3-ol; N-benzyl-2- {3- [2 - ({2-hydroxy-2- [5-hydroxy] -6- (hydroxymethyl) pyridin-2-yl] ethyl-amino) -2-methylpropyl] phenyl} -W-30-methylacetamide; 6- (1-hydroxy-2 - {[2- (3 - {2 - [4 - ( 2-hydroxyethyl) piperazin-1-yl] -2-oxoethyl) phenyl) -1,1-dimethylethyl] amino} ethyl) -2-. (hydroxymethyl) pyridine-3-ol; 6- (2 - {[2- (3 - {2 - [4 - (4-chlorophenyl) -4-hydroxypiperidin-1-35yl] -2-oxoethyl) phenyl) -1,1-dimethylethyl] amino) - 1-hydroxyethyl) -2- (hydroxymethyl) pyridine-3-ol; 1028599 6 - {2 - [(1,1-dimethyl-2- {3- [2- (4-methylpiperazin-1-yl) -2-oxoethyl] phenyl} ethyl) amino] -1-hydroxyethyl} - 2- (hydroxymethyl) pyridine-3-ol; 2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-methyl- N- (2-phenylethyl) acetamide; 6- {2 - [(1,1-dimethyl-2- {3- [2-oxo-2- (4-pyridin-2-yl-piperazin-1-yl) ethyl] phenyl] ethyl) amino] -1-hydroxyethyl } -2- (hydroxymethyl) pyridine-3-ol; N- [3- (dimethylamino) propyl] -2 - {3 - [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2 -methylpropyl] phenyl} -N-methylacetamide; N- (2-hydroxyethyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] - Phenyl} -N-propylacetamide; N- [2- (diethylamino) ethyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl} -N-methylacetamide; 6- {2 - [(1,1-dimethyl-2- {3- [2- (4-methyl-1,4-diazepan-1-yl) -20-2-oxoethyl] phenyl] ethyl) amino] -1 -hydroxyethyl] -2- (hydroxymethyl) pyridine-3-ol; 6- (2 - [{1,1-dimethyl-2- [3- (2-morpholin-4-yl-2-oxoethyl) phenyl] ethyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) pyridine -3-ol; 2- {3- [2 - ({2-hydroxy-2- (5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) -2-methylpropyl] phenyl-N-methyl-N - [(IS) -1-phenylethyl] acetamide; 6- (2 - [{1,1-dimethyl-2- [3- (2-oxo-2-piperidin-1-ylethyl) -phenyl] ethyl] amino) -1-hydroxyethyl] -2- (hydroxymethyl) -30-pyridine-3-ol / 6- (1-hydroxy-2 - {[2- (3- (2 - [(3R) -3-hydroxy-pyrrolidin-1-yl] ] -2-oxoethyl] phenyl) -1,1-dimethylethyl] amino] ethyl) -2- (hydroxymethylpyridine-3-ol; 6- (1-hydroxy-2 - {[2- (3- (2- [ (3R) -3-hydroxypiperidin-1-yl] -35 2-oxoethyl) phenyl) -1,1-dimethylethyl] amino] ethyl) -2- (hydroxymethyl) pyridine-3-ol; 1028599 4 * 6- {2 - [(2- (3- [2- (4-acetyl-1,4-diazepan-1-yl) -2-oxoethyl] phenyl} -1,1-dimethylethyl) amino] -1-hydroxyethyl} -2 - (hydroxymethyl) pyridine-3-ol; 6- (1-hydroxy-2 - {[2- (3- (2- (4- (4- (hydroxymethyl) piperidin-1-5-yl) -2-oxoethyl} phenyl) - 1,1-dimethylethyl] amino} ethyl) -2- (hydroxymethyl) pyridine-3-ol; N- [1- ((3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (- hydroxymethyl) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] -phenyl} acetyl) pyrrolidin-3-yl] -N-methylaceta medium; 2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (2 - methoxyethyl) - W-propylacetamide; W-ethyl-2- (3- [2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2 - methyl propyl] phenyl} - N - 15 (2-methoxyethyl) acetamide; N- [3- (dimethylamino) -2,2-dimethylpropyl] -2- (3 - (2 - ((2-hydroxy-2- [5 -hydroxy-6- (hydroxymethyl) pyridin-2-yl] -ethyl-amino) -2-methylpropyl] phenyl} acetamide, N- [3-fluoro-5- (trifluoromethyl) benzyl] -2- (3- (2- (2- (2- (2- ( (2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2 - (3 - [2 - ({2-hydroxy -2- [5-hydroxy-6- (hydroxymethyl) -pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -Μ- [(IS) - 1- (hydroxymethyl) -3-methylbutyl) acetamide 2- (3- (2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [ (1S) -2-hydroxy-1-phenylethyl] acetamide, N, N-diethyl-2- (3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridine-2 yl] ethyl} amino) -2-methylpropyl] phenyl} -30 acetamide; 2- (3- (2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-1 H -pyrazole -5-ylacetamide; 2- (3- (2 - ((2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) -35-pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -AT- (5-methyl-1H-pyrazol-3-yl) acetamide; 1028599 4 - N - (cyclohexylmethyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} acetamide, ethyl 4 - ({3- [2 - ({2-hydroxy-2- [5-hydroxy-6- ( hydroxymethyl) -5 pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl-jacetyl) -piperazine-1-carboxylate; N- (5-chloropyridin-2-yl) -2- {3— [2 - ({ 2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide, 2- (3- [2 - ({2-hydroxy-) 2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl) phenyl} -N- (6-methylpyridin-2-yl) acetamide; 2- {3- [ 2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenylJ-N- (3-15 methylpyridin-2-yl) acetamide; 2- (3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl) -A7-isoquinoline-1 -ylacetamide; N- (4,6-dimethyl-pyridin-2-yl) -2- {3- [2 - ({2-hydroxy-2- [5-20 hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl] amino) - 2-methylpropyl] phenyl} acetamide; 2- (3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} -N- (2- methoxybenzyl acetamide; N - [(IS) -1-benzyl-2-hydroxyethyl] -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) ) amino) -2-methylpropyl] phenyl) acetamide; N- (1-ethyl-1H-pyrazol-5-yl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-30 methylpropyl] phenyl} acetamide; N- (1,3-dimethyl-pyrazol-5-yl) -2- {3- [2- ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl]) ethyl) amino) -2-methylpropyl] phenyl} acetamide; N- (3-fluorobenzyl) -2- {3- [2 - ({2-hydroxy-2- [5-hydroxy-6-35 (hydroxymethyl) pyridin-2-yl] ethyl) amino) -2-methylpropyl] phenyl} acetamide; 1028599 <«1- ({3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyljacetyl) -L prolineamide; 6- {2 - [(2- {3- [2- (5-amino-3-t-butyl-122-pyrazol-1-yl) -2-5 oxoethyl] phenyl} -1,1-dimethylethyl) amino ] -1-hydroxyethyl} - 2- (hydroxymethyl) pyridine-3-ol; 2- (3- [2 - ({2-hydroxy-2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N - [(IS - 1-phenylethyl] acetamide; N- (3,4-dimethylbenzyl) -2- (3- (2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-methylpropyl} phenyl) acetamide N- [2- (4-chlorophenyl) ethyl] -2- (3- {2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] -2-methyl-15 propyl} phenyl) acetamide, 6 - {2 - [(2- (3- (2- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) -2-oxoethyl] phenyl} -1, 1-dimethylethyl) amino] -1-hydroxyethyl} 2- (hydroxymethyl) pyridine-3-ol; and N- (2-hydroxybenzyl) -2- (3- (2 - ((22?) - 2-hydroxy- 2- (5-hydroxy-6-hydroxymethyl-pyridin-2-yl) -ethylamino] -propyl} -phenyl) -acetamide; N-benzyl-2- (3- {(22?) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxy-methylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide, N- (3,4-dimethylbenzyl) -2- (3- ((22?) -2- [2-hydroxy -2- (5-25 hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide, N- (2,5-dimethylbenzyl) -2- (3- {(22?) -2- ( 2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} -phenyl) acetamide 2- (3- ((22?) -2- [2-hydroxy-2- ( 5-hydroxy-6-hydroxym ethylpyridin-2-yl) ethylamino] propyl} phenyl) -N- (2-methoxybenzyl) acetamide; N- (2-ethoxybenzyl) -2- (3- {(22?) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl) phenyl) -35-acetamide ; 1028599 N- (3,4-dichlorobenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl) acetamide and, N- (2-chloro-6-fluorobenzyl) -2- (3 - {(2R) -2- [2-hydroxy-2- (5-5 hydroxy-6-hydroxymethylpyridin-2-yl) ethylamino] propyl} phenyl acetamide. 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. A compound of the formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt, derived form or preparation thereof, for use as a medicament. 18. 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 preparation thereof, for the preparation of a medicament for the treatment of diseases, disorders and disorders selected from the group consisting of: 25. asthma of any 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, real asthma, intrinsic asthma caused by pathophysiological disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or unclear cause, non-atopic asthma, bronchitic asthma, emphysematous ast-35 ma, exercise-induced asthma, allergen-induced asthma, cold air-induced obese asthma, occupational asthma, asthma due to infection caused 1028599 * - * by bacterial infection, fungal infection, protozoal or viral infection, non-allergic asthma, early asthma, shortness of breath syndrome in children and bronchial lytis, 5. chronic.or acute bronchoconstriction chronic bronchitis, small airway obstruction and emphysema, obstructive airways or inflammatory diseases of the respiratory tract of any type, aetiology or pathogenesis, in particular an obstructive airways disease or inflammatory disease of the airways that is a member chosen is from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD comprising chronic bronchitis, pulmonary emphysema or dyspnea, whether or not associated with COPD, COPD characterized by irreversible, progressive airway obstruction, respiratory nodular syndrome in adults (ARDS), worsening of hyperreactivity va n the respiratory tract due to other drug treatment and respiratory disease associated with pulmonary hypertension, • bronchitis of any type, etiology or pathogenesis, in particular bronchitis which is a member selected from the group which consists of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, bronchitis crouposa, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, bronchitis by bronchococci or streptococci and vesicular bronchitis, • acute lung injury, 30. bronchitis for type, aetiology or pathogenesis, in particular bronchiectasia which is a member selected from the group consisting of cylindrical bronchiectasia, pocket-shaped bronchiectasia, fusiform bronchiectasia, capillary bronchiectasia, cystic bronchiectasia, dry bronchiectasia and follicular bronchiectasia. 1028599 «-f A method for treating a mammal, including a human, with a P2 agonist, comprising treating that mammal with an effective amount of a compound of the formula (1) as described in any one of claims 1 to 15 or with a pharmaceutically acceptable salt, derivative form or preparation thereof. Combination of a compound according to any of claims 1 to 15 with one or more other therapeutic agents selected from: (a) 5-lipoxygenase inhibitors (5-LO inhibitors) or antagonists of 5-lipoxygenase activating protein (FLAP) , (b) leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4 and LTE4 / (c) histamine receptor antagonists including H1 and H3 antagonists, (d) ai and (X2 adrenoceptor agonist vasoconstrictor sympathomimetic agents for use as decongestant, (e) muscarinic M3 receptor antagonists or anticholinergic agents, (f) PDE inhibitors, for example PDE3, PDE4 and PDE5 inhibitors, (g) theophylline, (h) sodium cromoglycate , (i) COX inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j) oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor), (k) monoclonal antibodies active against endogenous inflammatory entities, (1) anti-tumor necrosis factor agents (anti-TNF-α agents), (m) adhesion molecule inhibitors including VLA-4- antagonists, (n) quinine B1 and B2 receptor antagonists, 10285t (r) immunosuppressive agents, (p) inhibitors of matrix metalloproteases (MMPs),. (q) tachykinin,, NK2 and NK3 receptor antagonists, (r) elastase inhibitors, 5 (s) adenosine A2a receptor agonists, (t) inhibitors of urokinase, (u) compounds that act on dopamine receptors, for example D2 agonists, (v) modulators of the ΝΓκβ route, for example IKK inhibitors, (w) modulators of the cytokine signaling pathways, such as p38 MAP kinase, syk kinase or JAK kinase inhibitor, (x) agents that can be classified as mucolytic agents or antitussives, and 15 (y) antibiotics. -0-0-0 1028599