WO2002067909A1

WO2002067909A1 - New method of bronchodilatory therapy

Info

Publication number: WO2002067909A1
Application number: PCT/GB2002/000809
Authority: WO
Inventors: Giampietro Ventresca
Original assignee: Glaxo Group Limited
Priority date: 2001-02-23
Filing date: 2002-02-22
Publication date: 2002-09-06
Also published as: GB0104555D0

Abstract

As a first aspect of the invention we provide a method of inducing bronchodilation in a human patient which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

Description

New method of bronchodilatory therapy

This invention relates to a novel method of bronchodilatory therapy and to the novel use of a class of molecules in the manufacture of a medicament for the treatment of patients having need of bronchodilation.

Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue. Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.

There is evidence from both in vitro and in vivo studies to suggest that compounds active at the adenosine A2a receptor will have anti-inflammatory actions. The area has been reviewed by Cronstein (1994). Studies on isolated neutrophils show an A2 receptor-mediated inhibition of superoxide generation, degranulation, aggregation and adherence (Cronstein et al, 1983 and 1985; Burkey and Webster, 1993; Richter, 1992; Skubitz et al, 1988). When agents selective for the A2a receptor over the A2b receptor (eg CGS21680) have been used, the profile of inhibition appears consistent with an action on the A2a receptor subtype (Dianzani et al, 1994). Adenosine agonists may also down- regulate other classes of leucocytes (Elliot and Leonard, 1989; Peachell et al, 1989). Studies on whole animals have shown the anti-inflammatory effects of methotrexate to be mediated through adenosine and A2 receptor activation (Asako et al, 1993; Cronstein et al, 1993 and 1994). Adenosine itself, and compounds that raise circulating levels of adenosine also show anti- inflammatory effects in vivo (Green et al, 1991; Rosengren et al, 1995). A2 receptor agonists have also been shown to have effects on capsaicin sensitive afferent sensory nerves in airways tissue (Marimoto et al). A number of A2a receptor agonists have been described in the literature - for example:

Certain substituted 4'-carboxamido and 4'-thioamido adenosine derivatives which are useful for the treatment of inflammatory diseases are described in International Patent Application Nos. WO94/17090, WO96/02553, WO96/02543 (Glaxo Group).

Selective A2a agonists are described in WO98/28319, WO99/38877, WO99/41267, WO99/67263, WO99/67264, WO99/67265 and WO99/67266 (all of Glaxo Group).

Other A2a agonists having claimed selective activity are described in WO00/23457, WO00/77018, WO01/94368 and WO02/00676 (Pfizer).

These Glaxo and Pfizer A2a receptor agonists are all derivatives of adenosine which are derivatised in respect of modified substitution the purine ring and/or the ribose moiety.

A2a receptor agonists have also been described in WO00/78776, WO00/78777, WO00/78778 and WO00/78779 (CV Therapeutics) and in WO00/72799 and US patent 5,877,180 (University of Virginia Foundation).

A concern with the use of adenosine derivatives in the treatment of inflammatory conditions of the respiratory tract is the fact that adenosine has been shown to elicit dose-dependent bronchoconstriction in allergic and non allergic asthmatics (Cushley et al). Adenosine monophosphate has been reported to exhibit similar effects in atopic non-asthmatics (Phillips et al). The explanation for the bronchoconstriction effect of adenosine is not known, although it has been variously hypothesised that it is mediated via the adenosine A3 receptor (Kohno et al, 1996), the A1 receptor (Ali et al and Ghai et al) and A2 receptors (Gustafsson et al). Asthmatic-type responses have also been reported as being mediated via the A2b receptor (Feoktistov et al). Standard therapies for chronic asthmatics are set out in international guidelines (see eg British Thoracic Society et al Thorax (1993) 48 (suppl 1) S1-24). For the mildest asthmatics ("Step 1"), the prescribed therapy is occasional use of relief bronchodilators. The only licensed bronchodilators are the short acting beta-2 agonists (eg albuterol, terbutaline) which are specifically recommended for these mild patients or long acting beta-2 agonists (eg salmeterol, formoterol) which are recommended for more severe patients. With increased severity ("Steps 2-3") it is first recommended to add an inhaled anti-inflammatory agent such as a corticosteroid (such as fluticasone propionate, beclomethasone dipropionate or budesonide) or a mast cell stabiliser such as sodium cromoglycate or nedocromil sodium. Use of long acting beta-2 agonists or oral theophylline may also be appropriate in more severe patients within this category. For yet more severe asthmatics ("Steps 4-5") it is recommended to use high doses of inhaled steroids together with one or more of: long acting beta-2 agonists, oral theophylline, inhaled ipratropium, mast cell stabilisers finally adding oral prednisolone for the most severe patients.

In summary, standard therapy for all but the mildest patients includes an anti- inflammatory component which will generally have no effect for immediate relief of the symptoms of asthma. Asthmatic patients therefore additionally receive bronchodilatory therapy which may be used regularly (as in the case of the long- acting beta-2 agonists) or on-demand in the case of crisis (eg as in the case of short acting beta-2 agonists).

Whilst beta-2 agonists show evidence of anti-inflammatory effects in vitro and in animal models, there remains controversy as to whether or not anti-inflammatory effects of such agents are exhibited in man. Furthermore, the commonly used anti-inflammatory medicaments are believed to have no bronchodilatory activity.

Surprisingly we have discovered a class of compounds that has bronchodilatory activity and is also expected to possess anti-inflammatory activity. More specifically, we have discovered that contrary to expectations, selective A2a receptor agonists cause bronchodilation in asthmatic patients. As just noted, selective A2a agonists show anti-inflammatory effects in animal models and are expected to show anti-inflammatory effects in human subjects. Thus selective A2a agonists appear to fall into a novel and useful class of molecules which combine a bronchodilator effect with an anti-inflammatory effect and will be especially useful in the treatment of inflammatory airways disease such as asthma and COPD.

Thus as a first aspect of the invention we provide a method of inducing bronchodilation in a human patient which comprises administering to that patient an effective amount of a selective A2a receptor agonist. As a subsidiary aspect we provide a method of inducing bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

We also provide a method of relieving bronchoconstriction in a human patient which comprises administering to that patient an effective amount of a selective A2a receptor agonist. As a subsidiary aspect we provide a method of relieving bronchoconstriction in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

There is also provided a pharmaceutical composition for the inducing of bronchodilation in a human patient which comprises an effective amount of a selective A2a receptor agonist. As a subsidiary aspect we provide a pharmaceutical composition for inducing bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises an effective amount of a selective A2a receptor agonist.

We also provide a pharmaceutical composition for the relief of bronchoconstriction in a human patient which comprises an effective amount of a selective A2a receptor agonist. As a subsidiary aspect we provide a pharmaceutical composition for the relief of bronchoconstriction in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises an effective amount of a selective A2a receptor agonist. There is also provided the use of a selective A2a receptor agonist in the manufacture of a medicament for the induction of bronchodilation in a human patient. As a subsidiary aspect we provide the use of a selective A2a receptor agonist in the manufacture of a medicament for the induction of bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD).

We also provide the use of a selective A2a receptor agonist in the manufacture of a medicament for the relief of bronchoconstriction in a human patient. As a subsidiary aspect we provide the use of a selective A2a receptor agonist in the manufacture of a medicament for the relief of bronchoconstriction in a human patient suffering from an inflammatory disorder (eg asthma or COPD).

The bronchodilatory relief will advantageously be acute (i.e. rapid onset) relief as well as chronic relief.

Selective A2a receptor agonists will generally act at the A2a receptor with an agonist potency which is at least 2 times (preferably 5, especially at least 10 times) that at which they act at the A1 , A2b and A3 receptors when measured in assay systems expressing or containing comparable levels of each receptor.

Selective A2a receptor agonists will generally have an affinity for the A2a receptor which is at least 2 times (preferably 5, especially at least 10 times) greater than that for the A1 , A2b and A3 receptors. However A2a agonists with high affinity for A1, A2b or A3 receptors may still behave as selective A2a agonists if they have affinity but little or no agonist activity at these other adenosine receptors (eg if they are antagonists of some or all of them).

Preferably the selective A2a receptor agonist will also demonstrate A3 antagonist activity.

Agonist activity of selective A2a agonists eg at A2a, A1 and A3 receptors may be determined by reference to the following method: Agonist selectivity of compounds against other human adenosine receptors may be determined using Chinese hamster ovary (CHO) cells transfected with the gene for the relevant human adenosine receptor following a method based on that of Castanon and Spevak, 1994 . The CHO cells are also transfected with cyclic AMP response elements promoting the gene for secreted placental alkaline phosphatase (SPAP) (Wood, 1995). The effect of test compounds may be determined by their effects on basal levels of cAMP (A2a and A2b) or on forskolin-enhanced cAMP (A1 and A3) as reflected by changes in levels of SPAP. EC₅₀ values for compounds may then be determined as a ratio to that of the non-selective agonist N-ethyl carboxamide adenosine (NECA).

A "no effect" result in the above test is evidence either of no affinity for the receptor or of antagonistic activity.

Affinity for receptor sub-types may be determined following the methods of Klotz et al (A1 and A2a ), Robeva et al (A2b) and Varani et al (A3).

In the case of compounds exhibiting sub-type receptor binding, antagonist affinity may be determined from a competition experiment involving use of a known sub-type selective agonist ligand. For example a known A3 selective agonist is IB-MECA (iodobenzylmethylcarboximidoadenosine).

Preferably the selective A2a receptor agonist is a derivative of adenosine. Derivatives include compounds which have modified functionality on the purine and/or the ribose moieties of adenosine.

A first set of preferred selective A2a receptor agonists is defined by compounds of formula (I) as follows:

wherein R¹ and R² independently represent a group selected from:

(i) C_3.8cycloalkyl-;

(ϋ) hydrogen;

(iii) aryl₂CHCH₂-;

(iv) C^cycloalkylC^alkyl-;

(v) C^alkyl-;

(vi) arylC,_₆alkyl-;

(vϋ) R^N-C^alkyl-;

(ix) arylC₁.₅alkyl-CH(CH₂OH)-;

(x) arylC₁.₅alkyl-C(CH₂OH)₂-;

(xi) C₃.₈cycloalkyl independenl

-(CH₂)_PR⁶ groups;

(xii) H₂NC(=NH)NHC₁._{6 ,}alkyl-;

( (xxiiiiii)) aa ggrroouupp ooff ffoorrmmuullaa

or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (xiv) -C^alkyl-OH;

(xv) -C^haloalkyl; (xvi) a group of formula

(xvii) aryl; and (xviii) -(CH₂)_fSO₂NH_g(C^alkyl-)₂._g or -(CH₂)_fS0₂NH_g(arylC_Malkyl-)_aβ where f is

2 or 3 and g is an integer 0 to 2;

Z² represents C or N;

Z¹, Z³ and Z⁴ together with Z² and the carbon atom form a 5-membered heterocyclic aromatic ring;

R³ represents C^alkyl or cyclopropyl, save that where Z² represents C, R³ may also represent CH₂OH.

R⁴ and R⁵ independently represent hydrogen, C^alkyl, aryl, arylC,.₆alkyl- or

NR⁴R⁵ together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-C^alkylpiperazinyl;

R⁶ represents OH, NH₂, NHCOCH₃ or halogen;

R⁷ represents hydrogen, C^alkyl, -C.,.₆alkylaryl or -COC_Lealkyl;

X represents NR⁷, O, S, SO or SO₂; p represents 0 or 1 ; a and b independently represent an integer 0 to 4 provided that a + b is in the range 3 to 5; c, d and e independently represent an integer 0 to 3 provided that c + d + e is in the range 2 to 3;

Z Z³ and Z⁴ will independently represent C, N, O or S and, in the case of C and N, together with a sufficient number of hydrogen atoms to provide the ring with aromatic character. At least one of Z¹, Z², Z³, Z⁴ and Z⁵ will represent a heteroatom. Preferably at least one of Z\ Z³ and Z⁴ will represent a nitrogen atom. More preferably at least one of Z\ Z³and Z⁴will represent a nitrogen atom and at least one of the remainder will represent C or N. We prefer that two or three of Z\ Z², Z³ and Z⁴ are heteroatoms.

References to C_x._yalkyl include references to an aliphatic hydrocarbon grouping containing x to y carbon atoms which may be straight chain or branched and may be saturated or unsaturated. References to alkoxy may also be interpreted similarly.

References to aryl include references to mono- and bicyclic carbocyclic aromatic rings (e.g. phenyl, naphthyl) and heterocyclic aromatic rings, for example containing 1-3 hetero atoms selected from N, O and S (e.g. pyridinyl, pyrimidinyl, thiophenyl, imidazolyl, quinolinyl, furanyl, pyrrolyl, oxazolyl) all of which may be optionally substituted, e.g. by C^alkyl, halogen, hydroxy, nitro, C,. ₆alkoxy, cyano, amino, SO₂NH₂ or -CH₂OH.

Examples of C₃.₈cycloalkyl for R¹ and R² include monocyclic alkyl groups (e.g. cyclopentyl, cyclohexyl) and bicyclic alkyl groups (e.g. norbornyl such as exo- norborn-2-yl).

Examples of (aryl)₂CHCH₂- for R¹ and R² include Ph₂CHCH₂- or such a group in which one or both phenyl moieties is substituted, e.g. by halogen or C^alkyl.

Examples of C₃.₈cycloalkylC₁.₆alkyl- for R¹ and R² include ethylcyclohexyl. Examples of C,.₈alkyl for R¹ and R² include -(CH₂)₂C(Me)₃, -CH(Et)₂ and

CH₂=C(Me)CH₂CH₂-.

Examples of arylC,.₆alkyl- for R¹ and R² include -(CH₂)₂Ph, -CH₂Ph or either in which Ph is substituted (one or more times) by halogen (e.g. iodine), amino, methoxy, hydroxy, -CH₂OH or SO₂NH₂; -(CH₂)₂ pyridinyl (e.g. -(CH₂)₂pyridin-2-yl) optionally substituted by amino; (CH₂)₂imidazolyl (e.g. 1 H-imidazol-4-yl) or this group in which imidazoyl is N-substituted by C,.₆alkyl (especially methyl).

Examples of R⁴R⁵N-C₁^alkyl- for R¹ and R² include ethyl-piperidin-1-yl, ethyl- pyrrolidin-1-yl, ethyl-morpholin-1-yl, -(CH₂)₂NH(pyridin-2-yl) and -(CH^NK,.

Examples of C^alkyl-CH C^OH)- for R¹ and R² include Me₂CHCH(CH₂OH)-. Examples of arylC^alkyl-CHfCH H)- for R¹ and R² include PhCH₂CH(CH₂OH)- particularly

Examples of

for R¹ and R² include PhCH₂C(CH₂OH)₂-.

Examples of C₃.₈ cycloalkyl independently substituted by one or more -(CH₂)_PR⁶ groups (eg 1 , 2 or 3 such groups) for R¹ and R² include 2-hydroxy-cyclopentyl and 4-aminocyclohexyl (especially trans-4-amino-cyclohexyl).

Examples of H₂NC(=NH)NHC₁.₆alkyl for R¹ and R² include H₂NC(=NH)NH(CH₂)₂-

Examples of groups of formula

,(CH₂

-< X

/

(CH₂ 2)'b for R¹ and R² include pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, tetrahydro-1,1- dioxide thiophen-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl and 1 ,1- dioxo-hexahydro-1.lamda.6-thiopyran-4-yl, or a derivative in which the ring nitrogen is substituted by C_halky! (e.g. methyl), C^alkylacyl (e.g. acetyl), arylC,. ₆alkyl- (e.g. benzyl).

Examples of -C^alkyl-OH groups for R¹ and R² include -CH₂CH₂OH and -CH(CH₂OH)CH(CH₃)₂.

Examples of C,.₈haloalkyl for R¹ and R² include -CH₂CH₂CI and (CH₃)₂CIC(CH₂)₃-. Examples of groups of formula

for R¹ and R² include 2-oxopyrrolidin-4-yl, 2-oxopyrrolidin-3-yl, 2-oxopyrrolidin-5- yl or a derivative in which the ring nitrogen is substituted by C^alkyl (e.g. methyl) or benzyl. Examples of aryl for R¹ and R² include phenyl optionally substituted by halogen

(e.g. fluorine, especially 4-fluorine).

An example of a -(CH^SO^H_g^^alky z^ group f°^r R¹ and R²is

-(CH₂)₂SO₂NHMe, and an example of a -(CH₂)_fSO₂NH_g(arylC₁^alkyl)₂._g group for

R¹ and R²is -(CH₂)₂SO₂NHCH₂Ph.

An example of C^alkyl for R⁷ is methyl, an example of C^alkylaryl for R⁷ is benzyl, and an example of -COC,.₆alkyl for R⁷ is acetyl.

We prefer that R¹ and R² do not both represent hydrogen. We prefer R¹ to represent aryl₂CHCH₂-, C_halky!-, hydrogen or arylC^alky

We prefer R² to represent arylC_Lgalkyl-CHfCH H)-, R₄R₅N-C₁.₆alkyl-,

-CH(CH₂OH)C₁.₃alkyl, 4-aminocyclohexyl, pyrrolidinyl or arylCH₂CH₂-, especially where aryl represents (l-C^alkyl-IH-imidazoyl-4-yl).

We prefer R³ to represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl or CH₂OH (when Z² represents C), particularly methyl, ethyl or cyclopropyl, especially ethyl. We prefer R⁴ and R⁵ independently to represent hydrogen or aryl or NR⁴R⁵ together to represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-methylpiperazinyl.

We prefer that p represents 0. We prefer that R⁶ represents OH or NH₂. We prefer that a represents 2 and that b represents 1 or 2. We prefer X to represent NR⁷ (e.g. NH), O, S or SO₂, particularly O, S or NH. We prefer that c represents 0, and either that d represents 1 and e represents 1 or d represents 0 and e represents 2. We prefer that R⁷ represents hydrogen.

We particularly prefer R¹ to represent Ph₂CHCH₂-, hydrogen or CH(Et)₂, especially hydrogen or CH(Et)₂.

We particularly prefer R² to represent ethyl-piperidin-1-yl, PhCH₂CH(CH₂OH)-, - CH(CH₂OH)(CH(CH₃)₂, trans-4-amino-cyclohexyl, 2-(1-methyl-1 H-imidazoyl-4- yl)CH₂CH₂-, ethyl-morpholin-1-yl, pyrrolidin-3-yl, ethyl-pyridin-2-yl, H₂NC(=NH)NH(CH₂)₂-, cyclopentyl or ethylcyclohexyl, especially PhCH₂CH(CH₂OH)-, 2-(1-methyl-1H-imidazoyl-4-yl)CH₂CH₂- or ethyl-piperidin-1- yi-

In a first subset of compounds we prefer that the moiety

Group (a) is especially preferred; group (c) is also particularly preferred. In a second subset of compounds we prefer Z² to represent C. We prefer Z⁴ to represent N.

We prefer that the moiety

represents one of the following groups:

The above groups may be referred to hereinafter as (i) = triazolyl; (ii) = 4'-1 ,2,4 oxadiazolyl; (iii) = 4'-1,3,4 oxadiazolyl; (iv) = 1 ,3 oxazolyl; (v) = 1 ,3,4 thiadiazolyl; and (vi) = N-alkyl triazolyl. The groups above illustrated as (i) triazolyl, (ii) 4'- 1 ,2,4 oxadiazolyl, (iii) 4'-1,3,4 oxadiazolyl and (vi) N-alkyl triazolyl are preferred. The group above illustrated as (i) triazolyl is most preferred.

Other selective A2a agonist compounds may be defined by the following formulae (II) and (III):

wherein Z\ Z², Z³ and Z⁴ together with the carbon atom form a 5-membered heterocyclic aromatic ring and variables R¹ and R² are as previously defined (Z\ Z², Z³ and Z⁴will independently represent C, N, O or S and, in the case of C and N, together with a sufficient number of hydrogen atoms to provide the ring with aromatic character. At least one of Z Z², Z³ and Z⁴ will represent a heteroatom. Preferably at least one of Z\ Z², Z³ and Z⁴ will represent a nitrogen atom. More preferably at least one of Z\ Z², Z³ and Z⁴ will represent a nitrogen atom, two of the remainder independently will represent C or N and the fourth will represent C, N or O. In each case sufficient hydrogen atoms will be provided to give the ring aromatic character. However, we prefer that Z\ Z², Z³ and Z⁴ do not all represent nitrogen); and

wherein Z\ Z², Z³ and Z⁴ together with Z⁵ form a 5-membered heterocyclic aromatic ring and variables R¹ and R² are as previously defined (Z\ Z², Z³ and Z⁴ will independently represent C, N, O or S and, in the case of C and N, together with a sufficient number of hydrogen atoms to provide the ring with aromatic character. At least one of Z\ Z², Z³, and Z⁴ will represent carbon. We prefer that one or two of Z\ Z², Z³, and Z⁴ represent N and the remainder represent C. Carbon atoms in the ring may be substituted by hydroxy).

Compounds of formula (I), (II) and (III) may be prepared following the methods of WO98/28319, WO99/38877, WO99/41267, WO99/67263, WO99/67264, WO99/67265 and WO99/67266 (all of Glaxo Group).

Other selective A2a agonist compounds may be defined by the following formula (IV):

wherein:

R⁸ is alkyl or cyclopropylmethyl;

R⁹ is phenyl-alkylene or napthyl-alkylene, said alkylene chain being optionally further substituted by phenyl or napthyl, each phenyl or napthyl being optionally substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and cyano; n is 1 or 2;

A is NR^a, NR^aC(O), NR^aC(O)NR^a, NR^aC(O)O, OC(O)NR^a, C(O)NR^a, NR^aSO₂, SO₂NR^a, O, S or SO₂,

R^a is H, alkyl or benzyl optionally ring-substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and cyano;

R¹⁰ is a group of the formula -(CH₂)_q-R^p-B; q is O, 1 or 2; R^p is a bond, alkylene, cycloalkylene, phenylene or naphthylene, said cycloalkylene, phenylene and naphthylene each being optionally substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and alkoxyalkylene; B is (i) H, -NR^bR^b, R^bR^bN-alkylene, -OR^b, -COOR^b, -OCOR^b, -SO₂R^b, -CN, - SO₂NR R^b, -NR^bCOR^b, NR^bSO₂R^b or -CONR^bR^b, in which each R^b is the same or different and is selected form H, alkyl, phenyl and benzyl, provided that,

(a) when B is -OCOR , -SO₂R^b,-NR COR^b or -NR^bSO₂R^b, then the terminal R^b is not H, and

(b) R^p is a bond, p is 0 and B is H only when A is NR^a, NR^aC(O)NR^a, OC(O)NR^a, C(O)NR^a-, SO₂NR^a, O or S, (ii) an optionally-substituted, fully- or partially-saturated or-unsaturated, mono-or bicyclic, heterocyclic group, which is linked to R^p by a ring carbon atom, or (iii) N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each optionally substituted by one or more alkyl substituents, with the proviso that -(CH₂)_p-R^D-is not-CH₂-; and where A is NR^a, C(O)NR^a, OC(O)NR^a or SO₂NR^a, R^a and R¹⁰ taken together with the nitrogen atom to which they are attached can form an azetidine, pyrrolidine, piperidine or piperazine ring, optionally by one or more alkyl substituents; and wherein within this definition the expressions "alkyl", "alkylene", "alkoxy" and the like will be understood to relate to such groups preferably containing 1 to 6, especially 1-4 carbon atoms.

These compounds may be prepared following the method of WO00/23457.

Other selective A2a agonist compounds may be defined by the following formula (V):

wherein: R¹¹ is hydrogen or C,-C₆ alkyl optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C,-C₆ alkyl, C_rC₆ alkoxy, halo or cyano; R¹² is H or C_rC₆ alkyl; K is C C₆ alkylene;

R¹³ is (i) hydrogen, C C_β alkyl, -COOR¹⁴, -CN, -CONR¹⁴R¹⁴, C₃-C₈ cycloalkyl, phenyl or naphthyl, said C₃-C₈ cycloalkyl, phenyl and naphthyl being optionally substituted by C_rC₆ alkyl, phenyl, C_rC₆ alkoxy (C_rC₆) alkyl, R¹ R N(C_rC₆) alkyl, halo (C_rC₆) alkyl, fluoro (C_rC₆) alkoxy, (C₂-C₅) alkanoyl, halo, -OR¹⁴, cyano, -COOR¹⁴, C₃-C₈ cycloalkyl, -S(O)_mR¹⁵, -NR¹⁴R¹⁴, -SO₂NR¹⁴R¹⁴, - CONR¹⁴R¹⁴, -NR¹ COR¹⁵ or-NR¹⁴SO₂R¹⁵ or -NR¹⁴SO₂R¹⁵, or (ii) when A is C₂-C₆ alkylene, -NR¹⁴R¹⁴, -OR¹⁴, -OCOR¹⁵, -SO₂R¹⁵, -S0₂NR¹⁴R¹⁴ or -NR¹⁴COR¹⁵, or (iii) a C-linked, 4- to 11 -membered ring, mono- or bicyclic, heterocycle having either from 1 to 4 ring nitrogen atom(s), or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, being optionally C-substituted by oxo, C_rC₆ alkoxy(C₁- C₆) alkyl, R¹⁶R¹⁶N(C_rC₆) alkyl, halo (C_rC₆) alkyl, fluoro (C_rC₆) alkoxy, fluoro (C₂- C₅) alkanoyl, halo, cyano, -OR¹⁶, R¹⁷, -COR¹⁶, -NR¹⁶R¹⁶, -COOR¹⁶, -S(0)_mR¹⁷, - SO₂NR¹⁶R¹⁶, -CONR¹⁶, -NR¹⁶SO₂R¹⁷ or -NR¹⁶COR¹⁷ and optionally N-substituted by C C₆ alkoxy (C_rC₆) alkyl, R¹⁶R¹⁶N(C₂-C₆) alkyl, halo (C_rC₆) alkyl, fluoro (C₂- C₅) alkanoyl, R¹⁷, -COR¹⁶, -COOR¹⁷, -SO₂R¹⁷, -SO₂NR¹⁶R¹⁶ or -CONR¹⁶R¹⁶, or (iv) when A is C₂-C₆ alkylene, N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, each being optionally C-substituted by C C₆ alkyl, phenyl, C_rC₆ alkoxy (C_rC₆) alkyl, R¹ R¹⁴N(C_rC₆) alkyl, halo (C C₆) alkyl, fluoro (C C₆) alkoxy, C₂-C₅ alkanoyl, halo, -OR¹⁴, cyano, -COOR¹⁴, C₃- C₈ cycloalkyl, -S(O)_mR¹⁵, -NR¹ R¹⁴, -S0₂NR¹⁴R¹⁴, -CONR¹⁴R¹⁴, -NR¹⁴COR¹⁵ or - NR¹ SO₂R¹⁵, and said piperazinyl and homopiperazinyl being optionally N- substituted by

alkyl, phenyl, C_rC₆ alkoxy (C₂-C₆) alkyl, R¹⁴R¹⁴(C₂-C₆) alkyl, fluoro (C_rC₆) alkyl, C₂-C₅ alkanoyl, -COOR¹¹, C₃-C₈ cycloalkyl, -S0₂R¹⁵, - SO₂NR¹⁴R¹⁴ or -CONR¹⁴R¹⁴;

R¹⁴ is H, C_rC₆ alkyl, C₃-C₈ cycloalkyl or phenyl;

R¹⁵ is C_rC₆ alkyl, C₃-C₈ cycloalkyl or phenyl;

R¹⁶ is H, C_rC₆ alkyl, C₃-C₈ cycloalkyl, phenyl, naphthyl or het;

R¹⁷ is C_rC₆ alkyl, C₃-C₈ cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; and "het", used in the definitions of R¹⁶ and R¹⁷, means C-linked pyrrolyl, imidazoyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazoyl or quinoxalinyl, each being optionally substituted by C_rC₆ alkyl, C C₆ alkoxy, cyano or halo.

These compounds may be prepared following the method of WO00/77018.

Other selective A2a agonist compounds may be defined by the following formula (VI):

wherein:

R¹⁸ represents -NH-N=CH-cyclohexyl, -NH-N=CH-CH₂-CHMe₂, -O-CH₂-CH₂-(4- methyl-phenyl), -CC-(CH₂)₂.₁₅-Me (wherein -CC- represents two carbons connected to each other by a triple bond) or -O-(CH₂)₂-naphthyl, preferably -NH- N=CH-cyclohexyl or -NH-N=CH-CH₂-CHMe₂; and R¹⁹ represents HOCH₂- or EtHNCO-, preferably HOCH₂-.

Compounds of formula (VI) wherein R¹⁹ represents HOCH₂- and R¹⁸ represents - NH-N=CH-cyclohexyl or -NH-N=CH-CH₂-CHMe are known by the code numbers WRC0474 (SHA211) and WRC0470 respectively.

Compounds of formula (VI) may be prepared as described in WO00/72799 and references contained therein.

The previously mentioned compounds may all be used in the form of physiologically acceptable salts if desired eg in order to optimise the biological or physical properties of the molecule. The representation of formulae (I), (II), (III), (IV), (V) and (VI) indicate the absolute stereochemistry. When sidechains contain chiral centres the invention extends to mixtures of enantiomers (including racemic mixtures) and diastereoisomers as well as individual enantiomers. Generally it is preferred to use a compound of formula (I) in the form of a purified single enantiomer.

In use according to the invention the selective A2a receptor agonist may beneficially be combined in therapy with one or more further therapeutic agents, for example:

Short acting beta-2 agonists, eg albuterol (eg as free base or sulphate) or terbutaline (eg as sulphate);

Long acting beta-2 agonists, eg salmeterol (eg as xinafoate) or formoterol (eg as fumarate);

Glucocorticosteroids, eg fluticasone propionate, beclomethasone dipropionate, mometasone furoate, ciclesonide, budesonide, rofleponide, triamcinolone acetonide;

Anti-cholinergic medicaments, eg ipratropium (eg as bromide), oxitropium, tiotropium;

Non-steroidal anti-inflammatory and/or anti-allergic compounds, eg ketotifen, cromoglycate (eg as sodium), nedocromil (eg as sodium);

DA2-beta-2 agonist compounds, eg 4-hydroxy-7-[2-[[2-[[3-(2- phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone; PDE4 inhibitors, such as cilomilast.

It will be understood that any of the above mentioned medicaments may be used in alternative salt forms and, where appropriate, in the form of enantiomeric mixtures (eg racemates) or single enantiomers.

Combinations of medicaments in therapy may either be administered sequentially or (preferably) simultaneously.

The A2a agonist according to the invention (together if appropriate with any other pharmaceutically active substances) may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in anti-inflammatory therapy, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.

There is also provided a process for preparing such a pharmaceutical formulation which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, buccal, parenteral, topical, ocular or rectal administration, preferably for oral, parenteral or topical (e.g. by aerosol) administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl 2- hydroxy benzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate. For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

Compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre- filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator, solutions for nebulisation or drops (e.g. eye or nose drops).

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.

Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1 ,1 ,1,2- tetrafluoroethane, carbon dioxide or other suitable gas.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.

Capsules and cartridges of for example gelatin, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Solutions for inhalation by nebulisation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.

Selective A2a agonist compounds may conveniently be administered in amounts of, for example, 0.001 μg/kg to 50mg/kg body weight, preferably 0.01μg/kg to 10mg/kg body weight, 1 to 4 times daily or on demand. The precise dose will of course depend on the age and condition of the patient, the activity of the molecule selected and the particular route of administration chosen. The preferred route of administration is topical administration to the lung (eg administration by inhalation).

A preferred A2a agonist according to the invention is (2R,3R,4S,5R)-2-[6-Amino- 2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5- yl)-tetrahydro-furan-3,4-diol and salts thereof (eg the maleate) which may be prepared according to the method of Example 11 in W098/28319. A preferable dose of this compound is 0.06-125μg administered by inhalation each day.

Other compounds of particular interest are:

(2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1-ethyl-propylamino)-2-[2-(1- methyl-1H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol and salts thereof; and (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2- piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol and salts thereof which may be prepared according to the methods of Examples 5 and 6 respectively in WO99/38877. A preferable dose of these compounds is 0.06-

250μg administered by inhalation each day.

Other compounds of interest are:

(2R,3R,4S,5S)-2-[6-(1-Ethyl-propylamino)-2-(2-piρeridin-1-yl-ethylamino)-purin-

9-yl]-5-(3-methyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;

N-(4-{6-(2,2-Diphenyl-ethylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy- tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-cyclohexyl)-acetamide;

(2R,3R,4S,5S)-2-{6-(2,2-Diphenyl-ethylamino)-2-[2-(pyridin-2-ylamino)- ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;

(2R,3R,4S,5S)-2-{6-(3,3-Dimethyl-butylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; and (2R,3R,4S,5S)-2-[6-(1-Ethyl-propylamino)-2-(2-piperidin-1-yl-ethyIamino)-purin-

9-yl]-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol and salts thereof which may be prepared according to the methods of Examples 55, 24, 16, 7 and

57 respectively in WO99/38877. A preferable dose of these compounds is 0.06- 250μg administered by inhalation each day. Other compounds of interest are:

(2R,3R,4S,5R)-2-[6-(2,2-Diphenyl-ethylamino)-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(5-ethyl-4H-[1,2,4]triazol-3-yl)-tetrahydro-furan-3,4-diol; (2R,3R,4S,5R)-2-{6-(2,2-Diphenyl-ethylamino)-2-[2-(1-methyl-1H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(5-ethyl-[1 ,2,4]oxadiazol-3-yl)-tetrahydro-furan-3,4-diol; which may be prepared according to the methods of Examples 5 and 13 respectively in WO99/67264. A preferable dose of these compounds is 0.06- 250μg administered by inhalation each day.

Other compounds of interest are:

N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6- [(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1- propanesulphonamide and salts thereof (eg the potassium salt); and (2R,3R,4S,5R)-2-(6-[(2,2-diphenylethyl)amino]-2-{[1 -isopropyl-4- piperidinyl)amino]methyl}-9H-purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4- furandiol and salts thereof (eg the dihydroxybutanedioate salt) which may be prepared according to the methods of Examples 15(74) and 16(75) respectively in WO00/23457.

Another compound of interest is:

9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2- diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide and salts thereof ) which may be prepared according to the method of Example 9 in WOOO/77018.

Other compounds of interest are WRC0474 (SHA211) and WRC0470 which may be prepared as described in WO00/72799 and references contained therein.

The bronchodilatory medicaments according to the invention may be useful in the treatment of diseases of the respiratory tract which include actual or a susceptibility to bronchoconstriction or wherein bronchodilation would be beneficial. The principal such diseases are asthma and chronic obstructive pulmonary disease (COPD). Other diseases for which this therapy may be suitable include adult respiratory distress syndrome (ARDS), emphysema, cystic fibrosis and atopic/allergic diseases having a bronchial component eg allergic rhinitis. The bronchodilatory medicaments according to the invention may also be useful in the treatment of cough.

Brief Description of the Figures:

Figure 1: Mean FEV1 change (in litres) from baseline with time in Cohort 1 following the experiment of the Example.

Figure 2: Mean FEV1 change (in litres) from baseline with time in Cohort 2 following the experiment of the Example.

References:

Ali S, Mustafa SJ and Metzger WJ (1994) J Pharmacol Exper Therapeut 268(3),

1328-34; Asako H, Wolf, RE, Granger, DN (1993), Gastroenterology 104, pp 31-37;

Burkey TH, Webster, RO, (1993), Biochem. Biophys Acta 1175, pp 312-318;

Castanon MJ, Spevak W, (1994), Biochem. Biophys Res. Commun. 198, pp

626-631;

Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R, (1983), Trans. Assoc. Am. Physicians 96, pp 384-91 ;

Cronstein BN, Kramer SB, Rosenstein ED, Weissmann G, Hirschhorn R, (1985),

Ann N.Y. Acad. Sci. 451, pp 291-301;

Cronstein BN, Naime D, Ostad E, (1993), J. Clin. Invest. 92, pp 2675-82;

Cronstein BN, Naime D, Ostad E, (1994), Adv. Exp. Med. Biol., 370, pp 411-6; Cronstein BN, (1994), J. Appl. Physiol. 76, pp 5-13;

Cushley MJ, Tattersfield E and Holgate ST (1983) Br J Clin Pharmacol 15, 161-

165;

Dianzani C, Brunelleschi S, Viano I, Fantozzi R, (1994), Eur. J. Pharmacol 263, pp 223-226; Elliot KRF, Leonard EJ, (1989), FEBS Letters 254, pp 94-98;

Feoktistov I and Biaggioni I (1997) Pharmacol Revs 49, 381-402;

Ghai G, Zimmerman MB and Hopkins MF (1987) Life Sciences 41(10) 1215-24;

Green PG, Basbaum Al, Helms C, Levine JD, (1991), Proc. Natl. Acad Sci. 88, pp 4162-4165; Gustafsson LE, Wiklund NP and Cederqvist B (1986) Eur J Pharmacol 120(2), 179-85;

Klotz KN. Hessling J. Hegler J. Owman C. Kull B. Fredholm BB. Lohse MJ (1998) Naunyn-Schmiedebergs Archives of Pharmacology. 357(1):1-9; Kohno Y, Xiao-duo J, Mawhorter SD, Koshiba M, Jacobson KA. (1996).BIood 88 p3569-3574.

Marimoto et al (1993) Eur J Pharmacol 240, 121-126; Peachell PT, Lichtenstein LM, Schleimer RP, (1989), Biochem Pharmacol 38, 1717-1725; Phillips GD, Ng WH, Church MK and Holgate ST (1990) Am Rev Respir Dis 141 , 9-13; Richter J, (1992), J. Leukocyte Biol. 51, pp 270-275;

Robeva AS. Woodard RL. Jin XW. Gao ZH. Bhattacharya S. Taylor HE. Rosin DL. Linden J. (1996) Drug Development Research. 39(3-4):243-252; Rosengren S, Bong GW, Firestein GS, (1995), J. Immunol. 154, pp 5444-5451;

Skubitz KM, Wickman NW, Hammerschmidt DE, (1988), Blood 72, pp 29-33;

Varani K. Cacciari B. Baraldi PG. Dionisotti S. Ongini E. Borea PA. (1998) Life

Sciences. 63(5):PL 81-PL 87;

Wood KV. (1995) Curr Opinion Biotechnology 6 p50-58.

Example

A randomised, double blind, double dummy, placebo controlled, cross-over study to investigate the effects of cumulative inhaled doses of nebulised and dry-powder (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol

("drug") on airway hyper-responsiveness in mild asthmatic patients.

Protocol

The study was conducted in 24 mild asthmatics in 2 centres. There were 2 Cohorts in each centre - Cohort 1 received nebulised doses of drug or placebo via HaloLite nebuliser and Cohort 2 received dry powder doses of drug or placebo via Diskhaler inhaler. Subjects attended the unit for a screening visit before treatment commenced. They were required to demonstrate stable PC₂₀ (PC₂₀ is the provocative concentration causing a 20% fall in FEV1 from baseline) in response to adenosine monophosphate (AMP) challenge within 7 days prior to randomisation, at the beginning of the trial and at the end. Nebulised placebo consisted of 0.9% sodium chloride solution in water. Nebulised drug formulation consisted of 500μg/ml drug and 0.9% sodium chloride in water.

Dry powder placebo consisted of a Diskhaler blister containing lactose. Dry powder drug formulation consisted of a Diskhaler blister containing 25μg drug per blister and lactose.

Cohort 1 (n=6) received on 3 separate days:

A: 5 cumulative low doses of 0.06, 0.12, 0.24, 0.48 and 0.96 μg of drug via nebuliser (Haloϋ^'te) (total daily dose received = 1.86 μg). B: 5 cumulative high doses of 0.96, 1.92 3.84, 7.68 and 15.36 μg of drug via nebuliser (HaloLite) (total daily dose received = 29.76 μg). C: 5 doses of matched placebo via nebuliser

Cohort 2 (n = 6) received on 3 separate days:

A: 5 cumulative low doses each of 25 μg of drug via Diskhaler inhaler (total daily dose received = 125 μg). B: A single high dose of 75 μg of drug , then 2 doses each of 25 μg of drug and then 2 doses each of placebo via Diskhaler inhaler (total daily dose received

= 125 μg). C: 5 doses of matched placebo via Diskhaler inhaler.

Patients were monitored for changes in FEV1 before and after AMP challenge and dosing.

Results

The results are shown in Figures 1 and 2. The arrows indicate the 5 dosing time points.

Conclusion

From Figures 1 and 2 it can be seen that administration of (2R,3R,4S,5R)-2-[6- Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H- tetrazol-5-yl)-tetrahydro-furan-3,4-diol according to the study design resulted in a rapid dose-dependent increase in FEV1 of up to 150-200ml after administration of drug compared with placebo. This provides consistent evidence for a rapid-onset bronchodilatory effect in asthmatic patients of a magnitude which would be of therapeutic benefit.

' Patents and patent applications referred to herein are incorporated by reference.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

Claims

1. A method of inducing bronchodilation in a human patient which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

2. A method of inducing bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

3. A method of relieving bronchoconstriction in a human patient which comprises administering to that patient an effective amount of a selective

A2a receptor agonist.

4. A method of relieving bronchoconstriction in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises administering to that patient an effective amount of a selective A2a receptor agonist.

5. A pharmaceutical composition for the inducing of bronchodilation in a human patient which comprises an effective amount of a selective A2a receptor agonist.

6. A pharmaceutical composition for inducing bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises an effective amount of a selective A2a receptor agonist.

7. A pharmaceutical composition for the relief of bronchoconstriction in a human patient which comprises an effective amount of a selective A2a receptor agonist.

8. A pharmaceutical composition for the relief of bronchoconstriction in a human patient suffering from an inflammatory disorder (eg asthma or COPD) which comprises an effective amount of a selective A2a receptor agonist.

9. The use of a selective A2a receptor agonist in the manufacture of a medicament for the induction of bronchodilation in a human patient.

10. The use of a selective A2a receptor agonist in the manufacture of a medicament for the induction of bronchodilation in a human patient suffering from an inflammatory disorder (eg asthma or COPD).

11. The use of a selective A2a receptor agonist in the manufacture of a medicament for the relief of bronchoconstriction in a human patient.

12. The use of a selective A2a receptor agonist in the manufacture of a medicament for the relief of bronchoconstruction in a human patient suffering from an inflammatory disorder (eg asthma or COPD).

13. A composition, method or use according to any one of claims 1-12 wherein the selective A2a agonist is also an A3 antagonist.

14. A composition, method or use according to any one of claims 3, 4, 7, 8, 11 or 12 wherein the relief is acute relief.

15. A composition, method or use according to any one of claims 1-12 wherein the selective A2a agonist is a derivative of adenosine.

16. A composition, method or use according to claim 15 wherein the A2a agonist is (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)- purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol or a salt thereof.

17. A composition, method or use according to claim 15 wherein the A2a agonist is (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1 -ethyl-propylamino)-2-[2-(1 - methyl-1 H-imidazol-4-yI)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol or a salt thereof.

18. A composition, method or use according to any one of claims 1 to 12 wherein the selective A2a agonist is administered in combination with a beta- 2 agonist.

19. A composition, method or use according to any one of claims 1 to 12 wherein the selective A2a agonist is administered by inhalation.