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. W094/17090, W096/02553, W096/02543 (Glaxo Group).

Selective A2a agonists are described in W098/28319, W099/38877, W099/41267, W099/67263, W099/67264, W099/67265 and W099/67266 (all of Glaxo Group).

Other A2a agonists having claimed selective activity are described in WOOO/23457, WO00/77018, W001/94368 and W002/00676 (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, W000/78777, WO00/78778 and WO00/78779 (CV Therapeutics) and in WOOO/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 placenta 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. ECgo 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) C3-8cycloalkyl-; (ii) hydrogen; (iii) aryl2CHCH2- ; (iv) C3-8cycloalkylC1-6alkyl-; (v) C1-8alkyl-; (vi) ary -6alkyl-; (vii) R4R5N-C1-6alkyl-; (viii) C1-6alkyl-CH(CH2OH)-; (ix) ary -5alkyl-CH(CH2OH)-; (x) arylC, 5alkyl-C (CH20H) 2-; (xi) C3-8cycloalkyl independently substituted by one or more (e. g. 1,2 or 3) - (CH2) PR6 groups; (xii) H2NC (=NH) NHC, -6alkyl-; (xiii) a group of formula or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl ; (xiv) -C1-6alkyl-OH ; (xv)-C, haloalkyl ; (xvi) a group of formula (xvii) aryl ; and

(xviii) -(CH2)fSO2NHg(C1-4alkyl-)2-g or -(CH2)fSO2NHg(arylC1-4alkyl-)2-g 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 C13alkyl or cyclopropyl, save that where Z2 represents C, R3 may also represent CH20H.

R4 and R5 independently represent hydrogen, C1-6alkyl, aryl, arylC1-6alkyl- or NR4R5 together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-Caikyipiperaziny) ; R6 represents OH, NH2, NHCOCH3 or halogen ; R7 represents hydrogen, C1-6alkyl, -C1-6alkylaryl or -COC1-6alkyl ; X represents NR, 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; z1, 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, Z4 and Z5 will represent a heteroatom. Preferably at least one of Z1, Z3 and Z4 will represent a nitrogen atom. More preferably at least one of Z1, 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 Cl-alkyl 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 Cl-, alkyl, halogen, hydroxy, nitro, C 6alkoxy, cyano, amino, SO2NH2 or -CH2OH.

Examples of C38cycloalkyl for R'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 R'and RZ include Ph2CHCH2-or such a group in which one or both phenyl moieties is substituted, e. g. by halogen or Chalky).

Examples of C3-8cycloalkylC1-6alkyl- for R1 and R2 include ethylcyclohexyl.

Examples of. Cl-,, alkyl for R1 and R2 include -(CH2)2C(Me)3, -CH (Et) 2 and CH2=C (Me) CH2CH2.

Examples of arylC1-6alkyl- 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,-CH20H or SO2NH2; -(CH2)2 pyridinyl (e. g.-(CH2) 2pyridin-2-yl) optionally substituted by amino; (CH2) 2imidazolyl (e. g. 1H-imidazol-4-yl) or this group in which imidazoyl is N-substituted by C1-6alkyl (especially methyl).

Examples of R4R5N-C16alkyl-for R1 and R2 include ethyl-piperidin-1-yl, ethyl- pyrrolidin-1-yl, ethyl-morpholin-1-yl, -(CH2)2NH(pyridin-2-yl) and -(CH2)2NH2.

Examples of C1-6alkyl-CH(CH2OH)- for R4 and R2 include Me2CHCH(CH2OH)-.

Examples of arylC1-5alkyl-CH(CH2OH)- for R1 and R2 include PhCH2CH(CH2OH)- particularly Examples of arylC1-5alkyl-C(CH2OH)2- for R1 and R2 include PhCH2C(CH2OH)2-.

Examples of C38 cycloalkyl independently substituted by one or more -(CH2)pR6 groups (eg 1,2 or 3 such groups) for R'and R2 include 2-hydroxy-cyclopentyl and 4-aminocyclohexyl (especially trans-4-amino-cyclohexyl).

Examples of H2NC (=NH) NHC16alkyl for R'and R2 include H2NC (=NH) NH (CH2) 2- Examples of groups of formula

for R'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 C1-6alkyl (e. g. methyl), C1-6alkylacyl (e. g. acetyl), aryle 6alkyl- (e. g. benzyl).

Examples of -C1-6alkyl-OH groups for R1 and R2 include -CH2CH2OH and - CH (CH20H) CH (CH3) 2.

Examples of C1-8haloalkyl for R'and R2 include-CH2CH2CI and (CH3) 2CIC (CH2) 3- Examples of groups of formula (CH2) CO (cH2) d\ 7 NR < NR 2e 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 6alkyl (e. g. methyl) or benzyl.

Examples of aryl for R'and R2 include phenyl optionally substituted by halogen (e. g. fluorine, especially 4-fluorine).

An example of a -(CH2)fSO2NHg(C1-4alkyl)2-g group for R1 and R2 is - (CH2) 2SO2NHMe, and an example of a -(CH2)fSO2NHg(arylC1-4alkyl)2-g group for R1 and R2 is -(CH2)2SO2NHCH2Ph.

An example of C1-6alkyl for RI is methyl, an example of C1-6alkylaryl for R'is benzyl, and an example of -COC1-6alkyl for W is acetyl.

We prefer that R1 and R2 do not both represent hydrogen.

We prefer RI to represent aryl2CHCH2-, C1-8alkyl-, hydrogen or arylC1-6alkyl-.

We prefer R2 to represent arylC1-5alkyl-CH(CH2OH)-, R4R5N-C1-6alkyl-, - CH (CH20H) C1-3alkyl, 4-aminocyclohexyl, pyrrolidinyl or arylCH2CH2-, especially where aryl represents (1-C1-3alkyl-1H-imidazoyl-4-yl).

We prefer R3 to represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl or CH20H (when Z2 represents C), particularly methyl, ethyl or cyclopropyl, especially ethyl.

We prefer RI and RI 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 R'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 0, 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 R'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 (CH20H) (CH (CH3) 2, trans-4-amino-cyclohexyl, 2- (1-methyl-1 H-imidazoyl-4- <BR> <BR> <BR> yl)CH2CH, ethyl-morpholin-1-yl, pyrrolidin-3-yl, ethyl-pyridin-2-yl, H2NC (=NH) NH (CH2) 2-, cyclopentyl or ethylcyclohexyl, especially PhCH2CH (CH20H)-, 2-(1-methyl-1H-imidazoyl-4-yl)CH2CH2- or ethyl-piperidin-1- yl.

In a first subset of compounds we prefer that the moiety is selected from one of the following groups:

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 R'and R2 are as previously defined (Z1, 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 Z1, Z2, Z3 and Z4 will represent a heteroatom.

Preferably at least one of Z', Z2, Z3 and Il will represent a nitrogen atom. More preferably at least one of Z', Z2, Z3 and Il will represent a nitrogen atom, two of the remainder independently will represent C or N and the fourth will represent C, N or 0. In each case sufficient hydrogen atoms will be provided to give the ring aromatic character. However, we prefer that z1, Z2, Z3 and Z4 do not all represent nitrogen); and wherein z1, Z2, Z3 and Z4 together with Z5 form a 5-membered heterocyclic aromatic ring and variables R1 and R2 are as previously defined (Z1, 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 Z1, 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 W098/28319, W099/38877, W099/41267, W099/67263, W099/67264, W099/67265 and W099/67266 (all of Glaxo Group).

Other selective A2a agonist compounds may be defined by the following formula (IV): wherein: Ra is alkyl or cyclopropylmethyl ; R9 is phenyl-alkylene or napthyl-alkylene, said alkylen 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 or2 ; A is NRa, NRaC (O), NRaC (O) NRa, NRaC (O) O, OC (O) NRa, C (O) NRa, NRaSO2, SO2NRa, O, S or SO2, Ra 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-RP-B ; q is 0, 1 or 2 ; RP 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,-NRbRb, RbRbN-alkylene,-ORb,-COORb,-OCORb,-S02Rb,-CN,- SO2NRbRb,-NRbCORb, NRbSO2Rb or-CONRbRb, in which each Rb is the same or different and is selected form H, alkyl, phenyl and benzyl, provided that, (a) when B is-OCORb,-S02Rb,-NRbCORb or-NRbSO2Rb, then the terminal Rb is not H, and (b) RP is a bond, p is 0 and B is H only when A is NRa, NRaC (O) NRa, OC (O) NRa, C (O) NRa,, SO2NRa, O or S, (ii) an optionally-substituted, fully-or partially-saturated or-unsaturated, mono-or bicyclic, heterocyclic group, which is linked to RP 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-RP-is not-CH2-; and where A is NRa, C (O) NRa, OC (O) NRa or S02NRa, Ra and R'° taken together with the nitrogen atom to which they are attached can form an azetidine, pyrrolidine, piperidine or piperazin 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 WOOO/23457.

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

R"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 C1-C6 alkyl, C,-C6 alkoxy, halo or cyano; R12 is H or C1-C6 alkyl ; K is Ci-Ce alkylen ; R'3 is (i) hydrogen, C,-C6 alkyl,-COOR'4,-CN,-CONR'4R14, C3-C$ cycloalkyl, phenyl or naphthyl, said C3 C$ cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy (C1-C6) alkyl, R14R14N(C1-C6) alkyl, halo (C,-C6) alkyl, fluoro (C1-C6) alkoxy, (C2-C5) alkanoyl, halo, -OR14, cyano,-COOR'4, C3-C8 cycloalkyl,-S (O) mR15, -NR14R14, -SO2NR14R14, - CONR14R14, -NR14COR15 or -NR14SO2R15 or-NR14SO2R15, or (ii) when A is C2-C6 alkylene, -NR14R14, -OR14, -OCOR15, -SO2R15, -SO2NR14R14 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,-C6 alkoxy (Cl- C6) alkyl, R16R16N(C1-C6) alkyl, halo (C1-C6) alkyl, fluoro (C1-C6) alkoxy, fluoro (C2- C5) alkanol, halo, cyano, -OR16, R17, -COR16, -NR16R16, -COOR16, -S(O)mR17, - SO2NR16R16, -CONR16, -NR16SO2R17 or -NR16COR17 and optionally N-substituted by C1-C6 alkoxy (C1-C6) alkyl, R16R16N(C2-C6) alkyl, halo (C1-C6) alkyl, fluoro (C2- C5) alkanol, R17, -COR16, -COOR17, -SO2R17, -SO2NR16R16 or-CONR16R16, or (iv) when A is C2-C6 alkylen, N-linked azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or morpholinyl, each being optionally C-substituted by C,-C6 alkyl, phenyl, C,-Cs alkoxy (C,-C6) alkyl, R'4R14N (C,-C6) alkyl, halo (C,- C6) alkyl, fluoro (C1-C6) alkoxy, C2-C5 alkanoyl, halo, -OR14, cyano, -COOR14, C3- C8 cycloalkyl,-S (O) mR15, -NR14R14, -SO2NR14R14, -CONR14R14, -NR14COR15 or - NR'4SO2R", and said piperazinyl and homopiperazinyl being optionally N- substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy (C2-C6) alkyl, R14R14(C2-C6) alkyl, fluoro (Cl-C6) alkyl, C2-C5 alkanoyl, -COOR11, C3-C8 cycloalkyl, -SO2R15, - SO2NR14R14 or -CONR14R14; R'4 is H, C,-C6 alkyl, C3-C$ cycloalkyl or phenyl ; R'S is C1-C6 alkyl, C3-C8 cycloalkyl or phenyl ; R16 is H, C,-C6 alkyl, C3-C$ cycloalkyl, phenyl,. naphthyl or het; R17 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; m is 0, 1 or 2; and

"het", used in the definitions of R16 and R'7, 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 C1-C6 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 (Vl) : 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 R10 represents HOCH2- or EtHNCO-, preferably HOCH2-.

Compounds of formula (VI) wherein R'9 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 WOOO/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), (\/) 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 pharmaceutical 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 p-hydroxybenzoates 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 g/kg to 50mg/kg body weight, preferably 0. 01 g/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- (l S-hydroxymethyl-2-phenyi-ethylamino)-purin-9-yl]-5- (2-ethyl-2H-tetrazol-5- yl)-tetrahydro-furan-3, 4-diol and salts thereof (eg the maleat) which may be prepared according to the method of Example 11 in W098/28319. A preferable dose of this compound is 0.06-125, ug 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-1 H-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 W099/38877. A preferable dose of these compounds is 0.06- 250ug administered by inhalation each day.

Other compounds of interest are: (2R, 3R, 4S, 5S)-2- [6- (1-Ethyl-propylamino)-2- (2-piperidin-1-yl-ethylamino)-purin- 9-yl]-5- (3-methyl-isoxazol-5-yl)-tetrahydro-furan-3, 4-diol ; N- (4-16- (2, 2-Diphenyi-ethylamino)-9- [5S- (3-ethyl-isoxazol-5-yl)-3R, 4S-dihydroxy- tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-cyclohexyl)-acet amide ; (2R, 3R, 4S, 5S)-2-{6-(2, 2-Diphenyl-ethylamino)-2-[2-(pyridin-2-ylamino)- ethylamino]-purin-9-yi)-5- (3-ethyl-isoxazol-5-yi)-tetrahydro-furan-3, 4-diol ; (2R, 3R, 4S, 5S)-2- {6- (3, 3-Dimethyl-butylamino)-2- [2- (1-methyl-1 H-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-ethylamino)-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 W099/38877. 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- (1 S-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-1 H-imidazol4-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 W099/67264. A preferable dose of these compounds is 0.06- 250ug 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 WOOO/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 WOOO/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; BurkeyTH, Webster, RO, (1993), Biochem. BiophysActa 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.

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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- (1 S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahy dro-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 5OOpg/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 25ug 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 ug of drug via nebuliser (HaloLite) (total daily dose received = 1.86 ug).

B: 5 cumulative high doses of 0.96,1.92 3.84,7.68 and 15.36 ug of drug via nebuliser (HaloLite) (total daily dose received = 29.76 aug).

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 ug of drug via Diskhaler inhaler (total daily dose received =125 ug).

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

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- (1 S-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.