ZA200209875B

ZA200209875B - 2-aminocarbonyl-9H-purine derivatives.

Info

Publication number: ZA200209875B
Application number: ZA200209875A
Authority: ZA
Inventors: Mantell Simon John; Stephenson Peter Thomas
Original assignee: Pfizer
Priority date: 2000-06-06
Filing date: 2002-12-05
Publication date: 2003-12-05
Also published as: CR6829A; CN1810822A; ECSP024370A; YU82302A; MY128457A; TNSN01083A1; GEP20053513B; GB0018246D0; PE20020065A1; GB0014048D0; CN100374454C; GT200100105A; IL152783A; DOP2001000182A; AP2001002179A0; SV2002000477A

Description

2-AMINOCARBONYL-9H-PURINE DERIVATIVES e This invention relates to purine derivatives. More particularly, this invention relates to 2-aminocarbonyl-9H-purine derivatives and to processes for ) 5 the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, infer alia, diseases of the respiratory tract.

Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3.

Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O,"), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis-and release of arachidonate products such as leukotriene B, (LTB,). LTB, is a potent chemo- attractant that recruits additional neutrophils to the inflammatory focus, whereas released O, and HNE adversely affect the pulmonary extraceliular matrix. The

A2 receptor subtype mediating many of these responses (0, and LTB, /HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.

Selective agonist activity at the A2a receptor is considered to offer . greater therapeutic benefit than the use of non-selective adenosine receptor i» agonists because interaction with other subtypes is associated with detrimental ~ effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the

A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. - Furthermore, many patients with respiratory disease will be co-prescribed B,- agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase.

Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.

We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor.

They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine

A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage) ~ induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also. be used in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non- steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.

Accordingly, in a first embodiment, the present invention provides a compound of the formula:

R! ) AN" 4 T ToT oT

AS a a lo! 0] tt OH ’ oo / 0)

OH or a pharmaceutically acceptable salt or solvate thereof, wherein

R'is H, C,-C, alkyl or fluorenyl, said C,-C; alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C,-C, alkyl, C,-C; alkoxy, halo or cyano; (A) R%is H or C,-C; alkyl, R" is H or C,-C, alkyl, and X is either (i) unbranched

C.-C; alkylene optionally substituted by C,-C, alkyl or C,-C, cycloalkyl, or (ii) a group of the formula: ~(CHy)y— W - (CH,),- where W is C,-C, cycloalkylene optionally substituted by C,-C, alkyl, n is 0 or 1 andpisOor1,or ‘ 20 (B) Ris Hor C,-C, alkyl, and R? and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C, alkyl, or

(C) R%is H or C,-C, alkyl, and R" and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, . piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionaily substituted by C,-C; alkyl; ' 5 either, R® and R*, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C,-C, alkyl or C,-C, cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by -

NR°R’, or, R%®is H, C,-C; alkyl, C,-C, cycloalkyl or benzyl and R* is (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-y} or homaopiperidin-4-yl, each being optionally substituted by C,-C; alkyl, C,-C, cycloalkyl, phenyl, benzyl or het, or (b) -(C,-C,, alkylene)-R®, (¢) -(C,-C; alkylene)-R", or (d) C,-C; alkyl or C,-C; cycloalkyl;

R® is CH,OH or CONR™R™,;

R® and R” are either each independently H or C,-C, alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C,-C, alkyl;

R®is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1- h yl, homopiperidin-1-yl, homopiperazin-1-yi or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C,-C, alkyl, C;-Cq cycloalkyl, phenyl, C,-C, alkoxy-(C,-Ce)-alkyl, R®°R°N-(C,-C,)-alkyl, fluoro-(C,-

s

C,)-alkyl, -CONR®R?®, -COOR® or C,-C; alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C,-C;)-alkoxy, : halo, -OR®, cyano, -S(0),,R", -NR°R?, -SO,NR°R®, -NR°COR™" or -NR’SO,R", and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C,-C; alkylene group by C,-C; alkyl, phenyl, C.-C, alkoxy-(C,-C;)-alkyl, R°R°N-(C,-C,)-alkyl, fluoro-(C,-Cq)-alkyl, C,-

C; alkanoyl, -COOR", C,-C, cycloalkyl, -SO,R™, -SO,NR°R® or -CONR°R?, or (ii) NR"'R",

Ris H, C,-C; alkyl, C,-C; cycloalkyl or phenyl;

R" is C,-C, alkyl, C,-C, cycloalkyl or phenyl;

R" is H, C,-C, alkyl, C,-C, cycloalkyl or benzyl;

Ris H, C,-C; alkyl, C,-C, cycloalkyl, phenyl, benzyl, fluoro-(C,-C;)-alkyl, -

CONR®R?, -COOR?, C.-C; alkanoy! or -SO,NR°R?;

R® is (a) phenyl, pyridin-2-yl, pyridin-3-yi or pyridin-4-yl, each being optionally substituted by C,-C; alkyl, C,-C, alkoxy, -(C,-C, alkylene)-(C,-C; alkoxy), halo, cyano, -(C,-C, alkylene)-CN, -CO,H, -(C,-C; alkylene)-CO,H, -CO,(C,-C; alkyl), -(C,-C, alkylene)-CO,(C,-C, alkyl), -(C,-C, alkylene)-NR"R", -CONR"R" or - (C,-C, alkylene)-CONR™R™", or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by

C,-C, alkyl, C;-C; cycloalkyl, phenyl, benzyl or het;

R'is H or C,-C; alkyl optionally substituted by cyclopropyl; mis0,1or2;

Y is CO, CS, SO, or C=N(CN); and : “het”, used in the definition of R*and R¥, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C.-C; alkyl, C.-C, cycloalkyl, C,-C4 alkoxy, C,-C, cycloalkoxy, hydroxy, oxo or halo.

In a second embodiment, the present invention provides a compound of the formula:

R1 in”

N ~ N rR" R? Re

CT 1

NT ~ NG WN 0 0 -11 OH

R® t 0

OH or a pharmaceutically acceptable salt or solvate thereof, wherein

R'is H, C,-Cg alkyl or fluorenyl, said C,-C; alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl! being optionally substituted by C,-C, alkyl, C,-C, alkoxy, halo or cyano; - 20 RZ2is Hor C,-C; alkyl; ) either, R® and R*, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring

Claims

] 1. A compound of the formula: R? HN" N NN rR" R? R® 4 g LL NE ~ «Ny 0] o} 1 OH 0) OH or a pharmaceutically acceptable salt or solvate thereof, wherein R'is H, C,-C; alkyl or fluorenyl, said C,~C; alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C,-C; alkyl, C,-C; alkoxy, halo or cyano; (A) R?is H or C,-C, alkyl, R™ is H or C,-C, alkyl, and X is either (i) unbranched C,-C; alkylene optionally substituted by C,-C; alkyl or C;-C, cycloalkyl, or (ii) a group of the formula: —(CH,),—W - (CH,),- where W is C,-C, cycloalkylene optionally substituted by C,-C; alkyl, n is 0 or 1 andpisQor1,or (B) R™ is H or C,-C; alkyl, and R? and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C; alkyl, or

(C) R%is H or C,-C; alkyl, and R'® and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, ’ piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C; alkyl;

either, R® and R*, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C,-C, alkyl or C;-C; cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by - NR°R’, or, R® is H, C,-C; alkyl, C,-C, cycloalkyl or benzyl and R* is (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C; alkyl, C,-C, cycloalkyl, phenyl, benzyl or het, or (b) -(C,-C; alkylene)-R®, (c) -(C,-C; alkylene)-R™, or (d) C,-C, alkyl or C;-C4 cycloalkyl;

R% is CH,OH or CONR"R", R® and R’ are either each independently H or C,-C; alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C,-C, alkyl; Ris (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1- yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C,-C; alkyl, C;-C, cycloalkyl, phenyl, C,-C, alkoxy-(C,-Cs)-alkyl, R*R°N~(C,-C)-alkyl, fluoro-(C,-

Cs)-alkyl, -CONR®R?®, -COOR?® or C,-C; alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C,-C;)-alkoxy, ’ halo, -OR?, cyano, -S(0),,R", -NR°R®, -SO,NR°R?, -NR?*COR" or -NR°SO,R", and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C,-C; alkylene group by C,-C, alkyl, phenyl, C,-C, alkoxy-(C-C;)-alkyl, R°R°N-(C,-C;)-alkyl, fluoro-(C,-C;)-alkyl, C,- C; alkanoyl, -COOR?", C,-C, cycloalkyl, -SO,R", -SO,NR®R® or -CONR°R?®, or (ii) NR"R", R%is H, C,-C; alkyl, C,-C, cycloalkyl or phenyl; R" is C,-C alkyl, C,-C, cycloalkyl or phenyi; R" is H, C,-C; alkyl, C,-C, cycloalkyl or benzyl;

R'is H, C,-C, alkyl, C,-C, cycloalkyl, phenyl, benzyl, fluoro-(C,-C,)-alkyl, - CONRR?, -COOR?", C,-C; alkanoyl or -SO,NR°R?; R'is (a) phenyl, pyridin-2-yl, pyridin-3-yi or pyridin-4-yl, each being optionally substituted by C,-C, alkyl, C,-C; alkoxy, -(C,-C; alkylene)-(C,-C, alkoxy), halo, cyano, -(C,-C; alkylene)-CN, -CO,H, -(C,-C; alkylene}-CO,H, -CO,(C,-C, alkyl), -(C,-C, alkylene)-CO,(C,-C; alkyl), -(C,-C, alkylene)-NR"R", -CONR"R" or - (C,-C, alkylene)-CONR"R", or (b) azetidin-2-yl, azetidin-3-yi, pyrrolidin-2-yi, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C, alkyl, C,-C, cycloalkyl, phenyi, benzyl or het; R™ is H or C,-C, alkyl optionally substituted by cyclopropyl; mis0,1o0r2;

Y is CO, CS, SO, or C=N(CN); and ’ “het”, used in the definition of R*and R™®, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C,-C, alkyl, C,-C, cycloalkyl, C,-C; alkoxy, C,-C, cycloalkoxy, hydroxy, oxo or halo.
2. A compound as claimed in claim 1 wherein R' is C,-C; alkyl optionally substituted by 1 or 2 phenyl substituents, said phenyl being optionally substituted by C,-C; alkyl or halo.
3. A compound as claimed in claim 2 wherein R' is diphenylethyl, bis(3- methylphenyl)ethyl or bis(3-chlorophenyl)ethyl.
4. A compound as claimed in claim 3 wherein R' is 2,2-diphenylethyl, 2,2-bis(3- methylphenyl)ethyl or 2,2-bis(3-chlorophenyl)ethyl.
5. A compound as claimed in claim 4 wherein R' is 2,2-diphenylethyl.
6. A compound as claimed in any one of the preceding claims wherein R? is H.
7. A compound as claimed in any one of the preceding claims wherein R" is H.
8. A compound as claimed in any one of the preceding claims wherein X is 1,2- ethylene or 1,3-propylene.
9.A compound as claimed in claim 8 wherein X is 1,2-ethylene.
10. A compound as claimed in any one of claims 1 to 5 wherein R*is H, R"® is H and X is 1,2-ethylene, 1,3-propylene or a group of the formula:

—~(CHg),— W - (CH,),- where W is C.-C, cycloalkylene, nisOor1 and pis 0 or 1.
11. A compound as claimed in claim 10 wherein R?is H, R*® is H and X is 1,2- ethylene, 1,3-propylene or a group of the formula: —(CH,),— W - (CH), - where W is C.-C, cycloalkylene, nis 0 and p is O.
12. A compound as claimed in claim 11 wherein R%is H, R® is H and X is 1,2- ethylene, 1,3-propylene or 1,4-cyclohexylene.
13. A compound as claimed in claim 12 wherein R%is H, R" is H and X is 1,2- ethylene.
14. A compound as claimed in any one of claims 1 to 5 wherein R"is H and R? and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C,-C; alkyl.
15. A compound as claimed in claim 14 wherein Ris H and R? and X, taken together with the nitrogen atom to which they are attached, represent 3- pyrrolidinyl or 4-piperidinyl.
16. A compound as claimed in any one of claims 1 to 5 wherein R? is H and R"® ) and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C.-C; alkyl.
17. A compound as claimed in claim 16 wherein R? is H and R'® and X, taken together with the nitrogen atom to which they are attached, represent 3- ’ pyrrolidinyl or 4-piperidinyl.
18. A compound as claimed in any one of the preceding claims wherein R® is H.
19. A compound as claimed in any one of the preceding claims wherein R* is piperidin-3-yl or piperidin-4-yl, each optionally substituted by benzyl, pyridin-2- yl, pyridin-3-yl or pyridin-4-yl, said pyridin-2-yl, pyridin-3-yl and pyridin-4-yl each optionally substituted by C,-C; alkyl, C,-C, cycloalkyl, C,-C, alkoxy, C.-C, cycloalkoxy, hydroxy, oxo or halo.
20. A compound as claimed in claim 19 wherein R* is piperidin-3-yl or piperidin- 4-yl, each substituted by benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
21. A compound as claimed in claim 20 wherein R* is piperidin-4-yl substituted by pyridin-2-yl.
22. A compound as claimed in claim 21 wherein R* is 1-(pyridin-2-yl)piperidin- 4-yl.
23. A compound as claimed in any one of claims 1 to 18 wherein R* is -(C,-C, alkylene)-R°.
24. A compound as claimed in claim 23 wherein R* is —-CH,CH,R®.
25. A compound as claimed in any one of claims 1 to 18 wherein R* is -(C,-C, alkylene)-R".
26. A compound as claimed in claim 25 wherein R* is —-CH,R" or —CH,CH,R™.
27. A compound as claimed in any one of claims 1 to 18 wherein R* is C.-C, cycloalkyl.
28. A compound as claimed in claim 27 wherein R*is cyclohexyl.
29. A compound as claimed in any one of the preceding claims wherein R® is - CH,OH or -CONH(C,-C; alkyl).
30. A compound as claimed in claim 29 wherein R’ is -CONHCH,CH,.
31. A compound as claimed in claim 23 or 24 wherein R® is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C,-C; alkyl and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C,-C, alkylene group by C,-C, alkyl, or (ii) is NR"'R'2,
32. A compound as claimed in claim 31 wherein R® is piperidin-1-yl or tetrahydroisoquinolin-1-yl each optionally substituted on a ring carbon atom by C,-C; alkyl.
33. A compound as claimed in claim 32 wherein R® is piperidin-1-yl, 4- isopropylpiperidin-1-yl or tetrahydroisoquinolin-1-yl.
34. A compound as claimed in claim 31 wherein R® is NR"'R"? where NR"'R" js N(C,-C; alkyl),, N(C,-C; alkyl)(C,-C; cycloalkyl) or N(C,-C, alkyl)(benzyl).
35. A compound as claimed in claim 34 wherein NR"'R" is N,N- diisopropylamino, N,N-di-n-butylamino, N-cyclopentyl-N-isopropylamino, N- cyclohexyl-N-isopropylamino or N-benzyl-N-isopropylamino.
36. A compound as claimed in claim 31 wherein R"' is H or C,-C; alkyl and R" is H, C,-C; alkyl, C;-C4 cycloalkyl or benzyl.
37. A compound as claimed in claim 36 wherein R"" is C,-C; alkyl and R" is C,- CGC, alkyl, C;-C, cycloalkyl or benzyl.
38. A compound as claimed in claim 37 wherein R" is isopropyl or n-butyl and R'? is isopropyl, n-butyl, cyclopentyl, cyclohexyl or benzyl.
39. A compound as claimed in claim 25 or 26 wherein R* is either phenyl optionally substituted by -(C,-C, alkylene)-NR"R" or -CO_H, or piperidin-2-yl, piperidin-3-yl or piperidin-4-yl each optionally substituted by benzyl.
40. A compound as claimed in claim 39 wherein R'is phenyl, 4-(N,N- diethylamino)methylphenyl, 4-carboxypheny! or 1-benzylpiperidin-4-yl.
41. A compound as claimed in any one of the preceding claims wherein Y is

CO.
42. A compound as claimed in claim 1 wherein . R'® R? rR Ll 0 q SI hl ~"nHcon 0 iPr d YY hE —"nrcon NN

0

. i ~ ~~" wmcont NN 0 iQ : PO hg ~~—""NHcon lo) H ye he ~~" NHCONH le} ; PO hi ~ NHCONHCH lo} H rr le} y rr Nr 7 wean NY lo}

H nBu . Nr ~"rconH- MN sy fo) N Nr "WHCONHGH,Ph lo} H iPr N hg SN" NHconr NAN 0 Ho NHEONE iPr hd SiPr ’ fo) N ig S"TNHCONHCH,CHPh fo) i ~~" NHcon lo}

CO.H N hig ~~" NHCONH lo} NER),

FN . N NHCON rt I~ te) he ~~ Hoon lo) hi ~ won) , fo)

H TO) i S) , N ) HOON SN Nero H NC is N 0 Vor ipr 0 he

0] . ) ’ “NHCONH iPr RH \ hig AS: SN" H 5 Ril 0 NHCONHCH,Ph lo! } ~ \ to)

~~ C=" 0 y LQ ’ ~( (room 0 i N NHCONH ON Nipr Lor oo 0 iPr A NHCONH" >" ip : ys i .
43. A compound as claimed in claim 1 which is 6-[(2,2-diphenylethyl)amino}-9- {(2R,3R,4S,58)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-N- ‘ {2-[({[1-(2-pyridinyl)-4-piperidinyllamino}carbonyl)aminolethyl}-9H-purine-2- carboxamide or a pharmaceutically acceptable salt or solvate thereof.
44. A compound as claimed in claim 1 which is 4-[({[(2-{[(6-[(2.,2- diphenylethyl)amino}-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4- dihydroxytetrahydro-2-furanyl}-9H-purin-2- yhcarbonyllamino}ethyl)amino]carbonyl}-amino)methyllbenzoic acid or a pharmaceutically acceptable salt or solvate thereof.
45. A pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 44, together with a pharmaceutically acceptable excipient, diluent or carrier.
46. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for use as a medicament.
47. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively,for use as an A2a receptor agonist.
48. A compound of the formula (1) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 : respectively for use as an anti-inflammatory agent. ’
49. A compound of the formula (1) or a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for use in the treatment of a respiratory disease.
50. A compound as claimed in claim 49 where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, ’ chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
51. A compound of the formula (I) or a pharmaceutically acceptable salt, solvate or compasition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for use in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non- steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
52. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or compasition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for the manufacture of a medicament having A2a receptor agonist activity.
53. The use of a compound of the formula (1) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for the manufacture of an anti-inflammatory agent.
54. The use of a compound of the formula (1) or of a pharmaceutically : acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for the manufacture of a medicament for the treatment of a respiratory disease.
55. Use as claimed in claim 54 where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
586. The use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, as claimed in any one of claims 1 to 44 and 45 respectively, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroks, epilepsy, cerebral ischaemia, - 10 peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Hellobacter pylori gastritis, non-steroidal anti- inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing. fTUDED CHEST
57. A process for the preparation of a compound of the formula (1) as claimed in claim 1 which includes (a) for the preparation of a compound of the formula (I) wherein Y is CO and RY,

R% RY, RY, R®, Rand X are as defined in claim 1, reaction of a compound of the formula:

LLILZI20NCIT

R'

HN . N IN R'S Rr? 4 9 Ng N Sx” lo] 0 <1 OH R® E OH (I) with a compound of the formula: R*R*NCOZ' (11) wherein Z' is a leaving group; or (b) aminocarbonylation reaction of a compound of the formula: rR’ HN N EN ¢ Ag PY 3 N z Jo +1 OH . RS < OH (Xvi wherein Z* is a leaving group, with a compound of the formula: R*NH-X-NR-Y-NR°R* (Xvi wherein R', R?, R%, R* R® R", X and Y are as defined in claim 1, in the presence of carbon monoxide and a coupling catalyst; or (c) deprotection of a compound of the formula:

rR HN N ANY R'S Rr Rr? ! 0 Lol] NG Nr Sy NS ? 11 OR? © Ro - OR? (XX)

wherein R*' and R? are either each a protecting group, or, taken together, are a protecting group, R* is CH,OH, CH,OR® or CONR"R", R®is a protecting group and R', R% R?, R%, R"™, R", X and Y are as defined in claim 1, the protecting group(s) being removed together, separately or in any combination; or

(d) for the preparation of a compound of the formula (1) wherein Y is CS and R', R2 R? R* R® R"™and X are as defined in claim 1, reaction of a compound of the formula:

rR!

HN . N ANS 15 2 4 Tl I N x7 es 0] 0 <1 OH R® P OH (XXIVA) wherein Z°/ Z® is a leaving group, with an amine of the formula: R°R*NH ; or (e) for the preparation of a compound of the formula (I) wherein Y is SO, and RY, R% R? R* R® R'"™and X are as defined in claim 1, reaction of a compound of the formula: RR*NSO,Z’ (XXVIT) wherein Z’ is a leaving group, with compound of the formula (11) as defined in part (a); or (f) for the preparation of a compound of the formula (I) wherein Y is C=N(CN) and R', R? R?, R% R® R®and X are as defined in claim 1, reaction of a compound of the formula:

) R' HN N NN R® Rr? ¢ © Ll N x7 e=NEeN).Z8Z 0} 0 <1 OH R® 2 OH (XXIVB) wherein Z8 / Z° is a leaving group, with an amine of the formula: J R°R‘NH

; or

(g) reaction of a compound of the formula:

rR! HN" N ES CT AN N 0) Oo a1 OH . RS (Xv) OH wherein R" is an ester-forming group, with an amine of the formula: R'*NH-X-NR%-Y-NR*R*

xvii) wherein R', R% R®, R%, R%, R™, X and Y are as defined in claim 1 - any one of said processes being optionally followed by conversion of a compound of the formula (1) to a pharmaceutically acceptable salt thereof. ~
58. A compound of the formula: 1 a NSN j® wm ¢ TC CL N Mx lo} lo} Ile | . (mn } wherein R', R? R®, R" and X are as defined in claim 1.
59. A compound of the formula;

. — N EN ¢ T 2 OR'® ot OH 1 av) OH LLIN wherein R®is CONR“R™, Ris an ester-forming group and R" and R** are as defined in claim 1.
60. A compound of the formula: HN" R NNy"SN R* RR % T FI Be : TT 0 wi ORR oR xXx) wherein R? and R* are either each a protecting group, or, taken together, are a protecting group, R* is CH,OH, CH,OR® or CONR“R*, R®is a protecting group and R', R? R?, R%, R“, R*®, X and Y are as defined in claim 1.
61. A compound of the formula: R' HN” NN R* RR g ¢ TC : N™ SW STN Np 0 a) wherein R', R? R% R*, R", X and Y are as defined in claim 1.
62. A compound of the formula: HN" R N Nn R* RR PB 4 xT gy N N “x” My ge

R* . . 0 ooav) wherein R* is a protecting group and R!, R?, R®, R R"®, X and Y are as defined in claim 1.
63. A compound of the formula: ; HN” R N CLI N= al POV) wherein R* is a protecting group and R®, R R' and X are as defined in claim

1. CITT

-
64. A compound of the formula: we N ES 0 0 N AY ro. “ora POI) wherein R* Is an ester-forming group, R*' and R2 are either each a protecting group, or, taken together, are a protecting group, and R' is as defined in daim

“1.
65. A compound of the formula: {

we N ES ¢ T ! (0) — OR1s 0 N : au! Rand RAO ” OR22 POXIV) wherein R" is an ester-forming group, R* and RZ are either each a protecting group, or, taken together, are a protecting group, and R! and R* are as defined in claim 1. :

5 .
66. A compound of the formula; R? : HN" ¢ oN 0] ~~ R14 “SN RHO oR2 OOXV) oo wherein R*! and R? are either each a protecting group, or, taken together, are a protecting group, and R' and R* are as defined in claim 1.
67. A compound of the formula: .

we C1) PP Ris o HO fo) Ho on COXVII) wherein R* is an ester-forming group and R' is as defined in claim 1,
68. A compound of the formula: a CCLI I oe ASA : HO RHO i ‘bra COXXIX) : wherein R* and R* are either each a protecting group, or, taken together, are a protecting group, and R', R2, RR, R",XandY are as defined in claim 1.
69. A compound of the formula:

Rt Te NSN jf gop ¢ T PP 0 N Ne x= ~~" Rt HO RAO j “Rez XXX) wherein R*' and R* are either each a protecting group, or, taken together, are a S protecting group, and R', R? R?, R%, R*®, X and Y are as defined in claim 1.
70. A compound of the formula: : HN” R N 2089 AN cs.2m Be! ie XXIVA) wherein Z°/Z° is a leaving group and R!, R?, R®, R™® and X are as defined in claim 1. :

| .
71. A compound of the formula; .

NT N NN R® Rg? ¢ TC iP Bs N “x7 Ne=NeN ZZ o v1 OH L (XXx1vB)

wherein wherein Z°/Z° is a leaving group and R', R?, R®, R™® and Xare as defined in claim 1. :
72. Ethyl 6-[(2,2-diphenylethyl)amino}-9H-purine-2-carboxylate: ethyl 8-{(2R.3R.4R,5R)-3 4-bis(acetyloxy)-5-{(acetyloxy)methylltetrahydro-2- furanyi}-6-{(2,2-diphenylethyl)amino}-9H-purine-2-carboxylate; ethyl $-{(2R,3R.43,5R)-3 4-dihydroxy-5-(hydroxymethyi)tstrahydro-2-furanyi]-6- [(2,2-diphenylethyi)amino}-9H-purine-2-carboxylate; : ethyl &-(3aR.4R,6R.6aR)-8-(hydroxymethyl)-2,2-dimethyttetrahydrofurof3 4- df 3]dioxol-4-yi}-6-{(2,2-diphenylethyl}aminc}-0H-purine-2-carboxylate;

(3aS,4S,6R,6aR)-6-6-(2,2-diphenylethyi)amino}-2-(ethoxycarbonyl)-0H-purin- 9-yl]-2,2-dimethyitstrahydrofuro[3,4-d}[1, 3]dioxole-4-carboxylic acid; ethyl 9-{(3aR,4R,68,6aS)-6-{(ethylamino)carbonyi}-2,2- dimethyttetrahydrofurof3,4-d][1,3]dioxol-4-yi}-6-{(2,2-diphenylethyl\amino}- OH- purine-2-carboxylate; 8-{(3aR 4R,6S,6aS)-6-{(ethylamino)carbonyi}-2,2-dimethyitetrahydrofuro[3,4- dj[1 .3}dioxol-4-yi}-6-[(2,2-diphenylethyl)amino}-8H-purine-2-carboxylic acid; 9-{(3aR,4R,6S,6aS)-6-{(ethylamino)carbonyl}-2,2-dimethyitetrahydrofuro[3,4- d][1,3]dioxol-4-yi}-6-[(2,2-diphenyiethyl)amino]-N-{2-[({[1 -(2-pyridinyi)-4- piperidinyllamino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide: tert-butyl 2-[({[1-(2-pyridinyl)-4- piperidinyflamino}carbonyl}aminojethylcarbamate; N-(2-aminoethyl)-N*[1 -(2-pyridinyl)4-piperidinyflurea dihydrochloride; or N-(2-aminoethyl)-N"[1-(2-pyridinyl)}-4-piperidinyljurea.
73. A compound of the formula: a py CCIE L] ko! ASA o . Ye , | ) R s ( . OH or a pharmaceutically acceptable salt or solvate thereof, wherein R'is H, C,-C, alkyl or fiuorenyl, said C,-C, alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C,-C, alkyl, C,-C, alkoxy, halo or cyano; Ris H or C,-C; alkyl;

either, R® and R?, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C,-C, alkyl or C;-C; cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by - NR°R’, or, R%is H, C,-C; alkyl, C,-C, cycloalkyl or benzyl and R* is (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C,-C, alkyl, C,-C, cycloalkyl, phenyl, benzyl or het, or (b) <(C»C, alkylene)-R®, or (c) -(C,-C; alkylene)-R"; R°®is CH,0OH or CONR"R"; R® and R’ are either each independently H or C,-C, alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C,-C; alkyl; . R%is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1- yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C.-C; alkyl, C,-C, cycloalkyl, phenyl, C.-C, alkoxy-(C,-C)-alkyl, R°R°N-(C,-C,)-alkyl, fluoro-(C,- C,)-alkyl, -CONR’R®, -COOR® or C,-C; alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C,-C;)-alkoxy, halo, -OR?, cyano, -S(0),,R", -NR°R?, -SO,NR°R?, -NR*COR'® or -NR°SO.R™, - and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C,-C, alkylene group by C.-C; alkyl, phenyl, C,-C;, alkoxy-(C,-C,)-alkyl, R°R®N-(C-C,)-alkyl, fluoro-(C,-Cg)-alkyl, C,- Cs alkanoyl, -COOR', C,-C, cycloalkyl, -SO,R™, -SO,NR°R® or -CONR°R®, or (i) NR""R"; Ris H, C,-C; alkyl, C,-C, cycloalkyl or phenyl:

R™ is C.-C, alkyl, C,-C, cycloalkyl or phenyl; R" is H, C,-C; alkyl, C.-C, cycloalkyl or benzyl; R™is H, C,-C; alkyl, C4-C, cycloalkyl, phenyl, benzyl, fluoro-(C,-C)-alkyl, - CONR®R?, -COOR'", C,-C; alkanoyl or -SO,NR°R®; R™ is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C,-C, alkyl, C,-C, alkoxy, halo or cyano;

R'is H or C,-C, alkyl optionally substituted by cyclopropyl; R'is H or C,-C, alkyl; mis0,1o0r2; . X is unbranched C.-C; alkylene optionally substituted by C,-C, alkyl or CC, cycloalkyl; Yis CO, CS, SO, or C=N(CN); and h } WOMMSIGE: PCT/IB10#973 “het”, sed in the definition of R's a C-inked, 4-10 6-membered ring - heterocycle having elther from 1 4 fing nitrogen hetersatome or 1 or 2 nitragen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, * Optionally substituted by C,-C, ali, CG; cycloalioyl, CC, alkoxy, CC, cycloalkoxy, hydroxy, oxo or hal,
74. A compound as claimed in any one of claims 1, 46 — 49,51-54,58 -71 or 73, substantially as herein described and exemplified.
75. A pharmaceutical composition as claimed in claim 45, substantially as herein described and exemplified.
76. The use as claimed in claim 56, substantially as herein described and exemplified.
77. A process as claimed in claim 57, substantially as herein described and exemplified,