ZA200007720B - 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives. - Google Patents

Description

. 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives

This invention relates to new chemical compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.

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.

The primary function of leukocytes is to defend the host from invading organisms such as bacteria and parasites. Once a tissue is injured or infected a : series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.

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). In addition raised leveis of circulating adenosine in man (as a resuit of adenosine deaminase deficiency) results in immunosuppression (Hirschorn, 1993).

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, WO96/02553, WO96/02543 (Glaxo Group). Substituted 4'-carboxamidoadenosine derivatives useful in the : treatment of dementia are described in AU 8771946 (Hoechst Japan).

Substituted 4'-hydroxymethy! adenosine derivatives which are useful for the treatment of gastrointestinal motility disorders are described in EP-A-423776 and EP-A-423777 (Searle). Substituted 4’-hydroxymethyl adenosine derivatives which are useful as platelet aggregation inhibitors are described in BE-768925 (Takeda). 4'-Hydroxymethyl adenosine derivatives and 4’-esters thereof which are useful as anti-hypertensive agents or have other cardiovascular activity are described in US 4663313, EP 139358 and US 4767747 (Warner Lambert), US 4985409 (Nippon Zoki) and US 5043325 (Whitby Research). 4-

Hydroxymethyladenosine derivatives useful in the treatment of autoimmune

. disorders are described in US 5106837 (Scripps Research Institute). 4'-

Hydroxymethyladenosine derivatives useful as anti-allergic agents are described in US 4704381 (Boehringer Mannheim). Certain 4'-tetrazolylalkyl adenosine derivatives which are useful in the treatment of heart and circulatory disorders are generically described in DT-A-2621470 (Pharma-Waldhof). Other 4'- carboxamidoadenosine derivatives useful in the treatment of cardiovascular conditions are described in US 5219840, GB 2203149 and GB 2199036 (Sandoz), WO94/02497 (US Dept. Health), US 4968697 and EP 277917 (Ciba

Geigy), US 5424297 (Univ. Virginia) and EP 232813 (Warner Lambert). Other 4'-carboxamidoadenosine derivatives lacking substitution on the purine ring in the 2-position are described in DT 2317770, DT 2213180, US 4167565, US 3864483 and US 3966917 (Abbott Labs), DT 2034785 (Boehringer Mannheim),

JP 58174322 and JP 58167599 (Tanabe Seiyaku), WO92/05177 and US 5364862 (Rhone Poulenc Rorer), EP 66918 (Procter and Gamble),

WO086/00310 (Nelson), EP 222330, US 4962194, WO88/03147 and

WO088/03148 (Warner Lambert) and US 5219839, WO095/18817 and

WQ093/14102 (Lab UPSA). 4'-Hydroxymethyladenosine derivatives lacking substitution on the purine ring in the 2-position are described in WO95/11904 : (Univ Florida). 4'-Substituted adenosine derivatives useful as adenosine kinase inhibitors are described in W094/18215 (Gensia). Other 4'-halomethyl, methyl, thioalkylmethyl or alkoxymethyl adenosine derivatives are described in EP 161128 and EP 181129 (Warner Lambert) and US 3983104 (Schering). Other 4'-carboxamidoadenosine derivatives are described in US 7577528 (NIH),

WO091/13082 (Whitby Research) and WO985/02604 (US Dept Health).

Certain tetrazole containing deoxynucleotides which were found to lack anti- infective activity are described in Baker et al (1974) Tetrahedron 30, 2938- 2942. Other tetrazole containing adenosine derivatives which show activity as platelet aggregation inhibitors are described in Mester and Mester (1972)

Pathologie-Biologie, 20 (Suppl) 11-14. Certain nitrile containing ribose . derivatives are described in Schmidt et al (1974) Liebigs. Ann. Chem. 1856- 1863.

Other publications include: WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/01426 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk

A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4’ position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans.

WO 98/28319 (Glaxo Group Limited) was published subsequent to the earliest priority date of this application and describes 4'-substituted tetrazole 2-(purin-9- yl)-tetrahydrofuran-3,4-diol derivatives.

We have now found a novel group of compounds with broad anti-inflammatory properties which inhibit leukocyte recruitment and activation and which are agonists of the adenosine 2a receptor. The compounds are therefore of potential therapeutic benefit in providing protection from leukocyte-induced tissue damage in diseases where leukocytes are implicated at the site of inflammation. The compounds of the invention may also represent a safer alternative to corticosteroids in the treatment of inflammatory diseases, whose uses may be limited by their side-effect profiles.

More particularly, the compounds of this invention may show an improved profile over known A2a-selective agonists in that they generally lack significant agonist activity at the human A3 receptor. This profile can be considered of benefit as

A3 receptors are also found on leucocytes (eg eosinophil) and other inflammatory cells (eg mast cell) and activation of these receptors may have pro-inflammatory effects (Kohno et al, 1996; Van Schaick et al 1996). It is even considered that the bronchoconstrictor effects of adenosine in asthmatics may be mediated via the adenosine A3 receptor (Kohno et al, 1996). 5

Thus, according to the invention we provide compounds of formula (1):

NHR!

NZ N

R®NH rr J

N=N N . )

N. 4

RY 0)

HOY “on wherein R' and R? independently represent a group selected from: (i) C, scycloalkyl-; (ii) hydrogen; (iii) ary,CHCH,-; (iv) C,scycloalkylC, salkyl-;

Vv) C,salkyl-; (vi) arylC, zalkyl-; (vii) R*‘R°N-C, alkyl; (vii) C,salkyl-CH(CH,OH)-; (ix) arylC, calkyl-CH(CH,OH)-; (x) arylC, s;alkyl-C(CH,OH),-; (xi) C, cycloalkyl independently substituted by one or more (e.g. 1, 2 or 3) -(CH,),R® groups; (xii) H,NC(=NH)NHC, calkyl-; (xiii) a group of formula

CH

= (CH), or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (xiv) -C,salkyl-OH; (xv) -C,shaloalkyl; (xvi) a group of formula (CH.COCH em ~~ (xvii) aryl; and (xviii) -(CH,)SO,NH(C,, alkyl), or -(CH,)SO,NH(aryIC, alkyl-),-,;

R® represents methyl, ethyi, -CH=CH,, n-propyl, -CH,CH=CH,, -CH=CHCH,, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, cyclobutyl, cyclobutenyi, -(CH,) halogen, -(CH,),Y(CH,H, -(CH,),COOCH,, -(CH,),0COCH,, -(CH,),CON(CH,).H((CH,),H), -(CH,),CO(CH,),H or -CH,C((CH,) ,H)=NO(CH,),H;

Y represents O, S or N(CH,);; a and b independently represent an integer 0 to 4 provided that a + b is in the range 3 to 5; ¢, d and e independently represent an integer 0 to 3 provided thatc +d + e is in the range 2 to 3; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1; q represents 2 or 3; h represents 2 or 3; i represents an integer 0 to 2 such that h+i is in the range 2 to 4 jrepresents an integer O to 2 such that h+i+j is in the range 2 to 4

' / . m and n independently represent an integer 0 to 2 such that m+n is in the range

Oto 2; o represents an integer 0 to 2 such that h+o is in the range 2 to 3; u and v independently represent 0 or 1 such that u+v is in the range O to 1;

R* and R® independently represent hydrogen, C,salkyl, aryl, arylC,alkyl- or

NR‘R® together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-C, ;alkylpiperazinyl.

R?® represents OH, NH,, NHCOCH, or halogen,

R’ represents hydrogen, C, salkyl, C, calkylaryl or -COC, alkyl ;

X represents NR’, O, S, SO or SO; provided that when R® represents methyl, ethyl or isopropyl then R' and/or R? independently must represent: (a) ~(CH,)SO,NH,(C,_jalky}-), ; or -(CH,)SO,NH(arylC, alkyl), where fis 2 or 3 and gis an integer O to 2; (b) C,scycloalkyl independently substituted by one or more -(CH,),NHCOCH, groups; (c) a group of formula (CHa —_ NCOCH, (CH,)» / or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (d) a group of formula (CH,)cCO(CH,)a \

NCOCH, — CH) and salts and solvates thereof.

References to C, alkyl include references to an aliphatic hydrocarbon grouping containing 1 to 6 carbon atoms which may be straight chain or branched and

\ ' may be saturated or unsaturated although will be preferably saturated. .

References to C, alkyl, C, alkyl, C, alkyl and C, alkyl may be interpreted similarly.

References to aryl include references to mono- and bicyclic carbocyclic aromatic rings (e.g. phenyl, naphthyl) and heterocyclic aromatic rings 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, qalkyl, halogen, hydroxy, nitro, C, alkoxy, cyano, amino,

SO,NH, or -CH,OH.

Examples of C, cycloalkyl for R' and R? include monocyclic alkyl groups (e.g. cyclopentyl, cyclohexyl) and bicyclic alkyi groups (e.g. norbornyl such as exo- norborn-2-yl).

Examples of (aryl),CHCH,- for R' and R? include Ph,CHCH,- or such a group in which one or both phenyl moieties is substituted, e.g. by halogen or C,_ alkyl.

Examples of C, ,cycloalky!C, alkyl- for R' and R? include ethylcyclohexyl.

Examples of C,,akyl for R' and R? include -(CH,),C(Me),, -CH(Et), and

CH,=C(Me)CH,CH,-.

Examples of arylC, alkyl- for R' and R? include -(CH,),Ph, -CH,Ph or either in which Ph is substituted (one or more times) by halogen (e.g. iodine), amino, methoxy, hydroxy, -CH,OH or SO,NH,; -(CH,), pyridinyl (e.g. -(CH,),pyridin-2-yl) optionally substituted by amino; (CH,),imidazolyl or this group in which imidazolyl is N-substituted by C, salkyl (especially methyl).

Examples of R*R°N-C, qalkyl- for R' and R? include ethyl-piperidin-1-yl, ethyi- pyrrolidin-1-yl, ethyl-morpholin-1-yl, -(CH,),NH(pyridin-2-yl) and -(CH,),NH,.

Examples of C, ;alkyl-CH(CH,OH)- for R' and R? include Me,CHCH(CH,OH)-.

Examples of arylC, salkyl-CH(CH,OH)- for R" and R? include PhCH,CH(CH,OH)- especially

Examples of aryl C, salkyl-C(CH,0H),- for R' and R? include PhCH,C(CH,0H),-.

Examples of C,, cycloalkyl independently substituted by one or more -(CH,),R® groups (eg 1, 2 or 3 such groups) for R' and R? include 2-hydroxy-cyclopentyl and 4-aminocyclohexy! (especially trans-4-amino-cyclohexyl).

Examples of H,NC(=NH)NHC, salkyl for R" and R? include H,NC(=NH)NH(CH,),-

Examples of groups of formula a y (CH,), for R' and R? include pyrrolidin-3-yl, piperidin-3-yl, piperidin- 4-yl or a derivative in which the ring nitrogen is substituted by C, alkyl (e.g. methyl) or benzyl, tetrahydro- 1,1-dioxide thiophen-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran- 4-yl and 1,1-dioxo-hexahydro-1.lamda.6-thiopyran-4-yl.

Examples of -C, calkyl-OH groups for R" and R? include -CH,CH,OH.

Examples of C,ghaloalkyl for R' and R? include -CH,CH,Cl and (CH,),CIC(CH,),-.

Examples of groups of formula

LT

CH for R' and R? include 2-oxopyrrolidin-4-yl, 2-oxo-pyrrolidin-5-yl or a derivative in which the ring nitrogen is substituted by C, calky! (e.g. methyl) or benzyl.

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

Examples of C,galkyl for R? include methyl and C,.alkylaryl for R" include benzyl. Examples of COC, alkyl for R” include -COCH,.

Claims (36)

Claims

1. A compound of formula (1): NHR' NZ RONH 1X J 0 “7 RY N HO" “on wherein R' and R? independently represent a group selected from: Q) C. scycloalkyl-; (i) hydrogen; (iii) aryl,CHCH,-; (iv) C,.scycloalkylC, calkyl-; Vv) C,salkyl-; (vi) arylC, salkyl-; (vii) R*R°N-C, alkyl; (viii) C,salkyl-CH(CH,OR)-; (ix) arylC, salkyl-CH(CH,OH)-; (x) arylC, salkyl-C(CH,OH),-; (xi) C. cycloalkyl independently substituted by one or more (e.g. 1, 2 or 3) ~(CH,),R® groups; (xii) ~~ H,NC(=NH)NHC, ;alkyl-; (xiii) a group of formula CH — (CH), or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (xiv) -C,qalkyl-OH; \ oo

(xv) -C, ghaloalkyl; (xvi) a group of formula (CH). re (xvii) aryl; and (xviii) -(CH,)SO,NH,(C, alkyl-), 4 or -(CH,)SONH(arylC, alkyl), ; R? represents methyl, ethyl, -CH=CH,, n-propyl, -CH,CH=CH,, -CH=CHCH,, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, cyclobutyl, cyclobutenyl, -(CH,),halogen, -(CH,),Y(CH,)H, -(CH,),COOCH,, -(CH,),0COCH,, -(CH,),CON(CH,),,H((CH,)H), -(CH,),CO(CH,),H or -CH,C((CH,),H)=NO(CH,) H; Y represents O, S or N(CH,);; 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 thatc +d + e is In the range 2 to 3; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1; q represents 2 or 3; . 20 h represents 2 or 3; i represents an integer 0 to 2 such that h+i is in the range 2 to 4 j represents an integer 0 to 2 such that h+i+j is in the range 2 to 4 m and n independently represent an integer 0 to 2 such that m+n is in the range Oto 2; o represents an integer 0 to 2 such that h+o is in the range 2 to 3; u and v independently represent 0 or 1 such that u+v is in the range 0 to 1;

R* and R® independently represent hydrogen, C,calkyl, aryl, arylC, alkyl- or : NR‘R® together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-C, salkylpiperazinyl. R® represents OH, NH,, NHCOCH, or halogen; R’ represents hydrogen, C, salkyl, C, calkylaryl or -COC, alkyl; X represents NR’, O, S, SO or SO; provided that when R® represents methyl, ethyl or isopropyl then R' and/or R? independently must represent: (a) -(CH,)SO,NH(C, ,alkyl-),, or -(CH,)SO,NH,(arylC, ,alkyl-), , where f is 2or3 and gis an integer 0 to 2; (b) C..cycloalkyl independently substituted by one or more -(CH,),NHCOCH, groups; (©) a group of formula SCH “A Es (CH,)u or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (9) a group of formula (CH,)eCO(CH Je \ NCOCH, — CH) — and salts and solvates thereof.

2. A compound of formula (1) according to claim 1 wherein R' and R? do not both represent hydrogen.

3. A compound according to claim 1 or claim 2 wherein R' represents aryl,CHCH,-, C,-;alky!, hydrogen or aryl C, ;alkyl-.

4. A compound according to any one of claims 1 to 3 wherein R’ represents Ph,CHCH,-.

: 5. A compound according to any one of claims 1 to 4 wherein R? represents R*R*N-C,-;alkyl-, arylC,salkyl-, arylC,alkylCH(CH,OH)-, aryl C,; alkyl or C, ; alkyl-CH(CH,OH)-.

6. A compound according to any one of claims 1 to 5 wherein R? represents -(CH,),(piperidin-1-yl).

7. A compound according to any one of claims 1 to 6 wherein R® represents C, ,alkyl, cyclobutyl, cyclopropylmethyl, -(CH,),0COCH,, -(CH,),,OH or -(CH,),halogen.

8. A compound according to any one of claims 1 to 7 wherein R® represents n-propyl, 2-propenyl!, cyclobutyl, cyclopropylmethyl, ~(CH,),O0COCH,, or -(CH,),.,OH.

9. A compound according to any one of claims 1 to 8 wherein R* and R® independently represent hydrogen, C,qalkyl or aryl or NR‘R® together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-methylpiperazinyl.

10. A compound according to any one of claims 1 to 9 wherein R° represents OH or NH,.

11. A compound according to any one of claims 1 to 10 wherein X represents NR’, O, S or SO,.

12. A compound of the formula (I) which is 2R,3R,4S,5R)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)- purin-9-yl}-5-[2-(3-hydroxy-propyl)-2H-tetrazol-5-yl}-tetrahydro-furan-3,4-diol; 2R,3R,4S,5R)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)- purin-9-yl}-5-(2-propyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol; Acetic acid 2-(5-{5R-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)- purin-9-yl]-3S 4R-dihydroxy-tetrahydro-furan-2R-yl}-tetrazol-2-yl)-ethyl ester; (2R,3S,4R,5R)-2-(2-Cyclopropylmethyl-2H-tetrazol-5-yl)-5-[6-(2, 2-diphenyl- ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl}-tetrahydro-furan-3,4-diol;

PCT/EP99/04269 (2R,3R,4S,5R)-2-[6-(2,2-Diphenyl-ethylamino)-2-(2-piperidin-1-yl- ethylamino)-purin-9-yil-5-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]- tetrahydro-furan-3,4-diol; (2R,3S,4R,BR)-2-[2-(2-Chloro-ethyl)-2H-tetrazol-5-yll-5[6-(2,2-diphenyl- ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan- 3,4-diol; (2R,3S,4R,5R)-2-(2-Cyclobutyl-2H-tetrazol-5-yl)-5-[6-(2, 2-diphenyl- ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl}-tetrahydro-furan- 3,4-diol; (2R,3S,4R,5R)-2-(2-Allyl-2H-tetrazol-5-yi)-5-[6-(2,2-diphenyl- ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-tetrahydro-furan- 3,4-diol; or a salt or solvate of any thereof.

13. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.

14. A compound of formula (I) as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.

15. Use of a compound of formula (I) as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of inflammatory diseases.

16. A method of prophylaxis of inflammatory diseases eg asthma which comprises administering to a subject an effective amount of a compound of formula (I) as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof.

17. A process for preparation of a compound of formula (l) as defined in any one of claims 1 to 12 which comprises (a) reacting a corresponding compound of formula (I) AMENDED SHEET

. NHR! N N ~~ N\ L YY > N=N N (In R*—N © HO “on wherein L represents a leaving group or a protected derivative thereof with a compound of formula R2NH, or a protected derivative thereof, wherein R’, R? and R’® are as defined in any one of claims 1 to 12; or (b) preparing a compound of formula (1) in which R' represents hydrogen by reducing a compound of formula (ll) N, N“ N N\ OT > N=N N (th) R'—N © HOY “on or a protected derivative thereof, wherein R? and R® are as defined in any one of clams 1to 12; or (c) deprotecting a compound of formula (1) which is protected; and where desired or necessary converting a compound of formula (I) or a salt thereof into another salt thereof,

18. A process for preparation of a compound of formula (I) as defined in any one of claims 1 to 12 without the proviso which comprises (a) reacting a corresponding compound of formula (X}

NHR' : N AN Ms RINK —y A N X)

HN . ~" N HO" “on with a compound of formula (XI) R*-L (XI) wherein L is a leaving group and R', R? and R® are as defined in any one of claims 1 to 12; or (b) reacting a corresponding compound of formula (XII) NHR' i A out PNG RMN” ON H with a compound of formula (V) or a protected derivative thereof, wherein R' and R? are as defined in any one of claims 1 to 12.

19. A process according to claim 18 which is a process for preparing the compound (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 and solvates thereof. 16 20. A process according to claim 19 which comprises reacting a corresponding compound of formula NH, Ves Ph N NN N with a compound of formula

N=N / NO ZA OL al on Ho" "oH or a protected derivative thereof, wherein L is a leaving group.

21. A compound of formula (lI) NHR! NZ SN A or Rp N=N N 0) R°—N © ~ N ’ HO™ “on wherein L represents a leaving group and R' is as defined in any one of claims 1 to 12, and R® represents n-propyl, 2-propenyl, cyclobutyl, cyclopropylmethyl, - (CH,),O0COCH,, or -(CH,), ,OH or a protected derivative thereof.

22. A compound of formula (lll) N, NZ >NN

\ . et J N=N N ay R*—N © ~ N id ’ HOY “on wherein R? is as defined in any one of claims 1 to 12 and R® represents n- propyl, 2-propenyi, cyclobutyl, cyclopropylmethyl, -(CH,),0COCH,, or ~+(CH,),,0H.

23. A compound of formula (IIIA)

N, PN L—s J N=N N (A) R*—N © ~ N /d HO" “oH wherein L represents a leaving group and R® represents n-propyl, 2-propenyl, cyclobutyl, cyclopropylmethyl, -(CH,),OCOCH,, or -(CH,),,OH or a protected derivative thereof.

24. A compound of formula (IV) 2 NT N N Lf Tr J N=N N o av)

RIN. 2 PANN NT] HO" “on wherein L' and L?independently represent a leaving group and R® represents n- propyl, 2-propenyl, cyclobutyl, cyclopropylmethyl, -(CH,),0COCH,, or -(CH,),,OH or a protected derivative thereof. :

25. A compound of formula (V) N=N / < RP—N_ 7 0) L N MV) "o' “OH wherein L represents a leaving group and R® represents n-propyl, 2-propenyl, cyclobutyl, cyclopropylmethyl, -(CH,),OCOCH,, or -(CH,),,OH or a protected derivative thereof.

26. A compound of formula (VI)

PCT/EP99/04269 N=N / Oalk a__N O o © wherein alk represents C,¢ alkyl eg methyl and R3 represents n-propyl, 2- propenyl, cyclobutyl, cyclopropyimethyl, -(CH,),0COCHj, or -(CH2,),.;0H.

27. A compound of formula (X) NHR’ N rd ET RENH x N (X) N=N

/ .0 HN _ ~~ N HO * ’ OH wherein R! and R? are as defined in any one of claims 1 to 12 or a protected derivative thereof.

28. A substance or composition for use in a method of treatment or prophylaxis of inflammatory diseases eg asthma, said substance or composition comprising a compound of formula (1) as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering to a subject an effective amount of said substance or composition. AMENDED SHEET

PCT/EP99/04269

29. A compound according to claim 1, or any one of claims 21- 27, substantially as herein described and illustrated.

30. A compound according to claim 12, substantially as herein described and illustrated.

31. A composition according to claim 13, or claim 14, substantially as herein described and illustrated.

32. Use according to claim 15, substantially as herein described and illustrated.

33. A substance or composition for use in a method of treatment or prophylaxis according to claim 28, substantially as herein described and illustrated.

34. A method according to claim 16, substantially as herein described and illustrated.

35. A process according to claim 17 or claim 18, substantially as herein described and illustrated.

36. A new compound, a new composition, a new use of a compound as claimed in any one of claims 1 to 12, a new non- therapeutic method of treatment, a substance or composition for a new use in a method of treatment, or a new process for preparation of a compound, substantially as herein described. AMENDED SHEET