OA11968A

OA11968A - Purine derivatives.

Info

Publication number: OA11968A
Application number: OA1200100332A
Authority: OA
Inventors: Simon John Mantell; Sandra Marina Monaghan
Original assignee: Pfizer
Priority date: 1999-06-15
Filing date: 2000-06-13
Publication date: 2006-04-17
Also published as: BG106289A; HN2000000097A; AU4944300A; EE200100681A; DZ3168A1; EP1185542A2; BR0011705A; IL147098A0; ZA200110208B; CA2379786A1; WO2000077018A3; AP2001002361A0; HUP0203419A3; US6900309B1; HUP0203419A2; IS6196A; MA26799A1; KR20020010707A; CA2379786C; PL354367A1

Claims

77 1 1968 * CLAIMS

or a pharmaceutically acceptable sait or solvaté thereof, wherein R1 is hydrogen or C^Cg alkyl optionally substituted by 1 or 2substituents each independently selected from phenyl and naphthyl, saidphenyl and naphthyl being optionally substituted by Ο<Οβ alkyl, Ο,-Cg alkoxy,halo or cyano; Rz is H or C^Cg alkyl; A is CrCs alkylene; R3 is (i) hydrogeh, C,-C6 alkyl, -COOR4, -CN, -CONR4R4, C3-C8 cycloalkyl,phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionallysubstituted by CrC„ alkyl, phenyl, C,-Ce alkoxyiC^CgJalkyl, R4R4N(C1-Ce)alkyl,halo(CrCe)alkyl, fiuoro(C.,-C6)alkoxy, C2-C5 alkanoyl, halo, -OR4, cyano, -COOR4, C3-C8 cycloalkyl, -S(O)mRs, -NR4R4, -SO2NR4R4, -CONR4R4, -NR4CORSor-NR4SO2R5, or (ii) when A is C2-C8 alkylene, -NR4R4, -OR4, -OCOR®, -SO2R5, -SO2NR4R4or-NR4COR5, or (iii) a C-linked, 4- to 11-membered ring, mono- or bicyclic, heterocyclehaving either from 1 to 4 ring nitrogen atom(s), or 1 or 2 nitrogen and 1 oxygenor 1 sulphur ring atoms, being optionally C-substituted by oxo, C5-C8 alkoxy (C,- 78 11968 * C8)alkyl, R6R6N(C1-C6)alkyl, halo(C,-C6)alkyl, fluoro(C1”Ce)alkoxy, fluoro(C2-Cs)alkanoyi, halo, cyano, -OR®, R7, -COR®, -NR8R6, -COOR8, -S(O)roR7,-SO2NR®R6, -CONR6R8, -NR8SOZR7 or-NR8COR7 and optionally N-substitutedby C,-Ce alkoxy(C.,-CB)alkyl, R8R6N(C2-Ce)alkyl, haio(C,-Ce)alkyI, fluoro(C2-C5)alkanoyl, R7, -COR®, -COOR7, -SO2R7, -SO2NR®R® or-CONReR®,or (iv) when A is C2-Ce alkylene, N-linked azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, homopiperazinyl or morpholinyi, each being optionally C-substitutedby C^Cg alkyl, phenyl, C^Cg alkoxy(C1-C6)alkyl, R4R4N(C1-Ce)alkyl, halo(C1-Cs)alkyl, fIuoro(C1-C6)alkoxy, C2-C5 alkanoyl, halo, -OR4, cyarto, -COOR4, C3-C8cycloalkyl, -S(O)mR5, -NR4R4, -SO2NR4R4, -C0NR4R4, -NR4CORS or-NR4SO2R5,and said piperazinyl and homopiperazinyl being optionally N-substituted by CrC6 alkyl, phenyl, C^Cg alkoxy(C2-Ce)alkyl, R4R4N(C2-Ce)alkyl, fluoro^-CJalkyl,C2-C5 alkanoyl, -COOR®, C3-C8 cycloalkyl, -SO2R5, -SO2NR4R4 or -CONR4R4; R4 is H, C,-Ce alkyl, C3-C8 cycloalkyl or phenyl; R5 is C,-Ce alkyl, C3-C8 cycloalkyl or phenyl; R® is H, C^Cg alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; R7 is C^Cg alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; m is 0,1 or 2; and "het”, used in the définitions of R8 and R7, means C-linked pyrrolyl, imidazolyl,triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl,pyrimidinyi, pyridazinyl, pyrazinyl, indolyi, isoindolyl, quinoiinyl, isoquinolinyl,benzimidazolyl, quinazolinyl, phthalazinyi, benzoxazoiyl or quinoxalinyl, eachbeing optionally substituted by C,-Ce alkyl, Ο,-Cg alkoxy, cyano or halo.
2. A compound as claimed in claim 1 wherein R1 is C^Cg alkyl optionallysubstituted by 1 or 2 phenyl substituents.
3. A compound as claimed in claim 2 wherein R1 is 2,2-diphenylethyl.
4. A compound as claimed in any one of the preceding daims wherein R2 is H. 1196 8 79
5. A compound as claimed in any one of the preceding daims wherein A is C,-C4 alkylene.
6. A compound as claimed in claim 5 wherein A is methylene, 1,2-ethylene or 1,3-propylene.
7. A compound as claimed în daim 6 wherein A is 1,2-ethylene.
8. A compound as claimed in any one of the preceding daims wherein R3 isphenyi optfonaiiy substituted as defined for this définition in claim 1; or, when Ais C2-CB alkylene, R3 is -NR4R4 wherein R4 is as defined in claim 1; or R3 is a C-iinked, 5- to 7-membered ring monocyclic heterocycle having eitherfrom 1 to 4ring nitragen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms,optionally substituted as defined for this définition in daim 1 ; or, when A is C2-C6 alkylene, R3 is N-linked pyrroiidinyi, piperidinyl or morphoiinyl, each beingoptionally C-substituted as defined for this définition in daim 1.
9. A compound as claimed in daim 8 wherein R3 is phenyi; or, when A is C2-Cealkylene, R3 is -NR4R4 wherein R4 is C,-C8 alkyi; or, R3 is a C-linked, 5- or 6-membered ring monocyclic aromatic heterocyde having from 1 to 4 ringnitrogen atom(s), optionally substituted as defined for this définition in daim 1:or, when A is C2-Ce alkylene, R3 is N-linked pyrroiidinyi, piperidinyl ormorphoiinyl, each being optionally C-substituted by CrCe alkyi or-OR4 whereinR4is as previously defined in claim 1.
10. A compound as claimed in claim 9 wherein R3 is phenyi; or, when A is C2-C„alkylene, R3 is -N(CH3)2; or R3 is C-iinked pyridinyl optionally substituted by —OR6, R7, CrCe alkoxy(C,-C6)alkyl, ReR6N(C,-Ce)alkyl or -NR6R® wherein Re andR7 are as previously defined in claim 1; or when A is C2-C6 alkylene, R3 ispyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yI. 1196 8 80
11. A compound as ciaimed in ciaim 10 wherein R3 is phenyi; or, when A is C2-Ce aikyiene, R3 is -N(CH3)2; or R3 is 2-pyridinyi; or when A is C2-CB alkyiene, R3is pyrrolidin-1-yl, piperidin-1-yl, 4-isopropylpiperidin-1-yl or morpholin-4-yl.
12. A compound as ciaimed in ciaim 11 wherein, when A is C2-C„ alkyiene, R3 ispiperidin-1-yl.
13. A compound as ciaimed in any one of daims 1 to 4 wherein -A-R3isphenethyl, 2-(dimethylamino)ethyl, 2-pyridinylmethyi, 2-(2-pyridinyl)ethyl, 3-(1-pyrrolidinyQpropyi, 2-(1-piperidinyl)ethyi, 2-(4-isopropyi-1-piperidinyl)ethyl or 2-{4-morpholinyl)ethyi.
14. A compound as ciaimed in ciaim 13 wherein -A-R3 is 2-(1-piperidinyl)ethyl.
15. A compound as ciaimed in daim 1 which is selected from the groupconsisting of 9-((2/^,3ft,4S,5R)-3,4~dihydroxy-5-(hydroxymethyl)tetrafiydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-/V-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxyrnethyl)tetrahydro-2-furanyl]-6-[(2,2- diphenylethyl)amino}-N-phenethyl-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5/?)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanylJ-6-[(2,2- diphenylethyl)aminoî-/V-(2-(4-isopropyl-1-piperidinyl)ethyi]-9K-purine-2- carboxamide; 9-[(2R,3R,4S,5R)-314-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2- diphenylethy!)amino]-N-[3-(1-pyrroiidinyl)propyl]-9H-purine-2-carboxarnide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2- diphenyIethyi)amino]-W-[2-(4-morpholinyi)ethylî-9H-purine-2-carboxamide; 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2- diphenylethyl)amino]-A/-(2-pyridinyimethyi)-9H-purine-2-carboxamide; 81 11968 9-[(2/?,3R4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furany!]-6-{(2,2-diphenylethyl)amino]-N-[2-(2-pyridinyl)ethyl]-9H-purine-2-carboxamide; and9-[(2R, 3R,4S,5R)-3,4-dihydroxy-5-{hydroxymethyl)tetrahyd ro-2-furanylj-/V-[2-(dimethylamino)ethyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxamide:and the pharmaceutically acceptable salts and solvatés thereof.
16. A compound as claimed in claim 1 which is 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-{hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)aminoî-A/-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide, or a pharmaceuticallyacceptable sait or solvaté thereof.
17. A compound as claimed in daim 1 wherein R1 is hydrogen or C, -Ceaikyl substituted by 1 or 2 substituents eachindependently selected from phenyl and naphthyi; R2 is hydrogen or CrC6 alkyl; A is C,-Ce aikylene; and R3 is phenyl, naphthyi, C3-C8 cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyi,amino, -NH(C,-C6 alkyi) or -N(C,-C6 aîkyl)2, said phenyl, naphthyi, C3-Cacycloalkyl, azetidinyl, pyrrolidinyl and piperidinyi being optionally substituted byone or more substituents each independently selected from CrC6 alkyl, C,-CBalkoxy, haio(C,-Ce)alkyl, halo and cyano: with the proviso that when R3 is N-linked, optionally substituted-azetidinyl, -pyrrolidinyl or -piperidinyi, or is amino, -NHCC^Cg alkyl) or -N(C1-Ce alkyl)2, A isC2-Ce aikylene.
18. A pharmaceuticai composition including a compound of the formula (I) or apharmaceutically acceptable sait or solvaté thereof, as claimed in any one ofthe preceding daims, together with a pharmaceutically acceptable excipient,diluent or carrier. 1196 8 82
19. A compound of the formula (I) or a pharmaceuticaily acceptable sait,solvaté or composition thereof, as claimed in any one claims 1 to 17 and 18,respectively, for use as a médicament.
20. The use of a compound of the formula (I) or of a pharmaceuticailyacceptable sait, solvaté or composition thereof, as claimed in any one daims 1to 17 and 18, respectively, for the manufacture of a médicament having A2areceptor agonist activity.
21. The use of a compound of the formula (I) or of a pharmaceuticailyacceptable sait, solvaté or composition thereof, as daimed in any one claims 1to 17 and 18, respectively, for the manufacture of an anti-inflammatory agent.
22. The use of a compound of the formula (I) or of a pharmaceuticailyacceptable sait, solvaté or composition thereof, as claimed in any one daims 1to 17 and 18, respectively, for the manufacture of a médicament for thetreatment of a respiratory disease.
23. Use as claimed in daim 22 where the disease is seiected from the groupconsisting of adult respiratory distress syndrome (ARDS), bronchitis, chronicbronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma,emphysema, bronchiectasis, chronic sinusitis and rhinitis.
24. The use of a compound of the formula (I) or of a pharmaceuticailyacceptable sait, solvaté or composition thereof, as daimed in any one claims 1to 17 and 18, respectively, for the manufacture of a médicament for thetreatment of septic shock, male erectiie dysfunction, hypertension, stroke,epiiepsy, cérébral ischaemia, peripheral vascular disease, post-ischaemicreperfusion injury, diabètes, rheumatoid arthritis, multiple sclerosis, psoriasis,dermatitis, aliergic dermatitis, eczema, uicerative colitis, Crohns disease,inflammatory bowei disease, Heliobacter pylori gastritis, non-Heliobacterpylori 83 gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro- intestinal tract or a psychotic disorder, or for wound healing. 11968
25. A process for the préparation of a compound of the formula (I), or apharmaceutically acceptable sait thereof, as claimed in daim 1 comprising a) aminocarbonyiation reaction of a compound of the formula:

wherein R1 is defined in daim 1 and X is a leaving group such as bromo, iodo,16 Sn(C,-C12 alkyl)3 or CF3SO2O-, with a compound of the formula: R2NH-A-R3 (III) 20 wherein A, R2 and R3 are as defined in claim 1, in the presence of carbonmonoxide and a suitabie coupling catalyst; or b) deprotection of a compound of the formula: 25 119 6 8 84.

wherein A, R1, R2 and R3are as defined in claim 1 and R8 and R9, when takenseparately, are protecting groups, or, when taken together, are a protecting 5 group; or c) deprotection of a compound of the formula:

10 wherein A, R1, R2 and R3are as defined in claim 1 and R”, R12 and R13, takenseparately, are protecting groups, or R11 is a protecting group and R12 and R13,taken together, are a protecting group: or 15 d) reaction of a compound of the formula: 85. 1196 8

wherein R1 is as defined in daim 1 and R17 is H or an ester-forming group, witha compound of the formula (III) as defined in part (a), and, where R17 is H, in the 5 presence of a peptide coupling agent: any one of said pracesses being optionally followed by conversion to apharmaceutically acceptable sait thereof. 10 26. A compound of the formula:

wherein X is a leaving group such as bromo, iodo, -SnfC^C^ alkyl)3 or15 CF3SO2O-, with the proviso that when X is bromo or iodo, R1 is not H; or 1196 8 86.

wherein R8 and R9, when taken separately, are protecting groups, or, whentaken together, are a protecting group; or

wherein R8 and R9, when taken separately, are protecting groups, or, whentaken together, are a protecting group, and R10 is a protecting group; or 10 87. 119 6 8

wherein R8 and R9, when taken separately, are protecting groups, or, whentaken together, are a protecting group, and R10 is a protecting group, with theproviso when R1 is H, that R8, R9 and R10 are not each t-butyldimethyisilyl or 5 acetyl; or

wherein R11, R12 and R13, taken separately, are protecting groups, or R11 is aprotecting group and R12 and R13, taken together, are a protecting group; or 10

o (XIII) ; or 11968 88.

wherein R” is a protecting group; or

5 wherein R14 is a protecting group: and A, R1, R2 and R3 are as defined in claim 1.
27. A compound of the formula:

(XXIV) : or 11968 89.

wherein R17 is H or an ester-forming group; or

wherein R11, R12 and R13, taken separately, are protecting groupe, or R11 is aprotecting group and R12 and R13, taken together, are a protecting group, andR17 is an ester-forming group ; or

wherein R17 is an ester-forming group; or 11968 90.

wherein R14is a protecting group and R15 is 0,-04 alkyl: and R1 is C,-Ce alkyl optionally substituted by 1 or 2 substituants eachindependently selected from phenyl and naphthyi, said phenyl and naphthylbeing optionally substituted by 0,-0β alkyl, Ο,-Οθ alkoxy, halo or cyano.
28. A compound as claimed in any one of daims 26 and 27 wherein R1 is 2,2-diphenylethyl, R2 is H and/or-A-R3 is 2-(1-piperidinyl)ethyl.
29. A compound of the formula (II) as claimed in daim 26 wherein X is iodo.
30. A compound of the formula (VI), (IX) or (X) as claimed in daim 26 whereinR8 and R9 when taken seperately are each acetyl or benzoyl or when takentogether are 1,1-dimethylmethylene.
31. A compound of the formula (IX) or (X) as claimed in claim 26 wherein R10 isa silyl protecting group, preferably t-butyldimethylsilyl ort-butyidiphenylsilyl.
32. A compound of the formula (XII) as claimed in daim 26 wherein R11, R12 andR13 when taken seperately are each acetyl or benzoyl, or R12 and R13 whentaken together are 1,1-dimethylmethylene.
33. A compound of the formula (XXI) or (XXII) as claimed in claim 26 or (XX)as claimed in claim 27, wherein R14is tetrahydro-2H-pyran-2-yl. 11968 91.
34. A compound of the formula (XXV), (XXVI) or (XXVII) as claimed in claim 27wherein R17 is aikyl, preferably methyl or ethyl.
35. A compound of the formula (XXVI) as claimed in claim 27 wherein R11, R125 and R13 when taken seperately are each acetyl or benzoyl, or R12 and R13 when taken together are 1,1-dimethylmethylene.