JP2009534339A - アデノシンａ２ａ受容体アゴニストとして使用するためのプリン誘導体 - Google Patents
アデノシンａ２ａ受容体アゴニストとして使用するためのプリン誘導体 Download PDFInfo
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- JP2009534339A JP2009534339A JP2009505780A JP2009505780A JP2009534339A JP 2009534339 A JP2009534339 A JP 2009534339A JP 2009505780 A JP2009505780 A JP 2009505780A JP 2009505780 A JP2009505780 A JP 2009505780A JP 2009534339 A JP2009534339 A JP 2009534339A
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- Prior art keywords
- optionally substituted
- amino
- alkyl
- dihydroxy
- cyclopentyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002465 adenosine A2a receptor agonist Substances 0.000 title 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title 1
- 150000003212 purines Chemical class 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 330
- -1 hydroxy, carboxy, amino Chemical group 0.000 claims description 133
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 57
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 56
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 46
- 229910052760 oxygen Inorganic materials 0.000 claims description 46
- 239000001301 oxygen Chemical group 0.000 claims description 46
- 229910052717 sulfur Chemical group 0.000 claims description 45
- 239000011593 sulfur Chemical group 0.000 claims description 45
- 125000005842 heteroatom Chemical group 0.000 claims description 44
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 41
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 36
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 18
- 230000002757 inflammatory effect Effects 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 12
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 9
- 229960005305 adenosine Drugs 0.000 claims description 9
- 102000005962 receptors Human genes 0.000 claims description 9
- 108020003175 receptors Proteins 0.000 claims description 9
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 8
- 230000004913 activation Effects 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 230000029663 wound healing Effects 0.000 claims description 6
- 206010063837 Reperfusion injury Diseases 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 238000002648 combination therapy Methods 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 208000028867 ischemia Diseases 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 201000000057 Coronary Stenosis Diseases 0.000 claims description 3
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 238000002399 angioplasty Methods 0.000 claims description 3
- 210000000424 bronchial epithelial cell Anatomy 0.000 claims description 3
- 239000002872 contrast media Substances 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 2
- 208000016192 Demyelinating disease Diseases 0.000 claims description 2
- 244000052616 bacterial pathogen Species 0.000 claims description 2
- 239000004090 neuroprotective agent Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 229940123038 Integrin antagonist Drugs 0.000 claims 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims 1
- 238000011360 adjunctive therapy Methods 0.000 claims 1
- 201000009267 bronchiectasis Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 149
- 238000002360 preparation method Methods 0.000 abstract description 22
- 239000000126 substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 133
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
- 238000006243 chemical reaction Methods 0.000 description 113
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 111
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000011541 reaction mixture Substances 0.000 description 66
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 63
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 60
- 239000002904 solvent Substances 0.000 description 59
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 55
- 239000000203 mixture Substances 0.000 description 53
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 52
- 239000000243 solution Substances 0.000 description 46
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 239000000543 intermediate Substances 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 229940080818 propionamide Drugs 0.000 description 36
- 239000003960 organic solvent Substances 0.000 description 35
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 239000002585 base Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 24
- 229910052786 argon Inorganic materials 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- 239000012300 argon atmosphere Substances 0.000 description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 19
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- 230000002441 reversible effect Effects 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 17
- 208000006673 asthma Diseases 0.000 description 17
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 17
- 235000009518 sodium iodide Nutrition 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 15
- MASVPNZBPHOQNL-TYJFDUFHSA-N n-[(1s,2r,3s,4r)-4-[2-chloro-6-(2,2-diphenylethylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]propanamide Chemical compound O[C@@H]1[C@H](O)[C@@H](NC(=O)CC)C[C@H]1N1C2=NC(Cl)=NC(NCC(C=3C=CC=CC=3)C=3C=CC=CC=3)=C2N=C1 MASVPNZBPHOQNL-TYJFDUFHSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 239000000377 silicon dioxide Substances 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 239000012948 isocyanate Substances 0.000 description 12
- 150000002513 isocyanates Chemical class 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- NRWPBTLQVZIEGO-UHFFFAOYSA-N 2-(1-propan-2-ylimidazol-4-yl)ethanamine Chemical compound CC(C)N1C=NC(CCN)=C1 NRWPBTLQVZIEGO-UHFFFAOYSA-N 0.000 description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 208000023504 respiratory system disease Diseases 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- MIVFLRKONVQVSU-DRABBMOASA-N n-[(1s,2r,3s,4r)-4-[2-chloro-6-(pentan-3-ylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]propanamide Chemical compound C1=NC=2C(NC(CC)CC)=NC(Cl)=NC=2N1[C@@H]1C[C@H](NC(=O)CC)[C@@H](O)[C@H]1O MIVFLRKONVQVSU-DRABBMOASA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 235000013877 carbamide Nutrition 0.000 description 8
- 229940043279 diisopropylamine Drugs 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- IJDYOKVVRXZCFD-RQJHMYQMSA-N [(1r,4s)-4-hydroxycyclopent-2-en-1-yl] acetate Chemical compound CC(=O)O[C@@H]1C[C@H](O)C=C1 IJDYOKVVRXZCFD-RQJHMYQMSA-N 0.000 description 7
- 239000004202 carbamide Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 230000000414 obstructive effect Effects 0.000 description 7
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 7
- 239000012285 osmium tetroxide Substances 0.000 description 7
- 125000003386 piperidinyl group Chemical group 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 125000004899 1-ethylpropylamino group Chemical group C(C)C(CC)N* 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 description 6
- 239000002260 anti-inflammatory agent Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000005445 isotope effect Effects 0.000 description 6
- NLVYSRVFNHRLDA-RCTLUFLUSA-N n-[(1s,2r,3s,4r)-4-[2-chloro-6-(naphthalen-1-ylmethylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]propanamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.O[C@@H]1[C@H](O)[C@@H](NC(=O)CC)C[C@H]1N1C2=NC(Cl)=NC(NCC=3C4=CC=CC=C4C=CC=3)=C2N=C1 NLVYSRVFNHRLDA-RCTLUFLUSA-N 0.000 description 6
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- NGXSWUFDCSEIOO-SCSAIBSYSA-N (3r)-pyrrolidin-3-amine Chemical compound N[C@@H]1CCNC1 NGXSWUFDCSEIOO-SCSAIBSYSA-N 0.000 description 5
- DKCWQRKXTQSULZ-UHFFFAOYSA-N 1h-imidazole;urea Chemical compound NC(N)=O.C1=CNC=N1 DKCWQRKXTQSULZ-UHFFFAOYSA-N 0.000 description 5
- PNWBPGZKOYHOIV-TYJFDUFHSA-N 9-[(1r,2s,3r,4s)-2,3-dihydroxy-4-(propanoylamino)cyclopentyl]-6-(2,2-diphenylethylamino)purine-2-carboxylic acid Chemical compound O[C@@H]1[C@H](O)[C@@H](NC(=O)CC)C[C@H]1N1C2=NC(C(O)=O)=NC(NCC(C=3C=CC=CC=3)C=3C=CC=CC=3)=C2N=C1 PNWBPGZKOYHOIV-TYJFDUFHSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 229940124630 bronchodilator Drugs 0.000 description 5
- 239000000168 bronchodilator agent Substances 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 5
- 210000003979 eosinophil Anatomy 0.000 description 5
- BNGCBNFCYFRFLY-FSNRGTNLSA-N n-[(1s,2r,3s,4r)-4-[2-[(3r)-3-aminopyrrolidin-1-yl]-6-(2,2-diphenylethylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]propanamide Chemical compound O[C@@H]1[C@H](O)[C@@H](NC(=O)CC)C[C@H]1N1C2=NC(N3C[C@H](N)CC3)=NC(NCC(C=3C=CC=CC=3)C=3C=CC=CC=3)=C2N=C1 BNGCBNFCYFRFLY-FSNRGTNLSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 5
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 description 4
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
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- ZSZBVCQVYPCNIF-UHFFFAOYSA-N propanamide;2,2,2-trifluoroacetic acid Chemical compound CCC(N)=O.OC(=O)C(F)(F)F ZSZBVCQVYPCNIF-UHFFFAOYSA-N 0.000 description 1
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- 125000006308 propyl amino group Chemical group 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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- 201000000306 sarcoidosis Diseases 0.000 description 1
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- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- ZHVMTESWXXCMID-UYSODQMBSA-N tert-butyl N-[(1S,4R)-4-(2,6-dichloropurin-9-yl)cyclopent-2-en-1-yl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate [(1S,4R)-4-(2,6-dichloropurin-9-yl)cyclopent-2-en-1-yl] ethyl carbonate Chemical compound C(C)OC(O[C@@H]1C=C[C@@H](C1)N1C2=NC(=NC(=C2N=C1)Cl)Cl)=O.C(=O)(OC(C)(C)C)N([C@@H]1C=C[C@@H](C1)N1C2=NC(=NC(=C2N=C1)Cl)Cl)C(=O)OC(C)(C)C ZHVMTESWXXCMID-UYSODQMBSA-N 0.000 description 1
- DGCUKMKXWAJAAE-RSLMWUCJSA-N tert-butyl n-[(1s,2r,3s,4r)-4-(2,6-dichloropurin-9-yl)-2,3-dihydroxycyclopentyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound O[C@@H]1[C@H](O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1N1C2=NC(Cl)=NC(Cl)=C2N=C1 DGCUKMKXWAJAAE-RSLMWUCJSA-N 0.000 description 1
- PMGISRXGCXWLJP-FIDNZITISA-N tert-butyl n-[(1s,2r,3s,4r)-4-(2,6-dichloropurin-9-yl)-2,3-dihydroxycyclopentyl]-n-propanoylcarbamate Chemical compound O[C@@H]1[C@H](O)[C@@H](N(C(=O)CC)C(=O)OC(C)(C)C)C[C@H]1N1C2=NC(Cl)=NC(Cl)=C2N=C1 PMGISRXGCXWLJP-FIDNZITISA-N 0.000 description 1
- QBUKCRUTPGNKAR-JMQONQOQSA-N tert-butyl n-[(1s,2r,3s,4r)-4-[2-(2-aminoethylcarbamoyl)-6-(2,2-diphenylethylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]carbamate Chemical compound O[C@@H]1[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1N1C2=NC(C(=O)NCCN)=NC(NCC(C=3C=CC=CC=3)C=3C=CC=CC=3)=C2N=C1 QBUKCRUTPGNKAR-JMQONQOQSA-N 0.000 description 1
- BMBYBHXTWLDORX-CFBHAYGYSA-N tert-butyl n-[(1s,2r,3s,4r)-4-[2-chloro-6-(2,2-diphenylethylamino)purin-9-yl]-2,3-dihydroxycyclopentyl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound O[C@@H]1[C@H](O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1N1C2=NC(Cl)=NC(NCC(C=3C=CC=CC=3)C=3C=CC=CC=3)=C2N=C1 BMBYBHXTWLDORX-CFBHAYGYSA-N 0.000 description 1
- OGDBLCCEJZQMDU-NWDGAFQWSA-N tert-butyl n-[(1s,4r)-4-(2,6-dichloropurin-9-yl)cyclopent-2-en-1-yl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound C1=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1N1C2=NC(Cl)=NC(Cl)=C2N=C1 OGDBLCCEJZQMDU-NWDGAFQWSA-N 0.000 description 1
- ZKWJSWJSPFYHRX-JKSUJKDBSA-N tert-butyl n-[(1s,4r)-4-[2-chloro-6-(pentan-3-ylamino)purin-9-yl]cyclopent-2-en-1-yl]-n-propanoylcarbamate Chemical compound C1=NC=2C(NC(CC)CC)=NC(Cl)=NC=2N1[C@@H]1C[C@H](N(C(=O)CC)C(=O)OC(C)(C)C)C=C1 ZKWJSWJSPFYHRX-JKSUJKDBSA-N 0.000 description 1
- WOKQSMNARGDKPR-BJKOFHAPSA-N tert-butyl n-[(1s,4r)-4-[6-[bis(4-methoxyphenyl)methylamino]-2-chloropurin-9-yl]cyclopent-2-en-1-yl]-n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)NC1=NC(Cl)=NC2=C1N=CN2[C@H]1C=C[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1 WOKQSMNARGDKPR-BJKOFHAPSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
- VBUWHAJDOUIJMV-UHFFFAOYSA-N tert-butyl n-propylcarbamate Chemical compound CCCNC(=O)OC(C)(C)C VBUWHAJDOUIJMV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
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- Rheumatology (AREA)
- Ophthalmology & Optometry (AREA)
- Emergency Medicine (AREA)
- Urology & Nephrology (AREA)
- Anesthesiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Heart & Thoracic Surgery (AREA)
- Otolaryngology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0607953.7A GB0607953D0 (en) | 2006-04-21 | 2006-04-21 | Organic compounds |
| PCT/EP2007/003436 WO2007121921A2 (en) | 2006-04-21 | 2007-04-19 | Purine derivatives for use as adenosin a2a receptor agonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009534339A true JP2009534339A (ja) | 2009-09-24 |
| JP2009534339A5 JP2009534339A5 (enExample) | 2011-06-23 |
Family
ID=36581050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009505780A Pending JP2009534339A (ja) | 2006-04-21 | 2007-04-19 | アデノシンａ２ａ受容体アゴニストとして使用するためのプリン誘導体 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20090105476A1 (enExample) |
| EP (1) | EP2012760A2 (enExample) |
| JP (1) | JP2009534339A (enExample) |
| KR (1) | KR20080110923A (enExample) |
| CN (1) | CN101426483A (enExample) |
| AU (1) | AU2007241344A1 (enExample) |
| BR (1) | BRPI0710655A2 (enExample) |
| CA (1) | CA2648813A1 (enExample) |
| GB (1) | GB0607953D0 (enExample) |
| MX (1) | MX2008013418A (enExample) |
| RU (1) | RU2008145701A (enExample) |
| WO (1) | WO2007121921A2 (enExample) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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-
2006
- 2006-04-21 GB GBGB0607953.7A patent/GB0607953D0/en not_active Ceased
-
2007
- 2007-04-19 JP JP2009505780A patent/JP2009534339A/ja active Pending
- 2007-04-19 MX MX2008013418A patent/MX2008013418A/es not_active Application Discontinuation
- 2007-04-19 AU AU2007241344A patent/AU2007241344A1/en not_active Abandoned
- 2007-04-19 EP EP07724373A patent/EP2012760A2/en not_active Withdrawn
- 2007-04-19 CA CA002648813A patent/CA2648813A1/en not_active Abandoned
- 2007-04-19 BR BRPI0710655-6A patent/BRPI0710655A2/pt not_active IP Right Cessation
- 2007-04-19 US US12/297,940 patent/US20090105476A1/en not_active Abandoned
- 2007-04-19 KR KR1020087028380A patent/KR20080110923A/ko not_active Withdrawn
- 2007-04-19 WO PCT/EP2007/003436 patent/WO2007121921A2/en not_active Ceased
- 2007-04-19 CN CNA2007800144345A patent/CN101426483A/zh active Pending
- 2007-04-19 RU RU2008145701/15A patent/RU2008145701A/ru not_active Application Discontinuation
Also Published As
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|---|---|
| GB0607953D0 (en) | 2006-05-31 |
| WO2007121921A3 (en) | 2008-01-10 |
| CA2648813A1 (en) | 2007-11-01 |
| KR20080110923A (ko) | 2008-12-19 |
| BRPI0710655A2 (pt) | 2011-08-16 |
| EP2012760A2 (en) | 2009-01-14 |
| CN101426483A (zh) | 2009-05-06 |
| MX2008013418A (es) | 2008-11-04 |
| WO2007121921A2 (en) | 2007-11-01 |
| RU2008145701A (ru) | 2010-05-27 |
| AU2007241344A1 (en) | 2007-11-01 |
| US20090105476A1 (en) | 2009-04-23 |
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