ZA200701021B - 2-propynyl adenosine analogs with modified 5'-ribose groups having A2A agonist activity - Google Patents

Info

Publication number

ZA200701021B

ZA200701021B ZA200701021A ZA200701021A ZA200701021B ZA 200701021 B ZA200701021 B ZA 200701021B ZA 200701021 A ZA200701021 A ZA 200701021A ZA 200701021 A ZA200701021 A ZA 200701021A ZA 200701021 B ZA200701021 B ZA 200701021B

Authority

ZA

South Africa

Prior art keywords

compound

alkylene

piperidine

carboxylic acid

hydrogen

Prior art date

2004-08-02

Links

• Espacenet
• Global Dossier
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• 230000000694 effects Effects 0.000 title claims description 32
• 239000000556 agonist Substances 0.000 title description 28
• UBWAYMVIDZVHHG-ZRFIDHNTSA-N (2r,3r,4s,5r)-2-(6-amino-2-prop-1-ynylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical class C12=NC(C#CC)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O UBWAYMVIDZVHHG-ZRFIDHNTSA-N 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 202
• 125000002947 alkylene group Chemical group 0.000 claims description 90
• -1 Cs.geycloalkyl Chemical group 0.000 claims description 89
• 125000003118 aryl group Chemical group 0.000 claims description 83
• 229910052739 hydrogen Inorganic materials 0.000 claims description 83
• 239000001257 hydrogen Substances 0.000 claims description 80
• 125000000217 alkyl group Chemical group 0.000 claims description 72
• 125000001072 heteroaryl group Chemical group 0.000 claims description 71
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 150000002431 hydrogen Chemical group 0.000 claims description 41
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
• 239000000203 mixture Substances 0.000 claims description 37
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 238000000034 method Methods 0.000 claims description 34
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
• 238000011282 treatment Methods 0.000 claims description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
• 229910052792 caesium Inorganic materials 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 125000005843 halogen group Chemical group 0.000 claims description 24
• 238000003384 imaging method Methods 0.000 claims description 24
• 125000004429 atom Chemical group 0.000 claims description 23
• 239000003795 chemical substances by application Substances 0.000 claims description 23
• 229910052757 nitrogen Inorganic materials 0.000 claims description 22
• 206010061218 Inflammation Diseases 0.000 claims description 21
• 238000005481 NMR spectroscopy Methods 0.000 claims description 21
• 230000004054 inflammatory process Effects 0.000 claims description 21
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
• 230000028709 inflammatory response Effects 0.000 claims description 18
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 18
• 102000009346 Adenosine receptors Human genes 0.000 claims description 17
• 108050000203 Adenosine receptors Proteins 0.000 claims description 17
• IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Chemical group CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 16
• QEGNUYASOUJEHD-UHFFFAOYSA-N gem-dimethylcyclohexane Chemical group CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 claims description 16
• UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical group CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 16
• 230000010412 perfusion Effects 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 241000124008 Mammalia Species 0.000 claims description 14
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 14
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
• 239000007788 liquid Substances 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 13
• 230000002107 myocardial effect Effects 0.000 claims description 13
• 239000012217 radiopharmaceutical Substances 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 125000006413 ring segment Chemical group 0.000 claims description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
• 239000003242 anti bacterial agent Substances 0.000 claims description 11
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 11
• HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical group COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 claims description 11
• 229950005741 rolipram Drugs 0.000 claims description 11
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
• 241000894006 Bacteria Species 0.000 claims description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
• 210000004351 coronary vessel Anatomy 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
• 208000014674 injury Diseases 0.000 claims description 10
• FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 claims description 10
• 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims description 9
• 241000700605 Viruses Species 0.000 claims description 9
• 125000004414 alkyl thio group Chemical group 0.000 claims description 9
• 230000017531 blood circulation Effects 0.000 claims description 9
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
• 201000010099 disease Diseases 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
• 230000001575 pathological effect Effects 0.000 claims description 9
• 229960005141 piperazine Drugs 0.000 claims description 9
• 229940121896 radiopharmaceutical Drugs 0.000 claims description 9
• 230000002799 radiopharmaceutical effect Effects 0.000 claims description 9
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
• 230000002411 adverse Effects 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 150000001412 amines Chemical class 0.000 claims description 8
• 150000001413 amino acids Chemical class 0.000 claims description 8
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
• LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexyl-acetic acid Chemical group OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 claims description 8
• IGARGHRYKHJQSM-UHFFFAOYSA-N cyclohexylbenzene Chemical group C1CCCCC1C1=CC=CC=C1 IGARGHRYKHJQSM-UHFFFAOYSA-N 0.000 claims description 8
• 238000001802 infusion Methods 0.000 claims description 8
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 150000002978 peroxides Chemical class 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• XTVMZZBLCLWBPM-UHFFFAOYSA-N tert-butylcyclohexane Chemical group CC(C)(C)C1CCCCC1 XTVMZZBLCLWBPM-UHFFFAOYSA-N 0.000 claims description 8
• 230000008733 trauma Effects 0.000 claims description 8
• 239000002253 acid Substances 0.000 claims description 7
• 239000003443 antiviral agent Substances 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
• 208000029078 coronary artery disease Diseases 0.000 claims description 7
• 238000002592 echocardiography Methods 0.000 claims description 7
• 238000001990 intravenous administration Methods 0.000 claims description 7
• 210000000056 organ Anatomy 0.000 claims description 7
• 230000001717 pathogenic effect Effects 0.000 claims description 7
• 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 7
• 239000000126 substance Substances 0.000 claims description 7
• 208000024891 symptom Diseases 0.000 claims description 7
• 125000005505 thiomorpholino group Chemical group 0.000 claims description 7
• 238000002054 transplantation Methods 0.000 claims description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
• 201000000057 Coronary Stenosis Diseases 0.000 claims description 6
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
• 239000003429 antifungal agent Substances 0.000 claims description 6
• 229940121375 antifungal agent Drugs 0.000 claims description 6
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
• 244000052769 pathogen Species 0.000 claims description 6
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 6
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
• 238000002583 angiography Methods 0.000 claims description 5
• 230000001775 anti-pathogenic effect Effects 0.000 claims description 5
• 238000002347 injection Methods 0.000 claims description 5
• 239000007924 injection Substances 0.000 claims description 5
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
• 229920006395 saturated elastomer Polymers 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• BKVIYDNLLOSFOA-OIOBTWANSA-N thallium-201 Chemical compound [201Tl] BKVIYDNLLOSFOA-OIOBTWANSA-N 0.000 claims description 5
• 230000001225 therapeutic effect Effects 0.000 claims description 5
• AULUDJRRNHDTJI-UHFFFAOYSA-N 1,1,3,3-tetramethylcyclohexane Chemical group CC1(C)CCCC(C)(C)C1 AULUDJRRNHDTJI-UHFFFAOYSA-N 0.000 claims description 4
• GCYUJISWSVALJD-UHFFFAOYSA-N 1,1-diethylcyclohexane Chemical group CCC1(CC)CCCCC1 GCYUJISWSVALJD-UHFFFAOYSA-N 0.000 claims description 4
• XAZKFISIRYLAEE-UHFFFAOYSA-N 1,3-dimethylcyclopentane Chemical group CC1CCC(C)C1 XAZKFISIRYLAEE-UHFFFAOYSA-N 0.000 claims description 4
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
• FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical group FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 claims description 4
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
• QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 4
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• 230000008484 agonism Effects 0.000 claims description 4
• 125000002837 carbocyclic group Chemical group 0.000 claims description 4
• HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical group OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 claims description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
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• CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 claims description 3
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