NZ538590A - Partial and full agonists of A1 adenosine receptors - Google Patents

Info

Publication number

NZ538590A

NZ538590A NZ538590A NZ53859003A NZ538590A NZ 538590 A NZ538590 A NZ 538590A NZ 538590 A NZ538590 A NZ 538590A NZ 53859003 A NZ53859003 A NZ 53859003A NZ 538590 A NZ538590 A NZ 538590A

Authority

NZ

New Zealand

Prior art keywords

purin

compound

formula

optionally substituted

diol

Prior art date

2002-08-15

Links

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• Global Dossier
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• 230000036961 partial effect Effects 0.000 title abstract description 8
• 101150007969 ADORA1 gene Proteins 0.000 title abstract 2
• 239000000556 agonist Substances 0.000 title description 28
• 150000001875 compounds Chemical class 0.000 claims abstract description 327
• 239000001257 hydrogen Substances 0.000 claims abstract description 72
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 72
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 59
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 32
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 26
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 22
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
• 239000003379 purinergic P1 receptor agonist Substances 0.000 claims abstract description 20
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 18
• 201000010099 disease Diseases 0.000 claims abstract description 17
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 14
• 125000002252 acyl group Chemical group 0.000 claims abstract description 12
• 208000003734 Supraventricular Tachycardia Diseases 0.000 claims abstract description 6
• 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 3
• 208000010125 myocardial infarction Diseases 0.000 claims abstract description 3
• 125000001475 halogen functional group Chemical group 0.000 claims abstract 2
• 238000002360 preparation method Methods 0.000 claims description 97
• 125000004545 purin-9-yl group Chemical group N1=CN=C2N(C=NC2=C1)* 0.000 claims description 97
• -1 2-trifluoromethylphenyl Chemical group 0.000 claims description 78
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 34
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 33
• 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 30
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 28
• 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 16
• 229960005305 adenosine Drugs 0.000 claims description 16
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
• 102000005962 receptors Human genes 0.000 claims description 13
• 108020003175 receptors Proteins 0.000 claims description 13
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 241000124008 Mammalia Species 0.000 claims description 9
• 230000003243 anti-lipolytic effect Effects 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
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• 206010015037 epilepsy Diseases 0.000 claims description 6
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• 208000030159 metabolic disease Diseases 0.000 claims description 5
• 235000020824 obesity Nutrition 0.000 claims description 5
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 229940122614 Adenosine receptor agonist Drugs 0.000 claims description 4
• 206010003658 Atrial Fibrillation Diseases 0.000 claims description 4
• 206010003662 Atrial flutter Diseases 0.000 claims description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims description 4
• 208000028867 ischemia Diseases 0.000 claims description 4
• WDASMIRQGXPOGJ-ZDXOVATRSA-N (2r,3r,4s,5r)-2-[6-(cyclopentylamino)purin-9-yl]-5-[2-(2-methylphenyl)ethenyl]oxolane-3,4-diol Chemical compound CC1=CC=CC=C1C=C[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C3=NC=NC(NC4CCCC4)=C3N=C2)O1 WDASMIRQGXPOGJ-ZDXOVATRSA-N 0.000 claims description 3
• KZAFGTJSARYXDI-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-(cyclopentylamino)purin-9-yl]-5-[2-[2-(trifluoromethyl)phenyl]ethynyl]oxolane-3,4-diol Chemical compound C([C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C2=NC=NC(NC3CCCC3)=C2N=C1)#CC1=CC=CC=C1C(F)(F)F KZAFGTJSARYXDI-WGQQHEPDSA-N 0.000 claims description 3
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
• FZOKRCLVLPATSB-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-(cyclopentylamino)purin-9-yl]-5-(2-phenylethenyl)oxolane-3,4-diol Chemical compound N1=CN=C2N([C@@H]3O[C@@H]([C@H]([C@H]3O)O)C=CC=3C=CC=CC=3)C=NC2=C1NC1CCCC1 FZOKRCLVLPATSB-WGQQHEPDSA-N 0.000 claims description 2
• 206010002388 Angina unstable Diseases 0.000 claims description 2
• 208000007718 Stable Angina Diseases 0.000 claims description 2
• 208000006011 Stroke Diseases 0.000 claims description 2
• 208000007814 Unstable Angina Diseases 0.000 claims description 2
• 230000000747 cardiac effect Effects 0.000 claims description 2
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 2
• 230000004936 stimulating effect Effects 0.000 claims description 2
• 125000001544 thienyl group Chemical group 0.000 claims description 2
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• 238000006243 chemical reaction Methods 0.000 description 66
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• 238000000034 method Methods 0.000 description 46
• 125000003118 aryl group Chemical group 0.000 description 45
• 125000001424 substituent group Chemical group 0.000 description 45
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• 239000000243 solution Substances 0.000 description 41
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• 230000002829 reductive effect Effects 0.000 description 31
• 229910001868 water Inorganic materials 0.000 description 31
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 239000004480 active ingredient Substances 0.000 description 27
• 125000003545 alkoxy group Chemical group 0.000 description 26
• 229910052736 halogen Inorganic materials 0.000 description 26
• 150000002367 halogens Chemical class 0.000 description 26
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 23
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
• 150000001412 amines Chemical class 0.000 description 22
• 239000000047 product Substances 0.000 description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• 125000004181 carboxyalkyl group Chemical group 0.000 description 20
• 125000003342 alkenyl group Chemical group 0.000 description 19
• 230000000694 effects Effects 0.000 description 19
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• 239000003826 tablet Substances 0.000 description 19
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
• SSYDTHANSGMJTP-UHFFFAOYSA-N oxolane-3,4-diol Chemical compound OC1COCC1O SSYDTHANSGMJTP-UHFFFAOYSA-N 0.000 description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
• 125000004432 carbon atom Chemical group C* 0.000 description 17
• 125000000392 cycloalkenyl group Chemical group 0.000 description 17
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• 125000000304 alkynyl group Chemical group 0.000 description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
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• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 12
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• 239000000843 powder Substances 0.000 description 12
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• 125000000547 substituted alkyl group Chemical group 0.000 description 11
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• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 9
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
• 125000003710 aryl alkyl group Chemical group 0.000 description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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