AU2005285284B2 - Purine derivatives as A3 and A1 adenosine receptor agonists - Google Patents

Info

Publication number

AU2005285284B2

AU2005285284B2 AU2005285284A AU2005285284A AU2005285284B2 AU 2005285284 B2 AU2005285284 B2 AU 2005285284B2 AU 2005285284 A AU2005285284 A AU 2005285284A AU 2005285284 A AU2005285284 A AU 2005285284A AU 2005285284 B2 AU2005285284 B2 AU 2005285284B2

Authority

AU

Australia

Prior art keywords

alkyl

hydroxy

halo

group

alkoxy

Prior art date

2004-09-09

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 101150046889 ADORA3 gene Proteins 0.000 title claims description 40
• 239000003379 purinergic P1 receptor agonist Substances 0.000 title description 11
• 101150007969 ADORA1 gene Proteins 0.000 title description 3
• 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title description 2
• 150000003212 purines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 120
• -1 hydroxy, amino Chemical group 0.000 claims description 114
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
• 229910052739 hydrogen Inorganic materials 0.000 claims description 71
• 239000001257 hydrogen Substances 0.000 claims description 69
• 125000005843 halogen group Chemical group 0.000 claims description 66
• 238000000034 method Methods 0.000 claims description 59
• 125000003118 aryl group Chemical group 0.000 claims description 46
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 39
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 36
• 150000003839 salts Chemical class 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000001424 substituent group Chemical group 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 25
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
• 241000124008 Mammalia Species 0.000 claims description 17
• 125000000217 alkyl group Chemical group 0.000 claims description 16
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 108050000203 Adenosine receptors Proteins 0.000 claims description 14
• 102000009346 Adenosine receptors Human genes 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 13
• 239000000556 agonist Substances 0.000 claims description 11
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 230000003213 activating effect Effects 0.000 claims description 7
• 150000001602 bicycloalkyls Chemical group 0.000 claims description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000004104 aryloxy group Chemical group 0.000 claims description 6
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 5
• 125000003853 4-amino-3-iodobenzyl group Chemical group [H]N([H])C1=C(I)C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims description 4
• 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 4
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
• 125000006482 3-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(I)=C1[H])C([H])([H])* 0.000 claims description 4
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
• 125000003106 haloaryl group Chemical group 0.000 claims description 4
• 230000000302 ischemic effect Effects 0.000 claims description 4
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
• YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims description 3
• 125000004136 7-norbornyl group Chemical group [H]C1([H])C([H])([H])C2([H])C([H])([H])C([H])([H])C1([H])C2([H])* 0.000 claims description 3
• 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 3
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• 230000006378 damage Effects 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• 238000001727 in vivo Methods 0.000 claims description 3
• 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
• 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 2
• 238000000338 in vitro Methods 0.000 claims description 2
• 125000002346 iodo group Chemical group I* 0.000 claims description 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 9
• 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims 2
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 2
• 125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 claims 1
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims 1
• 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
• 238000005481 NMR spectroscopy Methods 0.000 description 73
• 238000010265 fast atom bombardment Methods 0.000 description 51
• 239000000243 solution Substances 0.000 description 48
• 239000000203 mixture Substances 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 238000004128 high performance liquid chromatography Methods 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 20
• 239000000460 chlorine Substances 0.000 description 19
• 239000007787 solid Substances 0.000 description 19
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 239000000872 buffer Substances 0.000 description 18
• MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 18
• 239000002904 solvent Substances 0.000 description 17
• WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 16
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
• 238000009739 binding Methods 0.000 description 16
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
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• 239000000725 suspension Substances 0.000 description 13
• OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 12
• 230000015572 biosynthetic process Effects 0.000 description 12
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• 238000003786 synthesis reaction Methods 0.000 description 12
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• 125000003545 alkoxy group Chemical group 0.000 description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
• 235000019439 ethyl acetate Nutrition 0.000 description 11
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
• 239000003921 oil Substances 0.000 description 10
• 235000019198 oils Nutrition 0.000 description 10
• 239000003208 petroleum Substances 0.000 description 10
• 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 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
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• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
• 238000011282 treatment Methods 0.000 description 8
• IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 7
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