CA2531510A1 - Spiro '1-azabicyclo '2.2.2!octan-3,5'-oxazolidin-2'one! derivatives with affinity to the alpha7 nicotinic acetylcholine receptor - Google Patents

Info

Publication number

CA2531510A1

CA2531510A1 CA002531510A CA2531510A CA2531510A1 CA 2531510 A1 CA2531510 A1 CA 2531510A1 CA 002531510 A CA002531510 A CA 002531510A CA 2531510 A CA2531510 A CA 2531510A CA 2531510 A1 CA2531510 A1 CA 2531510A1

Authority

CA

Canada

Prior art keywords

azabicyclo

octan

spiro

oxazolidin

thiophen

Prior art date

2003-07-08

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 125000003003 spiro group Chemical group 0.000 title claims description 62
• 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 title 1
• 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 260
• 238000000034 method Methods 0.000 claims abstract description 110
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 239000003814 drug Substances 0.000 claims abstract description 20
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• 238000004519 manufacturing process Methods 0.000 claims abstract description 13
• -1 2-pyrimidyl Chemical group 0.000 claims description 251
• 229960000649 oxyphenbutazone Drugs 0.000 claims description 65
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• 239000001257 hydrogen Substances 0.000 claims description 51
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 37
• 125000004122 cyclic group Chemical group 0.000 claims description 37
• 238000011282 treatment Methods 0.000 claims description 36
• 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 27
• 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 27
• 238000011321 prophylaxis Methods 0.000 claims description 26
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
• 229910052736 halogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 25
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 230000006735 deficit Effects 0.000 claims description 23
• 150000002431 hydrogen Chemical class 0.000 claims description 23
• 229910052717 sulfur Inorganic materials 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 20
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
• 208000035475 disorder Diseases 0.000 claims description 18
• 125000005843 halogen group Chemical group 0.000 claims description 17
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 229910052760 oxygen Inorganic materials 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
• 125000004434 sulfur atom Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 206010057852 Nicotine dependence Diseases 0.000 claims description 9
• 208000028017 Psychotic disease Diseases 0.000 claims description 9
• YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 claims description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
• 229960002715 nicotine Drugs 0.000 claims description 9
• 229910052722 tritium Inorganic materials 0.000 claims description 9
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• 208000024827 Alzheimer disease Diseases 0.000 claims description 8
• 208000019901 Anxiety disease Diseases 0.000 claims description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
• 208000012902 Nervous system disease Diseases 0.000 claims description 8
• 208000025966 Neurological disease Diseases 0.000 claims description 8
• 208000002193 Pain Diseases 0.000 claims description 8
• 208000018737 Parkinson disease Diseases 0.000 claims description 8
• 208000000323 Tourette Syndrome Diseases 0.000 claims description 8
• 208000016620 Tourette disease Diseases 0.000 claims description 8
• 230000036506 anxiety Effects 0.000 claims description 8
• 201000000980 schizophrenia Diseases 0.000 claims description 8
• 208000000044 Amnesia Diseases 0.000 claims description 7
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 7
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 7
• 208000020925 Bipolar disease Diseases 0.000 claims description 7
• 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 7
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 7
• 208000023105 Huntington disease Diseases 0.000 claims description 7
• 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 7
• 206010026749 Mania Diseases 0.000 claims description 7
• 208000026139 Memory disease Diseases 0.000 claims description 7
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• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 7
• 230000003935 attention Effects 0.000 claims description 7
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
• 208000028683 bipolar I disease Diseases 0.000 claims description 7
• 230000001713 cholinergic effect Effects 0.000 claims description 7
• 230000007278 cognition impairment Effects 0.000 claims description 7
• 235000019788 craving Nutrition 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 7
• 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 claims description 7
• 230000006984 memory degeneration Effects 0.000 claims description 7
• 208000023060 memory loss Diseases 0.000 claims description 7
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 230000036407 pain Effects 0.000 claims description 7
• 230000000391 smoking effect Effects 0.000 claims description 7
• 210000000225 synapse Anatomy 0.000 claims description 7
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 6
• 125000006017 1-propenyl group Chemical group 0.000 claims description 6
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
• 230000004913 activation Effects 0.000 claims description 6
• 230000008484 agonism Effects 0.000 claims description 6
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
• 230000009286 beneficial effect Effects 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 6
• 125000006038 hexenyl group Chemical group 0.000 claims description 6
• 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 claims description 6
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 6
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
• 230000000694 effects Effects 0.000 claims description 5
• SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 5
• ONLUCDBUROZPQZ-QGZVFWFLSA-N (5r)-3-(2-pyridin-3-yl-1,3-thiazol-4-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound C([C@@]1(OC2=O)C3CCN(CC3)C1)N2C(N=1)=CSC=1C1=CC=CN=C1 ONLUCDBUROZPQZ-QGZVFWFLSA-N 0.000 claims description 4
• PLUFRMLMVYJVRA-QGZVFWFLSA-N (5r)-3-(2-pyridin-3-yl-1,3-thiazol-5-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound C([C@@]1(OC2=O)C3CCN(CC3)C1)N2C(S1)=CN=C1C1=CC=CN=C1 PLUFRMLMVYJVRA-QGZVFWFLSA-N 0.000 claims description 4
• YGFUQGIYPFXQRL-QGZVFWFLSA-N (5r)-3-(2-pyridin-4-yl-1,3-thiazol-4-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound C([C@@]1(OC2=O)C3CCN(CC3)C1)N2C(N=1)=CSC=1C1=CC=NC=C1 YGFUQGIYPFXQRL-QGZVFWFLSA-N 0.000 claims description 4
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
• 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
• 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
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• JUXGDTBXNQMZFI-HXUWFJFHSA-N (5r)-3-[5-(3-methoxyphenyl)thiophen-2-yl]spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound COC1=CC=CC(C=2SC(=CC=2)N2C(O[C@@]3(C4CCN(CC4)C3)C2)=O)=C1 JUXGDTBXNQMZFI-HXUWFJFHSA-N 0.000 claims description 3
• NJGIYZOSEBWUOK-LJQANCHMSA-N (5r)-3-[5-[3-(trifluoromethoxy)phenyl]thiophen-2-yl]spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound FC(F)(F)OC1=CC=CC(C=2SC(=CC=2)N2C(O[C@@]3(C4CCN(CC4)C3)C2)=O)=C1 NJGIYZOSEBWUOK-LJQANCHMSA-N 0.000 claims description 3
• 241000124008 Mammalia Species 0.000 claims description 3
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• 125000004429 atom Chemical group 0.000 claims description 3
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000001153 fluoro group Chemical group F* 0.000 claims description 3
• 125000002346 iodo group Chemical group I* 0.000 claims description 3
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