AU2004255920B2 - Spiro [1-azabicyclo [2.2.2] octan-3,5'-oxazolidin]-2'-one derivatives with affinity to the alpha7 nicotinic acetylcholine receptor - Google Patents
Spiro [1-azabicyclo [2.2.2] octan-3,5'-oxazolidin]-2'-one derivatives with affinity to the alpha7 nicotinic acetylcholine receptor Download PDFInfo
- Publication number
- AU2004255920B2 AU2004255920B2 AU2004255920A AU2004255920A AU2004255920B2 AU 2004255920 B2 AU2004255920 B2 AU 2004255920B2 AU 2004255920 A AU2004255920 A AU 2004255920A AU 2004255920 A AU2004255920 A AU 2004255920A AU 2004255920 B2 AU2004255920 B2 AU 2004255920B2
- Authority
- AU
- Australia
- Prior art keywords
- azabicyclo
- octan
- oxazolidin
- spiro
- thiophen
- 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.)
- Ceased
Links
- TYAGAVRSOFABFO-UHFFFAOYSA-N spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical class O1C(=O)NCC11C(CC2)CCN2C1 TYAGAVRSOFABFO-UHFFFAOYSA-N 0.000 title claims description 5
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 title description 2
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 260
- 229960000649 oxyphenbutazone Drugs 0.000 claims description 239
- -1 2-pyrimidyl Chemical group 0.000 claims description 226
- 125000003003 spiro group Chemical group 0.000 claims description 182
- 238000000034 method Methods 0.000 claims description 108
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 51
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 claims description 45
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 44
- 125000004122 cyclic group Chemical group 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 30
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 30
- 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
- 230000006735 deficit Effects 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 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
- 229960002715 nicotine Drugs 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229910052722 tritium Inorganic materials 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 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
- 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
- 230000003935 attention Effects 0.000 claims description 8
- 201000000980 schizophrenia Diseases 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 7
- 208000000044 Amnesia Diseases 0.000 claims description 7
- 208000020925 Bipolar 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
- 206010026749 Mania Diseases 0.000 claims description 7
- 208000026139 Memory disease Diseases 0.000 claims description 7
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- 208000025569 Tobacco Use disease Diseases 0.000 claims description 7
- 201000006704 Ulcerative Colitis 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
- 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
- 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
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 6
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 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
- 208000015802 attention deficit-hyperactivity disease Diseases 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
- 125000001072 heteroaryl group Chemical group 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
- 230000004913 activation Effects 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 5
- 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
- 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
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 4
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 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
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 230000008485 antagonism Effects 0.000 claims description 3
- 125000004429 atom Chemical group 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
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 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 claims description 2
- 230000001939 inductive effect Effects 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 2
- 230000005062 synaptic transmission Effects 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- FDIWDKGCJZJCIU-GOSISDBHSA-N (5r)-3-(2-phenyl-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=CC=C1 FDIWDKGCJZJCIU-GOSISDBHSA-N 0.000 claims 1
- WSLDNOHFXKPNIO-QGZVFWFLSA-N (5r)-3-(2-pyridin-2-yl-1,3-oxazol-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)=COC=1C1=CC=CC=N1 WSLDNOHFXKPNIO-QGZVFWFLSA-N 0.000 claims 1
- FJWRCVGCNDWSSL-QGZVFWFLSA-N (5r)-3-(2-pyridin-2-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=CC=N1 FJWRCVGCNDWSSL-QGZVFWFLSA-N 0.000 claims 1
- XQDQRGMEQFOARI-GOSISDBHSA-N (5r)-3-(5-pyridin-2-ylfuran-3-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(C=1)=COC=1C1=CC=CC=N1 XQDQRGMEQFOARI-GOSISDBHSA-N 0.000 claims 1
- GGQAXZVZTOUDQU-GOSISDBHSA-N (5r)-3-(5-pyridin-4-ylfuran-3-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(C=1)=COC=1C1=CC=NC=C1 GGQAXZVZTOUDQU-GOSISDBHSA-N 0.000 claims 1
- ILUZTUFUDSONFD-JOCHJYFZSA-N (5r)-3-(5-quinolin-4-ylthiophen-2-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound C1N(CC2)CCC2[C@@]11OC(=O)N(C=2SC(=CC=2)C=2C3=CC=CC=C3N=CC=2)C1 ILUZTUFUDSONFD-JOCHJYFZSA-N 0.000 claims 1
- OXGSXHYIHDSUPE-QGZVFWFLSA-N (5r)-3-(5-thiophen-2-ylfuran-3-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(C=1)=COC=1C1=CC=CS1 OXGSXHYIHDSUPE-QGZVFWFLSA-N 0.000 claims 1
- FJPHZJGPVQQDFI-QGZVFWFLSA-N (5r)-3-(5-thiophen-3-ylthiophen-3-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(C=1)=CSC=1C=1C=CSC=1 FJPHZJGPVQQDFI-QGZVFWFLSA-N 0.000 claims 1
- HWKOGMDTJUNMJM-MRXNPFEDSA-N (5r)-3-[4-(1,3-thiazol-4-yl)thiophen-2-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(SC=1)=CC=1C1=CSC=N1 HWKOGMDTJUNMJM-MRXNPFEDSA-N 0.000 claims 1
- GAPGOBONZPQUTH-MRXNPFEDSA-N (5r)-3-[5-(1,3-thiazol-5-yl)thiophen-2-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)=CC=C1C1=CN=CS1 GAPGOBONZPQUTH-MRXNPFEDSA-N 0.000 claims 1
- 108010009685 Cholinergic Receptors Proteins 0.000 claims 1
- 102000034337 acetylcholine receptors Human genes 0.000 claims 1
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims 1
- 239000007787 solid Substances 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 31
- 239000002904 solvent Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 239000002585 base Substances 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 20
- 125000002524 organometallic group Chemical group 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
- 239000003446 ligand Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 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 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical group I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 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 6
- 239000002253 acid Substances 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 230000006315 carbonylation Effects 0.000 description 5
- 238000005810 carbonylation reaction Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 5
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- TYAGAVRSOFABFO-VIFPVBQESA-N (5s)-spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound O1C(=O)NC[C@]11C(CC2)CCN2C1 TYAGAVRSOFABFO-VIFPVBQESA-N 0.000 description 4
- WAQFYSJKIRRXLP-UHFFFAOYSA-N 2,4-dibromothiophene Chemical compound BrC1=CSC(Br)=C1 WAQFYSJKIRRXLP-UHFFFAOYSA-N 0.000 description 4
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000006880 cross-coupling reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 4
- 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 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 229920002873 Polyethylenimine Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- PTTNOIXNKYFOFH-UHFFFAOYSA-N 2-(4-bromothiophen-2-yl)pyridine Chemical compound BrC1=CSC(C=2N=CC=CC=2)=C1 PTTNOIXNKYFOFH-UHFFFAOYSA-N 0.000 description 2
- KAUUGBWNSHNIAV-UHFFFAOYSA-N 2-bromo-5-pyridin-4-yl-1,3,4-thiadiazole Chemical compound S1C(Br)=NN=C1C1=CC=NC=C1 KAUUGBWNSHNIAV-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 150000001414 amino alcohols Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 2
- NAFBIYLNNXZOFN-UHFFFAOYSA-N methyl n-(1,3-thiazol-2-yl)carbamate Chemical compound COC(=O)NC1=NC=CS1 NAFBIYLNNXZOFN-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- FDVMXHWVRNBCQS-UHFFFAOYSA-N (3,5-dibromofuran-2-yl)-trimethylsilane Chemical compound C[Si](C)(C)C=1OC(Br)=CC=1Br FDVMXHWVRNBCQS-UHFFFAOYSA-N 0.000 description 1
- HLOPDIWMXWVQTN-UHFFFAOYSA-N (3-bromo-5-pyridin-2-yl-2h-furan-3-yl)-trimethylsilane Chemical compound C[Si](C)(C)C1(Br)COC(C=2N=CC=CC=2)=C1 HLOPDIWMXWVQTN-UHFFFAOYSA-N 0.000 description 1
- BKNASHMEUCNUHC-CYBMUJFWSA-N (5r)-3-(4-bromofuran-2-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound BrC1=COC(N2C(O[C@@]3(C4CCN(CC4)C3)C2)=O)=C1 BKNASHMEUCNUHC-CYBMUJFWSA-N 0.000 description 1
- UKAYATXHBBUJRY-GOSISDBHSA-N (5r)-3-(4-pyridin-4-ylfuran-2-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(OC=1)=CC=1C1=CC=NC=C1 UKAYATXHBBUJRY-GOSISDBHSA-N 0.000 description 1
- IOQWLUAQJKWRCD-CYBMUJFWSA-N (5r)-3-(5-bromothiophen-2-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound S1C(Br)=CC=C1N1C(=O)O[C@@]2(C3CCN(CC3)C2)C1 IOQWLUAQJKWRCD-CYBMUJFWSA-N 0.000 description 1
- QAUNMLMGCGOLRW-LJQANCHMSA-N (5r)-3-(5-phenylthiophen-2-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)=CC=C1C1=CC=CC=C1 QAUNMLMGCGOLRW-LJQANCHMSA-N 0.000 description 1
- NNYOLBRVKKYQIZ-GOSISDBHSA-N (5r)-3-(5-pyridin-3-ylfuran-3-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(C=1)=COC=1C1=CC=CN=C1 NNYOLBRVKKYQIZ-GOSISDBHSA-N 0.000 description 1
- FDESMSOITOBLPD-QGZVFWFLSA-N (5r)-3-[5-(furan-3-yl)furan-2-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(O1)=CC=C1C=1C=COC=1 FDESMSOITOBLPD-QGZVFWFLSA-N 0.000 description 1
- 229930182840 (S)-nicotine Natural products 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- VHWYVQYCDIZTTK-UHFFFAOYSA-N 1-(5-bromothiophen-2-yl)pyrazole Chemical compound S1C(Br)=CC=C1N1N=CC=C1 VHWYVQYCDIZTTK-UHFFFAOYSA-N 0.000 description 1
- GKPGEBCMRMQOPF-UHFFFAOYSA-N 2,3-dibromofuran Chemical compound BrC=1C=COC=1Br GKPGEBCMRMQOPF-UHFFFAOYSA-N 0.000 description 1
- MKEJZKKVVUZXIS-UHFFFAOYSA-N 2,4-dibromo-1,3-thiazole Chemical compound BrC1=CSC(Br)=N1 MKEJZKKVVUZXIS-UHFFFAOYSA-N 0.000 description 1
- KBVDUUXRXJTAJC-UHFFFAOYSA-N 2,5-dibromothiophene Chemical compound BrC1=CC=C(Br)S1 KBVDUUXRXJTAJC-UHFFFAOYSA-N 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
- KGKAFMMOTOBORH-UHFFFAOYSA-N 2-(4-bromofuran-2-yl)pyridine Chemical compound BrC1=COC(C=2N=CC=CC=2)=C1 KGKAFMMOTOBORH-UHFFFAOYSA-N 0.000 description 1
- NVQXBSUUWVZRCA-UHFFFAOYSA-N 2-bromo-5-phenyl-1,3,4-thiadiazole Chemical compound S1C(Br)=NN=C1C1=CC=CC=C1 NVQXBSUUWVZRCA-UHFFFAOYSA-N 0.000 description 1
- FFLPUSJBOSXYLZ-UHFFFAOYSA-N 2-bromofuran Chemical compound BrC1=CC=[C]O1 FFLPUSJBOSXYLZ-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- DWHIUTFLOLMYFY-UHFFFAOYSA-N 3-(4-bromofuran-2-yl)pyridine Chemical compound BrC1=COC(C=2C=NC=CC=2)=C1 DWHIUTFLOLMYFY-UHFFFAOYSA-N 0.000 description 1
- IJWDIYFAZBRWNO-UHFFFAOYSA-N 3-(5-bromo-1,3-thiazol-2-yl)spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound S1C(Br)=CN=C1N1C(=O)OC2(C3CCN(CC3)C2)C1 IJWDIYFAZBRWNO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LXWLEQZDXOQZGW-UHFFFAOYSA-N 3-bromofuran Chemical compound BrC=1C=COC=1 LXWLEQZDXOQZGW-UHFFFAOYSA-N 0.000 description 1
- QSFXYLROOODCOI-UHFFFAOYSA-N 4-(4-bromofuran-2-yl)pyridine Chemical compound BrC1=COC(C=2C=CN=CC=2)=C1 QSFXYLROOODCOI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- XFDCNXIWKCIBAE-UHFFFAOYSA-N 5-bromo-1,3-thiazol-2-amine;hydrochloride Chemical compound Cl.NC1=NC=C(Br)S1 XFDCNXIWKCIBAE-UHFFFAOYSA-N 0.000 description 1
- KTWDTPBHCWJWGJ-UHFFFAOYSA-N 5-pyridin-4-yl-1,3,4-thiadiazol-2-amine Chemical compound S1C(N)=NN=C1C1=CC=NC=C1 KTWDTPBHCWJWGJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 101100149678 Caenorhabditis elegans snr-3 gene Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000767684 Thoe Species 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- HYGWNUKOUCZBND-UHFFFAOYSA-N azanide Chemical compound [NH2-] HYGWNUKOUCZBND-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- OVBXTKIWZAHFAC-UHFFFAOYSA-N butane;pyrazine;tin Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=CC=N1 OVBXTKIWZAHFAC-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000003683 electrophilic halogenation reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960005051 fluostigmine Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- CYEFKCRAAGLNHW-UHFFFAOYSA-N furan-3-ylboronic acid Chemical compound OB(O)C=1C=COC=1 CYEFKCRAAGLNHW-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- PUYCICVJCRLABY-UHFFFAOYSA-N heptane;oxolane Chemical compound C1CCOC1.CCCCCCC PUYCICVJCRLABY-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 239000011539 homogenization buffer Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 150000002816 nickel compounds Chemical class 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- WUOFQGMXQCSPPV-UHFFFAOYSA-N tributyl(1,3-thiazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CS1 WUOFQGMXQCSPPV-UHFFFAOYSA-N 0.000 description 1
- YYQKQPYPLADFMK-UHFFFAOYSA-N tributyl(1,3-thiazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CSC=N1 YYQKQPYPLADFMK-UHFFFAOYSA-N 0.000 description 1
- GOWNSHUNTJWVOM-UHFFFAOYSA-N tributyl(1,3-thiazol-5-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=CS1 GOWNSHUNTJWVOM-UHFFFAOYSA-N 0.000 description 1
- CFQJBWKKHCMCGJ-UHFFFAOYSA-N tributyl(pyridin-3-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CN=C1 CFQJBWKKHCMCGJ-UHFFFAOYSA-N 0.000 description 1
- UNEPXPMBVGDXGH-UHFFFAOYSA-N tributyl(pyridin-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=NC=C1 UNEPXPMBVGDXGH-UHFFFAOYSA-N 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48552303P | 2003-07-08 | 2003-07-08 | |
| US60/485,523 | 2003-07-08 | ||
| PCT/GB2004/002904 WO2005005435A1 (en) | 2003-07-08 | 2004-07-06 | Spiro ′1-azabicyclo ′2.2.2!octan-3,5′-oxazolidin -2′-one! derivatives with affinity to the alpha7 nicotinic acetylcholine receptor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2004255920A1 AU2004255920A1 (en) | 2005-01-20 |
| AU2004255920B2 true AU2004255920B2 (en) | 2008-05-15 |
Family
ID=34062082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004255920A Ceased AU2004255920B2 (en) | 2003-07-08 | 2004-07-06 | Spiro [1-azabicyclo [2.2.2] octan-3,5'-oxazolidin]-2'-one derivatives with affinity to the alpha7 nicotinic acetylcholine receptor |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US7514567B2 (enExample) |
| EP (1) | EP1654264A1 (enExample) |
| JP (1) | JP2007516200A (enExample) |
| KR (1) | KR20060057569A (enExample) |
| CN (1) | CN1829721A (enExample) |
| AR (1) | AR045040A1 (enExample) |
| AU (1) | AU2004255920B2 (enExample) |
| BR (1) | BRPI0412382A (enExample) |
| CA (1) | CA2531510A1 (enExample) |
| IL (1) | IL172762A0 (enExample) |
| MX (1) | MXPA06000231A (enExample) |
| NO (1) | NO20060612L (enExample) |
| NZ (1) | NZ545132A (enExample) |
| SA (1) | SA04250212B1 (enExample) |
| TW (1) | TW200524942A (enExample) |
| WO (1) | WO2005005435A1 (enExample) |
| ZA (1) | ZA200600154B (enExample) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0518949A2 (pt) * | 2004-12-15 | 2008-12-16 | Astrazeneca Ab | composto, uso de um composto, mÉtodo para induÇço da interrupÇço do hÁbito de fumar, composiÇço farmacÊutica, e, uso de uma composiÇço farmacÊutica |
| WO2008021338A2 (en) | 2006-08-15 | 2008-02-21 | Wyeth | Tricyclic oxazolidone derivatives useful as pr modulators |
| TW200815428A (en) | 2006-08-15 | 2008-04-01 | Wyeth Corp | Oxazolidone derivatives as PR modulators |
| US7649007B2 (en) | 2006-08-15 | 2010-01-19 | Wyeth Llc | Oxazolidine derivatives as PR modulators |
| US7538107B2 (en) | 2006-08-15 | 2009-05-26 | Wyeth | Oxazinan-2-one derivatives useful as PR modulators |
| US7652018B2 (en) | 2006-08-15 | 2010-01-26 | Wyeth Llc | Imidazolidin-2-one derivatives useful as PR modulators |
| BRPI0718199A2 (pt) * | 2006-10-03 | 2013-11-12 | Galleon Pharmaceuticals Inc | Composição, e, métodos para estabilizar o ritmo da respiração de um mamífero, e para aumentar a ventilação por minuto no nível dos centros de controle respiratório do tronco cerebral no nucleus tractus solitarius de um indivíduo. |
| SA08290475B1 (ar) | 2007-08-02 | 2013-06-22 | Targacept Inc | (2s، 3r)-n-(2-((3-بيردينيل)ميثيل)-1-آزا بيسيكلو[2، 2، 2]أوكت-3-يل)بنزو فيوران-2-كربوكساميد، وصور أملاحه الجديدة وطرق استخدامه |
| US8309577B2 (en) | 2008-04-23 | 2012-11-13 | Bristol-Myers Squibb Company | Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands |
| US7863291B2 (en) | 2008-04-23 | 2011-01-04 | Bristol-Myers Squibb Company | Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands |
| ES2567786T3 (es) * | 2008-07-17 | 2016-04-26 | Bayer Cropscience Ag | Compuestos heterocíclicos como pesticidas |
| TW201031664A (en) | 2009-01-26 | 2010-09-01 | Targacept Inc | Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide |
| UA107791C2 (en) * | 2009-05-05 | 2015-02-25 | Dow Agrosciences Llc | Pesticidal compositions |
| US8759550B2 (en) * | 2009-08-27 | 2014-06-24 | Yeda Research And Development Co. Ltd. | Oligo- and polyfurans, preparation and uses thereof |
| US8278320B2 (en) | 2009-10-28 | 2012-10-02 | Bristol-Myers Squibb Company | Azabicyclo[2.2.1]heptane compounds as alpha-7 nicotinic acetylcholine receptor ligands |
| JP2013509417A (ja) | 2009-10-28 | 2013-03-14 | ブリストル−マイヤーズ スクイブ カンパニー | α７ニコチン性アセチルコリン受容体リガンドとしてのアザ二環式化合物 |
| BR112012026530B1 (pt) * | 2010-04-16 | 2018-03-20 | Bayer Intellectual Property Gmbh | Compostos heterocíclicos como pesticidas, composição os compreendendo e suas utilizações, bem como método para controle de pragas de pragas |
| JP2013525457A (ja) | 2010-04-30 | 2013-06-20 | ブリストル−マイヤーズ スクイブ カンパニー | アルファ−７ニコチン性アセチルコリン受容体リガンドプロドラッグとしてのアザ−二環式アミンｎ−オキシド化合物 |
| BR112013001516A2 (pt) * | 2010-07-22 | 2016-06-07 | Novartis Ag | compostos de tiofeno 2,3,5-trissubstituídos e empregos destes |
| US9173396B2 (en) | 2010-10-22 | 2015-11-03 | Bayer Intellectual Property Gmbh | Heterocyclic compounds as pesticides |
| CN104302640A (zh) | 2012-03-16 | 2015-01-21 | 埃克希金医药品有限公司 | 3,5-二氨基吡唑激酶抑制剂 |
| BR112015009751A2 (pt) | 2012-10-31 | 2017-07-11 | Bayer Cropscience Ag | novos compostos heterocíclicos como pesticidas |
| NZ631142A (en) | 2013-09-18 | 2016-03-31 | Axikin Pharmaceuticals Inc | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
| MY191736A (en) | 2014-12-23 | 2022-07-13 | Axikin Pharmaceuticals Inc | 3,5-diaminopyrazole kinase inhibitors |
| ES2908801T3 (es) | 2016-06-07 | 2022-05-04 | Jacobio Pharmaceuticals Co Ltd | Nuevos derivados heterocíclicos útiles como inhibidores de SHP2 |
| DK3601239T3 (da) | 2017-03-23 | 2024-09-30 | Jacobio Pharmaceuticals Co Ltd | Novel heterocyclic derivatives useful as shp2 inhibitors |
| CN112839935A (zh) | 2018-09-26 | 2021-05-25 | 北京加科思新药研发有限公司 | 可用作shp2抑制剂的新型杂环衍生物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855290A (en) * | 1985-05-10 | 1989-08-08 | State Of Israel, Represented By Prime Minister's Office, Israel Institute For Biological Research | Derivatives of quinuclidine |
| UA54375C2 (uk) * | 1994-08-24 | 2003-03-17 | Астра Актієболаг | Спіро-азабіциклічні сполуки, способи їх одержання та фармацевтична композиція |
| WO2001066546A1 (en) * | 2000-03-09 | 2001-09-13 | Mitsubishi Pharma Corporation | Spiro compounds, process for preparing the same and use thereof as drugs |
-
2004
- 2004-07-06 KR KR1020067000400A patent/KR20060057569A/ko not_active Ceased
- 2004-07-06 AU AU2004255920A patent/AU2004255920B2/en not_active Ceased
- 2004-07-06 US US10/563,271 patent/US7514567B2/en not_active Expired - Fee Related
- 2004-07-06 EP EP04743249A patent/EP1654264A1/en not_active Withdrawn
- 2004-07-06 WO PCT/GB2004/002904 patent/WO2005005435A1/en not_active Ceased
- 2004-07-06 NZ NZ545132A patent/NZ545132A/en unknown
- 2004-07-06 CA CA002531510A patent/CA2531510A1/en not_active Abandoned
- 2004-07-06 CN CNA2004800218491A patent/CN1829721A/zh active Pending
- 2004-07-06 MX MXPA06000231A patent/MXPA06000231A/es active IP Right Grant
- 2004-07-06 BR BRPI0412382-4A patent/BRPI0412382A/pt not_active IP Right Cessation
- 2004-07-06 JP JP2006518343A patent/JP2007516200A/ja active Pending
- 2004-07-07 AR ARP040102394A patent/AR045040A1/es not_active Application Discontinuation
- 2004-07-08 TW TW093120518A patent/TW200524942A/zh unknown
- 2004-07-11 SA SA04250212A patent/SA04250212B1/ar unknown
-
2005
- 2005-12-22 IL IL172762A patent/IL172762A0/en unknown
-
2006
- 2006-01-06 ZA ZA200600154A patent/ZA200600154B/en unknown
- 2006-02-08 NO NO20060612A patent/NO20060612L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200600154B (en) | 2007-04-25 |
| AU2004255920A1 (en) | 2005-01-20 |
| KR20060057569A (ko) | 2006-05-26 |
| EP1654264A1 (en) | 2006-05-10 |
| CA2531510A1 (en) | 2005-01-20 |
| AR045040A1 (es) | 2005-10-12 |
| NO20060612L (no) | 2006-04-06 |
| NZ545132A (en) | 2009-07-31 |
| SA04250212B1 (ar) | 2009-08-11 |
| IL172762A0 (en) | 2006-04-10 |
| MXPA06000231A (es) | 2006-04-11 |
| US7514567B2 (en) | 2009-04-07 |
| JP2007516200A (ja) | 2007-06-21 |
| US20060154945A1 (en) | 2006-07-13 |
| CN1829721A (zh) | 2006-09-06 |
| WO2005005435A1 (en) | 2005-01-20 |
| BRPI0412382A (pt) | 2006-09-19 |
| TW200524942A (en) | 2005-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2004255920B2 (en) | Spiro [1-azabicyclo [2.2.2] octan-3,5'-oxazolidin]-2'-one derivatives with affinity to the alpha7 nicotinic acetylcholine receptor | |
| EP1539765B1 (en) | Biaryl diazabicycloalkane amides as nicotinic acetylcholine agonists | |
| AU2003224546B2 (en) | Heterocyclic compounds | |
| AU2003224545B2 (en) | Thienyl compounds | |
| JP2007516200A5 (enExample) | ||
| AU1907301A (en) | New use and novel n-azabicyclo-amide derivatives | |
| NZ577474A (en) | Azatricyclo[3.3.1.1]decane derivatives and their uses as nicotinic acetylcholine receptors ligands | |
| UA71598C2 (en) | Furopiridines aralkilamines, a pharmaceutical composition based thereon, a method for the preparation thereof and furopiridine derivatives | |
| JP2008524208A (ja) | ニコチン性アセチルコリン受容体リガンド | |
| MXPA06007027A (es) | Ligandos del receptor nicotinico de acetilcolina. | |
| WO2006065217A1 (en) | Nicotinic acetycholine receptor ligands | |
| CN101124232A (zh) | 烟碱乙酰胆碱受体的配体 | |
| CA2546093A1 (en) | 5-substituted imidazoles | |
| HK1077571B (en) | Biaryl diazabicycloalkane amides as nicotinic acetylcholine agonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE INVENTION TITLE TO READ SPIRO [1-AZABICYCLO [2.2.2] OCTAN3,5 -OXAZOLIDIN]-2 -ONE DERIVATIVES WITH AFFINITY TO THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |