WO2003010146A1 - Composes derives de quinoleine et quinoxaline, preparation et utilisations - Google Patents
Composes derives de quinoleine et quinoxaline, preparation et utilisations Download PDFInfo
- Publication number
- WO2003010146A1 WO2003010146A1 PCT/FR2002/002594 FR0202594W WO03010146A1 WO 2003010146 A1 WO2003010146 A1 WO 2003010146A1 FR 0202594 W FR0202594 W FR 0202594W WO 03010146 A1 WO03010146 A1 WO 03010146A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- quinoline
- carboxylate
- methyl
- hydroxy
- radical
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title abstract description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 6
- 239000000203 mixture Substances 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 277
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 238000011282 treatment Methods 0.000 claims abstract description 27
- -1 COOR 15 CH 2 OH Chemical group 0.000 claims description 375
- 150000003254 radicals Chemical class 0.000 claims description 321
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 232
- 125000003118 aryl group Chemical group 0.000 claims description 231
- 229910052739 hydrogen Inorganic materials 0.000 claims description 208
- 239000001257 hydrogen Substances 0.000 claims description 141
- 239000002253 acid Substances 0.000 claims description 86
- 125000000217 alkyl group Chemical group 0.000 claims description 83
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 81
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 70
- 150000002431 hydrogen Chemical class 0.000 claims description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 52
- 125000005843 halogen group Chemical group 0.000 claims description 47
- 150000005840 aryl radicals Chemical class 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 42
- SCYNBLANGNGTRN-UHFFFAOYSA-N methyl 4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=CC=C1OCC1=CC=CC=C1 SCYNBLANGNGTRN-UHFFFAOYSA-N 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 125000004434 sulfur atom Chemical group 0.000 claims description 20
- 239000011734 sodium Substances 0.000 claims description 19
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 16
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 230000007170 pathology Effects 0.000 claims description 15
- 230000009467 reduction Effects 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims description 9
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 210000000653 nervous system Anatomy 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 5
- AMSGQUZJHUTXMU-UHFFFAOYSA-N 7-hexyl-8-hydroxy-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound OC1=CC(C(O)=O)=NC2=C(O)C(CCCCCC)=CC=C21 AMSGQUZJHUTXMU-UHFFFAOYSA-N 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 229910005965 SO 2 Inorganic materials 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 150000007942 carboxylates Chemical class 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 230000000147 hypnotic effect Effects 0.000 claims description 5
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 5
- 230000000626 neurodegenerative effect Effects 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 239000000932 sedative agent Substances 0.000 claims description 5
- 230000001624 sedative effect Effects 0.000 claims description 5
- 230000003997 social interaction Effects 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- IQSHMJKUNXCFPD-UHFFFAOYSA-N 8-amino-4-oxo-6-phenyl-1h-quinoline-2-carboxylic acid Chemical compound C=1C2=C(O)C=C(C(O)=O)N=C2C(N)=CC=1C1=CC=CC=C1 IQSHMJKUNXCFPD-UHFFFAOYSA-N 0.000 claims description 4
- JKORTLPLDDTUES-UHFFFAOYSA-N 8-benzamido-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C12=NC(C(=O)O)=CC(O)=C2C=CC=C1NC(=O)C1=CC=CC=C1 JKORTLPLDDTUES-UHFFFAOYSA-N 0.000 claims description 4
- 208000026139 Memory disease Diseases 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 230000003340 mental effect Effects 0.000 claims description 4
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 3
- PBCSDDOCZANXMI-UHFFFAOYSA-N 3-methylquinoline-2-carboxylic acid Chemical compound C1=CC=C2N=C(C(O)=O)C(C)=CC2=C1 PBCSDDOCZANXMI-UHFFFAOYSA-N 0.000 claims description 3
- ZMCSLNYAYWEOAG-UHFFFAOYSA-N 4-oxo-8-(2-phenylethyl)-1h-quinoline-2-carboxylic acid Chemical compound C12=NC(C(=O)O)=CC(O)=C2C=CC=C1CCC1=CC=CC=C1 ZMCSLNYAYWEOAG-UHFFFAOYSA-N 0.000 claims description 3
- JZHJBKKZNIUHDB-UHFFFAOYSA-N 5-(4-chlorophenyl)-8-hydroxyquinoline-2-carboxylic acid Chemical compound C=1C=C(O)C2=NC(C(=O)O)=CC=C2C=1C1=CC=C(Cl)C=C1 JZHJBKKZNIUHDB-UHFFFAOYSA-N 0.000 claims description 3
- GEYFFJVVBSDHIJ-UHFFFAOYSA-N 6,8-diamino-4-oxo-1h-quinoline-2-carboxylic acid;hydrochloride Chemical compound Cl.N1=C(C(O)=O)C=C(O)C2=CC(N)=CC(N)=C21 GEYFFJVVBSDHIJ-UHFFFAOYSA-N 0.000 claims description 3
- QHOLLSQPOJJAKS-UHFFFAOYSA-N 8-(dimethylamino)-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=C(C(O)=O)N=C2C(N(C)C)=CC=CC2=C1O QHOLLSQPOJJAKS-UHFFFAOYSA-N 0.000 claims description 3
- XZJGUUDAJQZMPB-UHFFFAOYSA-N 8-amino-4-oxo-5-phenyl-1h-quinoline-2-carboxylic acid Chemical compound C12=C(O)C=C(C(O)=O)N=C2C(N)=CC=C1C1=CC=CC=C1 XZJGUUDAJQZMPB-UHFFFAOYSA-N 0.000 claims description 3
- IHGPCXJBDNSLHZ-UHFFFAOYSA-N 8-amino-6-cyano-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=C(C(O)=O)N=C2C(N)=CC(C#N)=CC2=C1O IHGPCXJBDNSLHZ-UHFFFAOYSA-N 0.000 claims description 3
- NTEIRPXEMKATIP-UHFFFAOYSA-N 8-hydroxy-3-methyl-7-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-4-oxo-1H-quinoline-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)NCCCC1=CC=C2C(=O)C(C)=C(C(O)=O)NC2=C1O NTEIRPXEMKATIP-UHFFFAOYSA-N 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- UWYBFPHSDKCLQJ-UHFFFAOYSA-N OC1=C(C(=NC2=C(C=CC=C12)O)C(=O)O)C1=CC=CC=C1.OC1=CC(=NC2=C(C=C(C=C12)C1=C(C=CC=C1)OC)O)C(=O)O.OC1=CC(=NC2=C(C(=CC=C12)C1=CC=CC=C1)O)C(=O)O Chemical compound OC1=C(C(=NC2=C(C=CC=C12)O)C(=O)O)C1=CC=CC=C1.OC1=CC(=NC2=C(C=C(C=C12)C1=C(C=CC=C1)OC)O)C(=O)O.OC1=CC(=NC2=C(C(=CC=C12)C1=CC=CC=C1)O)C(=O)O UWYBFPHSDKCLQJ-UHFFFAOYSA-N 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- DTMGPZIOEMDWNU-UHFFFAOYSA-N methyl 4-(3-amino-4-oxo-4-phenylbutyl)-8-hydroxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(O)C2=NC(C(=O)OC)=CC=1CCC(N)C(=O)C1=CC=CC=C1 DTMGPZIOEMDWNU-UHFFFAOYSA-N 0.000 claims description 3
- VLBGUJISSQQTSG-UHFFFAOYSA-N methyl 6-(3-methylphenyl)-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=C(C=2C=C(C)C=CC=2)C=C1OCC1=CC=CC=C1 VLBGUJISSQQTSG-UHFFFAOYSA-N 0.000 claims description 3
- PJLIWYBVQAHMMB-UHFFFAOYSA-N methyl 8-hydroxy-4-[(4-methylphenyl)sulfonylamino]quinoline-2-carboxylate Chemical compound C=12C=CC=C(O)C2=NC(C(=O)OC)=CC=1NS(=O)(=O)C1=CC=C(C)C=C1 PJLIWYBVQAHMMB-UHFFFAOYSA-N 0.000 claims description 3
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- 229940005483 opioid analgesics Drugs 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- YTUBFEWOWXMSFW-UHFFFAOYSA-M sodium;7-bromo-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound [Na+].BrC1=CC=C2C(O)=CC(C([O-])=O)=NC2=C1O YTUBFEWOWXMSFW-UHFFFAOYSA-M 0.000 claims description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- GSFPZXGQGSVWCW-UHFFFAOYSA-N 6-(4-fluorophenyl)-8-hydroxy-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=C(O)C2=NC(C(=O)O)=CC(O)=C2C=C1C1=CC=C(F)C=C1 GSFPZXGQGSVWCW-UHFFFAOYSA-N 0.000 claims description 2
- UHNVKFRQECHGQV-UHFFFAOYSA-N 6-benzyl-4-oxo-8-phenylmethoxy-1H-quinoline-2-carboxylic acid Chemical compound C=1C(OCC=2C=CC=CC=2)=C2NC(C(=O)O)=CC(=O)C2=CC=1CC1=CC=CC=C1 UHNVKFRQECHGQV-UHFFFAOYSA-N 0.000 claims description 2
- MNIMZIMHTWRHCR-UHFFFAOYSA-N 8-amino-6-(3-hydroxypropyl)-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=C(C(O)=O)N=C2C(N)=CC(CCCO)=CC2=C1O MNIMZIMHTWRHCR-UHFFFAOYSA-N 0.000 claims description 2
- GWGAVUZLKUMIHT-UHFFFAOYSA-N 8-cyano-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=CC=C(C#N)C2=NC(C(=O)O)=CC(O)=C21 GWGAVUZLKUMIHT-UHFFFAOYSA-N 0.000 claims description 2
- VQYZPNTXCOSGGO-UHFFFAOYSA-N 8-cyano-4-oxo-3-(2-phenylethynyl)-1h-quinoline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=C(C#N)C=CC=C2C(O)=C1C#CC1=CC=CC=C1 VQYZPNTXCOSGGO-UHFFFAOYSA-N 0.000 claims description 2
- QGZDUNPJLXDYNG-UHFFFAOYSA-N 8-cyano-6-ethyl-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound N1=C(C(O)=O)C=C(O)C2=CC(CC)=CC(C#N)=C21 QGZDUNPJLXDYNG-UHFFFAOYSA-N 0.000 claims description 2
- ZDDWWYQQPBCMQS-UHFFFAOYSA-N 8-fluoro-4-oxo-1h-quinoline-2-carboxylic acid Chemical compound C1=CC=C(F)C2=NC(C(=O)O)=CC(O)=C21 ZDDWWYQQPBCMQS-UHFFFAOYSA-N 0.000 claims description 2
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- 238000009835 boiling Methods 0.000 description 6
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- 239000000284 extract Substances 0.000 description 6
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- 241000282376 Panthera tigris Species 0.000 description 4
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- OJSMQJCOIAFMLB-UHFFFAOYSA-N benzyl 5-bromo-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C12=NC(C(=O)OCC=3C=CC=CC=3)=CC=C2C(Br)=CC=C1OCC1=CC=CC=C1 OJSMQJCOIAFMLB-UHFFFAOYSA-N 0.000 description 3
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- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
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- DCWXTRFVYSFAQH-UHFFFAOYSA-N methyl 4-(2-phenylethynyl)-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(OCC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1C#CC1=CC=CC=C1 DCWXTRFVYSFAQH-UHFFFAOYSA-N 0.000 description 3
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- PJTUWNXMLLXTKG-UHFFFAOYSA-N methyl 4-chloro-8-methoxyquinoline-2-carboxylate Chemical compound C1=CC=C(OC)C2=NC(C(=O)OC)=CC(Cl)=C21 PJTUWNXMLLXTKG-UHFFFAOYSA-N 0.000 description 3
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- DXIJWTHDGDZDHL-UHFFFAOYSA-N methyl 6,8-diamino-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(N)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 DXIJWTHDGDZDHL-UHFFFAOYSA-N 0.000 description 3
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- HKJZNACXDMKUBI-UHFFFAOYSA-N methyl 6-bromo-8-cyano-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(Br)C=C(C#N)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 HKJZNACXDMKUBI-UHFFFAOYSA-N 0.000 description 3
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
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- NBEZMNLZGBWWOQ-UHFFFAOYSA-N 4-oxo-8-(pyridin-2-ylamino)-1h-quinoline-2-carboxylic acid;hydrochloride Chemical compound Cl.C12=NC(C(=O)O)=CC(O)=C2C=CC=C1NC1=CC=CC=N1 NBEZMNLZGBWWOQ-UHFFFAOYSA-N 0.000 description 2
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- RDFYLERWPFZYGS-UHFFFAOYSA-N methyl 3-bromo-8-cyano-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC=C2C(O)=C(Br)C(C(=O)OC)=NC2=C1C#N RDFYLERWPFZYGS-UHFFFAOYSA-N 0.000 description 2
- HEKMKVYZFILUGN-UHFFFAOYSA-N methyl 3-bromo-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC=C2C(O)=C(Br)C(C(=O)OC)=NC2=C1O HEKMKVYZFILUGN-UHFFFAOYSA-N 0.000 description 2
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- ZURZSIJPXZXQSS-UHFFFAOYSA-N methyl 4-(5-hydroxypentyl)-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(CCCCCO)=C2C=CC=C1OCC1=CC=CC=C1 ZURZSIJPXZXQSS-UHFFFAOYSA-N 0.000 description 2
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- CGZHRYQBVQDECP-UHFFFAOYSA-N methyl 4-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(CCCNC(=O)OC(C)(C)C)=C2C=CC=C1OCC1=CC=CC=C1 CGZHRYQBVQDECP-UHFFFAOYSA-N 0.000 description 2
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- JURXJGNXGKISIM-UHFFFAOYSA-N methyl 4-oxo-5-phenyl-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C(C=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 JURXJGNXGKISIM-UHFFFAOYSA-N 0.000 description 2
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- VYVHYYZPQXMWLW-UHFFFAOYSA-N methyl 5-bromo-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound BrC1=CC=C(O)C2=NC(C(=O)OC)=CC(O)=C21 VYVHYYZPQXMWLW-UHFFFAOYSA-N 0.000 description 2
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- UTWGEGLHXDVNFW-UHFFFAOYSA-N methyl 6-amino-8-nitro-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(N)C=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 UTWGEGLHXDVNFW-UHFFFAOYSA-N 0.000 description 2
- SOFZVRWCLWKOCY-UHFFFAOYSA-N methyl 6-bromo-8-cyano-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(Br)C=C(C#N)C2=NC(C(=O)OC)=CC(O)=C21 SOFZVRWCLWKOCY-UHFFFAOYSA-N 0.000 description 2
- DQVRNICOGWQCJN-UHFFFAOYSA-N methyl 6-hept-1-ynyl-8-methoxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound N1=C(C(=O)OC)C=C(O)C2=CC(C#CCCCCC)=CC(OC)=C21 DQVRNICOGWQCJN-UHFFFAOYSA-N 0.000 description 2
- SNHMVLJXVBGXCA-UHFFFAOYSA-N methyl 8-(2-phenylethynyl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(C#CC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 SNHMVLJXVBGXCA-UHFFFAOYSA-N 0.000 description 2
- QIIUCDVYBNJUOD-UHFFFAOYSA-N methyl 8-(benzylamino)-4-oxo-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=CC=C1NCC1=CC=CC=C1 QIIUCDVYBNJUOD-UHFFFAOYSA-N 0.000 description 2
- SDLXITZJIJWTBE-UHFFFAOYSA-N methyl 8-amino-4-(2-phenylethyl)quinoline-2-carboxylate Chemical compound C=12C=CC=C(N)C2=NC(C(=O)OC)=CC=1CCC1=CC=CC=C1 SDLXITZJIJWTBE-UHFFFAOYSA-N 0.000 description 2
- PXWHAXHLKMUQOM-UHFFFAOYSA-N methyl 8-amino-4-hexylquinoline-2-carboxylate Chemical compound C1=CC=C2C(CCCCCC)=CC(C(=O)OC)=NC2=C1N PXWHAXHLKMUQOM-UHFFFAOYSA-N 0.000 description 2
- BLVOARXJHATAGB-UHFFFAOYSA-N methyl 8-amino-4-oxo-5-phenyl-1h-quinoline-2-carboxylate Chemical compound C=1C=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=1C1=CC=CC=C1 BLVOARXJHATAGB-UHFFFAOYSA-N 0.000 description 2
- UNVUPAVFVGLARJ-UHFFFAOYSA-N methyl 8-amino-4-oxo-5-piperazin-1-yl-1h-quinoline-2-carboxylate Chemical compound C=1C=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=1N1CCNCC1 UNVUPAVFVGLARJ-UHFFFAOYSA-N 0.000 description 2
- CMQWUFVUYYSKOH-UHFFFAOYSA-N methyl 8-amino-4-oxo-6-piperazin-1-yl-1h-quinoline-2-carboxylate Chemical compound C1=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=C1N1CCNCC1 CMQWUFVUYYSKOH-UHFFFAOYSA-N 0.000 description 2
- LSORWGJSDMIECP-UHFFFAOYSA-N methyl 8-amino-4-phenylquinoline-2-carboxylate Chemical compound C=12C=CC=C(N)C2=NC(C(=O)OC)=CC=1C1=CC=CC=C1 LSORWGJSDMIECP-UHFFFAOYSA-N 0.000 description 2
- PQSSKCRVBFVLGI-UHFFFAOYSA-N methyl 8-amino-6-bromo-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(Br)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 PQSSKCRVBFVLGI-UHFFFAOYSA-N 0.000 description 2
- VFAJOJQXCJWQSL-UHFFFAOYSA-N methyl 8-amino-6-methyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 VFAJOJQXCJWQSL-UHFFFAOYSA-N 0.000 description 2
- GAIJUJKCHWQVOF-UHFFFAOYSA-N methyl 8-bromo-4-oxo-6-propan-2-yl-1h-quinoline-2-carboxylate Chemical compound C1=C(C(C)C)C=C(Br)C2=NC(C(=O)OC)=CC(O)=C21 GAIJUJKCHWQVOF-UHFFFAOYSA-N 0.000 description 2
- UWUBBAPAMGSTNU-UHFFFAOYSA-N methyl 8-cyano-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC=C(C#N)C2=NC(C(=O)OC)=CC(O)=C21 UWUBBAPAMGSTNU-UHFFFAOYSA-N 0.000 description 2
- WRKYVKPOZZNLEB-UHFFFAOYSA-N methyl 8-cyano-4-oxo-6-(2-phenylethyl)-1h-quinoline-2-carboxylate Chemical compound C1=C(C#N)C2=NC(C(=O)OC)=CC(O)=C2C=C1CCC1=CC=CC=C1 WRKYVKPOZZNLEB-UHFFFAOYSA-N 0.000 description 2
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- PZJSZBJLOWMDRG-UHFFFAOYSA-N furan-2-ylboronic acid Chemical compound OB(O)C1=CC=CO1 PZJSZBJLOWMDRG-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
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- 201000004792 malaria Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- KELUQLSSIBQKFZ-UHFFFAOYSA-N methyl 3-bromo-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC=C2C(O)=C(Br)C(C(=O)OC)=NC2=C1 KELUQLSSIBQKFZ-UHFFFAOYSA-N 0.000 description 1
- LAKFEOUDEQFBGC-UHFFFAOYSA-N methyl 4-(3-amino-4-oxopent-1-ynyl)-8-nitroquinoline-2-carboxylate Chemical compound C1=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(C#CC(N)C(C)=O)=C21 LAKFEOUDEQFBGC-UHFFFAOYSA-N 0.000 description 1
- URXKBZBOACPSAE-UHFFFAOYSA-N methyl 4-(3-aminopropyl)-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(CCCN)=C2C=CC=C1OCC1=CC=CC=C1 URXKBZBOACPSAE-UHFFFAOYSA-N 0.000 description 1
- POXHEAWQSIQXSD-UHFFFAOYSA-N methyl 4-(4-benzylpiperazin-1-yl)-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(OCC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1N(CC1)CCN1CC1=CC=CC=C1 POXHEAWQSIQXSD-UHFFFAOYSA-N 0.000 description 1
- OKCWEYSRYNPYOZ-UHFFFAOYSA-N methyl 4-(4-methylpiperazin-1-yl)-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(OCC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1N1CCN(C)CC1 OKCWEYSRYNPYOZ-UHFFFAOYSA-N 0.000 description 1
- DEFUEBWJDRIBBB-UHFFFAOYSA-N methyl 4-[(4-methylphenyl)sulfonylamino]-8-nitroquinoline-2-carboxylate Chemical compound C=12C=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1NS(=O)(=O)C1=CC=C(C)C=C1 DEFUEBWJDRIBBB-UHFFFAOYSA-N 0.000 description 1
- GQMUGANZVPHRNS-UHFFFAOYSA-N methyl 4-[3-[(2-methylpropan-2-yl)oxycarbonylamino]prop-1-ynyl]-8-nitroquinoline-2-carboxylate Chemical compound C1=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(C#CCNC(=O)OC(C)(C)C)=C21 GQMUGANZVPHRNS-UHFFFAOYSA-N 0.000 description 1
- FTUUQZNYKWISDP-UHFFFAOYSA-N methyl 4-chloro-8-nitroquinoline-2-carboxylate Chemical compound C1=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(Cl)=C21 FTUUQZNYKWISDP-UHFFFAOYSA-N 0.000 description 1
- JQOJFYSJUVHOSD-UHFFFAOYSA-N methyl 4-chloro-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(Cl)=C2C=CC=C1OCC1=CC=CC=C1 JQOJFYSJUVHOSD-UHFFFAOYSA-N 0.000 description 1
- UPFSESCFYROAMX-UHFFFAOYSA-N methyl 4-hex-1-ynyl-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C1=CC=C2C(C#CCCCC)=CC(C(=O)OC)=NC2=C1OCC1=CC=CC=C1 UPFSESCFYROAMX-UHFFFAOYSA-N 0.000 description 1
- GTPSRQCZRRVPSG-UHFFFAOYSA-N methyl 4-hexyl-8-phenylmethoxyquinoline-2-carboxylate Chemical compound C1=CC=C2C(CCCCCC)=CC(C(=O)OC)=NC2=C1OCC1=CC=CC=C1 GTPSRQCZRRVPSG-UHFFFAOYSA-N 0.000 description 1
- CYJWTHXBKHRICM-UHFFFAOYSA-N methyl 4-oxo-8-(2-phenylethyl)-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=CC=C1CCC1=CC=CC=C1 CYJWTHXBKHRICM-UHFFFAOYSA-N 0.000 description 1
- RYNOCOSGEBARAN-UHFFFAOYSA-N methyl 4-oxo-8-phenylmethoxy-5-(trifluoromethyl)-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C(C(F)(F)F)=CC=C1OCC1=CC=CC=C1 RYNOCOSGEBARAN-UHFFFAOYSA-N 0.000 description 1
- CQZCIFYITJPJSQ-UHFFFAOYSA-N methyl 4-oxo-8-piperazin-1-yl-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=CC=C1N1CCNCC1 CQZCIFYITJPJSQ-UHFFFAOYSA-N 0.000 description 1
- DQYQSCHIDGHDBL-UHFFFAOYSA-N methyl 4-phenylmethoxy-8-(pyridin-2-ylamino)quinoline-2-carboxylate Chemical compound C=12C=CC=C(NC=3N=CC=CC=3)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 DQYQSCHIDGHDBL-UHFFFAOYSA-N 0.000 description 1
- CHQCECQSPUCTHT-UHFFFAOYSA-N methyl 5,7-dichloro-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C(Cl)=CC(Cl)=C1OCC1=CC=CC=C1 CHQCECQSPUCTHT-UHFFFAOYSA-N 0.000 description 1
- QKHRLVXSHOLWCG-UHFFFAOYSA-N methyl 5,7-dichloro-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound ClC1=CC(Cl)=C(O)C2=NC(C(=O)OC)=CC(O)=C21 QKHRLVXSHOLWCG-UHFFFAOYSA-N 0.000 description 1
- VRYCAJMIVIIJQA-UHFFFAOYSA-N methyl 5-(1-hydroxyethyl)-8-methoxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound CC(O)C1=CC=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 VRYCAJMIVIIJQA-UHFFFAOYSA-N 0.000 description 1
- WPGLCHSTKOGYTH-UHFFFAOYSA-N methyl 5-(4-benzylpiperazin-1-yl)-8-nitro-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C(N3CCN(CC=4C=CC=CC=4)CC3)=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 WPGLCHSTKOGYTH-UHFFFAOYSA-N 0.000 description 1
- CXXUETHBRHVVSN-UHFFFAOYSA-N methyl 5-bromo-8-nitro-4-oxo-1h-quinoline-2-carboxylate Chemical compound BrC1=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(O)=C21 CXXUETHBRHVVSN-UHFFFAOYSA-N 0.000 description 1
- RGMZTJFLQXIXAH-UHFFFAOYSA-N methyl 5-methyl-8-nitro-4-oxo-1h-quinoline-2-carboxylate Chemical compound CC1=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(O)=C21 RGMZTJFLQXIXAH-UHFFFAOYSA-N 0.000 description 1
- UVIWIFBYSMPJHI-UHFFFAOYSA-N methyl 6-(3,4-dichlorophenyl)-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=C(C=2C=C(Cl)C(Cl)=CC=2)C=C1OCC1=CC=CC=C1 UVIWIFBYSMPJHI-UHFFFAOYSA-N 0.000 description 1
- DMZPDLSPWOIOIO-UHFFFAOYSA-N methyl 6-(4-chlorophenyl)-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=C(C=2C=CC(Cl)=CC=2)C=C1OCC1=CC=CC=C1 DMZPDLSPWOIOIO-UHFFFAOYSA-N 0.000 description 1
- OBAQDADDOCEMDQ-UHFFFAOYSA-N methyl 6-(4-chlorophenyl)-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(O)C2=NC(C(=O)OC)=CC(O)=C2C=C1C1=CC=C(Cl)C=C1 OBAQDADDOCEMDQ-UHFFFAOYSA-N 0.000 description 1
- GXLZWTXRMVRSQB-UHFFFAOYSA-N methyl 6-(5-cyanopent-1-ynyl)-8-nitro-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(C#CCCCC#N)C=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 GXLZWTXRMVRSQB-UHFFFAOYSA-N 0.000 description 1
- GNQAKHSBFXJHOU-UHFFFAOYSA-N methyl 6-[3-[(2-methylpropan-2-yl)oxycarbonylamino]prop-1-ynyl]-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=C(C#CCNC(=O)OC(C)(C)C)C=C1OCC1=CC=CC=C1 GNQAKHSBFXJHOU-UHFFFAOYSA-N 0.000 description 1
- JJINVNOTYVHRCY-UHFFFAOYSA-N methyl 6-bromo-8-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(Br)C=C(O)C2=NC(C(=O)OC)=CC(O)=C21 JJINVNOTYVHRCY-UHFFFAOYSA-N 0.000 description 1
- XXCWLNFBJZCYJU-UHFFFAOYSA-N methyl 6-cyano-8-nitro-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C#N)C=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(O)=C21 XXCWLNFBJZCYJU-UHFFFAOYSA-N 0.000 description 1
- DBVZPJAWBQZNNL-UHFFFAOYSA-N methyl 6-cyano-8-nitro-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(C#N)C=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 DBVZPJAWBQZNNL-UHFFFAOYSA-N 0.000 description 1
- GVPRAOXCXLPZAQ-UHFFFAOYSA-N methyl 6-formyl-8-methoxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C=O)C=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 GVPRAOXCXLPZAQ-UHFFFAOYSA-N 0.000 description 1
- YFLULJRJFLUXCB-UHFFFAOYSA-N methyl 6-heptyl-8-methoxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound N1=C(C(=O)OC)C=C(O)C2=CC(CCCCCCC)=CC(OC)=C21 YFLULJRJFLUXCB-UHFFFAOYSA-N 0.000 description 1
- LCPFTRDLTVCSGG-UHFFFAOYSA-N methyl 6-iodo-8-methoxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(I)C=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 LCPFTRDLTVCSGG-UHFFFAOYSA-N 0.000 description 1
- RWBQJQIXHYLDET-UHFFFAOYSA-N methyl 7-[3-[(2-methylpropan-2-yl)oxycarbonylamino]prop-1-ynyl]-4-oxo-8-phenylmethoxy-1h-quinoline-2-carboxylate Chemical compound C12=NC(C(=O)OC)=CC(O)=C2C=CC(C#CCNC(=O)OC(C)(C)C)=C1OCC1=CC=CC=C1 RWBQJQIXHYLDET-UHFFFAOYSA-N 0.000 description 1
- LZTIFNABSMHUPG-UHFFFAOYSA-N methyl 7-acetamido-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC(NC(C)=O)=CC2=NC(C(=O)OC)=CC(O)=C21 LZTIFNABSMHUPG-UHFFFAOYSA-N 0.000 description 1
- QAOKWUQHDRNJFX-UHFFFAOYSA-N methyl 8-(4-benzylpiperazin-1-yl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(N3CCN(CC=4C=CC=CC=4)CC3)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 QAOKWUQHDRNJFX-UHFFFAOYSA-N 0.000 description 1
- AXOWGKLVUSQECM-UHFFFAOYSA-N methyl 8-(4-methylpiperazin-1-yl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(N3CCN(C)CC3)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 AXOWGKLVUSQECM-UHFFFAOYSA-N 0.000 description 1
- TXMGMCGNFORJNK-UHFFFAOYSA-N methyl 8-(dimethylamino)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=CC=C(N(C)C)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 TXMGMCGNFORJNK-UHFFFAOYSA-N 0.000 description 1
- KQDIYFBXYYIGAY-UHFFFAOYSA-N methyl 8-amino-4-(2-phenylethynyl)quinoline-2-carboxylate Chemical compound C=12C=CC=C(N)C2=NC(C(=O)OC)=CC=1C#CC1=CC=CC=C1 KQDIYFBXYYIGAY-UHFFFAOYSA-N 0.000 description 1
- YOTXNBRRJPTKFJ-UHFFFAOYSA-N methyl 8-amino-4-(3-amino-4-oxopent-1-ynyl)quinoline-2-carboxylate Chemical compound C1=CC=C(N)C2=NC(C(=O)OC)=CC(C#CC(N)C(C)=O)=C21 YOTXNBRRJPTKFJ-UHFFFAOYSA-N 0.000 description 1
- DRSWGZDUEBUEOD-UHFFFAOYSA-N methyl 8-amino-4-hex-1-ynylquinoline-2-carboxylate Chemical compound C1=CC=C2C(C#CCCCC)=CC(C(=O)OC)=NC2=C1N DRSWGZDUEBUEOD-UHFFFAOYSA-N 0.000 description 1
- FWKRHMXJSGEQBX-UHFFFAOYSA-N methyl 8-amino-4-oxo-5-piperidin-1-yl-1h-quinoline-2-carboxylate Chemical compound C=1C=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=1N1CCCCC1 FWKRHMXJSGEQBX-UHFFFAOYSA-N 0.000 description 1
- RRNCLKRARYEHEI-UHFFFAOYSA-N methyl 8-amino-4-oxo-6-(2-phenylethyl)-1h-quinoline-2-carboxylate Chemical compound C1=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=C1CCC1=CC=CC=C1 RRNCLKRARYEHEI-UHFFFAOYSA-N 0.000 description 1
- PJXCVNMZKVIBEU-UHFFFAOYSA-N methyl 8-amino-4-piperidin-1-ylquinoline-2-carboxylate Chemical compound C=12C=CC=C(N)C2=NC(C(=O)OC)=CC=1N1CCCCC1 PJXCVNMZKVIBEU-UHFFFAOYSA-N 0.000 description 1
- WTBLNSQPAOWZSM-UHFFFAOYSA-N methyl 8-amino-5-(3-aminopropyl)-4-oxo-1h-quinoline-2-carboxylate;hydrochloride Chemical compound Cl.NCCCC1=CC=C(N)C2=NC(C(=O)OC)=CC(O)=C21 WTBLNSQPAOWZSM-UHFFFAOYSA-N 0.000 description 1
- WBQCGAHTLIPFKX-UHFFFAOYSA-N methyl 8-amino-5-methyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound CC1=CC=C(N)C2=NC(C(=O)OC)=CC(O)=C21 WBQCGAHTLIPFKX-UHFFFAOYSA-N 0.000 description 1
- GZLQRWBNJIKKJA-UHFFFAOYSA-N methyl 8-amino-6-anilino-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(N)C2=NC(C(=O)OC)=CC(O)=C2C=C1NC1=CC=CC=C1 GZLQRWBNJIKKJA-UHFFFAOYSA-N 0.000 description 1
- UTYVKGDCIULZDL-UHFFFAOYSA-N methyl 8-amino-6-chloro-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(Cl)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 UTYVKGDCIULZDL-UHFFFAOYSA-N 0.000 description 1
- UOPIURSHKNVSJL-UHFFFAOYSA-N methyl 8-amino-6-cyano-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C#N)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 UOPIURSHKNVSJL-UHFFFAOYSA-N 0.000 description 1
- YFWAAOHGSQLDGA-UHFFFAOYSA-N methyl 8-amino-6-hydroxy-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(O)C=C(N)C2=NC(C(=O)OC)=CC(O)=C21 YFWAAOHGSQLDGA-UHFFFAOYSA-N 0.000 description 1
- KQIXPXKMYZPQQN-UHFFFAOYSA-N methyl 8-cyano-6-(2-phenylethynyl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(C#CC=3C=CC=CC=3)C=C(C#N)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 KQIXPXKMYZPQQN-UHFFFAOYSA-N 0.000 description 1
- TZTFGXQCVXLPGK-UHFFFAOYSA-N methyl 8-cyano-6-ethynyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C#C)C=C(C#N)C2=NC(C(=O)OC)=CC(O)=C21 TZTFGXQCVXLPGK-UHFFFAOYSA-N 0.000 description 1
- KJMRGQBWCOZKAF-UHFFFAOYSA-N methyl 8-hydroxy-4-(4-methylpiperazin-1-yl)quinoline-2-carboxylate Chemical compound C=12C=CC=C(O)C2=NC(C(=O)OC)=CC=1N1CCN(C)CC1 KJMRGQBWCOZKAF-UHFFFAOYSA-N 0.000 description 1
- FSEFCBCEULEUEN-UHFFFAOYSA-N methyl 8-hydroxy-4-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]quinoline-2-carboxylate Chemical compound C1=CC=C(O)C2=NC(C(=O)OC)=CC(CCCNC(=O)OC(C)(C)C)=C21 FSEFCBCEULEUEN-UHFFFAOYSA-N 0.000 description 1
- JGBOSEIYPPRSJI-UHFFFAOYSA-N methyl 8-hydroxy-4-oxo-5-phenyl-1h-quinoline-2-carboxylate Chemical compound C=1C=C(O)C2=NC(C(=O)OC)=CC(O)=C2C=1C1=CC=CC=C1 JGBOSEIYPPRSJI-UHFFFAOYSA-N 0.000 description 1
- SMRYHANNHHPETB-UHFFFAOYSA-N methyl 8-hydroxy-4-piperazin-1-ylquinoline-2-carboxylate Chemical compound C=12C=CC=C(O)C2=NC(C(=O)OC)=CC=1N1CCNCC1 SMRYHANNHHPETB-UHFFFAOYSA-N 0.000 description 1
- HIRZXFNBCKJFLR-UHFFFAOYSA-N methyl 8-hydroxy-5-(hydroxymethyl)-4-oxo-1h-quinoline-2-carboxylate Chemical compound OCC1=CC=C(O)C2=NC(C(=O)OC)=CC(O)=C21 HIRZXFNBCKJFLR-UHFFFAOYSA-N 0.000 description 1
- LPPLRSHPSRMUJJ-UHFFFAOYSA-N methyl 8-hydroxy-6-(4-methoxyphenyl)-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(O)C2=NC(C(=O)OC)=CC(O)=C2C=C1C1=CC=C(OC)C=C1 LPPLRSHPSRMUJJ-UHFFFAOYSA-N 0.000 description 1
- YNWHILNTOCJDPN-UHFFFAOYSA-N methyl 8-hydroxy-7-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=CC(CCCNC(=O)OC(C)(C)C)=C(O)C2=NC(C(=O)OC)=CC(O)=C21 YNWHILNTOCJDPN-UHFFFAOYSA-N 0.000 description 1
- JPTAIIVDQFZPOM-UHFFFAOYSA-N methyl 8-methoxy-3-methylquinoline-2-carboxylate Chemical compound C1=CC=C2C=C(C)C(C(=O)OC)=NC2=C1OC JPTAIIVDQFZPOM-UHFFFAOYSA-N 0.000 description 1
- VVJGNJKTMUCQMW-UHFFFAOYSA-N methyl 8-methoxy-4-oxo-6-prop-1-enyl-1h-quinoline-2-carboxylate Chemical compound C1=C(C=CC)C=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 VVJGNJKTMUCQMW-UHFFFAOYSA-N 0.000 description 1
- RCKNRCXYWSNRCT-UHFFFAOYSA-N methyl 8-methoxy-5-methyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound CC1=CC=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 RCKNRCXYWSNRCT-UHFFFAOYSA-N 0.000 description 1
- GGJXRUAVOXFFAQ-UHFFFAOYSA-N methyl 8-methoxy-5-phenylquinoline-2-carboxylate Chemical compound C=1C=C(OC)C2=NC(C(=O)OC)=CC=C2C=1C1=CC=CC=C1 GGJXRUAVOXFFAQ-UHFFFAOYSA-N 0.000 description 1
- DWEGQIVEWYAJHC-UHFFFAOYSA-N methyl 8-methoxy-6-methyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound C1=C(C)C=C(OC)C2=NC(C(=O)OC)=CC(O)=C21 DWEGQIVEWYAJHC-UHFFFAOYSA-N 0.000 description 1
- YNRMQTUOOLBRHW-UHFFFAOYSA-N methyl 8-methoxyquinoline-2-carboxylate Chemical compound C1=CC=C(OC)C2=NC(C(=O)OC)=CC=C21 YNRMQTUOOLBRHW-UHFFFAOYSA-N 0.000 description 1
- UBQUZXQNJHTUFG-UHFFFAOYSA-N methyl 8-nitro-4-(3-phenylmethoxyprop-1-ynyl)quinoline-2-carboxylate Chemical compound C=12C=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1C#CCOCC1=CC=CC=C1 UBQUZXQNJHTUFG-UHFFFAOYSA-N 0.000 description 1
- BXYAIZVYJLCQSD-UHFFFAOYSA-N methyl 8-nitro-4-oxo-3-(2-phenylethynyl)-1h-quinoline-2-carboxylate Chemical compound COC(=O)C1=NC2=C([N+]([O-])=O)C=CC=C2C(O)=C1C#CC1=CC=CC=C1 BXYAIZVYJLCQSD-UHFFFAOYSA-N 0.000 description 1
- DHAYHSBOGCGJDE-UHFFFAOYSA-N methyl 8-nitro-4-oxo-3-(2-trimethylsilylethynyl)-1h-quinoline-2-carboxylate Chemical compound C1=CC=C2C(O)=C(C#C[Si](C)(C)C)C(C(=O)OC)=NC2=C1[N+]([O-])=O DHAYHSBOGCGJDE-UHFFFAOYSA-N 0.000 description 1
- HNUKEZYKKQYPAE-UHFFFAOYSA-N methyl 8-nitro-4-oxo-6-phenyl-1h-quinoline-2-carboxylate Chemical compound C1=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC(O)=C2C=C1C1=CC=CC=C1 HNUKEZYKKQYPAE-UHFFFAOYSA-N 0.000 description 1
- SFFKPRMRJQQFFS-UHFFFAOYSA-N methyl 8-nitro-4-piperidin-1-ylquinoline-2-carboxylate Chemical compound C=12C=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1N1CCCCC1 SFFKPRMRJQQFFS-UHFFFAOYSA-N 0.000 description 1
- ATUITBIURDFKFZ-UHFFFAOYSA-N methyl 8-nitro-5-(2-phenylethynyl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C(C#CC=3C=CC=CC=3)=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 ATUITBIURDFKFZ-UHFFFAOYSA-N 0.000 description 1
- YASQEXWASXWTBY-UHFFFAOYSA-N methyl 8-nitro-5-phenyl-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C(C=3C=CC=CC=3)=CC=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 YASQEXWASXWTBY-UHFFFAOYSA-N 0.000 description 1
- FFLDOHPZGVXJID-UHFFFAOYSA-N methyl 8-nitro-6-(2-phenylethynyl)-4-phenylmethoxyquinoline-2-carboxylate Chemical compound C=12C=C(C#CC=3C=CC=CC=3)C=C([N+]([O-])=O)C2=NC(C(=O)OC)=CC=1OCC1=CC=CC=C1 FFLDOHPZGVXJID-UHFFFAOYSA-N 0.000 description 1
- YIMGAXLOALRTGB-UHFFFAOYSA-N methyl 8-phenylmethoxy-4-(2-piperazin-1-ylpyrimidin-4-yl)quinoline-2-carboxylate Chemical compound C=12C=CC=C(OCC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1C(N=1)=CC=NC=1N1CCNCC1 YIMGAXLOALRTGB-UHFFFAOYSA-N 0.000 description 1
- PXTHRAUZDGXWNI-UHFFFAOYSA-N methyl 8-phenylmethoxy-4-(3-phenylmethoxyprop-1-ynyl)quinoline-2-carboxylate Chemical compound C=12C=CC=C(OCC=3C=CC=CC=3)C2=NC(C(=O)OC)=CC=1C#CCOCC1=CC=CC=C1 PXTHRAUZDGXWNI-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000001690 micro-dialysis Methods 0.000 description 1
- UVEWQKMPXAHFST-UHFFFAOYSA-N n,1-diphenylmethanimine Chemical compound C=1C=CC=CC=1C=NC1=CC=CC=C1 UVEWQKMPXAHFST-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- GGOQYHOZFCWTNM-UHFFFAOYSA-N n-prop-2-ynylacetamide Chemical compound CC(=O)NCC#C GGOQYHOZFCWTNM-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- WXWCDTXEKCVRRO-UHFFFAOYSA-N para-Cresidine Chemical compound COC1=CC=C(C)C=C1N WXWCDTXEKCVRRO-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- FFUQCRZBKUBHQT-UHFFFAOYSA-N phosphoryl fluoride Chemical compound FP(F)(F)=O FFUQCRZBKUBHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 238000001485 positron annihilation lifetime spectroscopy Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- MKIGYFVFEVEKJW-UHFFFAOYSA-M sodium 8-hydroxy-4-piperazin-1-ylquinoline-2-carboxylate Chemical compound [Na+].C1=C(C([O-])=O)N=C2C(O)=CC=CC2=C1N1CCNCC1 MKIGYFVFEVEKJW-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- ZLYQLJAOAXWIQQ-UHFFFAOYSA-M sodium;4-hexyl-8-hydroxyquinoline-2-carboxylate Chemical compound [Na+].C1=CC=C2C(CCCCCC)=CC(C([O-])=O)=NC2=C1O ZLYQLJAOAXWIQQ-UHFFFAOYSA-M 0.000 description 1
- VHMYURDEMHAAFO-UHFFFAOYSA-M sodium;8-hexyl-4-oxo-1h-quinoline-2-carboxylate Chemical compound [Na+].C1=C(C([O-])=O)N=C2C(CCCCCC)=CC=CC2=C1O VHMYURDEMHAAFO-UHFFFAOYSA-M 0.000 description 1
- VMESNKILOOHXOA-UHFFFAOYSA-M sodium;8-hydroxy-4-oxo-3-phenyl-1h-quinoline-2-carboxylate Chemical compound [Na+].[O-]C(=O)C=1N=C2C(O)=CC=CC2=C(O)C=1C1=CC=CC=C1 VMESNKILOOHXOA-UHFFFAOYSA-M 0.000 description 1
- KASYCCOFFRMRBF-UHFFFAOYSA-M sodium;8-hydroxy-4-oxo-7-phenyl-1h-quinoline-2-carboxylate Chemical compound [Na+].C=1C=C2C(O)=CC(C([O-])=O)=NC2=C(O)C=1C1=CC=CC=C1 KASYCCOFFRMRBF-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- WRSWIWOVJBYZAW-UHFFFAOYSA-M zinc;methanidylbenzene;bromide Chemical compound Br[Zn+].[CH2-]C1=CC=CC=C1 WRSWIWOVJBYZAW-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the present invention relates to compounds derived from quinoline and quinoxaline, their preparation and their uses, in particular in the therapeutic, vaccine field or for the development of active compounds.
- the present invention relates in particular to the use of the compounds of general formula (I):
- the present invention follows from the demonstration of particularly advantageous biological and therapeutic properties of compounds of formula (I).
- the present invention arises in particular from the demonstration that compounds modulating the activity of xanthurenic acid can be used for the treatment of disorders of the nervous system, in particular central.
- the invention derives more particularly from the synthesis, development and characterization of compounds modulating the activity of xanthurenic acid, which can be used for the modulation of neurotransmission, in particular dopaminergic.
- Such compounds can be used in particular for the treatment of pathologies of the central nervous system such as mental, neurological or traumatic disorders.
- the compounds are particularly intended for the treatment of anxiety, depression, bipolar depression, ADH syndrome, fibromyalgia, memory disorders or social interactions, such as sedative or hypnotic, sleep or sleep disorders.
- treatment designates preventive, curative, palliative treatment, as well as the management of patients (reduction of suffering, improvement of lifespan, improvement of quality of life, slower progression of the disease), etc.
- treatment can also be carried out in combination with other agents or treatments, in particular addressing the late events of the pathology or other active ingredients.
- the invention therefore resides in the use of compounds of general formula (I) as described above for the preparation of a pharmaceutical composition intended for the treatment of pathologies of the nervous system.
- - E is a COOH, COOR CH 2 OH, CHO, CH 2 COOH, CH 2 COOR ⁇ radical or a group chosen from the following:
- Ri represents (i) a (C 1 -C 12 ) alkyl radical or (ii) a (C 6 -C 18 ) aryl (C 1 - C ⁇ 2 ) alkyl radical;
- R 2 represents (i) a hydrogen atom, (ii) an (C ⁇ -C ⁇ 2 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ ) radical 8 ) aryl (C 1 -C ⁇ 2 ) alkyl, (v) a hydroxyl radical;
- R 3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl radical, (iv) a (C ⁇ -C ⁇ 2 ) alkyl radical, (v) a (C 6 ) radical -C ⁇ 8 ) aryl, (vi) a radical (C 6 -C ⁇ 8 ) aryl (C 1 -C ⁇ 2 ) alkyl or (vii) a radical (C 3 -C 17 ) heteroaryl;
- - Z is (i) a nitrogen atom or (ii) a radical CRj;
- - R 4 represents (a) a hydrogen atom, (b) a radical (-C 12 ) alkyl, (c) a radical (C 2 -C ⁇ 2 ) alkyn-1-yl, (d) a radical (C 6 -C ⁇ 8 ) aryl, (e) a radical (C 6 - C 18 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (f) a radical OR 8 , (g) a radical NR 9 R 9 ' , (h) a heteroaryl (Cl -Cl 7) radical or (i) a (C 2 -C ⁇ 2 ) alken-1-yl radical;
- R 5 , R and R 7 independently of one another represent (i) a hydrogen atom, (ii) a halogen atom, (iii) an (-C 12 ) alkyl radical, (iv) an aryl (C 6 -C ⁇ 8 ) radical, (v) an (C 6 -C ⁇ 8 ) aryl (C r C 12 ) alkyl radical, (vi) an NR 9 R 9 ' radical, (vii) a COR 10 radical , (viii) a radical (C 2 -C ⁇ 2 ) alken-1-yl, (ix) a radical (C 2 -C ⁇ 2 ) alkyn-1-yl, (x) a radical (CpC ⁇ ) heteroaryl, (xi) a (C 3 -C ⁇ 7 ) heteroaryl (C ⁇ -C ⁇ 2 ) alkyl radical, (xii) a cyano radical or (xiii) a nitro radical;
- R 8 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl (C 1 -C 12 ) alkyl radical;
- R 9 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 - C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (v) an acyl radical, (vi) a tert-butyloxycarbonyl radical, (vii) a (-C ⁇ ) heteroaryl radical or (viii) a (C 6 -C ⁇ 8 ) radical ) arylsulfonyl or (C C ⁇ 2 ) alkylsulfonyl;
- R 9 which may be the same or different from R 9 represents (i) a hydrogen atom, (ii) a (C ⁇ -C 12 ) alkyl radical, (iii) an (C 6 -C ⁇ 8 ) aryl radical, (iv) an (C 6 -C 18 ) aryl (C ⁇ -C 12 ) alkyl radical, (v) an acyl radical, (vi) a tert-butyloxycarbonyl radical, (vii) a heteroaryl (C ⁇ -C ⁇ 7 ) radical or (viii) a (C 6 - C ⁇ 8 ) arylsulfonyl or (C ⁇ -C 12 ) alkylsulfonyl radical;
- R 9 ' can also represent a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NR ⁇ radical or an oxygen or sulfur atom
- - Rio represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical or (iii) a (C 6 -C ⁇ 8 ) aryl radical or (iv) an NHR 2 radical;
- R ⁇ represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C) radical 18 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (v) a heteroaryl (Ci-C ⁇ ) radical, (vi) a (C ⁇ -C ⁇ 7 ) heteroaryl (C ⁇ -C ⁇ 2 ) alkyl or (vii) a COR 10 radical ;
- - X is (i) a halogen atom, (ii) an OR 8 radical, (iii) an NR 9 R 9 radical> (iv) an (C 6 -C ⁇ 8 ) aryl radical, (v) a radical ( C 6 -C 18 ) aryl (C C ⁇ 2 ) alkyl, (vi) (C 3 -C 12 ) alkyl, (vii) a radical (C 2 -C ⁇ 2 ) alken-l-yl, (viii) a radical ( C 2 -C ⁇ 2 ) alkyn-l-yl (ix) a (C 1 -C 17 ) heteroaryl radical, (x) a COR 10 radical, (xi) a cyano radical or (xii) a nitro radical.
- the compounds of formula (I) which contain one or more asymmetric carbon atoms can be present in their racemic, enantiomeric and diastereoisomeric forms. These forms are also part of the invention.
- the invention also resides in the use of compounds of general formula (I) as described above for the preparation of a pharmaceutical composition intended for modulating the activity of xanthurenic acid.
- the invention also resides in the use of compounds of general formula (I) as described above for the preparation of a pharmaceutical composition intended for the modulation of dopaminergic neurotransmission.
- the compounds of the invention have the capacity to antagonize the binding of XA to its receptor, or, on the contrary, to mimic this binding (agonist).
- certain compounds of the invention constitute allosteric modulators of XA, that is to say are capable of improving the binding of XA to its receptors.
- the invention also relates to pharmaceutical compositions, compounds of formula (I) and methods of treatment using them.
- Xanthurenic acid is preferably excluded from the present invention. It is preferred to use xanthurenic acid derivatives and in particular compounds of formula (I) in which at least one of the groups R 3 , R 5 , R ⁇ and R 7 is different from the hydrogen atom and advantageously with X represents a hydroxyl radical and Z represents COH.
- alken-1-yl radicals are preferably straight or branched chain hydrocarbon radicals having 2 to 12 carbon atoms and comprising a double bond in position -1. They preferably contain from 2 to 6 carbon atoms. These radicals are unsubstituted or may be substituted by one or more substituents, identical or different, preferably chosen from the radicals OR 8 , aryl, NR 9 R 9 >, R 8 , R 9 and R 9 > having the same meanings as above.
- alkyn-1-yl radicals are straight or branched chain hydrocarbon radicals having 2 to 12 carbon atoms and comprising a triple bond in position 1. They preferably contain from 2 to 6 carbon atoms. These radicals are unsubstituted or may be substituted by one or more substituents, identical or different, preferably chosen from the radicals OR 8 , aryl, NR 9 R 9 >, R 8 , R 9 and R 9 > having the same meanings as above.
- alkyl radicals denote straight or branched chain hydrocarbon radicals having from 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, n- decyle, n-dodecyle etc.
- C1-C4 radicals are preferred.
- alkyl radicals are unsubstituted or may be substituted by one or more identical or different substituents preferably chosen from the aryl, OR, -NR 9 R 9 ' , CONHR 2 radicals ; R 8 , R 9 and R 9 ' having the same meanings as above.
- ⁇ represents a substituted alkyl radical
- the substituents are preferably chosen from the aryl radicals, OR 8 , -NR 9 R 9 ' , CONHR 2, R 9 and R 9 > having the same meanings as above and R 8 represents (ii) a (C 1 -C 12 ) alkyl radical or (iii) a (C 6 -C ⁇ 8 ) aryl (C ⁇ -C 12 ) alkyl radical.
- alkoxy radicals correspond to the alkyl radicals defined above, linked to the rest of the molecule via an -O- (ether) bond. Particularly preferred are methoxy or benzyloxy radicals.
- aryl radicals are mono-, bi- or tri-cyclic aromatic hydrocarbon systems, preferably mono- or bi-cyclic aromatic hydrocarbon systems having from 6 to 18 carbon atoms, even more preferably 6 carbon atoms. Mention may be made, for example, of the phenyl, naphthyl and bi-phenyl radicals.
- the aryl radicals can be optionally substituted by one or more, identical or different, substituents preferably chosen from halogen atoms and (C 1 - 2 ) alkyl and (C ⁇ -C 1 ) alkoxy radicals, a cyano group, a CONHR 2 or NR 9 R 9 ' radical.
- acyl radicals correspond to the alkyl or aryl radicals defined above, linked to the rest of the molecule via a —CO- (carbonyl) bond.
- the acyl radicals are -CO ⁇ CpC ⁇ ) alkyl or -CO- (C 6 -C ⁇ 8 ) aryl radicals. Mention may be made, for example, of the acetyl and benzoyl radicals.
- the “arylsulfonyl” and “alkylsulfonyl” radicals are aryl or aryl radicals linked to the rest of the molecule via an SO 2 bond. Among these radicals, there may be mentioned for example the p-tolylsulfonyl radical.
- heteroaryl radicals denote aryl radicals of which 1 to 4 carbon atoms are replaced by heteroatoms chosen from N, O, S and comprising 1 to 17 carbon atoms and in particular from 1 to 10 carbon atoms.
- heteroatoms chosen from N, O, S and comprising 1 to 17 carbon atoms and in particular from 1 to 10 carbon atoms.
- arylalkyl denotes an alkyl radical substituted by an aryl radical.
- arylalkyl radicals mention may be made of benzyl, phenethyl and phenethylpropyl radicals.
- heteroarylalkyl denotes an alkyl radical substituted by a heteroaryl radical.
- heteroarylalkyl radicals mention may be made of 2-pyridinylethyl, 3-pyridinylethyl radicals.
- cycloheteroalkyl radicals therefore denote nitrogen rings of 4 to 7 carbon atoms containing a nitrogen atom and one carbon atom of which can be replaced by a heteroatom chosen from O, S, SO 2 or NRn. In the case where the heteroatom is NRn, it can be substituted or not.
- cycloheteroalkyl radicals that may be mentioned are the morpholino, thiomorpholino, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4- (2-pyrimidine) -piperazin radicals 1 -yle and 4-phenyl-piperazin-1 -yle.
- halogen is meant a fluorine, chlorine, bromine or iodine atom.
- X represents a halogen atom
- the bromine atom is preferred.
- - E is a COOH, COOR b CHO, CH 2 COOH, CH 2 COOR ⁇ radical or a group chosen from the following:
- - Ri represents a (C 1 -C 12 ) alkyl or (C 6 -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl radical; and or
- R 2 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 - C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl or (v) a hydroxyl radical; and or
- R 3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl, (iv) a (C 1 -C 12 ) alkyl radical, (vi) a (C 6 ) radical -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl; and or
- - Z is (i) a nitrogen atom or (ii) a CR 4 radical; and or
- R 4 represents (a) a hydrogen atom, (b) a (C 1 -C 12 ) alkyl radical, (c) a (C 2 -C ⁇ 2 ) alkyn-1-yl radical, (d) a radical (C 6 -C 18 ) aryl, (e) an OR 8 radical in which R 8 represents hydrogen, (f) a (Cl -Cl 7) heteroaryl radical or (g) a NR 9 R 9 ' radical in which R 9 represents hydrogen, acyl or (C 6 -C ⁇ 8 ) arylsulfonyl and R 9 > represents hydrogen, acyl or NRgR 9 > represents a cycloheteroalkyl radical of type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or an oxygen or sulfur atom, and / or
- R 5 , R ⁇ , R 7 independently of one another represent (i) a hydrogen atom, (ii) a halogen atom, (iii) an (C 1 -C 12 ) alkyl radical, (iv) an aryl (C 6 -C 18 ) radical, (v) an NR 9 R 9 > radical in which R 9 represents hydrogen, and R 9 > represents hydrogen, acyl or (C 6 -C ⁇ 8 ) arylsulfonyl or NR 9 R 9 > represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or an oxygen or sulfur atom, (vi) a CORio radical in which Rio represents hydrogen, (vii) a (C 2 -
- - X is (i) a halogen atom, (ii) an OR 8 radical in which R 8 is a hydrogen atom, a (C r C ⁇ 2 ) alkyl or (C 6 -C ⁇ 8 ) aryl (C 1 -C ⁇ 2 ) alkyl, (iii) a radical (C 6 -C 18 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (iv) a radical (C 6 -C ⁇ 8 ) aryl, (v) a radical (C 1 -C 17 ) heteroaryl, (vi) a radical NR 9 R 9 > in which R 9 is hydrogen, (C 6 - C ⁇ 8 ) aryl (C ⁇ -C 12 ) alkyl or acyl or (-C 12 ) alkylsulfonyl and (C 6 -C ⁇ 8 ) arylsulfonyl and R 9 ' represents hydrogen, acyl or (C 6 -C ⁇ 8
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom
- Rn represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ ) radical 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (v) a heteroaryl (Ci-C ⁇ ) radical, (vi) a (C ⁇ -C ⁇ 7 ) heteroaryl (C ⁇ -C ⁇ 2 ) alkyl or (vii) a CORio radical;
- R 1 is an unsubstituted alkyl or benzyl radical, preferably when E represents a COORi radical.
- E represents a CONHR radical 2 with 2 is a hydroxyl radical.
- R 3 is (i) a hydrogen atom, (ii) an (C 1 -C 12 ) alkyl radical unsubstituted or substituted by amino or alkylamino, or (iii) a (C 6 -C ⁇ 8 ) aryle.
- Z is (i) a nitrogen atom or (ii) a radical CR 4 in which R 4 represents (a) a hydrogen atom, (b) a radical (C 1 -C 12 ) alkyl unsubstituted or substituted by phenyl or NR 9 R 9 > with R 9 hydrogen or tert-butyloxycarbonyl and R 9 > hydrogen, or also by NR 9 R 9 > which represents a cycloheteroalkyl radical of type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom, (c) a radical (C 2 -C ⁇ 2 ) alkyn-1-yl unsubstituted or substituted by phenyl, hydroxyl, benzyloxy or NR 9 R 9 ' with R 9 represents tert-butyloxycarbonyl and R 9 > hydrogen, or NR 9 R 9 "represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , SO 2 , or NRn radical or also an oxygen or sulfur atom.
- - E is a COOH, COOR 15 CHO, CH 2 COOH, CH 2 COOR ⁇ radical or a group chosen from the following:
- - Ri represents a (C 1 -C 12 ) unsubstituted alkyl or benzyl radical
- R 2 represents a hydroxyl radical
- - Z is (i) a nitrogen atom or (ii) a CR 4 radical in which R 4 represents (a) a hydrogen atom, (b) an unsubstituted or substituted alkyl (C 1 -C 12 ) radical by phenyl, hydroxyl or by NR 9 R 9 > with R 9 hydrogen or tert-butyloxycarbonyl and R 9 > hydrogen or also by NR 9 R 9 ' which represents a cycloheteroalkyl radical of type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom
- R 9 hydrogen, or also by NR 9 R 9 > which represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom, (d) a radical (C 6 -C ⁇ 8 ) aryl unsubstituted or substituted by halogen, (e) a radical OR 8 in which R 8 represents hydrogen, (f) a radical NR 9 R 9 > in which R 9 represents hydrogen or tosyle and R 9 >hydrogen; or a radical NR 9 R 9 ' which represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents a CH 2 , S0 2 , or NRn radical or also an oxygen or sulfur atom
- R 3 is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl, (iv) a radical (C ⁇ ⁇ C ⁇ 2 ) alkyl unsubstituted or substituted by amino, alkylamino, ( v) a radical (C 6 -C ⁇ 8 ) aryl;
- R 5 , R, R 7 independently of one another represent (i) a hydrogen atom, (ii) a halogen atom, (iii) an unsubstituted (C ⁇ -C ⁇ 2 ) alkyl radical or substituted by hydroxyl, phenyl or NR 9 R 9 > with R 9 hydrogen or tert-butyloxycarbonyl and R 9 > hydrogen, (iv) a phenyl radical unsubstituted or substituted by halogen, alkoxy, alkyl, (v) a radical (C 6 -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (vi) a radical NR 9 R 9 > in which R 9 represents hydrogen and R 9 > hydrogen, (vii) a CORio radical in which Rio represents hydrogen, (viii) an unsubstituted (C 2 -C ⁇ 2 ) alken-1-yl radical, (ix) a (C -C ⁇ 2 ) alkyn-1-
- - X is (i) a halogen atom, (ii) an OR 8 radical in which R 8 is hydrogen, (C ⁇ -C 6 ) alkyl or benzyl, (iii) a NR 9 R 9 radical> in which R 9 is hydrogen, acetyl or benzoyl and Rg> hydrogen, acetyl or benzoyl, or (iv) phenyl. and their pharmaceutically acceptable salts.
- Z is a radical CR.
- Z represents C i with i a hydroxyl radical
- X represents a halogen atom, preferably bromine, and in particular at least one of R 3, R 5, R O and R 7 is other than hydrogen, preferably R 5 and R 7 does not represent a halogen atom.
- Z represents CR 4 with R 4 a hydroxyl radical
- X represents a hydroxyl radical and advantageously at least one of the groups R 3 , R 5 , R ⁇ and R 7 is different from the hydrogen atom.
- Methyl 8-methoxy-3-methylaminomethyl-quinoline-2-carboxylate Methyl 8-hydroxy-3-methylaminomethyl-quinoline-2-carboxylic acid 3-Benzyl-8-methoxy-quinoline-2-carboxylate Acid 3 -benzyl-8 -methoxy-quinoline-2-carboxylic 4-Hydroxy-8-bromo-quinoline-2-methyl carboxylate
- Methyl 6- (3 '-pyridinyl) ethyl-8-amino-4-hydroxy-quinoline-2-carboxylate 6- (5'-cyanopentyl) -8-amino-4-hydroxy-quinoline-2-carboxylate 6 -cyano-8-amino-4-hydroxy-quinoline-2-methyl carboxylate
- Methyl 6- (N-diphenylimine) -8-nitro-4-benzyloxy-quinoline-2-carboxylate
- Methyl 6- (N-anilino) -8-nitro-4-benzyloxy-quinoline-2-carboxylate
- Very particularly preferred compounds are the following compounds:
- the compounds of the invention may be in the form of pharmaceutically acceptable salts, in particular basic or acid addition salts, preferably compatible with pharmaceutical use.
- pharmaceutically acceptable acids non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane acids. or ethanesulfonic, camphoric, etc.
- pharmaceutically acceptable bases non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
- the invention also relates to the use of the compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of pathologies of the nervous system, in particular mental or neurological disorders, particularly anxiety, depression, memory or social interaction disorders, such as sedative or hypnotic, for the treatment of neurodegenerative pathologies, such as Parkinson's disease, Alzheimer's or ALS, schizophrenia, dependence on certain drugs, especially opioids, pain or obesity.
- pathologies of the nervous system in particular mental or neurological disorders, particularly anxiety, depression, memory or social interaction disorders, such as sedative or hypnotic
- neurodegenerative pathologies such as Parkinson's disease, Alzheimer's or ALS, schizophrenia, dependence on certain drugs, especially opioids, pain or obesity.
- the invention relates in particular to the use of the compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of mental or neurological disorders, particularly anxiety, depression, memory disorders or social interactions, such as sedative or hypnotic, or for the treatment of neurodegenerative pathologies, such as Parkinson's disease, Alzheimer's or ALS, dependence on certain drugs, 1.5 including opiates.
- the invention also relates to pharmaceutical compositions, in particular a medicament intended for the treatment of pathologies of the central nervous system, containing as a principle at least one compound of formula (I) as defined above or their pharmaceutically acceptable salts and a vehicle or a pharmaceutically acceptable excipient.
- the invention also relates to novel compounds of formula (I) as such. These are more particularly the compounds in which R 1 is an unsubstituted or benzyl alkyl radical or R 2 is a hydroxyl radical, and preferably R 3 is (i) a hydrogen atom, (ii) a halogen atom , (iii) a hydroxyl, (iv) a radical (C ⁇ -C ⁇ 2 ) alkyl unsubstituted or substituted by amino, alkylamino, or (v) a radical (C 6 -C ⁇ 8 ) aryl and / or Z is (i ) a nitrogen atom or (ii) a CR 4 radical in which R 4 represents (a) a hydrogen atom, (b) a (C 1 -C 12 ) alkyl radical unsubstituted or substituted by phenyl, hydroxyl or NR 9 R 9 ' with R 9 hydrogen or tert-butyloxycarbonyl and R 9 >
- the compounds or compositions according to the invention can be administered in different ways and in different forms.
- they can be administered systemically, orally, by inhalation or by injection, such as for example by intravenous, intramuscular, subcutaneous, trans-dermal, intra-arterial, etc., intravenous routes, intramuscular, subcutaneous, oral and inhalation are preferred.
- the compounds are generally packaged in the form of liquid suspensions, which can be injected using syringes or infusions, for example.
- the compounds are generally dissolved in saline, physiological, isotonic, buffered solutions, etc., compatible with pharmaceutical use and known to those skilled in the art.
- compositions can contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc.
- Agents or vehicles which can be used in liquid and / or injectable formulations are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, etc.
- the compounds can also be administered in the form of gels, oils, tablets, suppositories, powders, capsules, capsules, aerosols, etc., optionally by means of dosage forms or devices ensuring sustained and / or delayed release.
- an agent such as cellulose, carbonates or starches is advantageously used.
- the flow rate and / or the dose injected can be adapted by a person skilled in the art according to the patient, the pathology concerned, the mode administration, etc.
- the compounds are administered at doses which can vary between 0.1 and 500 mg / kg of body weight, more generally from 0.3 to 100 mg / kg, typically between 3 and 50 mg / kg.
- repeated injections can be given, if necessary.
- delayed or prolonged systems can be advantageous.
- the compounds of the invention are particularly useful for modulating the activity of XA on the nervous system.
- the invention follows from the demonstration of the role of XA as a neurotransmitter.
- the compounds of the invention can also be used to selectively modulate neurotransmission, in particular dopaminergic neurotransmission.
- the compounds of the invention can be used either to inhibit the activity of XA, or to mimic or increase this activity.
- the results presented show that compounds of the invention are XA antagonists, XA agonists, or allosteric XA modulators.
- compound 19f has an activity ten times more powerful than XA.
- the compounds 3x and 22c for example are capable of increasing the binding of XA to its receptor by a factor greater than 100.
- the compounds in particular capable of increasing the binding of XA to its receptor preferably have a formula ( I) in which Z represents CR 4 with R 4 a hydroxyl radical, X represents a halogen atom, preferably bromine, or a cyano group, and in particular at least one of the groups R 3 , R 5 , R ⁇ and R 7 is different from the hydrogen atom, advantageously with R 5 and R 7 not representing a halogen atom.
- These compounds also have the capacity to selectively increase dopamine in the prefontal cortex (experiments carried out in particular in rats with measurements obtained by microdialysis).
- the compounds of formula (I) can be obtained from commercial intermediates or optionally modified by implementing a combination of chemical reactions known to those skilled in the art such as those described below for the functionalization of the products .
- Ri, R 3 , R 5 , R ⁇ , R 7 and X have the same meanings as in formula (I) and E is COORi and CH 2 COOR ⁇ .
- This reaction is generally carried out under the conditions described in J. Org. Chem., 1990, 55, 2820-2822.
- one operates within an inert solvent such as benzene or toluene in the presence of para-toluene sulfonic acid at reflux of the solvent.
- R 3 , R 5 , R ⁇ , R 7 and X have the same meanings as in formula (I).
- This reaction is generally carried out in basic medium according to the conditions described in Tetrahedron Lett, 1984, 25, 923-926 or J. Am. Chem. Soc, 1998, 6, 1218-1222.
- the operation is preferably carried out, in the presence of sodium methylate, in an inert solvent such as an aliphatic alcohol such as methanol, at a temperature of 60 ° C.
- R 5 , R 6 and R 7 have the same meanings as in formula (I), X 'has the same meanings as X and can also represent a nitro radical, Me represents a methyl radical and Bn represents a radical benzyl
- the reaction is carried out according to the conditions described in J. Med. Chem., 1985, 28, 298-302 or J. Org. Chem. 1966, 31, 3369-3374.
- one operates in an aliphatic alcohol such as methanol, ethanol, at the boiling temperature of the reaction medium.
- Reactions b and c are generally carried out in diphenyl ether at a temperature of 250 ° C or in polyphosphoric acid at 100 ° C.
- reaction d takes place either when X ′ is benzyloxy by catalytic hydrogenation in the presence of Pd on carbon, in an inert solvent such as ethyl acetate, an aliphatic alcohol (methanol , ethanol for example) or acetic acid, at room temperature or by means of A1C1 3 in an inert solvent such as a chlorinated solvent (dichloroethane for example), in the presence of dimethylaniline, at room temperature or at reflux in a mixture of acetic acid / hydrochloric acid 37% and, in this case, the hydrolysis of the ester occurs simultaneously, either when X 'is methoxy in H 3 P0 4 medium in the presence of Kl and, in this case, the hydrolysis of the ester occurs simultaneously.
- an inert solvent such as ethyl acetate, an aliphatic alcohol (methanol , ethanol for example) or acetic acid
- the reduction of nitro (reaction e) is a catalytic reduction by means of hydrogen, in the presence of Pd on carbon, in an inert solvent such as an aliphatic alcohol (methanol for example), at ambient temperature.
- an inert solvent such as an aliphatic alcohol (methanol for example)
- the reduction of nitro to amino is carried out according to the conditions described in JOC, 1985, 50, 26, 5782-5789 and, preferably, in THF using Na 2 S 2 0 4 at room temperature (18 ° to 25 ° C approximately) or at 60 ° C.
- the compounds of formula (I) for which Z is a radical CR 4 , R 4 is a halogen atom and E is a radical COORi can be prepared by the action of a corresponding compound of formula (I) for which Z is a radical CR 4 and Ri is a hydroxyl radical with a halogenating agent.
- a phosphorus oxyhalide phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyfluoride
- the operation is carried out at the boiling point of the reaction medium.
- the compounds of formula (I) for which Z is a radical CR 4 , t is a hydrogen atom, R 3 is a hydrogen atom and E is a COORi radical and the other substituents are not halogenated can be prepared by catalytic hydrogenation of the compounds of formula (I) for which Z is a radical CR 4 , R 4 is a halogen atom.
- This hydrogenation is carried out using hydrogen, preferably in the presence of Pd on carbon, in an inert solvent such as an aliphatic alcohol (methanol for example), at room temperature and at variable pressure.
- the compounds of formula (I) for which Z is a radical CR, R 4 is an aryl, heteroaryl or arylalkyl radical and E is COORi and / or one of the substituents R 5 , R 6 , R 7 or X is a radical aryl, heteroaryl or arylalkyl can be prepared by the action of a corresponding compound of formula (I) for which Z is a radical C- R 4 , t is a halogen atom and / or one of the substituents R 5 , Rg , R 7 or X is a halogen atom with a derivative of formula ⁇ > B (OH) 2 for which i ' is an aryl, heteroaryl or arylalkyl radical.
- the halogen atoms are chlorine or bromine atoms.
- This reaction is preferably carried out in the presence of Pd (PPh 3 ) and K 3 P0 4 , in an inert solvent such as dimethylformamide or toluene, at a temperature of 90 to 115 ° C.
- R 5 , R 6 , R 7 , X have the same meanings as in formula (I), E is COORi, OTf represents a triflate radical, R "represents a hydrogen atom, an alkyl radical, a radical aryl or a heteroaryl radical.
- reaction b is carried out in the presence of a palladium halide such as PdCl 2 , copper iodide, triphenylphosphine and triethylamine, in an inert solvent such as acetonitrile, at a temperature between 30 and 60 ° C.
- a palladium halide such as PdCl 2 , copper iodide, triphenylphosphine and triethylamine
- reaction c is generally carried out by means of hydrogen, in the presence of Pd on carbon, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example), acetic acid, at room temperature.
- a chlorinated solvent dichloromethane for example
- methanol aliphatic alcohol
- R 4 is a radical NR 9 R 9 ' where R 9 represents (i) a hydrogen atom, (ii) an (Ci-C ⁇ ) alkyl radical, (iii) an (C 6 -C ⁇ 8 ) aryl radical, (iv) an (C 6 -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl radical or (v) a heteroaryl (R-Cl 7) radical and R 9 .
- R 9 which may be the same or different from R 9 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C 6 ) aryl radical, (iv) a (C 6 -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl radical or (v) a heteroaryl (C 1 -C 17 ) radical;
- NR 9 R 9 ' represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents CH 2 , O, S, S0 2 , or NRn
- Rn represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ ) radical 8 ) aryl (C ⁇ -C ⁇ 2 ) alkyl, (v) a radical (C 1 -C 17 ) heteroaryl, (vi) a radical (C ⁇ -C ⁇ 7 ) heteroaryl (C ⁇ -C 12 ) alkyl or (vii) a radical CORio;
- the reaction is carried out by means of triflic anhydride, in a chlorinated solvent such as dichloromethane, in the presence of pyridine, at a temperature ranging from 0 ° C to 25 ° C.
- Reaction b is generally carried out in the presence of a palladium (0) (Pd 2 (dba) 3 ) or palladium (II) complex such as Pd (OAc) 2 in the presence of the amine HNR 9 R 9 ' , cesium carbonate and racemic BINAP in an inert solvent such as toluene, at a temperature between 30 and 60 ° C.
- a palladium (0) Pd 2 (dba) 3
- palladium (II) complex such as Pd (OAc) 2
- OAc palladium (OAc) 2
- an inert solvent such as toluene
- R 9 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ 8 ) aryl (C ⁇ -) radical C 12 ) alkyl or (v) a (C1-C17) heteroaryl radical and Rg> which may be identical or different from R 9 represents (i) a hydrogen atom, (ii) a (C 1 -C 12 ) radical alkyl, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ 8 ) aryl (C ⁇ -C ⁇ 2 ) alky
- NR 9 R 9 ' represents a cycloheteroalkyl radical of the type:
- n 2 or 3
- m 2 or 3
- Y represents CH 2 , O, S, S0 2 , or NRn
- Rn represents (i) a hydrogen atom, (ii) an (Cj-C ⁇ ) alkyl radical, (iii) a (C 6 -C ⁇ 8 ) aryl radical, (iv) a (C 6 -C ⁇ 8 ) radical aryl (C ⁇ -C ⁇ 2 ) alkyl, (v) a heteroaryl radical (C ⁇ -C ⁇ 7 ), (vi) a heteroaryl (C ⁇ -C ⁇ ) radical (C ⁇ -C 12 ) alkyl or (vii) a CORio radical; and E is COORi can be prepared according to the following reaction scheme:
- the reaction is carried out by means of triflic anhydride, in a chlorinated solvent such as dichloromethane, in the presence of pyridine, at a temperature ranging from 0 ° C to 25 ° C.
- Reaction b is generally carried out in the presence of a palladium (0) (Pd (dba) 3 ) or palladium (II) complex such as Pd (OAc) 2 in the presence of the amine HNR 9 R 9 >, cesium carbonate and racemic BINAP in an inert solvent such as toluene, at a temperature between 30 and 60 ° C.
- a palladium (0) (Pd (dba) 3 ) or palladium (II) complex such as Pd (OAc) 2
- an inert solvent such as toluene
- reaction c is generally carried out by means of hydrogen, in the presence of Pd on carbon, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example), acetic acid, at room temperature.
- a chlorinated solvent dichloromethane for example
- methanol aliphatic alcohol
- the reaction is generally carried out in the presence of a palladium (II) complex (Pd (OAc)) in the presence of the zinc cyanide amine, zinc powder, cesium carbonate and DPPF within an inert solvent such as DMA, at a temperature of 120 ° C.
- Pd palladium
- the reduction of the reaction a is generally carried out by means of hydrogen, in the presence of Pd on deactivated carbon, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example) , acetic acid, at room temperature.
- R 5 , R ⁇ , R 7 , X have the same meanings as in formula (I)
- E is COORi
- S0 2 Ar is arylsulfonyl.
- the reaction a is carried out by the action of an arylsulfonylisocyanate according to the method described in J. Med. Chem., 1990, 33, 3130-3133.
- the operation is carried out in an inert solvent such as a chlorinated solvent (dichloromethane for example), at the boiling temperature of the reaction medium.
- Deprotection b is carried out using sulfuric acid at 0 ° C.
- hydrochloric acid there is hydrolysis of the ester and obtaining the compound for which Z is C- NR 9 R 9 > and R 9 is arylsulfonyl and R 9 > hydrogen and E is COOH.
- This oxidation is carried out by any method of oxidizing a methyl to an aldehyde known to a person skilled in the art and making it possible not to touch the rest of the molecule such as that described in Tetrahedron, 1996, 52, 4659- 4672.
- Se0 2 is used in an inert solvent such as dioxane, at a temperature of 80 ° C.
- the methylated intermediates can be prepared according to one of the following reaction schemes:
- R 3 , R 5 , R ⁇ , R 7 and X have the same meanings as in formula (I) and Me is methyl.
- This reaction is carried out according to the conditions described in J. Med. Chem., 1998, 41, 4062-4077 or J. Chem. Soc. 1946, 56-57.
- this condensation takes place in acetic acid in the presence of sodium acetate at 60 ° C.
- R 3 , R 5 , R 6 , R 7 and X have the same meanings as in formula (I).
- This reaction is carried out according to the conditions described in Org. Prep. Procedé. Int, 1991, 386-387. Preferably this reaction is carried out in aqueous ethanol in the presence of a base such as KOH or piperidine at the boiling temperature of the reaction medium.
- R 3 , R 5 , R 6 , R 7 and X have the same meanings as in formula (I).
- This reaction is carried out under the conditions described in J. Chem. Soc, 1951, 1521-1527.
- the formation of the enamine takes place in methanol in the presence of HCl.
- the second step is done in diphenylether at 250 ° C.
- the compounds of formula (I) for which E is a radical -CH 2 OH can be obtained by reduction of a corresponding compound of formula (I) for which E is CHO.
- This reduction is carried out by any method of oxidizing a methyl to an aldehyde known to a person skilled in the art and making it possible not to touch the rest of the molecule and, preferably, by means of sodium borohydride, in an inert solvent such as methanol or ethanol, at a temperature varying from 0 ° C. to
- the compounds of formula (I) for which E is a COOH radical can also be prepared by oxidation of a corresponding compound of formula (I) for which E is a CHO radical.
- This oxidation is carried out according to the conditions described in Tetrahedron, 1996, 52, 4659-4672.
- the operation is carried out by means of H 2 NS0 3 H in the presence of an aqueous solution of sodium hypochlorite, in an inert organic solvent such as THF, at ambient temperature.
- the compounds of formula (I) for which E is a COOH radical can be prepared by hydrolysis of the compounds of formula (I) corresponding for which E is a COORi radical.
- This reaction is carried out by any method known to those skilled in the art making it possible to pass from an ester to the corresponding acid.
- the operation is carried out in an acid medium, for example with hydrochloric acid within acetic acid or in an alcoholic medium, at a temperature between 20 ° C. and the boiling point of the reaction medium.
- an acid medium for example with hydrochloric acid within acetic acid or in an alcoholic medium, at a temperature between 20 ° C. and the boiling point of the reaction medium.
- a basic medium for example with LiOH, in an inert solvent such as water or tetrahydrofuran, at room temperature.
- Ri st alkyl radical can also be prepared by esterification of a corresponding compound of formula (I) for which E is a COOH radical.
- This esterification is carried out by any method of esterification of an acid known to those skilled in the art.
- an aliphatic acid (C 1 -C 12 in a straight or branched chain) is reacted, in the presence of an acid such as sulfuric acid or hydrochloric acid, at the boiling temperature of the reaction medium.
- the compounds of formula (I) for which E is a COOR Î radical, R I is arylalkyl can be prepared by the action of a corresponding compound of formula (I) for which E is a COOH radical with an arylalkyl halide.
- This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of NaH, at room temperature.
- the compounds of formula (I) for which E represents a CO-NHR 2 radical can be prepared by the action of a corresponding compound of formula (I) for which E is a COOH or COORi radical and of an amine H 2 NR 2 in which R 2 has the same meanings as in formula (I).
- This reaction is generally carried out in an inert solvent such as THF in the presence of isobutyl chloroformate at temperatures varying between 0 ° C. and
- R 3 , R 5 , R 6 , R 7 and X have the same meanings as in formula (I), Me is methyl.
- reaction b The reaction is carried out according to the conditions described in Synthesis, 1983, 4, 316-319. Preferably, the operation is carried out in acetonitrile at reflux of the solvent.
- the dehydration of the amide (reaction b) is carried out by means of phosphorus oxychloride according to the method described in J. Med. Chem., 1988, 31, 84-91. Preferably the reaction is carried out in DMF at 20 ° C. This dehydration can also be done under the conditions described in Org. Prep ; proceed Int, 1994, 26,4, 429-438 and preferably within dichloromethane in the presence of trifluoroacetic anhydride and triethylamine at room temperature.
- the reaction is carried out in DMF in the presence of ammonium chloride at a temperature of up to 120 ° C. (J. Med Chem, 1979, 22,7 816-823).
- the compounds of formula (I) for which X represents a tetrazolyl radical and Ri, R 3 , R 5 , R 6 , R 7 and X have the same meanings as in formula (I), can be prepared by azide reaction sodium in acetic acid medium at a temperature up to 115 ° C.
- the bromination reaction a is carried out according to the method described in J.Am. Chem. Soc, 1998, 120, 1218-1222.
- 1,3-dibromo-5,5 dimethylhydantoin (DBH) is used in an inert solvent such as CC1 4 under reflux of the solvent.
- Reaction b in the case of aliphatic amines, is carried out according to the conditions described in Indian J. Chem; Sect B, EN 1984, 23,1 33-39 and, preferably, in a solvent such as ethanol in the presence of NEt 3 at reflux.
- the reaction can be carried out according to the conditions described in J. Chem Soc. Chem. Comm, EN, 1992, 18, 1300-1302 or J. Med Chem 1991, 2209-2218 and preferably within racetonitrile or benzene in the presence of K 2 C0 3 or DMF, at temperatures varying from 50 to 80 ° C.
- Reaction c is carried out under the conditions described in Tetrahedron.Lett. 1999, 40, 43, 7599-7603.
- the operation is preferably carried out with Pd (PPh 3 ) 4 in an inert solvent such as DME in the presence of Na 2 C0 3 at reflux of the solvent.
- the compounds of formula (I) for which one of the substituents R 3 , R 5 , R 6 , R 7 or X is an alkyn-1-yl (C 6 -C ⁇ 8 ) aryl (C 2 -Ci 2 ) radical alkyn-l-yle, (C 4 - Ci 2 ) heteroaryl (C 2 -C 12 ) alkyn-l-yle, (C 2 -C 12 ) (C 6 -C ⁇ 8 ) alkyl aryl (C 2 -C ⁇ 2 ) alkyl, (C 4 - C ⁇ 2 ) heteroaryl (C 2 -C ⁇ 2 ) alkyl can be prepared by the action of a corresponding compound of formula (I) for which one of the substituents R 3 , R 5 , R 6 , R 7 or X is a halogen atom and, preferably a bromine, with a derivative of formula:
- R represents a hydrogen atom or an alkyl radical, an aryl radical or a heteroaryl radical optionally followed by a reduction.
- This reaction is generally carried out in the presence of a palladium halide and that PdCl 2 , copper iodide, triphenylphosphine and triethylamine, in an inert solvent such as racetonitrile, at a temperature between 30 and 60 ° C.
- the reduction is preferably carried out by means of hydrogen, in the presence of Pd on carbon, in an inert solvent such as a chlorinated solvent (dichloromethane for example), an aliphatic alcohol (methanol for example) or l acetic acid, at room temperature.
- the compounds of formula (I) for which one of the substituents R 3 , R 5 , R ⁇ , R 7 or X is an alkyl or arylalkyl radical can be prepared by the action of a corresponding compound of formula (I) for which l 'one of the substituents R 3 , R 5 , R 5 , R 7 or X is a halogen atom and, preferably, a bromine atom, with a derivative R'"ZnX" for which R '"is an alkyl radical or arylalkyl and X "bromine or iodine.
- This reaction is generally carried out in the presence of Pd (PPh 3 ), in an inert solvent such as THF or DMF at a temperature varying between 50 and 100 ° C.
- the compound of formula (I) for which Z is CR 4 , R 4 , R 3 , R, R 7 are hydrogen, X is OR 8 , R 8 is benzyl, E is COORi, Ri is benzyl and R 5 is an atom bromine can be prepared by direct bromination of the corresponding compound of formula (I) for which Z is CR 4 , R 4 , R 3 , R 5 , R, R 7 are hydrogen, X is OR 8 , R 8 is benzyl, E is COORi, Ri is benzyl.
- This reaction is carried out under the conditions described in J. Chem. Soc, 1971, 3682-3653.
- the procedure is carried out using 2,4,4,6-tetrabromocyclohexa- 2,5-dienone, in a chlorinated solvent such as dichloromethane at a temperature ranging from -10 ° C to 25 ° C.
- the compound of formula (I) for which Z is CR 4 , R 4 is hydroxyl and R 5 , R, R 7 are hydrogen, X is ORg, Rg is benzyl, E is COORi, Ri is methyl and R 3 is an atom bromine can be prepared by direct bromination of the corresponding compound of formula (I) for which Z is CR, R 4 , R 3 , R 5 , R ⁇ , R 7 are hydrogen, X is OR 8 , R 8 is benzyl, E is COORi, Ri is methyl.
- This reaction is preferably carried out by means of N-bromosuccinimide in the presence of diisopropylamine, in a chlorinated solvent such as dichloromethane at a temperature ranging from -10 ° C to 25 ° C or in carbon tetrachloride at reflux.
- a chlorinated solvent such as dichloromethane
- the compounds of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is an (Cl) alkyl radical substituted by NR 9 R 9 >, R 9 is alkyl, aryl or arylalkyl and R 9 ' is hydrogen, alkyl, aryl or arylalkyl can be prepared by the action of a corresponding compound for which one of the substituents R 3 , R 5 , R 6 , R 7 or X is a CHO radical with an amine of formula HNR 9 R 9 >, R 9 is alkyl, aryl or arylalkyl and R 9 > is hydrogen, alkyl, aryl or arylalkyl.
- This reaction is generally carried out in the presence of NaBH 4 , in a protic solvent such as methanol, at a temperature of 0 ° C.
- the compounds of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is a radical NR 9 R 9 > for which R 9 is COR 10 and R 9 > is hydrogen or COR 10 may be prepared by the action of a corresponding compound of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is a radical NR 9 R 9 ' and R 9 and R 9 > is are hydrogen with a derivative R 10 COC1 for which R 10 has the same meanings as in formula (I).
- This reaction is generally carried out in the presence of NEt 3 in acetonitrile at room temperature
- the compounds of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is a radical NR 9 R 9 > and R 9 is an alkyl radical optionally substituted by aryl or arylalkyl and R 9 > is hydrogen, alkyl, aryl or arylalkyl can be prepared by the action of a corresponding compound of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is a radical NR 9 R 9 ' and R 9 is hydrogen and R 9 > is hydrogen with an aldehyde R 9 "CHO, R 9 " is a hydrogen atom or an alkyl radical optionally substituted by aryl or arylalkyl.
- This reaction is generally carried out under conditions in the presence of NaBH 4 , in an inert solvent such as an aliphatic alcohol and preferably methanol, at a temperature of 0 ° C.
- the compounds comprising a radical OR 8 and R 8 are alkyl or aryl can be prepared by the action of a corresponding compound of formula (I) comprising a radical OR 8 and R 8 are hydrogen with a derivative R 12 Br for which R ⁇ 2 is an alkyl or arylalkyl radical.
- This reaction is carried out in a solvent such as DMF using NaH as base at room temperature
- the compounds of formula (I) comprising a radical NR 9 R 9 > in which R 9 is hydrogen and R 9 > hydrogen can be prepared by reduction of a corresponding compound comprising a nitro radical.
- This reaction is generally carried out by any known method of reduction of a nitro.
- the operation is carried out using hydrogen, in the presence of Pd on charcoal, in an inert solvent such as an aliphatic alcohol (methanol for example), at ambient temperature.
- an inert solvent such as an aliphatic alcohol (methanol for example)
- the reduction of nitro to amino is carried out according to the conditions described in JOC, 1985, 50, 26, 5782-5789.
- One generally operates in THF using Na 2 S 2 0 4 at 60 ° C.
- the compounds of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is an iodine can be prepared by the action of a corresponding compound of formula (I) for which one of the substituents R 5 , R 6 , R 7 or X is a radical NR 9 R 9 OR R 9 is hydrogen and R 9 > hydrogen with KL
- the reaction is carried out in an aqueous medium in the presence of sulfuric acid, sodium nitrite and K1 at a temperature ranging from 0 ° C to 70 ° C.
- room temperature means a temperature between 15 and 25 ° C.
- Some compounds of formula (I) may require the use of groups protecting certain functions which could interfere with the reaction.
- These protective groups are chosen from the groups commonly used in organic synthesis.
- For the protection of the amines it is possible, for example, to use the benzyl, diphenylmethyl and butoxycarbonyl groups.
- For the protection of OH it is possible in particular to use benzyl, tert-butyl and trialkylsilyl groups.
- Methyl 4-Hydroxy-6-isopropyl-8-bromo-quinoline-2-carboxylate 42b By replacing in example 1.1, 2-methoxy-4-bromoaniline by 2-bromo-4-isopropylaniline, the product is obtained intermediate 2 - [(2-bromo-4-isopropylphenyl) amino] -but-2-methylenedioate 42a. Yid: 90%.
- Methyl 7-bromo-8-benzyloxy-4-hydroxy-quinoline-2-carboxylate 50b By replacing 2-methoxybromoaniline in example 1.1 with 3-bromo-2-benzyloxyaniline, 2 - [(3- bromo-2-ber ⁇ zyloxyphenyl) amino] but-2- methyl enedioate 50a in the form of a yellow solid. YId: 58%.
- Methyl 5-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 72b By replacing, in Example 1.1, 2-methoxybromoaniline with 5-bromo-2-nitroaniline, 2 - [(5-bromo-2-m ⁇ ophenyl) amino] but-2-enenedioate 72a is obtained under the form of a solid orange. Yid: 33%.
- Methyl 8-carboxamide-4-hydroxy-quinoline-2-carboxylate 37b By replacing in example 1.1 2-methoxybromoaniline by ranthralinamide, we obtain methyl 2 - [(2-carboxamidephenyl) amino] but-2-enioate 37a in the form of a white solid. YId: 94%.
- Methyl 4-Hydroxy-8-nitro-6-phenyl-quinoline-2-carboxylate 86b By replacing in example 1.1, 2-methoxy-4-bromoaniline by 2-nitro-4-phenylaniline, the product is obtained intermediate 2 - [(3-nitro-l, methyl -biphenyl-4-yl) amino] -but-2-enedioate 86a. Yid: .83%.
- 1H-NMR 300 MHz, CDC1 3 ): ⁇ 11.18 (large s, IH, NH), 8.39 (s, IH arom.), 7.72 (d, IH, J ⁇ 8Hz, IH arom.
- Methyl 4,8-Dihydroxy-5-phenyl-quinoline-2-carboxylate 18b By replacing in example 2, methyl 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2-carboxylate 15a by methyl 4-hydroxy-8-benzyloxy-5-phenyl-quinoline-2-carboxylate 18a, the title product is obtained in the same way. YId: 84%.
- Methyl 3-phenylethyl-8-amino-4-hydroxy-quinino-2-carboxylate 68b By replacing in example 2 the methyl 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2-carboxylate 15a with methyl 3-phenylethynyl-8-niuO-4-hydroxy-quinoline-2-carboxylate 68a the title product is obtained. YId: 85%.
- Methyl 5-piperazin-1-yl-8-amino-4-hydroxy-quinino-2-carboxylate 78b By replacing in example 2 the 4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate methyl 2g with methyl 5- (N- (N-benzyl) piperazinyl) -8-nitro-4-benzyloxy-quinoline-2-carboxylate 78a, the title compound is obtained in the form of an orange solid. YId: 61%>.
- Methyl 4,6-dihydroxy-8-amino-quinoline-2-carboxylate 79c By replacing in example 2, methyl 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2-carboxylate 15a by methyl 6-benzyloxy-8-nitro-4-hydroxy-quinoline-2-carboxylate 79b, the title product is obtained. YId: 85%.
- Methyl 6-cyano-8-amino-4-hydroxy-quinoline-2-carboxylate 120b By replacing in example 2 the methyl 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2-carboxylate 15a with methyl 6-cyano-8-nitro-4-benzyloxyquinoline-2-carboxylate 120a, the title compound is obtained in the form of an orange solid. Yid: 41%.
- Methyl 6,8-diamino-4-hydroxy-quinoline-2-carboxylate 32c By replacing, in Example 2, methyl 4-hydroxy-5-hydroxymethyl-8-benzyloxy-quinoline-2-carboxylate 2g with 6- methyl amino-8-nitro-4-benzyloxyquinoline-2-carboxylate 32b, the title compound is obtained in the form of a yellow solid. YId: 87%.
- Acid hydrochloride 4 - (/ Y-methylamino) -8-amino-quinoline-2-carboxylic 38d By replacing in example 2, 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2 -methyl carboxylate 15a with methyl 4- (N-methylamino) -8-amino-quinoleme-2-carboxylate 38c, the title compound is obtained in the form of a yellow solid. YId: 82%.
- Methyl 7-acetylamino-4-hydroxy-quinoline-2-carboxylate 116b By replacing in example 2, methyl 8-benzyloxy-4- (toluene-4-sulfonylamino) - quinoline-2-carboxylate 15a by 7 methyl acetylarnino-4-benzyloxyquinoline-2-carboxylate 116a the title product is obtained in the same way. YId: 82%.
- Methyl 3,7-Dibromo-4,8-dihydroxy-quinoline-2-carboxylate 56b By replacing in example 3, methyl 4-hydroxy-5-bromo-8-benzyloxy-quinoline-2-carboxylate 2b by methyl 8-benzyloxy-3,7-dibromo-4-hydroxyquinoline-2-carboxylate 56a the title product is obtained in the same way. YId: 85%. 1H-NMR (300 MHz, DMSO-D 6 ): ⁇ 12.40 (large s, IH,
- Methyl 4-Hydroxy-6-iodo-8-methoxy-quinoline-2-carboxylate 2j Methyl 4-hydroxy-6-amino-8-methoxy-quinoline-2-carboxylate 2q (126mg, 0.5 Immole) is suspended in ice water (2ml). Add concentrated sulfuric acid (0.3ml). At 0 ° C, add the sodium nitrite (39mg, 0.57mmol). Leave to turn at this temperature for 1 hour. Then add the potassium iodide (115mg, 0.69mmol) dissolved in water (2ml) drop by drop. The reaction medium is then heated to 70 ° C for 1 h. Extract the aqueous medium with methylene chloride.
- 6-piperazin-1-yl-8-amino-4-hydroxy-quinoline-2-carboxylic acid hydrochloride 125c By replacing, in Example 7, methyl 4-hydroxy-8-amino-quinoline-2-carboxylate 3u with methyl 6- (N-piperazinyl) - 8-amino-4-hydroxy -quinoline-2-carboxylate 125b , the title compound is obtained in the form of a brown solid. Yid: 48%.
- 6-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylic acid 63c By replacing in example 8, methyl 4-hydroxy-8-benzyloxy-quinoline-2-carboxylate by 6-bromo-8 -cyano-4-hydroxy-quinoline-2-methylcarboxylate 63b, the title product is obtained in the same way. YId: 68%.
- Methyl 6-Bromo-8-cyano-4-benzyloxy-quinoline-2-carboxylate 65a By replacing, in Example 10, 7-bromo-8-benzyloxy-quinoline-2-carboxylic acid 4c with 6-bromo -8-cyano-4-hydroxy-quinoline-2-methyl carboxylate 63b, the title product is obtained in the same way. YId: 96%>.
- EXAMPLE 11 Benzyl 8-Benzyloxy-5-bromo-quinoline-2-carboxylate 5b Dissolve 0.74g (2 mmol) of benzyl 8-benzyloxy-quinoline-2-carboxylate 5a in 25 ml of dichloromethane. Cool to -10 ° C and add in small spatulas, without the temperature exceeding -5 ° C, 0.90g (2.2 mmol) of 2,4,4,6-tetrabromocyclohexa-2,5-dienone. Let rise to room temperature and stir overnight. Evaporate to dryness and chromatograph on a column of silica gel eluent: AcOEt ⁇ ex: 1/3 to obtain the title compound. YId: 86%.
- Methyl 4-Hydroxy-6-phenyl-8-methoxy-quinoline-2-carboxylate 18f Starting from methyl 4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 21 and replacing in the Example 14, 4-methoxybenzene boronic acid by benzene boronic acid, the title product is obtained in the same way. Yid: 50%.
- Methyl 8-methoxy-4- (4-chlorophenyl) -quinoline-2-carboxylate 9c Starting from methyl 4-chloro-8-methoxy-quinoline-2-carboxylate 8a and replacing it in Example 14, l 4-methoxybenzene boronic acid with 4-chlorobenzene boronic acid, the title product is obtained in the same way. YId: 87%>.
- Benzyl 4,8-Dibenzyloxy-7-phenyl-quinoline-2-carboxylate 50e Starting from benzyl 4,8-dibenzyloxy-7-bromoquinoline-2-carboxylate 50d and replacing in example 14, the acid 4-methoxybenzene boronic by benzene boronic acid, the title product is obtained in the same way. Yid: 60%.
- Methyl 8-Cyano-4-hydroxy-6-phenyl-quinoline-2-carboxylate 64a Starting from methyl 6-bromo-8-cyano-4-hydroxy-quinoline-2-carboxylate 63b and replacing in the Example 14, 4-methoxybenzene boronic acid by benzene boronic acid, the title product is obtained in the same way. YId: 84%.
- Methyl 5-phenyl-8-nitro-4-benzyloxy-quinoline-2-carboxylate 73a By replacing in example 14 the methyl 4-hyc oxy-6-bromo-8-benzyloxy-qumolein-2-carboxylate 2k by the methyl 5-bromo-8-nitro-4-benzyloxy-quinoline-2-carboxylate 72c and by replacing 4-methoxybenzene boronic acid with phenyl boronic acid, the title product is obtained. Yid: 74%.
- Methyl 5- (4-chlorophenyl) -8-methoxy-quinoline-2-carboxylate 81a Starting from methyl 8-methoxy-5-bromo-quinoline-2-carboxylate 5c and replacing it in Example 14, l 4-methoxybenzene boronic acid with 3-chlorobenzene boronic acid, the title product is obtained in the same way. Yid: 74% ”.
- Benzyl 4,8-Dibenzyloxy-7-phenylethynyl-quinoline-2-carboxyate 55a By replacing in example 15, methyl 4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k by 4 , Benzyl-8-dibenzyloxy-7-bromo-quinoline-2-carboxylate 50c the title product is obtained. YId: 58%.
- Methyl 8-Cyano-4-hydroxy-6 - [(trimethylsilyl) ethynyl] -quinoline-2-carboxylate 69a By replacing in Example 15, methyl 4-hydroxy-6-bromo-8-methoxy-quinoline-2-carboxylate 2k by methyl 6-bromo-8-cyano-4-benzyloxy-quinoline-2-carboxylate 65a, the title product is obtained. Yid: 27%.
- Methyl 3-phenylethynyl-8-nitro-4-hydroxy-quinoline-2-carboxylate 68a By replacing in example 15 methyl 4-hydroxy-6-bromo-8-methoxy-quinoleme-2-carboxylate 2k by Methyl 3-bromo-8-nitro-4-hydroxy-quinoline-2-carboxylate 45a gives the title product. Yid: 63% ".
- 1H NMR (300 MHz, CDC1 3 ): ⁇ 8.65 (dd, 1 H, J - 2 and 8 Hz, Harom.), 8.11 (dd, 1 H, J 2 and 8 Hz, H arom. ), 7.85 (m, 2 H, Harom. And OH), 7.55 (m, 3 Harom.), 4.16 (s, 3 H, OCH 3 ).
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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MARKOVAC, A. ET AL: "Antimalarials. 1. 2-Quinolinemethanols", XP002223905, retrieved from STN Database accession no. 77:43063 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MCNAMARA, DENNIS ET AL: "5,7-Dichlorokynurenic acid, a potent and selective competitive antagonist of the glycine site on NMDA receptors", XP002223889, retrieved from STN Database accession no. 115:42464 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MIKHAILOV, I. B. ET AL: "Xanthurenic acid inhibits the activity of an experimental epileptogenic focus in rat hippocampus", XP002192873, retrieved from STN Database accession no. 127:171437 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MOBERG, CHRISTINA ET AL: "Ligand-exchange chromatography of alkenes on stationary phases containing palladium(II) complexes. Enantiomeric separation of trans-1,2-divinylcyclohexane", XP002223886, retrieved from STN Database accession no. 117:47954 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MOBERG, CHRISTINA ET AL: "Preparation and properties of chelating ion exchangers with quinaldic acids as complexing groups. Influence of the structure of the coordinating ligands on the complexing properties", XP002223891, retrieved from STN Database accession no. 113:41839 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MOLINA, PEDRO ET AL: "A straightforward and practical formal synthesis of lavendamycin ethyl ester", XP002223882, retrieved from STN Database accession no. 121:57180 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MORISAWA, YASUHIRO ET AL: "Quinoline derivatives", XP002223873, retrieved from STN Database accession no. 84:4825 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MORONI, F. ET AL: "Kynurenates and thiokynurenates antagonize the strychnine- insensitive glycine receptor: Studies in the peripheral and the central nervous system", XP002192870, retrieved from STN Database accession no. 119:86407 CA * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MURAMATSU, ICHIRO ET AL: "Quinoline derivatives as degradation products from antibiotic thiopeptin B", XP002223904, retrieved from STN Database accession no. 77:152552 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; NAGARAJAN, K. ET AL: "Formation of phenanthridine derivatives from the adducts of 2-aminobiphenyl with acetylene dicarboxylic esters", XP002223903, retrieved from STN Database accession no. 79:31825 * |
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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; NICHOLS, ALFRED C. ET AL: "Anticonvulsant activity of antagonists for the NMDA-associated glycine binding site", XP002192875, retrieved from STN Database accession no. 120:208350 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; NIWA, HITOMI ET AL: "Preparation of 5,8-quinolinediones and their analogs, and antitumor agents and farnesyltransferase inhibitors containing them", XP002223870, retrieved from STN Database accession no. 132:22880 * |
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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; OKABE, NOBUO ET AL: "Xanthurenic acid monohydrate", XP002223881, retrieved from STN Database accession no. 124:303137 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; OKAMOTO, YASUSHI ET AL: "A supported epoxidation catalyst for nucleophilic olefins", XP002223894, retrieved from STN Database accession no. 109:128726 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; REIO, L.: "Third supplement for the paper chromatographic separation and identification of phenol derivatives and related compounds of biochemical interest using a "reference system"", XP002223909, retrieved from STN Database accession no. 72:96442 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SAGI, MATAICHI ET AL: "Studies on as-triazine derivatives. XIV. Synthesis and reverse electron-demand Diels-Alder reaction of ethyl 5,8-dichloro-1,2,4- benzotriazine-3-carboxylate", XP002223892, retrieved from STN Database accession no. 113:6290 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SANNA, PAOLO ET AL: "Synthesis of substituted 2-(ethoxycarbonyl)- and 2-carboxyquinoxalin-3-ones for evaluation of antimicrobial and anticancer activity", XP002223876, retrieved from STN Database accession no. 130:95533 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SARKIS, GEORGE Y. ET AL: "Synthesis and antileishmanial activity of some new substituted 2-quinoline carboxaldehyde thiosemicarbazones and their transition metal complexes", XP002223878, retrieved from STN Database accession no. 126:144095 * |
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