WO2009144395A1 - DÉRIVÉS POLYSUBSTITUES DE 2-HETEROARYL-6-PHENYL-IMIDAZO[1,2- α]PYRIDINES, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE - Google Patents
DÉRIVÉS POLYSUBSTITUES DE 2-HETEROARYL-6-PHENYL-IMIDAZO[1,2- α]PYRIDINES, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE Download PDFInfo
- Publication number
- WO2009144395A1 WO2009144395A1 PCT/FR2009/000303 FR2009000303W WO2009144395A1 WO 2009144395 A1 WO2009144395 A1 WO 2009144395A1 FR 2009000303 W FR2009000303 W FR 2009000303W WO 2009144395 A1 WO2009144395 A1 WO 2009144395A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyridin
- phenyl
- methanol
- imidazo
- ylimidazo
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 17
- 230000001225 therapeutic effect Effects 0.000 title description 5
- 150000003222 pyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 254
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 76
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 61
- 125000003118 aryl group Chemical group 0.000 claims abstract description 44
- 229910003827 NRaRb Inorganic materials 0.000 claims abstract description 43
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 39
- 150000002367 halogens Chemical class 0.000 claims abstract description 39
- 125000001424 substituent group Chemical group 0.000 claims abstract description 29
- 125000005843 halogen group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 22
- 125000004429 atom Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 163
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 75
- -1 CONRaRb Inorganic materials 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 50
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 17
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical group C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 229910052701 rubidium Inorganic materials 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 150000001638 boron Chemical class 0.000 claims description 12
- 125000005435 dihydrobenzoxazolyl group Chemical group O1C(NC2=C1C=CC=C2)* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000001041 indolyl group Chemical group 0.000 claims description 11
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 125000000335 thiazolyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- IIPNEMMUHWUJGM-UHFFFAOYSA-N 2-[3-(2-thiophen-3-ylimidazo[1,2-a]pyridin-6-yl)phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C2=CSC=C2)=C1 IIPNEMMUHWUJGM-UHFFFAOYSA-N 0.000 claims description 4
- UVYJLTVRCSLJJN-UHFFFAOYSA-N 2-[3-[2-(1h-indol-6-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3NC=CC3=CC=2)=C1 UVYJLTVRCSLJJN-UHFFFAOYSA-N 0.000 claims description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- MXFVBHGNBIYONI-UHFFFAOYSA-N [2-[2-(1,3-benzothiazol-2-yl)imidazo[1,2-a]pyridin-6-yl]-6-fluorophenyl]methanol Chemical compound OCC1=C(F)C=CC=C1C1=CN2C=C(C=3SC4=CC=CC=C4N=3)N=C2C=C1 MXFVBHGNBIYONI-UHFFFAOYSA-N 0.000 claims description 4
- BMVWTXDAYNELHS-UHFFFAOYSA-N [2-[2-(furan-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol;hydrochloride Chemical compound Cl.OCC1=CC=CC=C1C1=CN2C=C(C3=COC=C3)N=C2C=C1 BMVWTXDAYNELHS-UHFFFAOYSA-N 0.000 claims description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 3
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims description 3
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 2
- 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims description 2
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 2
- LXYQOEKTJNBFJR-UHFFFAOYSA-N 2-(1h-indol-6-yl)-6-[3-(methoxymethyl)phenyl]imidazo[1,2-a]pyridine Chemical compound COCC1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3NC=CC3=CC=2)=C1 LXYQOEKTJNBFJR-UHFFFAOYSA-N 0.000 claims description 2
- XDOMOCVVVAOXMN-UHFFFAOYSA-N 2-(5-bromo-2,3-dihydro-1-benzofuran-7-yl)-6-[3-[(2-methylpropan-2-yl)oxymethyl]phenyl]imidazo[1,2-a]pyridine Chemical compound CC(C)(C)OCC1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=3OCCC=3C=C(Br)C=2)=C1 XDOMOCVVVAOXMN-UHFFFAOYSA-N 0.000 claims description 2
- ZJGUWINMIGDSDK-UHFFFAOYSA-N 2-[3-(2-quinolin-3-ylimidazo[1,2-a]pyridin-6-yl)phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3C=CC=CC3=NC=2)=C1 ZJGUWINMIGDSDK-UHFFFAOYSA-N 0.000 claims description 2
- QZOSKERIWUSQFC-UHFFFAOYSA-N 2-[3-(2-thiophen-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2SC=CC=2)=C1 QZOSKERIWUSQFC-UHFFFAOYSA-N 0.000 claims description 2
- NBZGJWITRMLBQB-UHFFFAOYSA-N 2-[3-[2-(1-benzofuran-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2OC3=CC=CC=C3C=2)=C1 NBZGJWITRMLBQB-UHFFFAOYSA-N 0.000 claims description 2
- QDGFGFGBGTWOOR-UHFFFAOYSA-N 2-[3-[2-(1-benzofuran-5-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3C=COC3=CC=2)=C1 QDGFGFGBGTWOOR-UHFFFAOYSA-N 0.000 claims description 2
- RWDPXRUCOSQLRZ-UHFFFAOYSA-N 2-[3-[2-(1-methylbenzimidazol-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound N=1C2=CC=CC=C2N(C)C=1C(N=C1C=C2)=CN1C=C2C1=CC=CC(C(C)(C)O)=C1 RWDPXRUCOSQLRZ-UHFFFAOYSA-N 0.000 claims description 2
- HUNVWCRQWWLTKA-UHFFFAOYSA-N 2-[3-[2-(1-methylindol-5-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound C=1C=C2N(C)C=CC2=CC=1C(N=C1C=C2)=CN1C=C2C1=CC=CC(C(C)(C)O)=C1 HUNVWCRQWWLTKA-UHFFFAOYSA-N 0.000 claims description 2
- KTUIMYDKDREEQS-UHFFFAOYSA-N 2-[3-[2-(1h-indazol-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C3=CC=CC=C3NN=2)=C1 KTUIMYDKDREEQS-UHFFFAOYSA-N 0.000 claims description 2
- CYHGZFIKDJCCSX-UHFFFAOYSA-N 2-[3-[2-(1h-indol-4-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=3C=CNC=3C=CC=2)=C1 CYHGZFIKDJCCSX-UHFFFAOYSA-N 0.000 claims description 2
- XNENMXNJGXYKNF-UHFFFAOYSA-N 2-[3-[2-(2,6-difluoropyridin-4-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C(F)N=C(F)C=2)=C1 XNENMXNJGXYKNF-UHFFFAOYSA-N 0.000 claims description 2
- LUCBBMSCDMMXBX-UHFFFAOYSA-N 2-[3-[2-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound COC1=NC=CC=C1C1=CN(C=C(C=C2)C=3C=C(C=CC=3)C(C)(C)O)C2=N1 LUCBBMSCDMMXBX-UHFFFAOYSA-N 0.000 claims description 2
- MXYSPYKMLNLQNR-UHFFFAOYSA-N 2-[3-[2-(4-methylthiophen-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC1=CSC=C1C1=CN(C=C(C=C2)C=3C=C(C=CC=3)C(C)(C)O)C2=N1 MXYSPYKMLNLQNR-UHFFFAOYSA-N 0.000 claims description 2
- OBNYSNIJPCXYEF-UHFFFAOYSA-N 2-[3-[2-(5-chlorothiophen-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2SC(Cl)=CC=2)=C1 OBNYSNIJPCXYEF-UHFFFAOYSA-N 0.000 claims description 2
- GQDBRZYRKHZTKH-UHFFFAOYSA-N 2-[3-[2-(5-methyl-1,2-oxazol-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound O1C(C)=CC(C=2N=C3C=CC(=CN3C=2)C=2C=C(C=CC=2)C(C)(C)O)=N1 GQDBRZYRKHZTKH-UHFFFAOYSA-N 0.000 claims description 2
- IMBYYUMXBYKATR-UHFFFAOYSA-N 2-[3-[2-[1-(3-methylbutyl)pyrazol-4-yl]imidazo[1,2-a]pyridin-6-yl]phenyl]propan-2-ol Chemical compound C1=NN(CCC(C)C)C=C1C1=CN(C=C(C=C2)C=3C=C(C=CC=3)C(C)(C)O)C2=N1 IMBYYUMXBYKATR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- PARIYUZXFNOAJZ-UHFFFAOYSA-N 6-[3-(2-methoxyethoxymethyl)phenyl]-2-thiophen-2-ylimidazo[1,2-a]pyridine Chemical compound COCCOCC1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2SC=CC=2)=C1 PARIYUZXFNOAJZ-UHFFFAOYSA-N 0.000 claims description 2
- CZRFPGUSMVWPSV-UHFFFAOYSA-N 6-[3-(methoxymethyl)phenyl]-2-(1-methylindol-6-yl)imidazo[1,2-a]pyridine Chemical compound COCC1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3N(C)C=CC3=CC=2)=C1 CZRFPGUSMVWPSV-UHFFFAOYSA-N 0.000 claims description 2
- UMUNKZOHFAUVIN-UHFFFAOYSA-N 6-[6-[3-(hydroxymethyl)phenyl]imidazo[1,2-a]pyridin-2-yl]-3h-1,3-benzoxazol-2-one Chemical compound OCC1=CC=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3OC(=O)NC3=CC=2)=C1 UMUNKZOHFAUVIN-UHFFFAOYSA-N 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000034799 Tauopathies Diseases 0.000 claims description 2
- QGTWMBBJTXJRHX-UHFFFAOYSA-N [2,6-difluoro-3-(2-isoquinolin-5-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2C3=CC=NC=C3C=CC=2)=C1F QGTWMBBJTXJRHX-UHFFFAOYSA-N 0.000 claims description 2
- DLGYQNHXWHZJRO-UHFFFAOYSA-N [2,6-difluoro-3-(2-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2N=CC=CC=2)=C1F DLGYQNHXWHZJRO-UHFFFAOYSA-N 0.000 claims description 2
- CPEPAXIHLWFKRU-UHFFFAOYSA-N [2,6-difluoro-3-(2-quinolin-5-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2C3=CC=CN=C3C=CC=2)=C1F CPEPAXIHLWFKRU-UHFFFAOYSA-N 0.000 claims description 2
- CZFOOVNILIPOEA-UHFFFAOYSA-N [2,6-difluoro-3-(2-thiophen-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2SC=CC=2)=C1F CZFOOVNILIPOEA-UHFFFAOYSA-N 0.000 claims description 2
- ZQFXFQJMCDPYAK-UHFFFAOYSA-N [2,6-difluoro-3-(2-thiophen-3-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C2=CSC=C2)=C1F ZQFXFQJMCDPYAK-UHFFFAOYSA-N 0.000 claims description 2
- USSDIQSBSNYPIO-UHFFFAOYSA-N [2,6-difluoro-3-(3-methyl-2-thiophen-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol Chemical compound C=1N2C(C)=C(C=3SC=CC=3)N=C2C=CC=1C1=CC=C(F)C(CO)=C1F USSDIQSBSNYPIO-UHFFFAOYSA-N 0.000 claims description 2
- WSKUTUYBIULPIQ-UHFFFAOYSA-N [2,6-difluoro-3-[2-(1,3-thiazol-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2SC=CN=2)=C1F WSKUTUYBIULPIQ-UHFFFAOYSA-N 0.000 claims description 2
- DGUKKMWUXUOXNN-UHFFFAOYSA-N [2,6-difluoro-3-[2-(1-methylbenzimidazol-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound N=1C2=CC=CC=C2N(C)C=1C(N=C1C=C2)=CN1C=C2C1=CC=C(F)C(CO)=C1F DGUKKMWUXUOXNN-UHFFFAOYSA-N 0.000 claims description 2
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- LZJFAGAYDFPFMZ-UHFFFAOYSA-N [2,6-difluoro-3-[2-(1h-indol-5-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3C=CNC3=CC=2)=C1F LZJFAGAYDFPFMZ-UHFFFAOYSA-N 0.000 claims description 2
- YTKNRIADAATGCW-UHFFFAOYSA-N [2,6-difluoro-3-[2-(1h-indol-6-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound OCC1=C(F)C=CC(C2=CN3C=C(N=C3C=C2)C=2C=C3NC=CC3=CC=2)=C1F YTKNRIADAATGCW-UHFFFAOYSA-N 0.000 claims description 2
- ABSPTYAAYFBDBC-UHFFFAOYSA-N [2,6-difluoro-3-[2-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound COC1=NC=CC=C1C1=CN(C=C(C=C2)C=3C(=C(CO)C(F)=CC=3)F)C2=N1 ABSPTYAAYFBDBC-UHFFFAOYSA-N 0.000 claims description 2
- BIROAOJMOWNFFK-UHFFFAOYSA-N [2,6-difluoro-3-[2-(4-methylthiophen-2-yl)imidazo[1,2-a]pyridin-6-yl]phenyl]methanol Chemical compound CC1=CSC(C=2N=C3C=CC(=CN3C=2)C=2C(=C(CO)C(F)=CC=2)F)=C1 BIROAOJMOWNFFK-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Definitions
- the present invention relates to polysubstituted derivatives of 2-heteroaryl-6-phenyl-imidazo [1,2-a] pyridine, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving nuclear Nurr receptors. -1, also called NR4A2, NOT, TINUR, RNR-I, and HZF3.
- R 1 represents a heteroaryl or heterocyclic group, this group possibly being substituted by one or more atoms or groups chosen independently of one another from the following atoms or groups: halogen, (C 1 -C 10 ) alkyl, halo ( C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, IMIO (C 1 - C 10) alkoxy, oxo, (C r Ci 0) thioalkyl 5 -S (O) (C 1 -C 10) alkyl , -S (O) 2 (C 1 -C 10 - alkyl), hydroxyl, cyano, nitro, hydroxy (C 1 -C 10) alkylene, NRaRb (C 1 - C 10) alkylene, (Ci-C 10) alkoxy (C 1 -C 10 ) alkyleneoxy, NRaRb 5 CONRaRb, SO 2 NRaRb, NRcCOR
- X represents from 1 to 4 identical or different substituents of the other selected from hydrogen, halogen, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkoxy, NRaRb, nitro, cyano, the group (Q-Qo) alkyl which may be optionally substituted with one or more groups selected from halogen, (C 1 -C 10 ) alkoxy, (C 1 -C 10 ) haloalkoxy, NRaRb or hydroxyl; R represents in position 3, 5, 7 or 8 of the imidazo [1,2-a] pyridine of 1 to 4 substituents same or different from each other selected from hydrogen, halogen, (C 1 -
- R 2 and R 3 represent, independently of one another, a hydrogen atom, a (C 1 -C 10 ) alkyl group, optionally substituted by an Rf group; an aryl group optionally substituted by one or more substituents selected from halogen, (Ci-C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, halo (C 1 - C 10 ) alkoxy, NRaRb, hydroxyl, nitro or cyano;
- R 2 and X may form together with the carbon atoms which carries them a carbon ring of 5 to 7 carbon atoms;
- R 4 represents: a hydrogen atom, a (C 1 -C 10 ) alkyl group, optionally substituted by an Rf group; an aryl group optionally substituted by one or more substituents selected from halogen, (C 1 -C 10) alkyl, halo (C 1 -C 10) alkyl, (C 1 -C 10) alkoxy, halo (C 1 -C 10) alkoxy, TSfRaRb, hydroxyl, nitro, cyano, (C 1 -C 10) alkyl (CO) -, CONRaRb, NRcCORd, OC (O) NRaRb, OCO (C r Ci 0) alkyl, NRCC (O) ORe or aryl, the aryl being optionally substituted with one or more substituents selected from halogen
- Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10) alkyl, aryl (Ci-Ci O) alkylene or aryl; or Ra and Rb together with the nitrogen atom carrying them an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group being optionally substituted by a (C 1 -C 10) group ) alkyl, aryl or aryl (C 1 -C 10) alkylene; Rc and Rd represent, independently of one another, a hydrogen atom or a (C 1 -C 10) alkyl, aryl (Ci-Ci O) alkylene, aryl, or Rc and Rd together form a group (C 2 -C 5 ) alkylene; Re represents a (C 1 -C 10 ) alkyl, aryl (C 1 -C 10
- Rf represents a halogen atom, a (C 1 -C 10 ) alkoxy, halo (C 1 -C 10 ) alkoxy, hydroxyl, cyano, NRaRb, C (O) NRaRb, NRcCORd, OC (O) NRaRb, OCO (C 1 -C 10) alkyl, NRcCOORe, SO 2 NRaRb, NRcSO 2 Re, aryl (C r Ci 0) alkylene, aryl, aryl being optionally substituted with one or more substituents selected from halogen, (C 1 -C 10 ) alkyl, halo (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkoxy, halo (C 1 -C 10 ) alkoxy, NRaRb, hydroxyl, nitro, cyano or OCO (C 1 -C 10 ) alkyl; in the form of
- the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers.
- the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
- salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
- the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
- the groups CF 3 , CH 2 CF 3 By way of examples, mention may be made of the groups CF 3 , CH 2 CF 3 ,
- a haloalkoxy group an -O-alkyl radical where the alkyl group is as previously defined and substituted by one or more identical halogen atoms or different.
- groups OCF 3 , OCfIF 2 and OCCl 3 mention may be made of groups OCF 3 , OCfIF 2 and OCCl 3 .
- a thioalkyl group an S-alkyl radical where the alkyl group is as previously defined; an aryl group: a mono or bicyclic aromatic group containing from 6 to 10 atoms.
- aryl groups mention may be made of phenyl and naphthyl groups; a heteroaryl group: a mono or bicyclic aromatic group comprising from 5 to 10 atoms, of which from 1 to 4 heteroatoms chosen from N, O and S.
- heteroaryl groups mention may be made of: pyrrole, furan, thiophene, pyrazole , imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, thienothiophene, fiiro-furan, thieno-furan, furo-pyrrole, thieno-pyrrole, pyrrolo pyrrole, pyrrolo-isoxazole, furo-isoxazole, thieno-isoxazole, isoxazoloisoxazole, pyrrolo-oxazole, furo-oxazole, thienooxazole, oxazoloisoxazole, oxazolo-oxazole,
- a heterocyclic group a bicyclic group of 9 to 10 atoms comprising from 1 to 4 heteroatoms chosen from N, O and S, one ring of which is aromatic and the other ring being saturated or partially saturated, each of the rings comprising at most only 2 heteroatoms.
- bicyclic groups By way of examples of bicyclic groups, mention may be made of: benzodioxole, benzoxathiole, benzopyran, benzothiopyran, benzoxazine, benzothiazine, benzodioxin, benzothioxine, dioxolo-pyridine, oxathiolo-pyridine, pyrano-pyridine, thiopyrano-pyridine, oxazinopyridine, thiazino pyridine, dioxino-pyridine, thioxinopyridine, dioxolo-pyrimidine, oxathiolo-pyrimidine, pyrano-pyrimidine, thiopyranopyrimidine, oxazinopyrimidine, thiazino-pyrimidine, dioxinopyrimidine, thioxinopyrimidine, dioxolo-pyrazine, oxathiolo-pyrazine , pyr
- a first group of compounds consists of compounds for which:
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3-b] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, (C 1 -C 10 ) alkyl, oxo, NRaRb; (C 1 -C 10 ) alkoxy, aryl, CONRaRb; Ra and Rb represent, independently of
- a second group of compounds is composed of compounds for which: R 1 represents isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1 group, 2,3,4-tetrahydroquinolinyl, benzofuryl, dihydrobenzofuryl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3-Z] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, methyl, oxo, NRaRb; methoxy, ethoxy, phen
- Ra and Rb represent, independently of one another, a hydrogen atom or a methyl group; the other substituents being defined as above.
- a third group of compounds consists of compounds for which: X represents 1 or 2 hydrogen or halogen atoms; the other substituents being defined as above.
- a fourth group of compounds consists of compounds for which: X represents 1 or 2 hydrogen or fluorine atoms; the other substituents being defined as above.
- a fifth group of compounds is composed of compounds for which: R represents in position 3, 5, 7 or 8 of the imidazo [1,2-a] pyridine a hydrogen atom, or a (C 1 -C 10 ) alkyl group; the other substituents being defined as above.
- a sixth group of compounds consists of compounds for which:
- R represents in the 3, 5, 7 or 8 position of the imidazo [1,2-a] pyridine a hydrogen atom, or a methyl group; the other substituents being defined as above.
- a seventh group of compounds consists of compounds for which:
- R 2 and R 3 represent, independently of each other, a hydrogen atom or a (C 1 -C 10 ) alkyl group; the other substituents being defined as above.
- an eighth group of compounds consists of compounds for which:
- R 2 and R 3 represent, independently of one another, a hydrogen atom or a methyl group; the other substituents being defined as above.
- a ninth group of compounds is composed of compounds for which: R 4 represents a hydrogen atom, or a (C 1 -C 10) alkyl group, optionally substituted by a Rf group;
- Rf represents a (C 1 -C 10 ) alkoxy group; the other substituents being defined as above.
- R 4 represents a hydrogen atom, or a group selected from methyl, buethyl, methoxyethyl; the other substituents being defined as above.
- an eleventh group of compounds consists of compounds for which:
- the group R4 ⁇ ° is in position 2, 3 or 4 of the phenyl which carries it; the substituents are as defined above.
- a twelfth group of compounds consists of compounds for which:
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3- ⁇ ] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, (C 1 -C 10 ) alkyl, oxo, KRaRb; (C 1 -C 10 ) alkoxy, aryl, CONRaRb;
- Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 ) alkyl group
- X represents 1 or 2 hydrogen or halogen atoms
- R represents in the 3, 5, 7 or 8 position of the imidazo [1,2-a] pyridine a hydrogen atom, or a (C 1 -C 10 ) alkyl group
- R 2 and R 3 represent, independently of one another, a hydrogen atom or a (C 1 -C 10 ) alkyl group;
- R 4 represents a hydrogen atom, or a (C 1 -C 10 ) alkyl group, optionally substituted with an Rf group;
- Rf represents a (C 1 -C 10 ) alkoxy group; in the form of a base or an acid addition salt.
- a thirteenth group of compounds is composed of compounds for which:
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuryl, dihydrobenzofuryl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3- ⁇ ] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, methyl, oxo, NRaRb; ethoxy, phenyl, isopentyl, CONHC (CH 3 ) 3 , methoxy; Ra and Rb represent, independently of one another,
- X represents 1 or 2 hydrogen or fluorine atoms
- R represents in the 3, 5, 7 or 8 position of the imidazo [1,2-a] pyridine a hydrogen atom, or a methyl group;
- R 2 and R 3 represent, independently of one another, a hydrogen atom or a methyl group;
- R 4 represents a hydrogen atom, or a group selected from methyl, butyl, methoxy-ethyl; in the form of a base or an acid addition salt.
- a fourteenth group of compounds consists of compounds for which:
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3-e] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, (C 1 -C 10 ) alkyl, oxo, NRaRb; (C 1 -C 10 ) alkoxy, aryl, CONRaRb;
- Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 ) alkyl group
- X represents 1 or 2 hydrogen or halogen atoms
- R represents in the 3, 5, 7 or 8 position of the imidazo [1,2-a] pyridine a hydrogen atom, or a (C 1 -C 10 ) alkyl group
- R 2 and R 3 represent, independently of each other, a hydrogen atom or a (C 1 -C 10 ) alkyl group
- R 4 represents a hydrogen atom, or a (C 1 -C 10 ) alkyl group, optionally substituted with an Rf group;
- Rf represents a (C 1 -C 10 ) alkoxy group
- the group R4 ⁇ ° being in position 2, 3 or 4 of the phenyl which carries it; in the form of a base or an acid addition salt.
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuryl, dihydrobenzofuryl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3-e] pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl, pyrazolyl; these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, methyl, oxo, NRaRb; ethoxy, phenyl, isopentyl, CONHC (CH 3 ) 3, methoxy; Ra and Rb represent, independently of one another, a hydrogen
- X represents 1 or 2 hydrogen or fluorine atoms
- R represents in position 3, 5, 7 or 8 of the imidazo [1,2-a] pyridine a hydrogen atom, or a methyl group;
- R 2 and R 3 represent, independently of each other, a hydrogen atom or a methyl group
- R 1 represents a hydrogen atom, or a group selected from methyl, butyl, methoxy-ethyl
- the group R4 ⁇ ° being in position 2, 3 or 4 of the phenyl which carries it; in the form of a base or an acid addition salt.
- R 1 is isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo [1,3] dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo [2,3-e] pyridinyl, these groups possibly being substituted by one or more atoms or groups chosen independently of each other from halogen, (C 1 -C 10 ) alkyl, oxo, NRaRb, aryl;
- X represents a hydrogen
- R represents a hydrogen, or a (C 1 -C 10 ) alkyl group
- R 2 and R 3 represent, independently of one another, a hydrogen atom;
- R 4 represents a hydrogen atom, a (C 1 -C 10 ) alkyl group, this group being optionally substituted by an Rf group;
- Ra and Rb represent, independently of one another, a hydrogen atom or a group
- Rf represents a group (Ci-Qo) alkoxy; in the form of a base or an acid addition salt.
- the compounds of general formula (I) can be prepared according to the process described in Scheme 1.
- the compounds of the invention can be prepared according to Scheme 1 (Route A) by a metal catalyzed coupling reaction, such as palladium, between an imidazopyridine of the general formula (IV), wherein R and R1 are defined as previously and Y represents a halogen atom or a boron derivative, and a derivative of general formula (VII), in which R2, R3, R4 and X are defined as above and Z represents a boron or tin derivative if Y represents a halogen atom or a halogen if Y represents a boron derivative, to obtain the compounds of general formula (I), for example according to the method described by A. Gueiffer in HeIv. CMM. Acta 2001, 84, 3610-3615.
- the compounds of the general formula (XIII) can be subjected to a deprotection reaction, as described for example by T. Greene in “Protective Groups in Organic Synthesis” (Wiley Interscience), or by any another method known to those skilled in the art to obtain the compounds of general formula (I).
- the compounds of the invention can be prepared according to Scheme 1 (route D) by condensation between an aminopyridine of general formula (XIII), in which
- R2, R3, R4 and X are defined as above, R4 not being a hydrogen atom, and a haloketone of general formula (VI), in which R and R1 are defined as above to obtain the compounds of general formula ( I), for which R is in position 3 of the imidazopyridine nucleus.
- R 4 represents a hydrogen atom
- the compounds of general formula (XIV) may be fused with a haloketone of general formula (VI), in which R and R 1 are defined as above, to obtain the compounds of general formula (XII), for which R is in position 3 of imidazopyridine nucleus.
- the intermediates of the compounds of general formula (I) can be prepared according to the methods described in scheme 2.
- the compounds of general formula (IV) can be obtained by condensation between an aminopyridine of general formula (II), in which R is defined as above and Y represents a halogen atom or a boron derivative, and a haloketone of general formula (III), wherein R1 is defined as above for example according to the methods described by L. Cai in J. Med. Chem. 2007, 50, 4746, to obtain the compounds of general formula (IV), for which R is in position 5, 7 or 8 of the imidazopyridine ring.
- the compounds of general formula (IV) can be obtained by condensation between an aminopyridine of general formula (V), in which Y represents a halogen atom or a boron derivative, and a haloketone of general formula (VI), wherein R and R1 are defined as above to obtain the compounds of general formula (IV), for which R is in position 3 of the imidazopyridine ring.
- the compounds of general formula (XIIIa), (XIIIb) or (XIV) can be obtained by a metal catalyzed coupling reaction such as palladium, between an aminopyridine of general formula ( Va) or (Vb) protected by a protecting group R 'in which Y represents a halogen atom or a boron derivative, and a derivative of general formula (VIT), in which R2, R3 and X are defined as above, R6 is R4 (compounds XIHa and XIIIb) or a hydroxyl protecting group PG (compounds XTV) and Z is a boron or tin derivative if Y is halogen or halogen if Y is a boron derivative.
- a metal catalyzed coupling reaction such as palladium
- the compounds of general formula (VIII) can be obtained from the compounds of general formula (II), for example according to the method described by C. Townsend in Syn. Common. 1997, 27, 1763-1765.
- the compounds of general formula (EX) or (XI) in which R, R2, R3 and X are defined as above and R6 represents a group R4 (IX compounds) or a PG protecting group (compounds XI) may be obtained by a a metal-catalyzed coupling reaction, such as palladium, between an imidazopyridine of general formula (VIQ), in which R is defined as above and Y represents a halogen atom or a boron derivative, and a derivative of general formula (VII), wherein R2, R3 and X are defined as above, R6 represents a group R4 or a PG protecting group and Z represents a boron or tin derivative if Y represents a halogen atom or a halogen if
- the above intermediaries may be subject, if desired and if necessary, any protection / deprotection reactions known to those skilled in the art before and / or after any reactions described in the above diagrams.
- reaction By way of examples of reactions, mention may be made of: esterification or acid function amidification reactions, carbamoylation reactions, ester function hydrolysis reactions, hydroxyl function conversion reactions in alkoxy function, transition metal-catalyzed coupling reactions, protective reactions of the reactive functional groups, protective group removal reactions which can be carried by the protected reactive functions, salification reactions by an inorganic or organic acid or a base for to obtain the corresponding salt, the resolution reactions of the racemic enantiomeric forms, said products of formula (I) thus obtained being, if appropriate, in all the possible isomeric forms racemic, enantiomers and diastereoisomers.
- the compound of formula (VIII-I) can be prepared, for example, according to the method described in example No. 3.
- a first step it is possible to carry out a condensation between an aminopyridine substituted with a boron derivative such that for example, 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-ylamine and ethyl 2-bromoacetate.
- a second step the compound is subjected to a cyclization and chlorination reaction in the presence of a chlorinating agent such as phosphorus oxychloride which leads to the compound (VIII-I).
- a chlorinating agent such as phosphorus oxychloride
- the compound of formula (IX-I) can be prepared by a metal catalyzed coupling reaction, such as palladium, between 6-bromo-2-chloroimidazo [1,2-a] pyridine and acid 3 - (hydroxymethyl) phenylboronic, as described in Example No. 2.
- the compound of formula (IX-2) can be prepared by a metal catalyzed coupling reaction, such as palladium, between the compound of formula (VIII-I) and 2- (3-bromophenyl) propan-2 -ol, as described in Example No. 7
- the compound of formula (XI-I) can be prepared by the action of tert-butylchlorodimethylsilane on the compound of formula (IX-I), in the presence of a base such as than imidazole and in a solvent such as tetrahydrofuran, as described in Example No. 4.
- the compound of formula (XI-2) can be prepared by a metal-catalyzed coupling reaction, such as palladium, between (2-bromobenzyloxy) tert-butyldimethylsilane and the compound of formula (VIII-I), such as as described in Example No. 3.
- the compound of formula (XI-3) can be prepared by a metal catalyzed coupling reaction, such as palladium, between (2-bromo-6-fluorobenzyloxy) tert-butyldimethylsilane and the compound of formula 1), as described in Example No. 13.
- the compound of formula (XI-4) can be prepared by a metal catalyzed coupling reaction, such as palladium, between (3-bromo-2,6-difluorobenzyloxy) tert-butyldimethylsilane and the compound of formula ( VIII-I), as described in Example No. 14.
- the compound of formula (XIII-I) can be prepared by a metal-catalyzed coupling reaction, such as palladium, between 5-bromo-2 aminopyridine and a boronic acid derivative, for example 3- (hydroxymethyl) phenylboronic acid, as described in Example No. 6.
- the compound of formula (XIII-2) can be prepared by a metal catalyzed coupling reaction, such as palladium, between 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl) pyridin-2-ylamine and 2- (3-bromophenyl) propan-2-ol, as described in Example No. 8
- the compound of formula (XIV-I) can be prepared by the action of (tert-butylchlorodimethyl) silane on the compound of formula (XIH-1) in a solvent, for example tetrahydrofuran, in the presence of a base such as imidazole, as described in Example No. 6.
- the compound of formula (XIV-2) can be prepared by a metal catalyzed coupling reaction, such as palladium, between 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl) pyridin-2-ylamine and 3- (tertbutyldimethylsilyloxymethyl) -2,4-difluorobromobenzene, as described in Example No. 10
- the compound of formula (XIV-3) can be prepared by a metal catalyzed coupling reaction, such as palladium, between 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl) pyridin-2-ylamine and 2- (tertbutyldimethylsilyloxymethyl) -3-fluorobromobenzene, as described in Example No. 9
- Example 4 ⁇ 3- [2- (1H-Indol-6-yl) imidazo [1,2-a] pyridin-6-yl] phenyl ⁇ methanol hydrochloride (1: 1) (Compound Compound No. 33) 4.1 Ethyl (5-bromo-2-imino-1H-pyridin-1-yl) acetate hydrobromide
- 210 mg of tetrabutylammonium fluoride are introduced into a flask containing 180 mg of 6- [3 - [(tert-butyldimethylsilanyloxy) methyl] phenyl] -2- (1H-indol-6-yl) imidazo [1,2-a] pyridine in 4 ml of tetrahydrofuran.
- the reaction mixture is stirred at room temperature for 48 h and is concentrated under reduced pressure.
- the residue is purified by chromatography on silica gel, eluting with a dichloromethane / methanol mixture. 117 mg of compound are obtained.
- 2,3-dioxaborolan-2-yl) imidazo [1,2-a] pyridine obtained in 3.2, 20.35 g of cesium carbonate and 0.85 g of [1,1'-bis (diphenylphosphino) ferrocene ] dichloropalladium.
- the mixture is stirred under reflux for 2 hours with tetrahydrofuran. After cooling to room temperature, the solvents are evaporated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase washed twice with a saturated solution of sodium chloride is then dried over magnesium sulfate and concentrated under reduced pressure.
- the organic phase is decanted, washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate.
- the compound is purified by chromatography eluting with a mixture of dichloromethane and methanol. 4.25 g of white solid are obtained.
- 0.3 mmole of heteroarylboronic acid is weighed into a reaction tube, 0.36 mmol of finely powdered potassium phosphate and dried, 0.5 ml of degassed anhydrous ethanol, 0.18 mmol of the compound obtained are successively added thereto. in 7.2 in solution in 2 ml of toluene then the tube is purged with argon. 1 ml of the solution prepared in 12.1 is then added. The tube is closed and stirred for 16 h at 75 ° C. 0.5 ml of solution prepared in
- the cooled solution is diluted with 5 ml of ethyl acetate, 100 mg of silica-propanethiol (Biotage Si-Thiol) and the mixture is stirred for 4 hours at room temperature. The solid is separated by filtration and washed by
- 0.3 mmole of heteroarylboronic acid is weighed into a reaction tube, 0.36 mmol of finely powdered potassium phosphate and dried, 0.5 ml of degassed anhydrous ethanol, 0.18 mmol of the compound obtained are successively added thereto. in 13.1 in solution in 2 ml of toluene and the tube is purged with argon. 1 ml of the solution prepared in 12.1 is then added. The tube is closed and stirred for 16 h at 75 ° C. 0.5 ml of solution prepared in 12.2.1 is added and the heating is continued for 10 h.
- the cooled solution is diluted with 5 ml of ethyl acetate, 100 mg of silica-propanethiol (Biotage Si-Thiol) and the mixture is stirred for 4 hours at room temperature.
- the solid is filtered off and washed with 2x2 ml THF.
- the filtrate is evaporated to dryness and the residue is used as it is for the next step.
- 13.2.2 In a reaction tube, the compound obtained in 13.2.1, 0.36 mmol of cesium fluoride dissolved in 3 ml of methanol and 21 ⁇ l of acetic acid is mixed. The solution is stirred for 16 hours at room temperature, the solvents are then evaporated. The residue is purified by HPLC eluting with acetonitrile / water.
- the expected compound is obtained which is purified by HPLC eluting with an acetonitrile / water mixture.
- Table 2 illustrates the chemical structures of general formula (I);
- Table 3 illustrates the physicochemical characteristics of some examples of compounds according to the invention. In these paintings:
- the column “PF” gives the melting points of the products in degrees Celsius (oC) or, when the products have been isolated in the form of amorphous solid or oil, they are characterized by their mass [ M + H];
- N.D. means undetermined
- the compounds according to the invention have been the subject of pharmacological tests for determining their modulatory effect on NOT.
- the activity of the compounds according to the invention was evaluated on a cell line (N2A) endogenously expressing the Nurr1 mouse receptor and stably transfected with the NOT binding response element (NBRE) coupled to the luciferase reporter gene.
- N2A cell line
- NBRE NOT binding response element
- the Neuro-2A cell line comes from a standard commercial source (ATCC).
- the Neuro-2A clone was obtained from a spontaneous tumor from an albino mouse A strain by RJ Klebe et al. This Neuro-2A line is then stably transfected with 8NBRE-luciferase.
- N2A-8NBRE cells are grown to confluence in 75 cm 2 culture flasks containing DMEM supplemented with 10% fetal calf serum, 4.5 g / L glucose and 0.4 mg / ml Geneticin. .
- the cells are recovered with 0.25% trypsin for 30 seconds and then resuspended in DMEM without phenol red containing 4.5 g / l of glucose, 10% of delipidated serum Hyclone and deposited in white plates 96 wells with transparent bottom.
- the cells are deposited at a rate of 60,000 per well in 75 ⁇ L for 24 hours before the addition of the products.
- the products are applied in 25 ⁇ l and incubated for a further 24 hours.
- an equivalent volume (100 ⁇ L) of Steadylite is added to each well, then waited for 30 minutes to obtain a complete lysis of the cells and the maximum production of the signal.
- the plates are then measured in a microplate luminescence counter after being sealed with an adhesive film.
- the products are prepared as a stock solution at 10 -2 M, then diluted in 100% DMSO Each product concentration is previously diluted in culture medium before incubation with the cells thus containing 0.625% final of DMSO.
- Compounds Nos. 6, 7, 24, 50, 68, 79 and 86 have shown an EC 50 of 0.9, 1.6, 52, 202, 20, 5 and 71 nM, respectively. according to the invention have a modulating effect of NOT.
- the compounds according to the invention can therefore be used for the preparation of medicaments for their therapeutic application in the treatment or prevention of diseases involving NOT receptors.
- the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
- neurodegenerative diseases such as Parkinson's disease, Alzheimer's, tauopathies (eg, supranuclear progressive paralysis, fronto-temporal dementia, corticobasal degeneration, Pick's disease); brain trauma such as ischemia and head trauma and epilepsy; psychiatric illnesses such as schizophrenia, depression, substance dependence, attention deficit disorder and hyperactivity disorder; inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis; osteoarthritis, Crohn's disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune diseases such as type 1 diabetes, lupus, scleroderma, Guillain-Barré syndrome, Addison's disease and other immuno-mediated diseases; osteoporosis; cancers.
- neurodegenerative diseases such as Parkinson's disease, Alzheimer's, tauopathies (e
- the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
- These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.
- excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
- the active ingredient of formula (I) above, or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for prophylaxis or treatment of the disorders or diseases above.
- Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
- the compounds according to the invention can be used in creams, gels, ointments or lotions.
- a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
- the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
- the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.
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CN200980118314.9A CN102036987B (zh) | 2008-03-21 | 2009-03-20 | 2-杂芳基-6-苯基咪唑并[1,2-a]吡啶的多取代衍生物及其制备方法和治疗用途 |
CA2719127A CA2719127C (fr) | 2008-03-21 | 2009-03-20 | Derives polysubstitues de 2-heteroaryl-6-phenyl-imidazo[1,2-.alpha.]pyridines, leur preparation et leur application en therapeutique |
MX2010010261A MX2010010261A (es) | 2008-03-21 | 2009-03-20 | Derivados polisustituidos de 2-heteroaril-6-fenil-imidazo [1,2-a] piridinas, su preparacion y su aplicación en terapeutica. |
BRPI0908907A BRPI0908907A2 (pt) | 2008-03-21 | 2009-03-20 | derivados polissubstituídos de 2-heteroaril-6-fenil-imidazo[1,2-alfa]piridinas, e o respectivo preparo e a respectiva aplicação em terapêutica |
EA201071113A EA201071113A1 (ru) | 2008-03-21 | 2009-03-20 | ПОЛИЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 2-ГЕТЕРОАРИЛ-6-ФЕНИЛИМИДАЗО[1,2-α] ПИРИДИНОВ, ИХ ПОЛУЧЕНИЕ И ИХ ПРИМЕНЕНИЕ В ТЕРАПИИ |
EP09754045.4A EP2262805B1 (fr) | 2008-03-21 | 2009-03-20 | Dérivés polysubstitues de 2-heteroaryl-6-phenyl-imidazo[1,2-a]pyridines, leur préparation et leur application en thérapeutique |
NZ588084A NZ588084A (en) | 2008-03-21 | 2009-03-20 | POLYSUBSTITUTED DERIVATIVES OF 2-HETEROARYL-6-PHENYLIMIDAZO[1,2-a]PYRIDINES, AND PREPARATION AND THERAPEUTIC USE THEREOF |
JP2011500262A JP5508386B2 (ja) | 2008-03-21 | 2009-03-20 | 2−ヘテロアリール−6−フェニルイミダゾ[1,2−a]ピリジンの多置換誘導体、ならびにこの調製および治療への使用 |
AU2009253235A AU2009253235B8 (en) | 2008-03-21 | 2009-03-20 | Polysubstituted derivatives of 2-heteroaryl-6-phenyl-imidazo[1,2- a] pyridines, and preparation and therapeutic use thereof |
US12/881,815 US8338451B2 (en) | 2008-03-21 | 2010-09-14 | Polysubstituted derivatives of 2-heteroaryl-6-phenylimidazo[1,2-a]pyridines, and preparation and therapeutic use thereof |
IL208245A IL208245A0 (en) | 2008-03-21 | 2010-09-19 | Polysubstituted derivatives of 2-heteroaryl-6-phenyl-imidazo[1,2-a]pyridines, and preparation and therapeutic use thereof |
ZA2010/06726A ZA201006726B (en) | 2008-03-21 | 2010-09-20 | Polysubstituted derivatives of 2-heteroaryl-6-phenyl-imidazo[1,2-a] pyridines,and preparation and therapeutic use thereof |
MA33275A MA32249B1 (fr) | 2008-03-21 | 2010-10-19 | Dérivés polysubstitues de 2-heteroaryl-6-phenyl-imidazo[1,2- a]pyridines, leur préparation et leur application en thérapeutique |
US13/713,775 US20130123288A1 (en) | 2008-03-21 | 2012-12-13 | POLYSUBSTITUTED DERIVATIVES OF 2-HETEROARYL-6-PHENYLIMIDAZO[1,2-a]PYRIDINES, AND PREPARATION AND THERAPEUTIC USE THEREOF |
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AU (1) | AU2009253235B8 (fr) |
BR (1) | BRPI0908907A2 (fr) |
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WO2013029338A1 (fr) * | 2011-09-01 | 2013-03-07 | Glaxo Group Limited | Nouveaux composés |
CN111978325A (zh) * | 2019-05-22 | 2020-11-24 | 上海道熵生物科技有限公司 | 咪唑并哒嗪类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
CN111978318A (zh) * | 2019-05-22 | 2020-11-24 | 上海道熵生物科技有限公司 | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
CN111978325B (zh) * | 2019-05-22 | 2023-11-17 | 中国药科大学 | 咪唑并哒嗪类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
WO2022210999A1 (fr) | 2021-04-02 | 2022-10-06 | クミアイ化学工業株式会社 | Composé hétérocyclique et son utilisation |
WO2023285465A1 (fr) * | 2021-07-16 | 2023-01-19 | Sanofi | Dérivés de 6h-imidazo[1,2-a]pyrrolo[2,3-e]pyridine destinés à être utilisés en thérapie |
WO2023285466A1 (fr) * | 2021-07-16 | 2023-01-19 | Sanofi | Dérivés d'imidazo[1,2-b][1,2,4]triazol pour utilisation en thérapie |
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