CA2580621A1

CA2580621A1 - Nouveaux antibiotiques bicycliques

Nouveaux antibiotiques bicycliques Download PDF

Info

Publication number: CA2580621A1
Authority: CA; Canada
Prior art keywords: methoxy; pyran; alpha; tetrahydro; dihydro
Prior art date: 2004-09-24
Legal status : Abandoned

Application number

CA002580621A

Other languages

English (en)

Inventor

Christian Hubschwerlen

Jean-Philippe Surivet

Cornelia Zumbrunn-Acklin

Current Assignee

Actelion Pharmaceuticals Ltd

Original Assignee

Individual

Priority date

2004-09-24

Filing date

2005-09-20

Publication date

2006-03-30

2005-09-20 Application filed by Individual filed Critical Individual

2006-03-30 Publication of CA2580621A1 publication Critical patent/CA2580621A1/fr

Status Abandoned legal-status Critical Current

Links

229940088710 antibiotic agent Drugs 0.000 title abstract description 8
239000003242 anti bacterial agent Substances 0.000 title abstract description 7
125000002619 bicyclic group Chemical group 0.000 title description 10
125000000217 alkyl group Chemical group 0.000 claims abstract description 77
229910052736 halogen Inorganic materials 0.000 claims abstract description 32
125000003545 alkoxy group Chemical group 0.000 claims abstract description 29
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 25
150000002367 halogens Chemical group 0.000 claims abstract description 22
125000003118 aryl group Chemical group 0.000 claims abstract description 20
229910052720 vanadium Inorganic materials 0.000 claims abstract description 20
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 18
125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 13
150000001875 compounds Chemical class 0.000 claims description 450
-1 OCH2 Chemical group 0.000 claims description 239
239000000203 mixture Substances 0.000 claims description 194
LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 118
229910052739 hydrogen Inorganic materials 0.000 claims description 67
239000001257 hydrogen Substances 0.000 claims description 66
239000002904 solvent Substances 0.000 claims description 44
VUHCPMIDSUGHNO-UHFFFAOYSA-N 6-methoxy-1,5-naphthyridin-4-amine Chemical compound N1=CC=C(N)C2=NC(OC)=CC=C21 VUHCPMIDSUGHNO-UHFFFAOYSA-N 0.000 claims description 43
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 37
125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 34
208000015181 infectious disease Diseases 0.000 claims description 27
SZHYPQDQYNLZJP-UHFFFAOYSA-N 3-oxo-4h-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid Chemical compound S1CC(=O)NC2=NC(C(=O)O)=CC=C21 SZHYPQDQYNLZJP-UHFFFAOYSA-N 0.000 claims description 25
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 22
150000003839 salts Chemical class 0.000 claims description 22
DMBFCTCQROWGDZ-UHFFFAOYSA-N 8-aminoquinoline-2-carbonitrile Chemical compound C1=C(C#N)N=C2C(N)=CC=CC2=C1 DMBFCTCQROWGDZ-UHFFFAOYSA-N 0.000 claims description 20
229920002554 vinyl polymer Polymers 0.000 claims description 17
125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 claims description 13
229940080818 propionamide Drugs 0.000 claims description 13
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
238000011282 treatment Methods 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 9
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 8
229940002612 prodrug Drugs 0.000 claims description 8
239000000651 prodrug Substances 0.000 claims description 8
CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 7
JHIAOWGCGNMQKA-UHFFFAOYSA-N 2-methyl-8-quinolinamine Chemical compound C1=CC=C(N)C2=NC(C)=CC=C21 JHIAOWGCGNMQKA-UHFFFAOYSA-N 0.000 claims description 6
125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 6
125000004181 carboxyalkyl group Chemical group 0.000 claims description 6
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 5
238000004519 manufacturing process Methods 0.000 claims description 4
229910052700 potassium Inorganic materials 0.000 claims description 4
HDUOQGPJPLEPTI-KDOFPFPSSA-N (2s,5r)-5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethylamino)-n-(6-methoxy-1,5-naphthyridin-4-yl)oxane-2-carboxamide Chemical compound O1CCOC(C=N2)=C1C=C2CN[C@@H](CO1)CC[C@H]1C(=O)NC1=CC=NC2=CC=C(OC)N=C21 HDUOQGPJPLEPTI-KDOFPFPSSA-N 0.000 claims description 3
RBNCELKPLQWOPL-KNQAVFIVSA-N (2s,5r)-n-(2-cyanoquinolin-8-yl)-5-(2,3-dihydro-1,4-benzodioxin-6-ylmethylamino)oxane-2-carboxamide Chemical compound O1CCOC2=CC(CN[C@@H]3CC[C@H](OC3)C(NC=3C4=NC(=CC=C4C=CC=3)C#N)=O)=CC=C21 RBNCELKPLQWOPL-KNQAVFIVSA-N 0.000 claims description 3
SVAYVFWIEYFKAO-XLIONFOSSA-N (2s,5r)-n-(2-cyanoquinolin-8-yl)-5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethylamino)oxane-2-carboxamide Chemical compound O1CCOC(C=N2)=C1C=C2CN[C@@H](CO1)CC[C@H]1C(=O)NC1=CC=CC2=CC=C(C#N)N=C12 SVAYVFWIEYFKAO-XLIONFOSSA-N 0.000 claims description 3
QQMWQCBLSYLUIU-MOPGFXCFSA-N (3r,6s)-n-(1-benzofuran-2-ylmethyl)-6-[(3-methoxyquinolin-5-yl)oxymethyl]oxan-3-amine Chemical compound C1=CC=C2OC(CN[C@@H]3CC[C@H](OC3)COC3=CC=CC4=NC=C(C=C43)OC)=CC2=C1 QQMWQCBLSYLUIU-MOPGFXCFSA-N 0.000 claims description 3
MTTWQPKKDFKQPE-MSOLQXFVSA-N (3r,6s)-n-(1-benzofuran-2-ylmethyl)-6-[(6-methoxy-1,5-naphthyridin-4-yl)oxymethyl]oxan-3-amine Chemical compound C1=CC=C2OC(CN[C@@H]3CC[C@H](OC3)COC3=CC=NC4=CC=C(N=C43)OC)=CC2=C1 MTTWQPKKDFKQPE-MSOLQXFVSA-N 0.000 claims description 3
WHCPNFUAESTIFK-QUCCMNQESA-N (3r,6s)-n-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-6-[(6-methoxyquinolin-4-yl)oxymethyl]oxan-3-amine Chemical compound O1CCOC2=CC(CN[C@@H]3CC[C@H](OC3)COC3=CC=NC4=CC=C(C=C43)OC)=CC=C21 WHCPNFUAESTIFK-QUCCMNQESA-N 0.000 claims description 3
XQPROHOFNUSWCG-APWZRJJASA-N (3r,6s)-n-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-6-[(6-methoxyquinolin-4-yl)oxymethyl]oxan-3-amine Chemical compound O1CCOC(C=N2)=C1C=C2CN[C@@H](CO1)CC[C@H]1COC1=CC=NC2=CC=C(OC)C=C21 XQPROHOFNUSWCG-APWZRJJASA-N 0.000 claims description 3
RYJFLQNHKUSOSN-QUURXOELSA-N 2-[(2r,3r,6s)-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethylamino)-6-[(6-methoxyquinolin-4-yl)oxymethyl]oxan-2-yl]ethanol Chemical compound O1CCOC2=CC(CN[C@@H]3CC[C@H](O[C@@H]3CCO)COC3=CC=NC4=CC=C(C=C43)OC)=CC=C21 RYJFLQNHKUSOSN-QUURXOELSA-N 0.000 claims description 3
LZNFVGXESFCQMD-UHFFFAOYSA-N 3-[1-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl]piperidin-3-yl]-n-(6-methoxy-1,5-naphthyridin-4-yl)propanamide Chemical compound O1CCOC2=CC(CCN3CCCC(C3)CCC(=O)NC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 LZNFVGXESFCQMD-UHFFFAOYSA-N 0.000 claims description 3
RPBQBSWZBRIJSO-UHFFFAOYSA-N 3-methoxyquinoxalin-5-amine Chemical compound C1=CC=C(N)C2=NC(OC)=CN=C21 RPBQBSWZBRIJSO-UHFFFAOYSA-N 0.000 claims description 3
BHSRBGVGYNGPAV-UHFFFAOYSA-N 4-[3-[1-(1-benzofuran-2-ylmethyl)piperidin-3-yl]propoxy]-6-methoxyquinoline Chemical compound C1=CC=C2OC(CN3CCCC(C3)CCCOC3=CC=NC4=CC=C(C=C43)OC)=CC2=C1 BHSRBGVGYNGPAV-UHFFFAOYSA-N 0.000 claims description 3
PTJPUAAPHWGXIK-SJORKVTESA-N 6-[[[(3r,6s)-6-[(3-methoxyquinolin-5-yl)oxymethyl]oxan-3-yl]amino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN[C@@H]3CC[C@H](OC3)COC3=CC=CC4=NC=C(C=C43)OC)=CC=C21 PTJPUAAPHWGXIK-SJORKVTESA-N 0.000 claims description 3
HWRPVSZEPDHAPX-SJORKVTESA-N 6-[[[(3r,6s)-6-[(6-methoxy-1,5-naphthyridin-4-yl)oxymethyl]oxan-3-yl]amino]methyl]-4h-1,4-benzothiazin-3-one Chemical compound S1CC(=O)NC2=CC(CN[C@@H]3CC[C@H](OC3)COC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 HWRPVSZEPDHAPX-SJORKVTESA-N 0.000 claims description 3
WCUIUMSVLSFGOF-CVEARBPZSA-N 6-[[[(3r,6s)-6-[(6-methoxy-1,5-naphthyridin-4-yl)oxymethyl]oxan-3-yl]amino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN[C@@H]3CC[C@H](OC3)COC3=CC=NC4=CC=C(N=C43)OC)=CC=C21 WCUIUMSVLSFGOF-CVEARBPZSA-N 0.000 claims description 3
AEXGVGHPHQYFRY-WBVHZDCISA-N 6-[[[(3r,6s)-6-[(6-methoxyquinazolin-4-yl)oxymethyl]oxan-3-yl]amino]methyl]-4h-pyrido[3,2-b][1,4]thiazin-3-one Chemical compound S1CC(=O)NC2=NC(CN[C@@H]3CC[C@H](OC3)COC3=NC=NC4=CC=C(C=C43)OC)=CC=C21 AEXGVGHPHQYFRY-WBVHZDCISA-N 0.000 claims description 3
OVLUIXMXFMKOQJ-MJGOQNOKSA-N 6-[[[(3r,6s)-6-[(6-methoxyquinolin-4-yl)oxymethyl]oxan-3-yl]amino]methyl]-4h-1,4-benzoxazin-3-one Chemical compound O1CC(=O)NC2=CC(CN[C@@H]3CC[C@H](OC3)COC3=CC=NC4=CC=C(C=C43)OC)=CC=C21 OVLUIXMXFMKOQJ-MJGOQNOKSA-N 0.000 claims description 3
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ATPPWLOWFZEMHD-RTBURBONSA-N COC=1C=C2C(=CC=NC2=CC1)CC[C@@H]1CC[C@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O Chemical compound COC=1C=C2C(=CC=NC2=CC1)CC[C@@H]1CC[C@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O ATPPWLOWFZEMHD-RTBURBONSA-N 0.000 claims description 3
XYSAVGPMHCKSAR-IAGOWNOFSA-N COC=1C=C2C(=NC=NC2=CC1)CC[C@H]1CC[C@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O Chemical compound COC=1C=C2C(=NC=NC2=CC1)CC[C@H]1CC[C@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O XYSAVGPMHCKSAR-IAGOWNOFSA-N 0.000 claims description 3
AEXGVGHPHQYFRY-DOTOQJQBSA-N COC=1C=C2C(=NC=NC2=CC1)OC[C@H]1CC[C@@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O Chemical compound COC=1C=C2C(=NC=NC2=CC1)OC[C@H]1CC[C@@H](CO1)NCC=1C=CC=2SCC(NC2N1)=O AEXGVGHPHQYFRY-DOTOQJQBSA-N 0.000 claims description 3
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KWVGEELOIPGDKQ-DLBZAZTESA-N COC=1C=NC2=CC=CC(=C2C1)OC[C@H]1CC[C@@H](CO1)NCC=1C=CC=2OCC(NC2N1)=O Chemical compound COC=1C=NC2=CC=CC(=C2C1)OC[C@H]1CC[C@@H](CO1)NCC=1C=CC=2OCC(NC2N1)=O KWVGEELOIPGDKQ-DLBZAZTESA-N 0.000 claims description 3
VPQIRDWKIZGQOY-KGLIPLIRSA-N COC=1C=NC2=CC=CC(=C2N1)OC[C@@H]1CC[C@H](CO1)NC(=O)C=1C=CC=2SCC(NC2N1)=O Chemical compound COC=1C=NC2=CC=CC(=C2N1)OC[C@@H]1CC[C@H](CO1)NC(=O)C=1C=CC=2SCC(NC2N1)=O VPQIRDWKIZGQOY-KGLIPLIRSA-N 0.000 claims description 3
AEQXXIILHBADBJ-UXHICEINSA-N O1CCOC2=C1C=CC(=C2)CN[C@@H]2CC[C@H](OC2)COC2=CC=NC1=CC=C(C=C21)C#N Chemical compound O1CCOC2=C1C=CC(=C2)CN[C@@H]2CC[C@H](OC2)COC2=CC=NC1=CC=C(C=C21)C#N AEQXXIILHBADBJ-UXHICEINSA-N 0.000 claims description 3
OHNMCTWSCQOFCN-RBUKOAKNSA-N O1CCOC2=C1C=CC(=C2)CN[C@@H]2CN[C@H](CC2)COC2=CC=NC1=CC=C(C=C21)OC Chemical compound O1CCOC2=C1C=CC(=C2)CN[C@@H]2CN[C@H](CC2)COC2=CC=NC1=CC=C(C=C21)OC OHNMCTWSCQOFCN-RBUKOAKNSA-N 0.000 claims description 3
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LTQGLQZWHUZZEH-UXHICEINSA-N O=C1CSC2=C(N1)C=C(C=C2)CN[C@@H]2CC[C@H](OC2)COC=2C=CC=C1C=CC(=NC21)C#N Chemical compound O=C1CSC2=C(N1)C=C(C=C2)CN[C@@H]2CC[C@H](OC2)COC=2C=CC=C1C=CC(=NC21)C#N LTQGLQZWHUZZEH-UXHICEINSA-N 0.000 claims description 3
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ILPPLMBJCXRLGK-WTNAPCKOSA-N O[C@@H](CC1=C2C=C(C=NC2=CC=C1)OC)[C@@H]1CC[C@H](CO1)NCC=1C=CC=2OCC(NC2N1)=O Chemical compound O[C@@H](CC1=C2C=C(C=NC2=CC=C1)OC)[C@@H]1CC[C@H](CO1)NCC=1C=CC=2OCC(NC2N1)=O ILPPLMBJCXRLGK-WTNAPCKOSA-N 0.000 claims description 3
NGRPYWAJHHTWDY-JLSDUUJJSA-N O[C@@H](CC1=CC=NC2=CC=C(N=C12)OC)[C@@H]1CC[C@H](CO1)NC(=O)C=1C=CC=2SCC(NC2N1)=O Chemical compound O[C@@H](CC1=CC=NC2=CC=C(N=C12)OC)[C@@H]1CC[C@H](CO1)NC(=O)C=1C=CC=2SCC(NC2N1)=O NGRPYWAJHHTWDY-JLSDUUJJSA-N 0.000 claims description 3
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230000000877 morphologic effect Effects 0.000 claims description 3
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