ES2392819T3

ES2392819T3 - Nuevos compuestos antibacterianos heterocíclicos

Nuevos compuestos antibacterianos heterocíclicos Download PDF

Info

Publication number: ES2392819T3
Authority: ES; Spain
Prior art keywords: ethyl; oxo; carboxy; quinolyl; methylanilino
Prior art date: 2001-06-15
Legal status : Expired - Lifetime

Application number

ES02763207T

Other languages

English (en)

Spanish (es)

Inventor

Chengxin Zhi

George E. Wright

Current Assignee

Microbiotix Inc

Original Assignee

Microbiotix Inc

Priority date

2001-06-15

Filing date

2002-06-17

Publication date

2012-12-14

2002-06-17 Application filed by Microbiotix Inc filed Critical Microbiotix Inc

2012-12-14 Application granted granted Critical

2012-12-14 Publication of ES2392819T3 publication Critical patent/ES2392819T3/es

2022-06-17 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 391
125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 38
230000000844 anti-bacterial effect Effects 0.000 title description 14
-1 hydroxy, nitro, amino Chemical group 0.000 claims abstract description 199
125000001424 substituent group Chemical group 0.000 claims abstract description 97
229910052799 carbon Inorganic materials 0.000 claims abstract description 68
125000005843 halogen group Chemical group 0.000 claims abstract description 67
125000003118 aryl group Chemical group 0.000 claims abstract description 61
125000000217 alkyl group Chemical group 0.000 claims abstract description 58
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 40
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 38
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 36
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 36
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
125000003545 alkoxy group Chemical group 0.000 claims abstract description 33
229920006395 saturated elastomer Polymers 0.000 claims abstract description 29
229910052717 sulfur Inorganic materials 0.000 claims abstract description 28
150000002148 esters Chemical class 0.000 claims abstract description 24
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 22
125000005842 heteroatom Chemical group 0.000 claims abstract description 21
125000003342 alkenyl group Chemical group 0.000 claims abstract description 20
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 20
125000000304 alkynyl group Chemical group 0.000 claims abstract description 19
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
150000003839 salts Chemical class 0.000 claims abstract description 17
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 16
125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 16
125000004429 atom Chemical group 0.000 claims abstract description 15
125000004414 alkyl thio group Chemical group 0.000 claims abstract description 12
125000003107 substituted aryl group Chemical group 0.000 claims abstract description 12
125000002252 acyl group Chemical group 0.000 claims abstract description 11
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 9
229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
125000005119 alkyl cycloalkyl group Chemical group 0.000 claims abstract description 8
125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 7
125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 7
125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 6
125000001769 aryl amino group Chemical group 0.000 claims abstract description 5
125000000278 alkyl amino alkyl group Chemical group 0.000 claims abstract description 4
125000005110 aryl thio group Chemical group 0.000 claims abstract description 4
125000004104 aryloxy group Chemical group 0.000 claims abstract description 4
125000005844 heterocyclyloxy group Chemical group 0.000 claims abstract description 4
150000004677 hydrates Chemical class 0.000 claims abstract description 4
125000004043 oxo group Chemical group O=* 0.000 claims abstract description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 7
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 73
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 72
238000000034 method Methods 0.000 claims description 46
230000001580 bacterial effect Effects 0.000 claims description 43
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 40
229940035893 uracil Drugs 0.000 claims description 40
241000894006 Bacteria Species 0.000 claims description 33
241000894007 species Species 0.000 claims description 32
239000003242 anti bacterial agent Substances 0.000 claims description 29
UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 28
208000035143 Bacterial infection Diseases 0.000 claims description 26
101710183280 Topoisomerase Proteins 0.000 claims description 25
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
208000022362 bacterial infectious disease Diseases 0.000 claims description 23
239000008194 pharmaceutical composition Substances 0.000 claims description 22
241000192125 Firmicutes Species 0.000 claims description 20
230000003115 biocidal effect Effects 0.000 claims description 20
108020000946 Bacterial DNA Proteins 0.000 claims description 18
230000000694 effects Effects 0.000 claims description 18
239000003814 drug Substances 0.000 claims description 14
238000002360 preparation method Methods 0.000 claims description 13
108020004414 DNA Proteins 0.000 claims description 12
241000194033 Enterococcus Species 0.000 claims description 12
150000003254 radicals Chemical class 0.000 claims description 12
238000011282 treatment Methods 0.000 claims description 12
241000588724 Escherichia coli Species 0.000 claims description 11
LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 11
241000193830 Bacillus <bacterium> Species 0.000 claims description 9
241000191940 Staphylococcus Species 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 9
241000193403 Clostridium Species 0.000 claims description 8
241000186781 Listeria Species 0.000 claims description 8
241000194017 Streptococcus Species 0.000 claims description 8
229940124307 fluoroquinolone Drugs 0.000 claims description 8
125000001188 haloalkyl group Chemical group 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 8
241000204031 Mycoplasma Species 0.000 claims description 7
150000002367 halogens Chemical class 0.000 claims description 7
230000005764 inhibitory process Effects 0.000 claims description 7
241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims description 6
241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
241000589517 Pseudomonas aeruginosa Species 0.000 claims description 5
241000607764 Shigella dysenteriae Species 0.000 claims description 5
241000607626 Vibrio cholerae Species 0.000 claims description 5
230000001093 anti-cancer Effects 0.000 claims description 5
230000000840 anti-viral effect Effects 0.000 claims description 5
229940007046 shigella dysenteriae Drugs 0.000 claims description 5
229940118696 vibrio cholerae Drugs 0.000 claims description 5
LYNNETNJMPHXJF-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C=3C(=CC(F)=CC=3)F)F)C(=O)C=2)=C1 LYNNETNJMPHXJF-UHFFFAOYSA-N 0.000 claims description 4
CTTHOSAXMLPGMG-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[7-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]heptyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 CTTHOSAXMLPGMG-UHFFFAOYSA-N 0.000 claims description 4
FMNROQLLAZZFGR-UHFFFAOYSA-N 1-ethyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4CC)=O)=CC=3F)F)C(=O)C=2)=C1 FMNROQLLAZZFGR-UHFFFAOYSA-N 0.000 claims description 4
NNTJRXFQKMHWCH-UHFFFAOYSA-N 1-ethyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(CC)C=4C=3)F)C(=O)C=2)=C1 NNTJRXFQKMHWCH-UHFFFAOYSA-N 0.000 claims description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
229910052731 fluorine Inorganic materials 0.000 claims description 4
239000011737 fluorine Substances 0.000 claims description 4
230000002265 prevention Effects 0.000 claims description 4
230000009467 reduction Effects 0.000 claims description 4
229910021654 trace metal Inorganic materials 0.000 claims description 4
239000011782 vitamin Substances 0.000 claims description 4
235000013343 vitamin Nutrition 0.000 claims description 4
229940088594 vitamin Drugs 0.000 claims description 4
229930003231 vitamin Natural products 0.000 claims description 4
UOMJSMJFYIRYTP-HSZRJFAPSA-N 1-(2,4-difluorophenyl)-7-[(3r)-4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3[C@@H](CN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C=3C(=CC(F)=CC=3)F)F)C)C(=O)C=2)=C1 UOMJSMJFYIRYTP-HSZRJFAPSA-N 0.000 claims description 3
UOMJSMJFYIRYTP-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3C(CN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C=3C(=CC(F)=CC=3)F)F)C)C(=O)C=2)=C1 UOMJSMJFYIRYTP-UHFFFAOYSA-N 0.000 claims description 3
AAEJBCQDIPJIHN-UHFFFAOYSA-N 1-cyclooctyl-1,3-diazocane Chemical group C1CCCCCCC1N1CNCCCCC1 AAEJBCQDIPJIHN-UHFFFAOYSA-N 0.000 claims description 3
KKCOQCVPBASEDD-UHFFFAOYSA-N 1-cyclooctyl-1,4-diazocane Chemical group C1CCCCCCC1N1CCNCCCC1 KKCOQCVPBASEDD-UHFFFAOYSA-N 0.000 claims description 3
BSSRCWTVYSAQCP-OAQYLSRUSA-N 1-cyclopropyl-7-[(3r)-4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3[C@@H](CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)F)C)C(=O)C=2)=C1 BSSRCWTVYSAQCP-OAQYLSRUSA-N 0.000 claims description 3
BSSRCWTVYSAQCP-NRFANRHFSA-N 1-cyclopropyl-7-[(3s)-4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3[C@H](CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)F)C)C(=O)C=2)=C1 BSSRCWTVYSAQCP-NRFANRHFSA-N 0.000 claims description 3
YZACLCJBWPYSNU-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[2-[2-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]ethoxy]ethyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCOCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 YZACLCJBWPYSNU-UHFFFAOYSA-N 0.000 claims description 3
QMEXXOBVLGXEIR-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3,4-dimethylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(C)=CC=C1NC(NC1=O)=CC(=O)N1CCCCN1CCN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3C=2)C2CC2)F)CC1 QMEXXOBVLGXEIR-UHFFFAOYSA-N 0.000 claims description 3
BSSRCWTVYSAQCP-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3C(CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)F)C)C(=O)C=2)=C1 BSSRCWTVYSAQCP-UHFFFAOYSA-N 0.000 claims description 3
JMISSSBEKMBYLD-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3C(CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)OC)C)C(=O)C=2)=C1 JMISSSBEKMBYLD-UHFFFAOYSA-N 0.000 claims description 3
FVRJICZSAASHOD-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3)C(=O)C=2)=C1 FVRJICZSAASHOD-UHFFFAOYSA-N 0.000 claims description 3
GAZAYHFWBIBZGV-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 GAZAYHFWBIBZGV-UHFFFAOYSA-N 0.000 claims description 3
IDHYRQSMSDNNHK-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-[(3,4-dichlorophenyl)methylamino]-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(N3CCN(CCCCN4C(NC(NCC=5C=C(Cl)C(Cl)=CC=5)=CC4=O)=O)CC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 IDHYRQSMSDNNHK-UHFFFAOYSA-N 0.000 claims description 3
LGKFWTBHZUFRPF-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 LGKFWTBHZUFRPF-UHFFFAOYSA-N 0.000 claims description 3
YYQUTMPTKZCVJC-UHFFFAOYSA-N 1-ethyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(CC)C=4N=3)F)C(=O)C=2)=C1 YYQUTMPTKZCVJC-UHFFFAOYSA-N 0.000 claims description 3
CITJFDZQCOBOGW-UHFFFAOYSA-N 1-ethyl-7-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(CC)C=4N=3)F)C(=O)C=2)=C1 CITJFDZQCOBOGW-UHFFFAOYSA-N 0.000 claims description 3
FEMMPNIZRNDXHL-UHFFFAOYSA-N 1-tert-butyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C(C)(C)C)F)C(=O)C=2)=C1 FEMMPNIZRNDXHL-UHFFFAOYSA-N 0.000 claims description 3
HDUDWYLGKUIBBD-UHFFFAOYSA-N 7-[3-carboxy-4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3C(CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)F)C(O)=O)C(=O)C=2)=C1 HDUDWYLGKUIBBD-UHFFFAOYSA-N 0.000 claims description 3
WVSLJZDZMLBVSS-UHFFFAOYSA-N 7-[4-[4-[6-(3-chloro-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-1-cyclopropyl-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound CC1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)F)CCN1CCCCN(C(N1)=O)C(=O)C=C1NC1=CC=C(C)C(Cl)=C1 WVSLJZDZMLBVSS-UHFFFAOYSA-N 0.000 claims description 3
RICAYQWOHSLBTP-UHFFFAOYSA-N 7-[4-[4-[6-(3-chloro-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C(C)=CC=C1NC(NC1=O)=CC(=O)N1CCCCN1CCN(C=2C(=CC=3C(=O)C(C(O)=O)=CN(C=3C=2)C2CC2)F)CC1 RICAYQWOHSLBTP-UHFFFAOYSA-N 0.000 claims description 3
YGLSEVNIFPZVJH-UHFFFAOYSA-N 7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-1-(2-hydroxyethyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(CCO)C=4C=3)F)C(=O)C=2)=C1 YGLSEVNIFPZVJH-UHFFFAOYSA-N 0.000 claims description 3
PXGPMQZETUARJW-UHFFFAOYSA-N 7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-1-(4-fluorophenyl)-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C=3C=CC(F)=CC=3)F)C(=O)C=2)=C1 PXGPMQZETUARJW-UHFFFAOYSA-N 0.000 claims description 3
KDPDHQQFMFWGKJ-UHFFFAOYSA-N 8-ethyl-2-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3N=C4C(C(C(C(O)=O)=CN4CC)=O)=CN=3)C(=O)C=2)=C1 KDPDHQQFMFWGKJ-UHFFFAOYSA-N 0.000 claims description 3
125000005518 carboxamido group Chemical group 0.000 claims description 3
LUQOUUAOECRQJZ-UHFFFAOYSA-N ethyl 7-[4-[4-(6-anilino-2,4-dioxo-1h-pyrimidin-3-yl)butyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(N3CCN(CCCCN4C(NC(NC=5C=CC=CC=5)=CC4=O)=O)CC3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 LUQOUUAOECRQJZ-UHFFFAOYSA-N 0.000 claims description 3
239000001963 growth medium Substances 0.000 claims description 3
KTJZQGHYOHXLBR-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-4-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3N(C=C(C(=O)C=3)C(O)=O)C=3C(=CC(F)=CC=3)F)C(=O)C=2)=C1 KTJZQGHYOHXLBR-UHFFFAOYSA-N 0.000 claims description 2
NRSODYKCKMVMJO-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-6-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-4-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3N(C=C(C(=O)C=3)C(O)=O)C=3C(=CC(F)=CC=3)F)C(=O)C=2)=C1 NRSODYKCKMVMJO-UHFFFAOYSA-N 0.000 claims description 2
UXYMMKYCPVNQBM-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C=4C(=CC(F)=CC=4)F)=O)=CC=3F)OC)C(=O)C=2)=C1 UXYMMKYCPVNQBM-UHFFFAOYSA-N 0.000 claims description 2
RLTJVACKEUKLJE-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-7-[[1-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C=4C(=CC(F)=CC=4)F)F)CC3)C(=O)C=2)=C1 RLTJVACKEUKLJE-UHFFFAOYSA-N 0.000 claims description 2
VVZLIKKZHRGPKH-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(2,3-dihydro-1h-inden-5-ylamino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1CN(CCCCN2C(NC(NC=3C=C4CCCC4=CC=3)=CC2=O)=O)C(C)CN1C(C=1F)=C(F)C=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 VVZLIKKZHRGPKH-UHFFFAOYSA-N 0.000 claims description 2
LPUBDSFGCRLFMM-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3,4-dimethylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound CC1CN(C=2C(=C3C(C(C(C(O)=O)=CN3C3CC3)=O)=CC=2F)F)CCN1CCCCN(C(N1)=O)C(=O)C=C1NC1=CC=C(C)C(C)=C1 LPUBDSFGCRLFMM-UHFFFAOYSA-N 0.000 claims description 2
XHSSTBPTQHSWCP-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-(hydroxymethyl)piperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3C(CN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)F)CO)C(=O)C=2)=C1 XHSSTBPTQHSWCP-UHFFFAOYSA-N 0.000 claims description 2
TUAVKZURGLLRHQ-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CCN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)OC)C(=O)C=2)=C1 TUAVKZURGLLRHQ-UHFFFAOYSA-N 0.000 claims description 2
QSAAHDHQCXWFQZ-UHFFFAOYSA-N 1-cyclopropyl-7-[[1-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)CC3)C(=O)C=2)=C1 QSAAHDHQCXWFQZ-UHFFFAOYSA-N 0.000 claims description 2
CEEMTVQVNKSSHX-UHFFFAOYSA-N 1-ethyl-6-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-4-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3N(C=C(C(=O)C=3)C(O)=O)CC)C(=O)C=2)=C1 CEEMTVQVNKSSHX-UHFFFAOYSA-N 0.000 claims description 2
UDNFCWDKRJCZNT-UHFFFAOYSA-N 1-ethyl-7-[[1-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(CC)C=5C=4)F)CC3)C(=O)C=2)=C1 UDNFCWDKRJCZNT-UHFFFAOYSA-N 0.000 claims description 2
OEQDQOSPNTWRNH-UHFFFAOYSA-N 1-ethyl-7-[[1-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(CC)C=5C=4)F)CC3)C(=O)C=2)=C1 OEQDQOSPNTWRNH-UHFFFAOYSA-N 0.000 claims description 2
125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 claims description 2
WWWLKGLUSJPFNV-UHFFFAOYSA-N 4-oxo-3h-1,6-naphthyridine-3-carboxylic acid Chemical compound C1=NC=C2C(=O)C(C(=O)O)C=NC2=C1 WWWLKGLUSJPFNV-UHFFFAOYSA-N 0.000 claims description 2
ZMMAJVZOYAEFNK-UHFFFAOYSA-N 4-oxo-3h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)C=NC2=N1 ZMMAJVZOYAEFNK-UHFFFAOYSA-N 0.000 claims description 2
AAXFXBIGBZUQDH-UHFFFAOYSA-N 5-oxo-6h-pyrido[2,3-d]pyrimidine-6-carboxylic acid Chemical compound C1=NC=C2C(=O)C(C(=O)O)C=NC2=N1 AAXFXBIGBZUQDH-UHFFFAOYSA-N 0.000 claims description 2
SVTYDZIOECJVDC-UHFFFAOYSA-N 6-[4-[4-[2-amino-4-(3-ethyl-4-methylanilino)-6-oxopyrimidin-1-yl]butyl]piperazin-1-yl]-1-(2,4-difluorophenyl)-4-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C(N)N(CCCCN3CCN(CC3)C=3N(C=C(C(=O)C=3)C(O)=O)C=3C(=CC(F)=CC=3)F)C(=O)C=2)=C1 SVTYDZIOECJVDC-UHFFFAOYSA-N 0.000 claims description 2
ZEEGKCFKHLONIM-UHFFFAOYSA-N 6-[4-[4-[2-amino-4-(3-ethyl-4-methylanilino)-6-oxopyrimidin-1-yl]butyl]piperazin-1-yl]-1-cyclopropyl-4-oxopyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C(N)N(CCCCN3CCN(CC3)C=3N(C=C(C(=O)C=3)C(O)=O)C3CC3)C(=O)C=2)=C1 ZEEGKCFKHLONIM-UHFFFAOYSA-N 0.000 claims description 2
FRPWOBGYZSPBNV-UHFFFAOYSA-N 7-[[1-[4-[2-amino-4-(3-ethyl-4-methylanilino)-6-oxopyrimidin-1-yl]butyl]pyrrolidin-3-yl]methylamino]-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C(N)N(CCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(CC)C=5C=4)F)CC3)C(=O)C=2)=C1 FRPWOBGYZSPBNV-UHFFFAOYSA-N 0.000 claims description 2
125000003277 amino group Chemical group 0.000 claims description 2
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
HZEJLWYMAOTFKR-UHFFFAOYSA-N benzyl 1-cyclopropyl-7-[4-[2-[2-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]ethoxy]ethyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCOCCN3CCN(CC3)C=3C(=CC=4C(=O)C(C(=O)OCC=5C=CC=CC=5)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 HZEJLWYMAOTFKR-UHFFFAOYSA-N 0.000 claims description 2
RRSYMSXWWHOVFQ-UHFFFAOYSA-N ethyl 1-(2,4-difluorophenyl)-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(N3CCN(CCCCN4C(NC(NC=5C=C(CC)C(C)=CC=5)=CC4=O)=O)CC3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F RRSYMSXWWHOVFQ-UHFFFAOYSA-N 0.000 claims description 2
FKKVBJQNRRLLLI-UHFFFAOYSA-N ethyl 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]piperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC(N3CCN(CCCCN4C(NC(NC=5C=C(CC)C(C)=CC=5)=CC4=O)=O)CC3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 FKKVBJQNRRLLLI-UHFFFAOYSA-N 0.000 claims description 2
125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
125000004468 heterocyclylthio group Chemical group 0.000 claims description 2
150000003722 vitamin derivatives Chemical class 0.000 claims description 2
BQUBBSOIYZBBOF-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-7-[[1-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C=4C(=CC(F)=CC=4)F)F)CC3)C(=O)C=2)=C1 BQUBBSOIYZBBOF-UHFFFAOYSA-N 0.000 claims 1
GHMZHOOTMHDPQX-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-2-methylpiperazin-1-yl]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCN3CC(C)N(CC3)C=3C(=CC=4C(=O)C(C(O)=O)=CN(C=4C=3)C3CC3)F)C(=O)C=2)=C1 GHMZHOOTMHDPQX-UHFFFAOYSA-N 0.000 claims 1
FYGWDABKQRNMHR-UHFFFAOYSA-N 1-cyclopropyl-7-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4C4CC4)=O)=CC=3F)OC)C(=O)C=2)=C1 FYGWDABKQRNMHR-UHFFFAOYSA-N 0.000 claims 1
CJOGUVFCFDFESU-UHFFFAOYSA-N 1-cyclopropyl-7-[[1-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]pyrrolidin-3-yl]methylamino]-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C4CC4)F)CC3)C(=O)C=2)=C1 CJOGUVFCFDFESU-UHFFFAOYSA-N 0.000 claims 1
JNBOWSQHZLVSPW-UHFFFAOYSA-N 1-ethyl-7-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3C(=C4C(C(C(C(O)=O)=CN4CC)=O)=CC=3F)OC)C(=O)C=2)=C1 JNBOWSQHZLVSPW-UHFFFAOYSA-N 0.000 claims 1
IBAOFQIOOBQLHE-UHFFFAOYSA-N 2-amino-3,9-dihydropurin-9-ium-6-one;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N=CN2 IBAOFQIOOBQLHE-UHFFFAOYSA-N 0.000 claims 1
OQNGGCLSPGCWAJ-UHFFFAOYSA-N 2-cyclopropyl-6-[4-[5-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]pentyl]piperazin-1-yl]-4-oxo-3h-pyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCCN3CCN(CC3)C=3N=C(C(C(O)=O)C(=O)C=3)C3CC3)C(=O)C=2)=C1 OQNGGCLSPGCWAJ-UHFFFAOYSA-N 0.000 claims 1
CHDPGQOTHNIJEC-UHFFFAOYSA-N 7-[4-[5-[6-amino-2-(3-ethyl-4-methylanilino)purin-9-yl]pentyl]piperazin-1-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C3N(CCCCCN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5C=4)C=4C(=CC(F)=CC=4)F)F)C=NC3=C(N)N=2)=C1 CHDPGQOTHNIJEC-UHFFFAOYSA-N 0.000 claims 1
SXWIOBUWCJMWCY-UHFFFAOYSA-N 7-[4-[5-[6-amino-2-(3-ethyl-4-methylanilino)purin-9-yl]pentyl]piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C3N(CCCCCN4CCN(CC4)C=4C(=CC=5C(=O)C(C(O)=O)=CN(C=5N=4)C4CC4)F)C=NC3=C(N)N=2)=C1 SXWIOBUWCJMWCY-UHFFFAOYSA-N 0.000 claims 1
SMRKBFJFYKOAOU-UHFFFAOYSA-N 7-[[1-[5-[2-amino-4-(3-ethyl-4-methylanilino)-6-oxopyrimidin-1-yl]pentyl]pyrrolidin-3-yl]methylamino]-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C)C(CC)=CC(NC=2N=C(N)N(CCCCCN3CC(CNC=4C(=CC=5C(=O)C(C(O)=O)=CN(CC)C=5C=4)F)CC3)C(=O)C=2)=C1 SMRKBFJFYKOAOU-UHFFFAOYSA-N 0.000 claims 1
FBDNQRCFXZVFHZ-UHFFFAOYSA-N ethyl 1-cyclopropyl-7-[4-[4-[6-(3-ethyl-4-methylanilino)-2,4-dioxo-1h-pyrimidin-3-yl]butyl]-3-methylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(N3CC(C)N(CCCCN4C(NC(NC=5C=C(CC)C(C)=CC=5)=CC4=O)=O)CC3)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 FBDNQRCFXZVFHZ-UHFFFAOYSA-N 0.000 claims 1
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238000003786 synthesis reaction Methods 0.000 description 33
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241000699670 Mus sp. Species 0.000 description 14
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BUYPPNJUNDITNW-UHFFFAOYSA-N 6-(3-ethyl-4-methylanilino)-3-(4-iodobutyl)-1h-pyrimidine-2,4-dione Chemical compound C1=C(C)C(CC)=CC(NC=2NC(=O)N(CCCCI)C(=O)C=2)=C1 BUYPPNJUNDITNW-UHFFFAOYSA-N 0.000 description 10
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