OA12316A - 3-Aminoquinazolin-2,4-dione antibacterial agents. - Google Patents

3-Aminoquinazolin-2,4-dione antibacterial agents. Download PDF

Info

Publication number: OA12316A
Authority: OA; OAPI
Prior art keywords: amino; dione; cyclopropyl; fluoro; quinazoline
Prior art date: 2000-01-24

Application number

OA1200200210A

Other languages

English (en)

Inventor

Paul Bird

Edmund Lee Ellsworth

Dai Quoc Nguyen

Joseph Peter Sanchez

Howard Daniel Hollis Showalter

Rajeshwar Singh

Michael Andrew Stier

Tuan Phong Tran

Brian Morgan Watson

Judy Yip

Original Assignee

Warner Lambert Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2000-01-24

Filing date

2000-12-12

Publication date

2006-05-15

2000-12-12 Application filed by Warner Lambert Co filed Critical Warner Lambert Co

2006-05-15 Publication of OA12316A publication Critical patent/OA12316A/en

Links

NMGODFWGUBLTTA-UHFFFAOYSA-N 3-amino-1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)NC2=C1 NMGODFWGUBLTTA-UHFFFAOYSA-N 0.000 title abstract description 14
239000003242 anti bacterial agent Substances 0.000 title description 7
125000000217 alkyl group Chemical group 0.000 claims abstract description 69
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 57
125000003118 aryl group Chemical group 0.000 claims abstract description 48
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 31
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 31
125000000304 alkynyl group Chemical group 0.000 claims abstract description 24
239000001257 hydrogen Substances 0.000 claims abstract description 24
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
125000003342 alkenyl group Chemical group 0.000 claims abstract description 22
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 9
229910052799 carbon Inorganic materials 0.000 claims abstract description 9
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 6
150000001875 compounds Chemical class 0.000 claims description 310
-1 wherein n is 0 or 1 Chemical group 0.000 claims description 193
239000000203 mixture Substances 0.000 claims description 94
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 88
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 68
239000004202 carbamide Substances 0.000 claims description 56
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 51
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 48
125000000547 substituted alkyl group Chemical group 0.000 claims description 41
125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 37
125000005017 substituted alkenyl group Chemical group 0.000 claims description 31
SDQJTWBNWQABLE-UHFFFAOYSA-N 1h-quinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)NC2=C1 SDQJTWBNWQABLE-UHFFFAOYSA-N 0.000 claims description 30
125000005843 halogen group Chemical group 0.000 claims description 29
125000004426 substituted alkynyl group Chemical group 0.000 claims description 29
KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims description 26
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 23
125000001424 substituent group Chemical group 0.000 claims description 18
125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 17
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 14
RYECOJGRJDOGPP-UHFFFAOYSA-N Ethylurea Chemical compound CCNC(N)=O RYECOJGRJDOGPP-UHFFFAOYSA-N 0.000 claims description 14
LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 14
208000035143 Bacterial infection Diseases 0.000 claims description 13
208000022362 bacterial infectious disease Diseases 0.000 claims description 13
125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 12
229910052717 sulfur Inorganic materials 0.000 claims description 12
241000124008 Mammalia Species 0.000 claims description 11
239000003085 diluting agent Substances 0.000 claims description 10
229910052760 oxygen Inorganic materials 0.000 claims description 10
239000000546 pharmaceutical excipient Substances 0.000 claims description 10
125000003107 substituted aryl group Chemical group 0.000 claims description 9
125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 9
108010054814 DNA Gyrase Proteins 0.000 claims description 7
125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 7
125000004122 cyclic group Chemical group 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 7
229910052740 iodine Inorganic materials 0.000 claims description 7
125000004429 atom Chemical group 0.000 claims description 6
230000002401 inhibitory effect Effects 0.000 claims description 6
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
229910052700 potassium Inorganic materials 0.000 claims description 4
RXUIXCIKQDTZBQ-UHFFFAOYSA-N 1-cyclopropylquinazoline-2,4-dione Chemical compound C1(CC1)N1C(NC(C2=CC=CC=C12)=O)=O RXUIXCIKQDTZBQ-UHFFFAOYSA-N 0.000 claims description 3
XMIQMMOCQFIYFM-UHFFFAOYSA-N pyrrolidine-3-carboxylic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C1CCNC1 XMIQMMOCQFIYFM-UHFFFAOYSA-N 0.000 claims description 3
XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 2
ZGCGNTZEVIIFAM-UHFFFAOYSA-N 1-fluoro-8-methylquinazoline-2,4-dione Chemical compound FN1C(=O)NC(=O)C2=C1C(C)=CC=C2 ZGCGNTZEVIIFAM-UHFFFAOYSA-N 0.000 claims description 2
NUZLMAGOIPFPSG-UHFFFAOYSA-N 3-amino-1-cyclopropyl-6-fluoro-7-[3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CCC(C(C)(C)O)C1 NUZLMAGOIPFPSG-UHFFFAOYSA-N 0.000 claims description 2
FPGPDSXCAGDSCS-UHFFFAOYSA-N 3-amino-7-(7-amino-5-methyl-3-azabicyclo[3.2.0]heptan-3-yl)-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound COC1=C(N2CC3(C)CC(N)C3C2)C(F)=CC(C(N(N)C2=O)=O)=C1N2C1CC1 FPGPDSXCAGDSCS-UHFFFAOYSA-N 0.000 claims description 2
QWFJOUZUSNZNMP-FOIQADDNSA-N 3-amino-7-[(3r)-3-[(1s)-1-amino-2-phenoxyethyl]pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound C([C@@H](N)[C@@H]1CCN(C1)C1=C(C2=C(C(N(N)C(=O)N2C2CC2)=O)C=C1F)C)OC1=CC=CC=C1 QWFJOUZUSNZNMP-FOIQADDNSA-N 0.000 claims description 2
QCDOITHYWYGQQG-XHSDSOJGSA-N 3-amino-7-[(3r,4s)-3-[(1s)-1-amino-3-methoxypropyl]-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound C1[C@@H](F)[C@@H]([C@@H](N)CCOC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C QCDOITHYWYGQQG-XHSDSOJGSA-N 0.000 claims description 2
FKEICTOGGGAVEH-ZETCQYMHSA-N 3-amino-7-[(3s)-3-aminopyrrolidin-1-yl]-1-cyclopropyl-6-fluoropyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1[C@@H](N)CCN1C(C(=C1)F)=NC2=C1C(=O)N(N)C(=O)N2C1CC1 FKEICTOGGGAVEH-ZETCQYMHSA-N 0.000 claims description 2
RXYNGNBFBLYGSY-UHFFFAOYSA-N 3-amino-7-[2-(aminomethyl)-1,3-thiazol-4-yl]-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(C)=C1C1=CSC(CN)=N1 RXYNGNBFBLYGSY-UHFFFAOYSA-N 0.000 claims description 2
VLPCEPGNRLOKKI-UHFFFAOYSA-N 3-amino-7-[2-(aminomethyl)-1,3-thiazol-4-yl]-8-chloro-1-cyclopropyl-6-fluoroquinazoline-2,4-dione Chemical compound S1C(CN)=NC(C=2C(=C3C(C(N(N)C(=O)N3C3CC3)=O)=CC=2F)Cl)=C1 VLPCEPGNRLOKKI-UHFFFAOYSA-N 0.000 claims description 2
ZFFKHRCQSMRYSW-UHFFFAOYSA-N 3-amino-7-[3-(1-aminoethyl)-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CC(C)C(C(C)N)C1 ZFFKHRCQSMRYSW-UHFFFAOYSA-N 0.000 claims description 2
KURNMRMNDDYRKZ-UHFFFAOYSA-N 3-amino-7-[3-(1-aminoethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CCCC(C(C)N)C1 KURNMRMNDDYRKZ-UHFFFAOYSA-N 0.000 claims description 2
DIPPDJOOYUFWLO-UHFFFAOYSA-N 3-amino-7-[3-(2-aminopropan-2-yl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylpyrido[4,3-d]pyrimidine-2,4-dione Chemical compound CC1=C(N2CC(C(F)C2)C(C)(C)N)N=CC(C(N(N)C2=O)=O)=C1N2C1CC1 DIPPDJOOYUFWLO-UHFFFAOYSA-N 0.000 claims description 2
RPBSNJWGNSKHOM-UHFFFAOYSA-N 3-amino-7-[3-(aminomethyl)-3-(methoxymethyl)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound C1C(COC)(CN)CCN1C1=C(F)C=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C RPBSNJWGNSKHOM-UHFFFAOYSA-N 0.000 claims description 2
LFARSGUVNIPJGM-UHFFFAOYSA-N 3-amino-7-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoropyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1C(C)(CN)CCN1C(C(=C1)F)=NC2=C1C(=O)N(N)C(=O)N2C1CC1 LFARSGUVNIPJGM-UHFFFAOYSA-N 0.000 claims description 2
BWXHDANGZXHVDO-UHFFFAOYSA-N 3-amino-7-[3-(aminomethyl)phenyl]-8-chloro-1-cyclopropyl-6-fluoroquinazoline-2,4-dione Chemical compound NCC1=CC=CC(C=2C(=C3C(C(N(N)C(=O)N3C3CC3)=O)=CC=2F)Cl)=C1 BWXHDANGZXHVDO-UHFFFAOYSA-N 0.000 claims description 2
KMOXXHGLMKCGRK-UHFFFAOYSA-N 3-amino-7-[3-(aminomethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoropyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1C(CN)CCCN1C(C(=C1)F)=NC2=C1C(=O)N(N)C(=O)N2C1CC1 KMOXXHGLMKCGRK-UHFFFAOYSA-N 0.000 claims description 2
YSWSMAOIADXSJJ-UHFFFAOYSA-N 3-amino-7-[4-(1-aminoethyl)-3,3-difluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound C1C(F)(F)C(C(N)C)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C YSWSMAOIADXSJJ-UHFFFAOYSA-N 0.000 claims description 2
UJHMHUJNQOUEMM-UHFFFAOYSA-N 3-amino-7-[4-(2-aminopropan-2-yl)-3,3-difluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(C)=C1N1CC(C(C)(C)N)C(F)(F)C1 UJHMHUJNQOUEMM-UHFFFAOYSA-N 0.000 claims description 2
HJUIXGXPYMFZOH-UHFFFAOYSA-N 3-amino-7-[4-(2-aminopropan-2-yl)-3,3-difluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound CC1=C(N2CC(F)(F)C(C(C)(C)N)C2)C=CC(C(N(N)C2=O)=O)=C1N2C1CC1 HJUIXGXPYMFZOH-UHFFFAOYSA-N 0.000 claims description 2
VWQSCDFRKGGQGQ-UHFFFAOYSA-N 3-amino-7-[4-(aminomethyl)-3,3-difluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxyquinazoline-2,4-dione Chemical compound COC1=C(N2CC(F)(F)C(CN)C2)C=CC(C(N(N)C2=O)=O)=C1N2C1CC1 VWQSCDFRKGGQGQ-UHFFFAOYSA-N 0.000 claims description 2
125000003386 piperidinyl group Chemical group 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims 10
125000004193 piperazinyl group Chemical group 0.000 claims 2
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
ILSRMENRGMPIHQ-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound CC1=CC(F)=CC(C(NC2=O)=O)=C1N2C1CC1 ILSRMENRGMPIHQ-UHFFFAOYSA-N 0.000 claims 1
QGOYJSXAFAHEOQ-UHFFFAOYSA-N 1-cyclopropyl-6-fluoroquinazoline-2,4-dione Chemical compound O=C1NC(=O)C2=CC(F)=CC=C2N1C1CC1 QGOYJSXAFAHEOQ-UHFFFAOYSA-N 0.000 claims 1
125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
GTRJJQDFRZCWKQ-NXEZZACHSA-N 3-amino-1-cyclopropyl-6-fluoro-7-[(3r)-3-[(1r)-1-(methylamino)ethyl]pyrrolidin-1-yl]pyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C1[C@H]([C@@H](C)NC)CCN1C(C(=C1)F)=NC2=C1C(=O)N(N)C(=O)N2C1CC1 GTRJJQDFRZCWKQ-NXEZZACHSA-N 0.000 claims 1
VLVSORUTOYXYIG-UHFFFAOYSA-N 3-amino-7-(2-amino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N(C1)CCC21CC2N VLVSORUTOYXYIG-UHFFFAOYSA-N 0.000 claims 1
QBAYAKOQUGQOHL-UHFFFAOYSA-N 3-amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(C)=C1N1CCC(C)(N)C1 QBAYAKOQUGQOHL-UHFFFAOYSA-N 0.000 claims 1
NICJESYMFMNVRX-UHFFFAOYSA-N 3-amino-7-(3-amino-3-phenylpyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoroquinazoline-2,4-dione Chemical compound C12=C(Cl)C(N3CC(N)(CC3)C=3C=CC=CC=3)=C(F)C=C2C(=O)N(N)C(=O)N1C1CC1 NICJESYMFMNVRX-UHFFFAOYSA-N 0.000 claims 1
MYNASXNPNLIHST-UHFFFAOYSA-N 3-amino-7-(3-amino-4-fluoropyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CC(N)C(F)C1 MYNASXNPNLIHST-UHFFFAOYSA-N 0.000 claims 1
LMKZWBWISAEVOS-UHFFFAOYSA-N 3-amino-7-(3-amino-4-methoxypyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound C1C(N)C(OC)CN1C1=C(F)C=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1OC LMKZWBWISAEVOS-UHFFFAOYSA-N 0.000 claims 1
SMRJEBDYHBYSSD-UHFFFAOYSA-N 3-amino-7-(3-aminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2,4-dioxoquinazoline-8-carbonitrile Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C#N SMRJEBDYHBYSSD-UHFFFAOYSA-N 0.000 claims 1
LXAOHWSBPOQFAW-UHFFFAOYSA-N 3-amino-7-(3-aminopyrrolidin-1-yl)-8-chloro-1-(cyclobutylamino)-6-fluoroquinazoline-2,4-dione Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)N(N)C(=O)N(NC3CCC3)C2=C1Cl LXAOHWSBPOQFAW-UHFFFAOYSA-N 0.000 claims 1
USGOLBXMHMCSCB-UHFFFAOYSA-N 3-amino-7-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione Chemical compound CC1=C(N2CC3C(N)C3C2)C(F)=CC(C(N(N)C2=O)=O)=C1N2C1CC1 USGOLBXMHMCSCB-UHFFFAOYSA-N 0.000 claims 1
WAKUORIXGDVWOW-KUHUBIRLSA-N 3-amino-7-[(3r)-3-[(1r)-1-amino-2-phenoxyethyl]pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound C([C@H](N)[C@@H]1CCN(C1)C1=C(C2=C(C(N(N)C(=O)N2C2CC2)=O)C=C1F)OC)OC1=CC=CC=C1 WAKUORIXGDVWOW-KUHUBIRLSA-N 0.000 claims 1
QZESCCOXPDVVLW-IUODEOHRSA-N 3-amino-7-[(3r)-3-[(1s)-1-amino-2-ethoxyethyl]pyrrolidin-1-yl]-1-cyclopropyl-8-methoxyquinazoline-2,4-dione Chemical compound C1[C@H]([C@H](N)COCC)CCN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1OC QZESCCOXPDVVLW-IUODEOHRSA-N 0.000 claims 1
QCDOITHYWYGQQG-HRCADAONSA-N 3-amino-7-[(3r,4r)-3-[(1r)-1-amino-3-methoxypropyl]-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound C1[C@H](F)[C@@H]([C@H](N)CCOC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C QCDOITHYWYGQQG-HRCADAONSA-N 0.000 claims 1
WTYRDLVCSKPCMR-VBNZEHGJSA-N 3-amino-7-[(3r,4r)-3-[(1r)-1-amino-3-methoxypropyl]-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methoxyquinazoline-2,4-dione Chemical compound C1[C@H](C)[C@@H]([C@H](N)CCOC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1OC WTYRDLVCSKPCMR-VBNZEHGJSA-N 0.000 claims 1
NIHCENZIYVQPQI-AFAVFJNCSA-N 3-amino-7-[(3r,4r)-3-[(1r)-1-amino-3-methoxypropyl]-4-methylpyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound C1[C@H](C)[C@@H]([C@H](N)CCOC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C NIHCENZIYVQPQI-AFAVFJNCSA-N 0.000 claims 1
DMVCNEPYSFWQBP-WQAKAFBOSA-N 3-amino-7-[(3r,4r)-3-[(1r)-1-aminoethyl]-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxyquinazoline-2,4-dione Chemical compound COC1=C(N2C[C@@H]([C@@H](F)C2)[C@@H](C)N)C=CC(C(N(N)C2=O)=O)=C1N2C1CC1 DMVCNEPYSFWQBP-WQAKAFBOSA-N 0.000 claims 1
JNBFVIXMWYHESF-HZUKXOBISA-N 3-amino-7-[(3r,4r)-3-[(1s)-1-amino-2-ethoxyethyl]-4-methylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound C1[C@H](C)[C@@H]([C@H](N)COCC)CN1C1=C(F)C=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1OC JNBFVIXMWYHESF-HZUKXOBISA-N 0.000 claims 1
DLJALTOFOUWOSY-WCQYABFASA-N 3-amino-7-[(3r,4s)-3-(2-aminopropan-2-yl)-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1C[C@@H](F)[C@@H](C(C)(C)N)C1 DLJALTOFOUWOSY-WCQYABFASA-N 0.000 claims 1
MOZUHBQCTICBJN-ZNMIVQPWSA-N 3-amino-7-[(3r,4s)-3-[(1r)-1-amino-2-ethoxyethyl]-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methoxyquinazoline-2,4-dione Chemical compound C1[C@@H](F)[C@@H]([C@@H](N)COCC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1OC MOZUHBQCTICBJN-ZNMIVQPWSA-N 0.000 claims 1
UQDOBNTYFUNMNV-ZNMIVQPWSA-N 3-amino-7-[(3r,4s)-3-[(1r)-1-amino-2-methoxyethyl]-4-fluoropyrrolidin-1-yl]-1-cyclopropyl-8-methylquinazoline-2,4-dione Chemical compound C1[C@@H](F)[C@@H]([C@@H](N)COC)CN1C1=CC=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C UQDOBNTYFUNMNV-ZNMIVQPWSA-N 0.000 claims 1
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IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
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JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
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241000894006 Bacteria Species 0.000 description 6
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230000008878 coupling Effects 0.000 description 6
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MMBZQEWHXIZIMA-UHFFFAOYSA-N 3-(dibenzylamino)-1-ethyl-6,7-difluoroquinazoline-2,4-dione Chemical compound O=C1N(CC)C2=CC(F)=C(F)C=C2C(=O)N1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 MMBZQEWHXIZIMA-UHFFFAOYSA-N 0.000 description 5
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 5
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 5
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IFZDYNYZWOBYIG-UHFFFAOYSA-N 2-amino-3-chloro-4,5-difluorobenzoic acid Chemical compound NC1=C(Cl)C(F)=C(F)C=C1C(O)=O IFZDYNYZWOBYIG-UHFFFAOYSA-N 0.000 description 4
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VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
239000007868 Raney catalyst Substances 0.000 description 4
229910000564 Raney nickel Inorganic materials 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
KFTZCNLLRKFMQH-BYPYZUCNSA-N [(3s)-pyrrolidin-3-yl]carbamic acid Chemical compound OC(=O)N[C@H]1CCNC1 KFTZCNLLRKFMQH-BYPYZUCNSA-N 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
CLCQGUABBALPKC-UHFFFAOYSA-N amino-[2-(cyclopropylamino)-4,5-difluorobenzoyl]carbamic acid Chemical compound OC(=O)N(N)C(=O)C1=CC(F)=C(F)C=C1NC1CC1 CLCQGUABBALPKC-UHFFFAOYSA-N 0.000 description 4
UFWCPDSEOVJAEA-UHFFFAOYSA-N amino-[3-chloro-2-(cyclopropylamino)-4,5-difluorobenzoyl]carbamic acid Chemical compound OC(=O)N(N)C(=O)C1=CC(F)=C(F)C(Cl)=C1NC1CC1 UFWCPDSEOVJAEA-UHFFFAOYSA-N 0.000 description 4
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 4
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PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 4
229910052681 coesite Inorganic materials 0.000 description 4
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125000004093 cyano group Chemical group *C#N 0.000 description 4
238000006073 displacement reaction Methods 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
150000004820 halides Chemical class 0.000 description 4
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238000001727 in vivo Methods 0.000 description 4
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150000002924 oxiranes Chemical class 0.000 description 4
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238000010561 standard procedure Methods 0.000 description 4
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FVRSGQOZJYBPQI-UHFFFAOYSA-N 1-(cyclopropylmethyl)-3-(dibenzylamino)-6,7-difluoroquinazoline-2,4-dione Chemical compound O=C1N(N(CC=2C=CC=CC=2)CC=2C=CC=CC=2)C(=O)C=2C=C(F)C(F)=CC=2N1CC1CC1 FVRSGQOZJYBPQI-UHFFFAOYSA-N 0.000 description 3
RWFOOMQYIRITHL-UHFFFAOYSA-N 1-methylquinazoline-2,4-dione Chemical compound C1=CC=C2C(=O)NC(=O)N(C)C2=C1 RWFOOMQYIRITHL-UHFFFAOYSA-N 0.000 description 3
AKAMNXFLKYKFOJ-UHFFFAOYSA-N 2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1F AKAMNXFLKYKFOJ-UHFFFAOYSA-N 0.000 description 3
DGOZIZVTANAGCA-UHFFFAOYSA-N 2-amino-4,5-difluorobenzoic acid Chemical compound NC1=CC(F)=C(F)C=C1C(O)=O DGOZIZVTANAGCA-UHFFFAOYSA-N 0.000 description 3
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
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CVOUTLIYRVEJSB-UHFFFAOYSA-N 5-benzyl-5-azaspiro[2.4]heptane-7-carboxamide Chemical compound C1C2(CC2)C(C(=O)N)CN1CC1=CC=CC=C1 CVOUTLIYRVEJSB-UHFFFAOYSA-N 0.000 description 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
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ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
239000012359 Methanesulfonyl chloride Substances 0.000 description 3
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
150000001350 alkyl halides Chemical class 0.000 description 3
238000005576 amination reaction Methods 0.000 description 3
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HRDCWPUIXQGAAM-UHFFFAOYSA-N amino(benzoyl)carbamic acid Chemical class OC(=O)N(N)C(=O)C1=CC=CC=C1 HRDCWPUIXQGAAM-UHFFFAOYSA-N 0.000 description 3
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ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
239000011575 calcium Substances 0.000 description 3
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125000004432 carbon atom Chemical group C* 0.000 description 3
230000003197 catalytic effect Effects 0.000 description 3
239000003638 chemical reducing agent Substances 0.000 description 3
RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 3
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UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000006185 dispersion Substances 0.000 description 3
MLANUBGYWOMWLZ-UHFFFAOYSA-N ethyl 2,3,4-trifluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C(F)=C1F MLANUBGYWOMWLZ-UHFFFAOYSA-N 0.000 description 3
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230000035772 mutation Effects 0.000 description 3
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239000011591 potassium Substances 0.000 description 3
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238000004809 thin layer chromatography Methods 0.000 description 3
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YVKARDDEPDIMAW-UHFFFAOYSA-N 3-amino-7-(3-amino-3-methylpyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione;hydrochloride Chemical compound Cl.FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(C)=C1N1CCC(C)(N)C1 YVKARDDEPDIMAW-UHFFFAOYSA-N 0.000 description 2
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JASKKDJDJMQUCW-UHFFFAOYSA-N 3-amino-7-[4-(aminomethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione Chemical compound FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CCC(CN)CC1 JASKKDJDJMQUCW-UHFFFAOYSA-N 0.000 description 2
ICWQWMNAYJVMHJ-UHFFFAOYSA-N 3-amino-7-[4-(aminomethyl)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxyquinazoline-2,4-dione;hydrochloride Chemical compound Cl.FC1=CC(C(N(N)C(=O)N2C3CC3)=O)=C2C(OC)=C1N1CCC(CN)CC1 ICWQWMNAYJVMHJ-UHFFFAOYSA-N 0.000 description 2
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MXNBDFWNYRNIBH-UHFFFAOYSA-N 3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1 MXNBDFWNYRNIBH-UHFFFAOYSA-N 0.000 description 2
ZQQSRVPOAHYHEL-UHFFFAOYSA-N 4-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1F ZQQSRVPOAHYHEL-UHFFFAOYSA-N 0.000 description 2
TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical class OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 2
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PRAZATCEOJHMET-UHFFFAOYSA-N 5-benzyl-5-azaspiro[2.4]heptane-7-carboxylic acid Chemical compound C1C2(CC2)C(C(=O)O)CN1CC1=CC=CC=C1 PRAZATCEOJHMET-UHFFFAOYSA-N 0.000 description 2
NQNNGQFUHXZUQQ-UHFFFAOYSA-N 7-(1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl)-3-amino-1-cyclopropyl-6-fluoro-8-methylquinazoline-2,4-dione;hydrochloride Chemical compound Cl.CC1=C(N2CC3NCCCC3C2)C(F)=CC(C(N(N)C2=O)=O)=C1N2C1CC1 NQNNGQFUHXZUQQ-UHFFFAOYSA-N 0.000 description 2
PPWBBORVAVZKHU-UHFFFAOYSA-N 7-(1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c]pyridin-2-yl)-3-amino-1-cyclopropyl-6-fluoropyrido[2,3-d]pyrimidine-2,4-dione Chemical compound C12=NC(N3CC4CNCCC4C3)=C(F)C=C2C(=O)N(N)C(=O)N1C1CC1 PPWBBORVAVZKHU-UHFFFAOYSA-N 0.000 description 2
JOUZPZZMCYIDOW-UHFFFAOYSA-N 8-methoxy-1h-quinazoline-2,4-dione Chemical compound N1C(=O)NC(=O)C2=C1C(OC)=CC=C2 JOUZPZZMCYIDOW-UHFFFAOYSA-N 0.000 description 2
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
241000283690 Bos taurus Species 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
101100063435 Caenorhabditis elegans din-1 gene Proteins 0.000 description 2
UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
108010041052 DNA Topoisomerase IV Proteins 0.000 description 2
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
235000019739 Dicalciumphosphate Nutrition 0.000 description 2
108090000790 Enzymes Proteins 0.000 description 2
102000004190 Enzymes Human genes 0.000 description 2
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
241000699670 Mus sp. Species 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
239000002262 Schiff base Substances 0.000 description 2
150000004753 Schiff bases Chemical class 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
229920002472 Starch Polymers 0.000 description 2
241000193996 Streptococcus pyogenes Species 0.000 description 2
AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical compound C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
238000010958 [3+2] cycloaddition reaction Methods 0.000 description 2
PCLHRTFHZMANIS-UHFFFAOYSA-N [3-(methoxymethyl)pyrrolidin-3-yl]methylcarbamic acid Chemical compound OC(=O)NCC1(COC)CCNC1 PCLHRTFHZMANIS-UHFFFAOYSA-N 0.000 description 2
FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 2
DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
150000008065 acid anhydrides Chemical class 0.000 description 2
229910052784 alkaline earth metal Inorganic materials 0.000 description 2
125000003282 alkyl amino group Chemical group 0.000 description 2
150000001356 alkyl thiols Chemical class 0.000 description 2
229960004050 aminobenzoic acid Drugs 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
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238000011482 antibacterial activity assay Methods 0.000 description 2
229940088710 antibiotic agent Drugs 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
150000001540 azides Chemical class 0.000 description 2
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
238000007664 blowing Methods 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
125000001246 bromo group Chemical group Br* 0.000 description 2
239000000872 buffer Substances 0.000 description 2
239000001506 calcium phosphate Substances 0.000 description 2
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
239000001768 carboxy methyl cellulose Substances 0.000 description 2
239000000969 carrier Substances 0.000 description 2
238000004296 chiral HPLC Methods 0.000 description 2
229940110456 cocoa butter Drugs 0.000 description 2
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239000003086 colorant Substances 0.000 description 2
229940125773 compound 10 Drugs 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
KZZKOVLJUKWSKX-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1CCC1 KZZKOVLJUKWSKX-UHFFFAOYSA-N 0.000 description 2
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
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125000006333 difluoro benzoyl group Chemical group 0.000 description 2
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125000006332 fluoro benzoyl group Chemical group 0.000 description 2
238000009472 formulation Methods 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
239000008187 granular material Substances 0.000 description 2
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
239000005457 ice water Substances 0.000 description 2
208000015181 infectious disease Diseases 0.000 description 2
239000002198 insoluble material Substances 0.000 description 2
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
JJXINDNYLSMEBI-UHFFFAOYSA-N isocyanato thiohypochlorite Chemical compound ClSN=C=O JJXINDNYLSMEBI-UHFFFAOYSA-N 0.000 description 2
ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
239000007937 lozenge Substances 0.000 description 2
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238000002844 melting Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
150000002739 metals Chemical class 0.000 description 2
QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
229920000609 methyl cellulose Polymers 0.000 description 2
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PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 2
239000002480 mineral oil Substances 0.000 description 2
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239000002808 molecular sieve Substances 0.000 description 2
DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
IHUQJPKASFTOBM-UHFFFAOYSA-N n-(2,4-dinitrophenyl)hydroxylamine Chemical compound ONC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O IHUQJPKASFTOBM-UHFFFAOYSA-N 0.000 description 2
OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 2
125000004433 nitrogen atom Chemical group N* 0.000 description 2
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IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
MFPSKADFMNXZIY-UHFFFAOYSA-N tert-butyl n-(2,7-diazaspiro[4.4]nonan-2-yl)carbamate Chemical compound C1N(NC(=O)OC(C)(C)C)CCC11CNCC1 MFPSKADFMNXZIY-UHFFFAOYSA-N 0.000 description 1
OWGYHEOEGOLPEK-UHFFFAOYSA-N tert-butyl n-(2-pyrrolidin-3-ylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCC1CCNC1 OWGYHEOEGOLPEK-UHFFFAOYSA-N 0.000 description 1
DIQWSFWWYVRXRO-UHFFFAOYSA-N tert-butyl n-(3-methylpyrrolidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1(C)CCNC1 DIQWSFWWYVRXRO-UHFFFAOYSA-N 0.000 description 1
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WIEJVMZWPIUWHO-UHFFFAOYSA-N tert-butyl n-(pyrrolidin-3-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCNC1 WIEJVMZWPIUWHO-UHFFFAOYSA-N 0.000 description 1
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ZVQYLSQGHKZRPJ-UHFFFAOYSA-N tert-butyl n-[(1-benzyl-3-phenylpyrrolidin-3-yl)methyl]carbamate Chemical compound C1C(CNC(=O)OC(C)(C)C)(C=2C=CC=CC=2)CCN1CC1=CC=CC=C1 ZVQYLSQGHKZRPJ-UHFFFAOYSA-N 0.000 description 1
HJUZGKGDCUOVML-DTWKUNHWSA-N tert-butyl n-[(1s)-1-[(3r)-pyrrolidin-3-yl]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)[C@@H]1CCNC1 HJUZGKGDCUOVML-DTWKUNHWSA-N 0.000 description 1
ICTZIUAWAKFRDZ-AGBAINOHSA-N tert-butyl n-[(2r)-2-[3-(dibenzylamino)-1-ethyl-6-fluoro-2,4-dioxoquinazolin-7-yl]-2-pyrrolidin-3-ylpropyl]carbamate Chemical compound O=C1N(CC)C2=CC([C@](C)(CNC(=O)OC(C)(C)C)C3CNCC3)=C(F)C=C2C(=O)N1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 ICTZIUAWAKFRDZ-AGBAINOHSA-N 0.000 description 1
VRLMNTJDNRPIFB-UHFFFAOYSA-N tert-butyl n-[(3-benzylpyrrolidin-3-yl)methyl]carbamate Chemical compound C=1C=CC=CC=1CC1(CNC(=O)OC(C)(C)C)CCNC1 VRLMNTJDNRPIFB-UHFFFAOYSA-N 0.000 description 1
CEFJWUXTHLISAP-UHFFFAOYSA-N tert-butyl n-[(4-methylpyrrolidin-3-yl)methyl]carbamate Chemical compound CC1CNCC1CNC(=O)OC(C)(C)C CEFJWUXTHLISAP-UHFFFAOYSA-N 0.000 description 1
QALVWAHCRSYNFG-UHFFFAOYSA-N tert-butyl n-[1-(1-benzyl-4-methylpyrrolidin-3-yl)ethyl]carbamate Chemical compound C1C(C)C(C(NC(=O)OC(C)(C)C)C)CN1CC1=CC=CC=C1 QALVWAHCRSYNFG-UHFFFAOYSA-N 0.000 description 1
LZUVJGDBPICSGK-UHFFFAOYSA-N tert-butyl n-[1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxoquinazolin-7-yl)-3-methoxypyrrolidin-3-yl]ethyl]carbamate Chemical compound C1C(OC)(C(C)NC(=O)OC(C)(C)C)CCN1C1=C(F)C=C2C(=O)N(N)C(=O)N(C3CC3)C2=C1C LZUVJGDBPICSGK-UHFFFAOYSA-N 0.000 description 1
CQTSDJNUHOTZNB-UHFFFAOYSA-N tert-butyl n-[1-[1-cyclopropyl-8-fluoro-6-methoxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-2,4-dioxoquinazolin-7-yl]pyrrolidin-3-yl]carbamate Chemical compound COC1=CC(C(N(NC(=O)OC(C)(C)C)C(=O)N2C3CC3)=O)=C2C(F)=C1N1CCC(NC(=O)OC(C)(C)C)C1 CQTSDJNUHOTZNB-UHFFFAOYSA-N 0.000 description 1
MNIHYAVDKLMINM-VIFPVBQESA-N tert-butyl n-[2-[(3s)-pyrrolidin-3-yl]propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)(C)[C@H]1CCNC1 MNIHYAVDKLMINM-VIFPVBQESA-N 0.000 description 1
ASHQLXVHLDPBBB-UHFFFAOYSA-N tert-butyl n-[7a-(aminomethyl)-3,3a,4,5,6,7-hexahydro-1h-isoindol-2-yl]carbamate Chemical compound C1CCCC2(CN)CN(NC(=O)OC(C)(C)C)CC21 ASHQLXVHLDPBBB-UHFFFAOYSA-N 0.000 description 1
JJOOCVNFHZXGPL-UHFFFAOYSA-N tert-butyl n-amino-n-benzoylcarbamate Chemical compound CC(C)(C)OC(=O)N(N)C(=O)C1=CC=CC=C1 JJOOCVNFHZXGPL-UHFFFAOYSA-N 0.000 description 1
JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
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230000001225 therapeutic effect Effects 0.000 description 1
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239000002562 thickening agent Substances 0.000 description 1
150000007970 thio esters Chemical class 0.000 description 1
125000005309 thioalkoxy group Chemical group 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
230000007704 transition Effects 0.000 description 1
125000004665 trialkylsilyl group Chemical group 0.000 description 1
150000003852 triazoles Chemical class 0.000 description 1
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125000004953 trihalomethyl group Chemical group 0.000 description 1
PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
238000001665 trituration Methods 0.000 description 1
JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
238000005406 washing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Animal Behavior & Ethology (AREA)
Communicable Diseases (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Virology (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Oncology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Molecular Biology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Agricultural Chemicals And Associated Chemicals (AREA)
Paper (AREA)

OA1200200210A 2000-01-24 2000-12-12 3-Aminoquinazolin-2,4-dione antibacterial agents. OA12316A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US17825200P	2000-01-24	2000-01-24
US24126700P	2000-10-18	2000-10-18

Publications (1)

Publication Number	Publication Date
OA12316A true OA12316A (en)	2006-05-15

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ID=26874138

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OA1200200210A OA12316A (en)	2000-01-24	2000-12-12	3-Aminoquinazolin-2,4-dione antibacterial agents.

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US (2)	US7094780B1 (es)
EP (1)	EP1255739B1 (es)
JP (1)	JP4811978B2 (es)
KR (1)	KR20020067701A (es)
CN (1)	CN1425008A (es)
AP (1)	AP2002002603A0 (es)
AR (1)	AR030186A1 (es)
AT (1)	ATE398110T1 (es)
AU (1)	AU783078B2 (es)
BG (1)	BG107023A (es)
BR (1)	BR0017010A (es)
CA (1)	CA2393802C (es)
CO (1)	CO5320600A1 (es)
CR (1)	CR6709A (es)
DE (1)	DE60039194D1 (es)
EA (1)	EA005585B1 (es)
EE (1)	EE200200412A (es)
ES (1)	ES2304992T3 (es)
GE (1)	GEP20053429B (es)
HK (1)	HK1054237A1 (es)
HN (1)	HN2001000009A (es)
HR (1)	HRP20020696A2 (es)
HU (1)	HUP0204101A3 (es)
IL (1)	IL150393A0 (es)
IS (1)	IS6448A (es)
MA (1)	MA26866A1 (es)
MX (1)	MXPA02005989A (es)
NO (1)	NO20023516D0 (es)
OA (1)	OA12316A (es)
PA (1)	PA8510101A1 (es)
PE (1)	PE20011060A1 (es)
PL (1)	PL356837A1 (es)
SK (1)	SK10572002A3 (es)
SV (1)	SV2001000288A (es)
TN (1)	TNSN01011A1 (es)
UY (1)	UY26551A1 (es)
WO (1)	WO2001053273A1 (es)
YU (1)	YU55902A (es)

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Also Published As

Publication number	Publication date
EE200200412A (et)	2003-10-15
NO20023516L (no)	2002-07-23
SV2001000288A (es)	2001-11-30
JP4811978B2 (ja)	2011-11-09
CR6709A (es)	2003-11-25
HUP0204101A3 (en)	2004-05-28
HN2001000009A (es)	2001-06-13
HUP0204101A2 (hu)	2003-04-28
WO2001053273A1 (en)	2001-07-26
BR0017010A (pt)	2002-11-05
PE20011060A1 (es)	2001-10-12
YU55902A (sh)	2006-01-16
PL356837A1 (en)	2004-07-12
JP2003520277A (ja)	2003-07-02
IS6448A (is)	2002-06-27
UY26551A1 (es)	2001-04-30
AU783078B2 (en)	2005-09-22
TNSN01011A1 (en)	2005-11-10
AR030186A1 (es)	2003-08-13
US20060183762A1 (en)	2006-08-17
NO20023516D0 (no)	2002-07-23
CO5320600A1 (es)	2003-09-30
AP2002002603A0 (en)	2002-09-30
EA005585B1 (ru)	2005-04-28
CN1425008A (zh)	2003-06-18
IL150393A0 (en)	2002-12-01
ATE398110T1 (de)	2008-07-15
US20060287308A1 (en)	2006-12-21
BG107023A (en)	2003-04-30
CA2393802C (en)	2011-04-19
AU2089901A (en)	2001-07-31
DE60039194D1 (de)	2008-07-24
MA26866A1 (fr)	2004-12-20
EA200200661A1 (ru)	2003-02-27
HK1054237A1 (zh)	2003-11-21
GEP20053429B (en)	2005-01-25
ES2304992T3 (es)	2008-11-01
US7094780B1 (en)	2006-08-22
HRP20020696A2 (en)	2003-12-31
CA2393802A1 (en)	2001-07-26
US7582627B2 (en)	2009-09-01
EP1255739B1 (en)	2008-06-11
MXPA02005989A (es)	2002-10-23
SK10572002A3 (sk)	2003-10-07
EP1255739A1 (en)	2002-11-13
KR20020067701A (ko)	2002-08-23
PA8510101A1 (es)	2003-06-30

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