TWI295671B - Tricyclic tetrahydroquinoline antibacterial agents - Google Patents

Info

Publication number

TWI295671B

TWI295671B TW092127679A TW92127679A TWI295671B TW I295671 B TWI295671 B TW I295671B TW 092127679 A TW092127679 A TW 092127679A TW 92127679 A TW92127679 A TW 92127679A TW I295671 B TWI295671 B TW I295671B

Authority

TW

Taiwan

Prior art keywords

pyrimidine

tetrahydro

trione

dimethyl

porphyrin

Prior art date

2002-10-07

Links

• Espacenet
• Global Dossier
• Discuss

• 239000003242 anti bacterial agent Substances 0.000 title description 6
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims description 127
• 241000237858 Gastropoda Species 0.000 claims description 111
• 239000000203 mixture Substances 0.000 claims description 98
• YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 claims description 94
• -1 1 ,1_dimethylethyl ester Chemical class 0.000 claims description 61
• 125000000217 alkyl group Chemical group 0.000 claims description 53
• 239000002253 acid Substances 0.000 claims description 35
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 34
• 229910052736 halogen Inorganic materials 0.000 claims description 33
• 150000002367 halogens Chemical class 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 31
• 150000002576 ketones Chemical class 0.000 claims description 30
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 27
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 23
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 claims description 14
• 125000000468 ketone group Chemical group 0.000 claims description 14
• 229920006395 saturated elastomer Polymers 0.000 claims description 14
• 125000003003 spiro group Chemical group 0.000 claims description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 11
• 101100212791 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YBL068W-A gene Proteins 0.000 claims description 11
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
• 150000001412 amines Chemical class 0.000 claims description 10
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 10
• 125000001424 substituent group Chemical group 0.000 claims description 10
• 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 9
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 9
• 239000004575 stone Substances 0.000 claims description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 239000011734 sodium Substances 0.000 claims description 8
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 150000004032 porphyrins Chemical class 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 239000011593 sulfur Substances 0.000 claims description 7
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
• 125000003277 amino group Chemical group 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 5
• 229960005181 morphine Drugs 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 239000001301 oxygen Substances 0.000 claims description 5
• 125000006413 ring segment Chemical group 0.000 claims description 5
• 238000003971 tillage Methods 0.000 claims description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 150000002825 nitriles Chemical class 0.000 claims description 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 229930194542 Keto Natural products 0.000 claims description 3
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
• 125000002950 monocyclic group Chemical group 0.000 claims description 3
• 229910052708 sodium Inorganic materials 0.000 claims description 3
• OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 claims description 2
• 240000001546 Byrsonima crassifolia Species 0.000 claims description 2
• 208000001613 Gambling Diseases 0.000 claims description 2
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 150000002148 esters Chemical class 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 230000011987 methylation Effects 0.000 claims description 2
• 238000007069 methylation reaction Methods 0.000 claims description 2
• 229910052707 ruthenium Inorganic materials 0.000 claims description 2
• 230000002194 synthesizing effect Effects 0.000 claims description 2
• 239000000825 pharmaceutical preparation Substances 0.000 claims 3
• 229940127557 pharmaceutical product Drugs 0.000 claims 3
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
• 208000035143 Bacterial infection Diseases 0.000 claims 2
• 239000000010 aprotic solvent Substances 0.000 claims 2
• 208000022362 bacterial infectious disease Diseases 0.000 claims 2
• 125000005843 halogen group Chemical group 0.000 claims 2
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
• YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
• 229940124277 aminobutyric acid Drugs 0.000 claims 1
• 229910052786 argon Inorganic materials 0.000 claims 1
• 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims 1
• 229910052797 bismuth Inorganic materials 0.000 claims 1
• JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 claims 1
• 125000005594 diketone group Chemical group 0.000 claims 1
• 239000012454 non-polar solvent Substances 0.000 claims 1
• 239000003586 protic polar solvent Substances 0.000 claims 1
• 230000008707 rearrangement Effects 0.000 claims 1
• 238000005507 spraying Methods 0.000 claims 1
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
• 229910021653 sulphate ion Inorganic materials 0.000 claims 1
• 239000011592 zinc chloride Substances 0.000 claims 1
• 235000005074 zinc chloride Nutrition 0.000 claims 1
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 137
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 103
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
• 239000000243 solution Substances 0.000 description 64
• 235000019439 ethyl acetate Nutrition 0.000 description 63
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• 239000007787 solid Substances 0.000 description 54
• 238000002360 preparation method Methods 0.000 description 52
• 238000005481 NMR spectroscopy Methods 0.000 description 47
• 238000006243 chemical reaction Methods 0.000 description 45
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
• 239000002904 solvent Substances 0.000 description 39
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• 238000002390 rotary evaporation Methods 0.000 description 27
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
• 101150041968 CDC13 gene Proteins 0.000 description 24
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
• NLZXWAPSKLJZPF-UHFFFAOYSA-N 3-(decylamino)-1,1,1-trifluoropropan-2-ol Chemical compound CCCCCCCCCCNCC(O)C(F)(F)F NLZXWAPSKLJZPF-UHFFFAOYSA-N 0.000 description 21
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 21
• 238000005160 1H NMR spectroscopy Methods 0.000 description 20
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 20
• 239000003795 chemical substances by application Substances 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
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• 150000001299 aldehydes Chemical class 0.000 description 16
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• 239000002002 slurry Substances 0.000 description 9
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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• 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 3
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