CN105712976A - 喹诺酮化合物 - Google Patents
喹诺酮化合物 Download PDFInfo
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- CN105712976A CN105712976A CN201610052007.7A CN201610052007A CN105712976A CN 105712976 A CN105712976 A CN 105712976A CN 201610052007 A CN201610052007 A CN 201610052007A CN 105712976 A CN105712976 A CN 105712976A
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- alkyl
- group
- amino
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- -1 Quinolone compound Chemical class 0.000 title claims abstract description 146
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 213
- 150000001875 compounds Chemical class 0.000 claims abstract description 193
- 125000005843 halogen group Chemical group 0.000 claims abstract description 132
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 121
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 98
- 150000003839 salts Chemical class 0.000 claims abstract description 81
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 66
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 31
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 11
- 230000000845 anti-microbial effect Effects 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims description 114
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 94
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 63
- 125000003282 alkyl amino group Chemical group 0.000 claims description 61
- 125000003368 amide group Chemical group 0.000 claims description 60
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 50
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 47
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 38
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 230000000844 anti-bacterial effect Effects 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- LFMFPKKYRXFHHZ-UHFFFAOYSA-N R24 Chemical compound C1=C(Cl)C(C)=CC=C1NC1=NC(N)=C(C=CC=C2)C2=N1 LFMFPKKYRXFHHZ-UHFFFAOYSA-N 0.000 claims 1
- 241000193163 Clostridioides difficile Species 0.000 abstract description 10
- 206010012735 Diarrhoea Diseases 0.000 abstract description 5
- 206010022678 Intestinal infections Diseases 0.000 abstract description 2
- ZFRUGZMCGCYBRC-UHFFFAOYSA-N 1h-1,8-naphthyridin-2-one Chemical compound C1=CC=NC2=NC(O)=CC=C21 ZFRUGZMCGCYBRC-UHFFFAOYSA-N 0.000 abstract 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 abstract 1
- 239000002585 base Substances 0.000 description 69
- 239000000203 mixture Substances 0.000 description 58
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 239000007787 solid Substances 0.000 description 24
- 229910052763 palladium Inorganic materials 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000003513 alkali Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 16
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 235000008504 concentrate Nutrition 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 11
- 239000004327 boric acid Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
- 125000002971 oxazolyl group Chemical group 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 8
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 125000001425 triazolyl group Chemical group 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000007660 quinolones Chemical class 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- 241000699800 Cricetinae Species 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 108010059993 Vancomycin Proteins 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 5
- 229960003165 vancomycin Drugs 0.000 description 5
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical class [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
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- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
本发明涉及喹诺酮化合物。本发明提供由式(I)表示的化合物或其盐,其中X是氢原子或氟原子;R是氢原子或烷基;R1是(1)任选被1至3个卤素原子取代的环丙基或(2)任选被1至3个卤素原子取代的苯基;R2是烷基、烷氧基、卤代烷氧基、卤素原子、氰基等;和R3是7?氧代?7,8?二氢?1,8?二氮杂萘基、3?吡啶基等。本发明的化合物具有优良的抗难辨梭菌的抗微生物活性,并有用于预防或治疗如难辨梭菌相关性腹泻的肠道感染。
Description
本申请是申请号为201280041352.0(国际申请日为2012年8月30日)、发明名称为“喹诺酮化合物”的进入国家阶段的PCT申请的分案申请
技术领域
本发明涉及喹诺酮类化合物及其制药用途。
背景技术
难辨梭菌(Clostridium difficile)感染与消费抗生素相关,所述抗生素扰乱肠道的正常微生物菌群,使难辨梭菌自身定居并产生疾病。目前,只有万古霉素或甲硝唑被推荐用于治疗,且许多患者遭受感染复发(Expert Opin.Ther.Patents(2010)20(10),pp.1389-1399)。
EP2177214Al描述了奥泽沙星对难辨梭菌的用途。
一些用作抗菌剂的喹诺酮类化合物披露于JP1-319463 A、W099/51588、WO99/03465、JP3-66301 B和WO99/07682中。
发明概述
本发明的目的是提供新的喹诺酮化合物,其具有优良的抗微生物活性,尤其为优良的抗难辨梭菌的抗微生物活性。本发明另一目的是提供含有所述喹诺酮化合物的药物组合物,其有用于预防或治疗多种感染性疾病,所述感染性疾病包括抗生素相关性腹泻(AAD)诸如难辨梭菌相关性腹泻(CDAD)。本发明再一目的是提供预防或治疗细菌感染包括AAD诸如CDAD的方法,其包括给人类或动物施用所述的喹诺酮化合物。
本发明提供如下项1至27中所述的喹诺酮化合物、包括所述化合物的药物组合物、所述化合物的用途、和预防或治疗细菌感染的方法。
项1.由式(I)表示的化合物
其中
X是氢原子或氟原子;
R是氢原子或烷基;
R1是(1)任选被1至3个卤素原子取代的环丙基或(2)任选被1至3个卤素原子取代的苯基;
R2是氢原子;任选被1或2个选自卤素原子和羟基的取代基取代的烷基;烷氧基;卤代烷氧基;卤素原子;氰基;环丙基;硝基;氨基;甲酰基;链烯基或炔基;或
R1和R2键合以形成任选被烷基取代的5-或6-元的环;
R3是
(1)下式的稠合杂环基团
其中
表示单键或双键,
X1是C(R5)或N,
R4是氢原子或烷基,和
R5是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)羟基,
(f)任选被1至3个卤素原子取代的烷基,
(g)链烯基或炔基,
(h)芳基,或
(i)任选被1至3个卤素原子取代的烷氧基,
当X1是C(R5)时,R4和R5任选地键合以形成任选被氧代取代的5-或6-元的环;
所述的稠合杂环基团任选被1或2个选自卤素原子、氰基、硝基、羟基和烷基的取代基取代,
(2)下式的基团
其中
X2是C(R8)或N,和
R6、R7和R8各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)烷基,其任选被1至3个选自卤素原子、烷氧基和氨基的取代基取代,
(g)链烯基,
(h)炔基,
(i)芳基,
(j)甲酰基或CH=N-OH,
(k)羧基,
(1)氨基甲酰基,
(m)任选被烷基取代的5-至10-元的芳香族杂环基,或
(n)链烯基氧基,
(3)下式的基团
其中
X3和X4是N,或
X3是N和X4是CR",其中R"是氢原子、氨基、羟基、任选被1至3个选自烷氧基和二甲基氨基的取代基取代的烷基、或巯基,或
X3是CH和X4是N,
R'是氢原子或任选被1至3个选自取代的羟基和氨基的取代基取代的烷基,和
R6定义如上,
(4)下式的基团
其中
表示单键或双键,和R6定义如上,
(5)3-吡啶基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)氨基,
(f)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(g)链烯基、炔基
(h)芳基,
(i)环烷基,
(j)烷氧基,
(k)烷基氨基,
(1)二烷基氨基,
(m)任选被1至3个卤素原子取代的苯基氨基,
(n)任选被烷氧基羰基取代的环状氨基,
(o)甲酰基,
(p)任选被烷基取代的氨基甲酰基,所述烷基任选被羟基取代,和
(q)任选被烷基取代的5-至10-元的芳香族杂环基,
(6)任选被卤素原子取代的4-吡啶基,
(7)5-嘧啶基,其任选被1或2个选自氨基、烷基氨基、二烷基氨基和羧基的取代基取代,
(8)2-吲哚基、3-吲哚基、5-吲哚基、6-吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基或苯并噻唑基,各自任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基,和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基,所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)环烷基烷基磺酰基,其任选被1至3个选自烷基和氧代的取代基取代,
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基,和
(x)-C(=N-CN)-SR9,其中R9是烷基,
(9)下式的基团
其中
Y1、Y2、Y3和Y4之一是N或N+(-O-),和其余三个各自是C(R25)、C(R26)和C(R27),
W是O、S、NH或N(R23)
R23是氢原子或烷基,和
R24、R25、R26和R27各自独立地为,
(a)氢原子,
(b)氰基,或
(c)硝基,
(10)下式的基团
其中
R28是氢原子或羟基,和
R29是氢原子或烷基,
(11)下式的基团
其中
X5是C(R11)或N,
X6是CH2、C(=0)、0、S、S02或N(R12),
X7是CH(R13)、C(=0)或N(R14),
X8是CH(R15)或C(=0),
R10、R12和R14各自独立地为,
(a)氢原子或
(b)烷基,和
R11、R13和R15各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)烷基氨基,
(g)二烷基氨基,
(h)任选被羟基取代的烷基,或
(i)链烯基,
当X5是C(R11)时,R1U和R11任选地键合以形成任选被烷基或氧代取代的5-或6-元的环,以及当X6是N(R12)和X7是CH(R13)时,R12和R13任选地键合以形成5-或6-元的环,
(12)下式的基团
其中R16是
(a)氢原子,
(b)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(c)任选被羧基取代的链烯基,
(d)甲酰基,
(e)羧基,
(f)氨基甲酰基,
(g)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,
(h)5-至10-元的芳香族杂环基,其任选被烷基、烷氧基羰基、羧基或苯基取代,或
(i)氰基,
(13)下式的基团
其中
R18是氢原子或任选被1至3个选自卤素原子和苯基的取代基取代的烷基,
n是0或1,
R19、R20和R33各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基,
(e)烷氧基,
(f)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基取代的烷基羰基,
(ii)烷基磺酰基,
(iii)氨基甲酰基,
(iv)烷基、环烷基或环烷基烷基,和
(v)5-至10-元的饱和杂环基,
(g)羧基,
(h)烷氧基羰基,
(i)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(j)甲酰基,
(k)任选被烷基取代的5-至10-元的芳香族杂环基,
(1)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基,
(m)硝基,
(n)任选被氨基取代的5-至10-元的饱和杂环基,
(o)苯基,或
(P)-NHC(SMe)=CHCN,
(14)下式的基团
其中
R30是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自卤素原子和羟基的取代基取代的烷基,
(e)链烯基,
(f)炔基,
(g)烷氧基,
(h)甲酰基,
(i)-CH=N-OH,或
(j)氨基甲酰基,
(15)萘基或异色烯基(isochromenyl),
(16)喹啉基或异喹啉基、或它们的氧化物衍生物,
(17)下式的基团
(18)下式的基团
其中
U是0或S,和
R31是(a)氢原子,
(b)卤素原子,
(c)任选被1至3个卤素原子取代的烷基,
(d)羧基,
(e)硝基,
(f)氰基,或
(g)氨基,
(19)下式的基团
其中
R32是(a)卤素原子,
(b)苯基,或
(c)下式的基团
(20)下式的基团
其中
R34和R35各自独立地为,
(a)氢原子,或
(b)氨基烷基,
或
R34和R35键合以形成任选被氨基或氧代取代的6-元环,
(21)下式的基团
其中R36是
(a)氢原子,
(b)卤素原子,
(c)硝基,或
(d)噻吩基,或
(22)下式的基团
或其盐。
项1A.项1的化合物,其中
X是氢原子或氟原子;
R是氢原子或烷基;
R1是(1)任选被1至3个卤素原子取代的环丙基或(2)任选被1至3个卤素原子取代的苯基;
R2是烷基、烷氧基、卤代烷氧基、氯原子或氰基;或R1和R2键合以形成任选被烷基取代的5-或6-元的环;和
R3是
(1)下式的稠合杂环基团
其中
表示单键或双键,
X1是C(R5)或N,
R4是氢原子或烷基,和
R5是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)羟基,
(f)任选被1至3个卤素原子取代的烷基,
(g)链烯基或炔基,
(h)芳基,或
(i)任选被1至3个卤素原子取代的烷氧基,
当X1是C(R5)时,R4和R5任选地键合以形成任选被氧代取代的5-或6-元的环;
所述的稠合杂环基团任选被1或2个选自卤素原子、氰基、硝基、羟基和烷基的取代基取代,
(2)下式的基团
其中
X2是C(R8)或N,和
R6、R7和R8各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)烷基,其任选被1至3个选自卤素原子、烷氧基和氨基的取代基取代,
(g)链烯基,
(h)炔基,
(i)芳基,
(j)甲酰基或CH=N-OH,
(k)羧基,
(1)氨基甲酰基,或
(m)任选被烷基取代的5-至10-元的芳香族杂环基,
(3)下式的基团
其中
X3和X4是N,或
X3是N和X4是CR",其中R"是氢原子、氨基、羟基、烷基或巯基,或
X3是CH和X4是N,
R'是氢原子或任选被1至3个选自取代的羟基和氨基的取代基取代的烷基,和
R6定义如上,
(4)下式的基团
其中
表示单键或双键,和R6定义如上,
(5)3-吡啶基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)氨基,
(f)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(g)链烯基或炔基,
(h)芳基,
(i)环烷基,
(j)烷氧基,
(k)烷基氨基,
(1)二烷基氨基,
(m)任选被1至3个卤素原子取代的苯基氨基,
(n)任选被烷氧基羰基取代的环状氨基,
(o)甲酰基,
(p)任选被烷基取代的氨基甲酰基,所述烷基任选被羟基取代,和
(q)任选被烷基取代的5-至10-元的芳香族杂环基,
(6)任选被卤素原子取代的4-吡啶基,
(7)5-嘧啶基,其任选被1或2个选自氨基、烷基氨基、二烷基氨基和羧基的取代基取代,
(8)2-吲哚基、3-吲哚基、5-吲哚基、6-吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基或苯并噻唑基,各自任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基,和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基,所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)环烷基烷基磺酰基,其任选被1至3个选自烷基和氧代的取代基取代,
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基,和
(x)-C(=N-CN)-SR9,其中R9是烷基,
(9)下式的基团
其中
Y1、Y2、Y3和Y4之一是N或N+(-O-),和其余三个各自是C(R25)、C(R26)和C(R27),
W是O、S或N(R23)
R23是氢原子或烷基,和
R24、R25、R26和R27各自独立地为,
(a)氢原子,
(b)氰基,或
(c)硝基,
(10)下式的基团
其中
R28是氢原子或羟基,和
R29是氢原子或烷基,
(11)下式的基团
其中
X5是C(R11)或N,
X6是CH2、C(=0)、0、S、S02或N(R12),
X7是CH(R13)、C(=0)或N(R14),
X8是CH(R15)或C(=0),
R10、R12和R14各自独立地为,
(a)氢原子或
(b)烷基,和
R11、R13和R15各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)烷基氨基,
(g)二烷基氨基,
(h)任选被羟基取代的烷基,或
(i)链烯基,
当X5是C(R11)时,R1U和R11任选地键合以形成任选被烷基或氧代取代的5-或6-元的环,以及当X6是N(R12)和X7是CH(R13)时,R12和R13任选地键合以形成5-或6-元的环,
(12)下式的基团
其中R16是
(a)氢原子,
(b)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(c)任选被羧基取代的链烯基,
(d)甲酰基,
(e)羧基,
(f)氨基甲酰基,
(g)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,
(h)5-至10-元的芳香族杂环基,其任选被烷基、烷氧基羰基、羧基或苯基取代,或
(i)氰基,
(13)下式的基团
其中
R18是氢原子或任选被1至3个选自卤素原子和苯基的取代基取代的烷基,和
R19和R20各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基,
(e)烷氧基,
(f)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基取代的烷基羰基,
(ii)烷基磺酰基,
(iii)氨基甲酰基,和
(iv)烷基或环烷基,
(g)羧基,
(h)烷氧基羰基,
(i)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(j)甲酰基,
(k)任选被烷基取代的5-至10-元的芳香族杂环基,
(1)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基,或
(m)硝基,
(14)下式的基团
其中
R30是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自卤素原子和羟基的取代基取代的烷基,
(e)链烯基,
(f)炔基,
(g)烷氧基,
(h)甲酰基,或
(i)-CH=N-OH,
(15)萘基或异色烯基,或
(16)喹啉基或异喹啉基、或它们的氧化物衍生物,
或其盐。
项2.项1或1A的化合物或其盐,其中X是氟原子。
项3.项1或1A的化合物或其盐,其中R3是下式的稠合杂环基团
其中X1和R4如项1中所定义,且所述的稠合杂环基团任选被1或2个选自卤素原子、氰基、硝基、羟基和烷基的取代基取代。
项4.项1或1A的化合物或其盐,其中R3是下式的基团
其中X2、R6和R7如项1中所定义。
项5.项1或1A的化合物或其盐,其中R3是下式的基团
其中X3、X4、R6和R'如项1中所定义。
项6.项1或1A的化合物或其盐,其中R3是下式的基团
其中和R6如项1中所定义。
项7.项1或1A的化合物,其中R3是下式的基团
其中R22是
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(e)链烯基或炔基,
(f)芳基,
(g)环烷基,
(h)烷氧基,
(i)甲酰基,或
(j)任选被烷基取代的氨基甲酰基,所述烷基任选被羟基取代,
或其盐。
项8.项1或1A的化合物或其盐,其中R3是被1或2个选自氨基、烷基氨基、二烷基氨基和羧基的取代基取代的5-嘧啶基。
项9.项1或1A的化合物,其中R3是2-吲哚基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基,和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基,所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)环烷基烷基磺酰基,其任选被1至3个选自烷基和氧代的取代基取代,
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基,和
(x)-C(=N-CN)-SR9,其中R9是烷基,
或其盐。
项10.项1或1A的化合物或其盐,其中R3是下式的基团
其中Y1、Y2、Y3、Y4、W和R24如项1中所定义。
项11.项1或1A的化合物或其盐,其中R3是下式的基团
其中R28和R29如项1中所定义。
项12.项1或1A的化合物或其盐,其中R3是下式的基团
其中X5、X6、X7、X8和R10如项1中所定义。
项13.项1或1A的化合物,其中R3是下式的基团
其中R16a是
(a)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(b)任选被羧基取代的链烯基,
(c)甲酰基,
(d)羧基,
(e)氨基甲酰基,
(f)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,
(g)5-至10-元的芳香族杂环基,其任选被烷基、烷氧基羰基、羧基或苯基取代,或
(h)氰基,
或其盐。
项14.项1或1A的化合物,其中R3是下式的基团
其中
R18a是烷基,和
R19a是(a)卤素原子,
(b)氰基,
(c)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基,
(d)烷氧基,
(e)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基取代的烷基羰基,
(ii)烷基磺酰基,
(iii)氨基甲酰基,和
(iv)烷基或环烷基,
(f)羧基,
(g)烷氧基羰基,
(h)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代
(i)甲酰基,
(j)任选被烷基取代的5-至10-元的芳香族杂环基,
(k)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基,或
(1)硝基,
或其盐。
项15.项1或1A的化合物或其盐,其中R3是下式的基团
其中R30如项1中所定义。
项16.项1或1A的化合物或其盐,其中R3是萘基或异色烯基。
项17.项1或1A的化合物或其盐,其中R3是喹啉基或异喹啉基、或它们的氧化物衍生物。
项18.项1或1A的化合物或其盐,其中R是氢原子。
项19.项1或1A的化合物或其盐,其中R1是环丙基、2-氟环丙基或2,4-二氟苯基。
项20.项1或1A的化合物或其盐,其中R2是甲基、甲氧基或氯原子。
项21.药物组合物,其包括项1或1A的化合物或其盐和药学上可接受的载体。
项22.抗微生物剂,其包括项1或1A的化合物或其盐。
项23.项1或1A的化合物或其盐,用作药物。
项24.项1或1A的化合物或其盐,用作抗微生物剂。
项25.项1或1A的化合物或其盐,其在预防或治疗细菌感染中的用途。
项26.项1或1A的化合物或其盐在制备用于预防或治疗细菌感染的药物中的用途。
项27.预防或治疗细菌感染的方法,其包括给人类或动物施用有效量的项1或1A的化合物或其盐。
式(I)的化合物或其盐(在下文中有时简称为化合物(I))对各种革兰氏阳性和革兰氏阴性菌具有优异的抗菌活性,并有用于预防或治疗由各种细菌引起的人类、其他动物和鱼类的各种感染性疾病,以及也用作医疗器械等的外部抗微生物剂或消毒剂。
附图简述
图1是曲线图,显示出实验实施例2中给动物施用化合物2-18的结果。
图2是曲线图,显示出实验实施例2中给动物施用万古霉素的结果。
发明详述
式(I)中基团的具体实例如下。
“卤素原子”的实例包括氟原子、氯原子、溴原子、和碘原子。
在“烷基氨基”、“二烷基氨基”、“烷基羰基”、“环烷基烷基磺酰基”、“环烷基烷基”、“氨基烷基”和“烷基磺酰基”中的“烷基”和“烷基”部分的实例包括直链或支链的C1-6烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、1-乙基丙基、异戊基、新戊基、叔戊基、己基、1,2,2-三甲基丙基、3,3-二甲基丁基、2-乙基丁基、异己基、3-甲基戊基等。
“链烯基”的实例包括直链或支链的C2-6烯基,如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、l-甲基-2-丙烯基、2-戊烯基、2-己烯基等。
“炔基”的实例包括直链或支链的C2-6炔基,如乙炔基、2-丙炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、2-戊炔基、2-己炔基等。
“卤代烷氧基”、“烷氧基羰基”和“烷氧基羰基氨基”中的“烷氧基”和“烷氧基”部分的实例包括直链或支链的C1-6烷氧基,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基、叔戊氧基、己氧基、异己氧基、3-甲基戊氧基等。
“卤代烷氧基”的实例包括被1至3个卤素原子取代的直链或支链的C1-6烷氧基。其实例包括氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基、溴甲氧基、二溴甲氧基、二氯氟甲氧基、2,2,2-三氟乙氧基、2-氯乙氧基、3,3,3-三氟丙氧基、2-氯丙氧基、3-氯丙氧基、3-溴丙氧基、4,4,4-三氟丁氧基、2-氯丁氧基、4-氯丁氧基、4-溴丁氧基、5,5,5-三氟戊氧基、5-氯戊氧基、6,6,6-三氟己氧基、6-氯己氧基等。其优选的实例包括二氟甲氧基。
“链烯基氧基”的实例包括直链或支链的C2-6链烯氧基,如乙烯氧基、1-丙烯氧基、2-丙烯氧基、1-丁烯氧基、2-丁烯氧基、3-丁烯氧基、l-甲基-2-丙烯氧基、2-戊烯氧基、2-己烯氧基等。
“芳基磺酰基”中的“芳基”和“芳基”部分的实例包括C6-14(优选C6-10)芳基,如苯基、萘基(例如1-萘基、2-萘基)等。其优选的实例包括苯基。
在“5-至10-元的芳香族杂环基羰基”和“5-至10-元的芳香族杂环基磺酰基”中的“5-至10-元的芳香族杂环基”和“5-至10-元的芳香族杂环基”部分的实例包括5-至10-元(优选5-或6-元)的芳香族杂环基团,其含有1至4个(优选1至3个,更优选1或2个)选自氮原子、氧原子和硫原子的杂原子。其实例包括呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、***基(例如,1,2,3-***基、1,2,4-***基)、四唑基、异噁唑基、噁唑基、呋咕基(furazanyl)、异噻唑基、噻唑基、吡啶基(例如,2-吡啶基、3-吡啶基、4-吡啶基)、哒嗪基、嘧啶基、吡嗪基、苯并呋喃基、异苯并呋喃基、苯并[b]噻吩基、苯并[c]噻吩基、吲哚基、异吲哚基、中氮茚基、吲唑基、苯并咪唑基、苯并***基、苯并噁唑基、1,2-苯并异噁唑基、苯并噻唑基、1,2-苯并异噻唑基、嘌呤基、喹啉基、异喹啉基、喹嗪基、噌啉基(cinnolinyl)、喹唑啉基、喹喔啉基、酞嗪基、二氮杂萘基、蝶啶基等。其优选的实例包括吡咯基、咪唑基、噁唑基、***基(例如,1,2,3-***基、1,2,4-***基)、四唑基、吡啶基(例如,2-吡啶基、3-吡啶基、4-吡啶基)、苯并咪唑基等。
“烷基氨基”的实例包括C1-6烷基氨基,如甲基氨基、乙基氨基、丙基氨基、异丙基氨基、丁基氨基、异丁基氨基、仲丁基氨基、叔丁基氨基、戊基氨基、异戊基氨基、新戊基氨基、叔戊基氨基、己基氨基等。
“二烷基氨基”的实例包括二(C1-6烷基)氨基,如二甲基氨基、二乙基氨基、二丙基氨基、二异丙基氨基、二丁基氨基、二异丁基氨基、二(仲丁基)氨基、二(叔丁基)氨基、二戊基氨基、二(叔戊基)氨基、二己基氨基、乙基甲基氨基等。
“氨基烷基”的实例包括氨基-C1-6烷基,如氨基甲基、2-氨基乙基、3-氨基丙基、4-氨基丁基、5-氨基戊基、6-氨基己基等。
在“环烷基氧基”、“环烷基羰基”、“环烷基烷基”和“环烷基烷基磺酰基”中的“环烷基”和“环烷基”部分的实例包括C3-8环烷基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片烷基(例如2-降冰片烷基(norbornanyl))等。
“环烷基烷基”的实例包括C3-8环烷基-C1-6烷基,如环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环庚基甲基、环辛基甲基、降冰片烷基甲基(例如降冰片烷-2-基甲基)等。
“环状氨基”的实例包括4-至7-元(优选5-或6-元)的环状氨基,其含有一个氮原子并任选地进一步含有一个选自氮原子、氧原子和硫原子的杂原子。其实例包括1-氮杂环丁烷基、1-吡咯烷基、1-咪唑烷基、1-吡唑烷基、哌啶子基、1-哌嗪基、吗啉代、硫代吗啉代、1-氮杂环庚烷基、1,4-氧杂氮杂环庚烷-4-基(1,4-oxazepan-4-yl)等。其优选的实例包括1-吡咯烷基、哌啶子基、1-哌嗪基、吗啉代、硫代吗啉代等。
“烷氧基羰基”的实例包括C1-6烷氧基-羰基,其中烷氧基部分是C1-6烷氧基。其实例包括甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基、己氧基羰基等。
“烷氧基羰基氨基”的实例包括C1-6烷氧基-羰基氨基,其中烷氧基部分是C1-6烷氧基。其实例包括甲氧基羰基氨基、乙氧基羰基氨基、丙氧基羰基氨基、异丙氧羰基氨基、丁氧基羰基氨基、异丁氧基羰基氨基、仲丁氧基羰基氨基、叔丁氧基羰基氨基、戊氧基羰基氨基、己氧基羰基氨基等。
“烷基羰基”的实例包括C1-6烷基-羰基,其中烷基部分是C1-6烷基。其实例包括乙酰基、乙基羰基、丙基羰基、异丙基羰基、丁基羰基、异丁基羰基、仲丁基羰基、叔丁基羰基、戊基羰基、己基羰基等。
“环烷基氧基”的实例包括C3-8环烷基氧基,如环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基、环庚基氧基、环辛基氧基等。
“环烷基羰基”的实例包括C3-8环烷基-羰基,如环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基羰基、环辛基等。
“5-至10-元的芳香族杂环基羰基”的实例包括5-至10-元(优选5-或6-元)的芳香族杂环基羰基,其中杂环基部分含有1至4个(优选1至3个,更优选1或2个)选自氮原子、氧原子和硫原子的杂原子。杂环基部分的实例与上述的5-至10-元的芳香族杂环基的实例相同。“5-至10-元的芳香族杂环基羰基”优选的实例包括吡啶基羰基(例如,2-吡啶基羰基、3-吡啶基羰基、4-吡啶基羰基)。
“芳基磺酰基”的实例包括C6-14(优选C6-10)芳基磺酰基,如苯基磺酰基、萘基磺酰基(例如,1-萘基磺酰基、2-萘基磺酰基)等。其优选的实例包括苯基磺酰基。
“环烷基烷基磺酰基”的实例包括C3-8环烷基-C1-6烷基磺酰基,如环丙基甲基磺酰基、环丁基甲基磺酰基、环戊基甲基磺酰基、环己基甲基磺酰基、环庚基甲基磺酰基、环辛基甲基磺酰基、降冰片烷基甲基磺酰基(例如降冰片烷-2-基甲基磺酰基)等。
“5-至10-元的芳香族杂环基磺酰基”的实例包括5-至10-元(优选5-或6-元)的芳香族杂环基磺酰基,其中杂环基部分含有1至4个(优选1至3个,更优选1或2个)选自氮原子、氧原子和硫原子的杂原子。杂环基部分的实例与上述的5-至10-元的芳香族杂环基的实例相同。“5-至10-元的芳香族杂环基磺酰基”优选的实例包括咪唑基磺酰基。
“烷基磺酰基”的实例包括C1-6烷基磺酰基,其中烷基部分是C1-6烷基。其实例包括甲基磺酰基、乙基磺酰基、丙基磺酰基、异丙基磺酰基、丁基磺酰基、异丁基磺酰基、仲丁基磺酰基、叔丁基磺酰基、戊基磺酰基、己基磺酰基等。
“任选被1至3个卤素原子取代的环丙基”的实例包括任选被1个氟原子取代的环丙基,例如环丙基、2-氟环丙基等。
“任选被1至3个卤素原子取代的苯基”的实例包括被2个氟原子取代的苯基,如2,4-二氟苯基等。
“5-至10-元的饱和杂环基”的实例包括5-至10-元(优选5-或6-元)的饱和杂环基,其含有1至4个(优选1至3个,更优选1或2个)选自氮原子、氧原子和硫原子的杂原子。其实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基等。
由R34和R35形成的“任选被氨基或氧代取代的6-元环”的实例包括任选含有一个氮原子的6-元环,且所述环任选被氨基或氧代取代。其实例包括环己烯和二氢吡啶,各自任选被氨基或氧代取代。
由R1和R2形成的“任选被烷基取代的5-或6-元的环”的实例包括5-或6-元(优选6-元)的环,其含有一个氮原子并任选进一步含有一个氧原子,且所述环任选被烷基取代。优选地,R1和R2任选地键合以形成-O-CH2-CH(CH3)-,其中氧原子键合到如下所示的喹诺酮环的苯环上。
由R4和R5形成的“任选被氧代取代的5-或6-元的环”的实例包括5-或6-元(优选6-元)的环,其含有一个氮原子并任选进一步含有一个氧原子,且所述环任选被氧代取代。优选地,R4和R5任选地键合以形成-CH2-O-(C=O)-,其中羰基键合到如下所示的喹诺酮环的苯基环上。
由R10和R11形成的“任选被烷基或氧代取代的5-或6-元环”的实例包括5-或6-元(优选5-元)的环,其含有2或3个氮原子,且所述环任选被烷基或氧代取代。优选地,R10和R11任选地键合以形成-(C=O)-NH-、-C(R31)=N-或-N=N-,其中R31是氢原子或烷基,和氮原子键合到如下所示的稠环的苯基环上。
由R12和R13形成的“5-或6-元的环”的实例包括任选含有一个氮原子的5-或6-元(优选6-元)的环。优选地,R12和R13任选地键合以形成如下所示的-(CH2)4-。
X是氢原子或氟原子,优选为氟原子。
R是氢原子或烷基,优选为氢原子。
R1是(1)任选被1至3个卤素原子取代的环丙基或(2)任选被1至3个卤素原子取代的苯基,优选地,环丙基、2-氟环丙基或2,4-二氟苯基。
R2是氢原子;任选被1或2个选自卤素原子和羟基的取代基取代的烷基;烷氧基;卤代烷氧基;卤素原子;氰基;环丙基;硝基;氨基;甲酰基;链烯基或炔基,优选为烷基、烷氧基、卤代烷氧基、氯原子或氰基,更优选为C1-6烷基、C1-6烷氧基、被1至3个卤素原子取代的C1-6烷氧基、氯原子或氰基,更加优选为甲基、甲氧基或氯原子。
式(A)或(B)的稠合杂环基团的实例包括下式的稠合杂环基团
其中X1和R4定义如上,且所述的稠合杂环基团任选被1或2选自卤素原子、氰基、硝基、羟基和烷基的取代基取代。
式(A)或(B)的稠合杂环基团优选的实例包括下式的稠合杂环基团
其中R4和R5定义如上,且所述的稠合杂环基团任选被1或2选自卤素原子、氰基、硝基、羟基和烷基的取代基取代。
式(A)或(B)的稠合杂环基团优选的其它实例包括下式的稠合杂环基团
其中X1和R4定义如上,且所述的稠合杂环基团任选被1或2选自卤素原子、氰基、硝基、羟基和烷基的取代基取代。
式(C)基团的实例包括下式的基团
其中X2、R6和R7定义如上。
式(C)基团优选的实例包括下式的基团
其中R6、R7和R8定义如上。
在上式中,R6、R7和R8各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)任选被1至3个选自卤素原子和氨基的取代基取代的烷基,
(g)链烯基,
(h)炔基,
(i)芳基,
(j)甲酰基,
(k)羧基,
(1)氨基甲酰基,或
(m)任选被烷基取代的5-至10-元的芳香族杂环基(例如吡啶基、***基)。
式(D)或(E)基团的实例包括下式的基团
其中R6定义如上。R6优选为氢原子、卤原子、硝基或氨基。
优选地,R3是任选地被1或2个选自下列的取代基取代的3-吡啶基
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)氨基,
(f)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(g)链烯基,
(h)芳基,
(i)环烷基,
(j)烷氧基,
(k)烷基氨基,
(1)二烷基氨基,
(m)任选被1至3个卤素原子取代的苯基氨基,
(n)任选被烷氧基羰基取代的环状氨基(例如1-哌嗪基、吗啉代),
(o)甲酰基,
(p)氨基甲酰基,和
(q)任选被烷基取代的5-至10-元的芳香族杂环基(例如***基)。
更优选地,R3是是下式基团
其中R22是
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(e)链烯基,
(f)芳基,
(g)环烷基,
(h)烷氧基,
(i)甲酰基,或
(j)氨基甲酰基。
优选地,R22是
(a)氰基,
(b)硝基,
(c)芳基,
(d)甲酰基,或
(e)氨基甲酰基。
优选地,R3是被1或2个选自氨基、烷基氨基和二烷基氨基的取代基取代的5-嘧啶基。
优选地,R3是2-吲哚基、3-吲哚基、5-吲哚基或6-吲哚基,各自任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基(例如吗啉代、1-哌嗪基),和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基(例如吡啶基羰基),所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)任选被1至3个选自烷基和氧代的取代基取代的环烷基烷基磺酰基(例如樟脑磺酰基),
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基(例如咪唑基磺酰基),和
(x)-C(=N-CN)-SR9,其中R9是烷基。
更优选地,R3是2-吲哚基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基(例如吗啉代、1-哌嗪基),和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基(例如吡啶基羰基),所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)任选被1至3个选自烷基和氧代的取代基取代的环烷基烷基磺酰基(例如樟脑磺酰基),
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基(例如咪唑基磺酰基),和
(x)-C(=N-CN)-SR9,其中R9是烷基。
式(F)或(G)基团的实例包括下式的基团
其中
R23是氢原子或烷基,和
R24、R25、R26和R27各自独立地为,
(a)氢原子,
(b)氰基,或
(c)硝基。
式(K)基团的实例包括下式的基团
其中X5、X6、X7、X8和R10定义如上。
式(K)基团优选的实例包括下式的基团
其中R10、R11、R12、R13、R14和R15定义如上。
当R10和R11键合以形成任选被烷基或氧代取代的5-或6-元环时,式(K)基团优选的实例包括下式的基团
其中R31是氢原子或烷基。
当R12和R13键合以形成5-或6-元的环时,式(K)基团优选的实例包括下式的基团
式(K)基团更优选的实例包括下式的基团
其中R10a是
(a)氢原子或
(b)烷基,和
R11a、R13a和R15a各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)烷基氨基,
(g)二烷基氨基,
(h)任选被羟基取代的烷基,或
(i)链烯基,
R10a和R11a任选地键合以形成任选被烷基或氧代取代的5-或6-元的环,
条件是R10a、R11a、R13a和R15a不同时为氢原子。
优选地,R3是下式的基团
其中R16是
(a)氢原子,
(b)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(c)任选被羧基取代的链烯基,
(d)甲酰基,
(e)羧基,
(f)氨基甲酰基,
(g)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,或
(h)5-至10-元的芳香族杂环基(例如四唑基、吡咯基、噁唑基、苯并咪唑基、***基),其任选被烷基、烷氧基羰基、羧基或苯基取代。
更优选地,R3是下式的基团
其中R16a是
(a)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(b)任选被羧基取代的链烯基,
(c)甲酰基,
(d)羧基,
(e)氨基甲酰基,
(f)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,或
(g)5-至10-元的芳香族杂环基(例如四唑基、吡咯基、噁唑基、苯并咪唑基、***基),其任选被烷基、烷氧基羰基、羧基或苯基取代。
优选地,R3是下式的基团
其中
R18是任选被1至3个选自卤素原子和苯基的取代基取代的烷基,和
R19和R20各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基(例如,1-哌嗪基),
(e)烷氧基,
(f)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基(例如,吗啉代)取代的烷基羰基,
(ii)烷基磺酰基,和
(iii)氨基甲酰基,
(g)羧基,
(h)烷氧基羰基,
(i)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(j)甲酰基,
(k)5-至10-元的芳香族杂环基(例如,噁唑基、苯并咪唑基),或
(1)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基。
更优选地,R3是下式的基团
其中
R18a是烷基,和
R19a是(a)卤素原子,
(b)氰基,
(c)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基(例如,1-哌嗪基),
(d)烷氧基,
(e)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基(例如,吗啉代)取代的烷基羰基,
(ii)烷基磺酰基,和
(iii)氨基甲酰基,
(f)羧基,
(g)烷氧基羰基,
(h)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(i)甲酰基,
(j)5-至10-元的芳香族杂环基(例如,噁唑基、苯并咪唑基),或
(k)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基。
化合物(I)优选的实例描述如下。
[化合物I-1]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;或
R1和R2任选地键合以形成-O-CH2-CH(CH3)-,其中氧原子键合在喹诺酮环的苯基环上;和
R3是下式的稠合的杂环基团
其中
X1是C(R5)或N,
R4是氢原子或C1-6烷基,和
R5是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)羟基,
(f)任选被1至3个卤素原子取代的C1-6烷基,
(g)C2-6炔基,
(h)C6-14芳基,或
(i)任选被1至3个卤素原子取代的C1-6烷氧基,
当X1是C(R5)时,R4和R5任选地键合以形成-CH2-O-(C=O)-,其中羰基键合在喹诺酮环的苯基环上,
所述稠合的杂环基团任选被1或2个选自卤素原子、氰基、硝基、羟基和C1-6烷基的取代基取代,
或其盐。
[化合物I-2]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;或
R1和R2任选地键合以形成-O-CH2-CH(CH3)-,其中氧原子键合在喹诺酮环的苯基环上;和
R3是下式的基团
其中
X2是C(R8)或N,和
R6、R7和R8各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)C1-6烷基,其任选被1至3个选自卤素原子和氨基的取代基取代,
(g)C2-6链烯基,
(h)C2-6炔基,
(i)C6-14芳基,
(j)甲酰基,
(k)羧基,
(1)氨基甲酰基,或
(m)任选被C1-6烷基取代的5-至10-元的芳香族杂环基(例如,吡啶基、***基),
或其盐。
[化合物I-3]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
X3和X4是N,或
X3是N和X4是CH,或
X3是CH和X4是N,和
R6是氢原子、卤素原子、硝基或氨基,
或其盐。
[化合物I-4]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
或其盐。
[化合物I-5]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;或
R1和R2任选地键合以形成-O-CH2-CH(CH3)-,其中氧原子键合在喹诺酮环的苯基环上;和
R3是下式的基团
其中R22是
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)C1-6烷基,其任选被1至3个选自卤素原子、C1-6烷基氨基、二(C1-6烷基)氨基和羟基的取代基取代,
(e)C2-6链烯基,
(f)C6-14芳基,
(g)C3-8环烷基,
(h)C1-6烷氧基,
(i)甲酰基,或
(j)氨基甲酰基,
或其盐。
[化合物I-6]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;或
R1和R2任选地键合以形成-O-CH2-CH(CH3)-,其中氧原子键合在喹诺酮环的苯基环上;和
R3是下式的基团
其中R22是
(a)氰基,
(b)硝基,
(c)C6-14芳基,
(d)甲酰基,或
(e)氨基甲酰基,
或其盐。
[化合物I-7]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是5-嘧啶基,其被1或2个选自氨基、C1-6烷基氨基和二(C1-6烷基)氨基的取代基取代,
或其盐。
[化合物I-8]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是2-吲哚基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)C1-6烷基,其任选被1至3个选自氨基、C1-6烷氧基-羰基氨基、C1-6烷基氨基和二(C1-6烷基)氨基的取代基取代,
(f)C1-6烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)C1-6烷氧基-羰基,
(ii)任选被选自下列的取代基取代的C1-6烷基-羰基
(A)任选被1至3个C1-6烷基取代的C3-8环烷基氧基,
(B)C1-6烷基氨基,
(C)二(C1-6烷基)氨基,
(D)任选被C1-6烷氧基-羰基取代的环状氨基(例如吗啉代、1-哌嗪基),和
(E)卤素原子,
(iii)任选被1至3个选自C1-6烷基和C1-6烷氧基的取代基取代的苯基羰基,
(iv)C3-8环烷基-羰基,
(v)任选被C1-6烷基取代的5-至10-元的芳香族杂环基羰基(例如,吡啶基羰基),所述C1-6烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和C1-6烷氧基的取代基取代,
(vii)任选被C1-6烷氧基取代的C6-14芳基磺酰基,
(viii)C3-8环烷基-C1-6烷基磺酰基,其任选被1至3个选自C1-6烷基和氧代的取代基取代(例如,樟脑磺酰基),
(ix)任选被1至3个C1-6烷基取代的5-至10-元的芳香族杂环基磺酰基(例如,咪唑基磺酰基),和
(x)-C(=N-CN)-SR9,其中R9是C1-6烷基,
或其盐。
[化合物I-9]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
R23是氢原子或C1-6烷基,和
R24、R25、R26和R27各自独立地为,
(a)氢原子,
(b)氰基,或
(c)硝基,
或其盐。
[化合物I-10]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
R28是氢原子或羟基,和
R29是氢原子或C1-6烷基,
或其盐。
[化合物I-11]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
R10、R12和R14各自独立地为,
(a)氢原子或
(b)C1-6烷基,和
R11、R13和R15各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)C1-6烷基氨基,
(g)二(C1-6烷基)氨基,
(h)任选被羟基取代的C1-6烷基,或
(i)C2-6链烯基,或
R10和R11任选地键合以形成-(C=O)-NH-、-C(R31)=N-或-N=N-,其中R31是氢原子或C1-6烷基,和氮原子键合在稠环的苯基环上,或
R12和R13任选地键合以形成-(CH2)4-,
或其盐。
[化合物I-12]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中R10a是
(a)氢原子或
(b)C1-6烷基,和
R11a、R13a和R15a各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)硝基,
(e)氨基,
(f)C1-6烷基氨基,
(g)二(C1-6烷基)氨基,
(h)任选被羟基取代的C1-6烷基,或
(i)C2-6链烯基,和
条件是R10a、R11a、R13a和R15a不同时为氢原子,
或其盐。
[化合物I-13]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中R31是氢原子或C1-6烷基,
或其盐。
[化合物I-14]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中R16a是
(a)C1-6烷基,其任选被1至3个选自氰基、C1-6烷基氨基和二(C1-6烷基)氨基的取代基取代,
(b)任选被羧基取代的C2-6链烯基,
(c)甲酰基,
(d)羧基,
(e)氨基甲酰基,
(f)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,或
(g)5-至10-元的芳香族杂环基(例如四唑基、吡咯基、噁唑基、苯并咪唑基、***基),其任选被C1-6烷基、C1-6烷氧基-羰基、羧基或苯基取代,
或其盐。
[化合物I-15]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
R18a是C1-6烷基,和
R19a是(a)卤素原子,
(b)氰基,
(c)任选被1至3个选自下列的取代基取代的C1-6烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)C1-6烷基氨基,
(vi)二(C1-6烷基)氨基,和
(vii)任选被C1-6烷基取代的环状氨基(例如,1-哌嗪基),
(d)C1-6烷氧基,
(e)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基(例如,吗啉代)取代的C1-6烷基-羰基,
(ii)C1-6烷基磺酰基,和
(iii)氨基甲酰基,
(f)羧基,
(g)C1-6烷氧基-羰基,
(h)任选被C1-6烷基取代的氨基甲酰基,所述C1-6烷基任选被氨基、C1-6烷基氨基、二(C1-6烷基)氨基或C1-6烷氧基-羰基氨基取代,
(i)甲酰基,
(j)5-至10-元的芳香族杂环基(例如,噁唑基、苯并咪唑基),或
(k)-CH=N-OR21,其中R21是氢原子或任选被C1-6烷基氨基或二(C1-6烷基)氨基取代的C1-6烷基,
或其盐。
[化合物I-16]
式(I)的化合物,其中
R是氢原子;
R1是环丙基、2-氟环丙基或2,4-二氟苯基;
R2是C1-6烷基(例如,甲基)、C1-6烷氧基(例如,甲氧基)或氯原子;和
R3是下式的基团
其中
R30是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自卤素原子和羟基的取代基取代的C1-6烷基,
(e)C2-6链烯基,
(f)C2-6炔基,
(g)C1-6烷氧基,
(h)甲酰基,或
(i)-CH=N-OH,
或其盐。
式(I)化合物的盐的实例包括药学上可接受的盐。式(I)化合物适宜的药学上可接受的盐是常规的无毒性的盐,包括,例如与碱或酸加成的盐,诸如与无机碱的盐,例如碱金属盐(例如钠盐、钾盐等)、碱土金属盐(例如钙盐、镁盐等)、铵盐;与有机碱的盐,例如有机胺盐(例如三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N'-二苄基乙二胺盐等);无机酸加成盐(例如盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐等);有机羧酸或磺酸加成盐(例如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、富马酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等);和与碱性或酸性氨基酸(例如精氨酸、天门冬氨酸、谷氨酸等)的盐。
化合物(I)可以例如根据下面的反应方案的方法制备。
反应方案I
其中X、R1和R2定义如上,R32是烷基和R33是烷基。
步骤a
通过化合物(1)在有或无溶剂存在下与卤化剂反应,可以将化合物(1)转化为酰基卤。所述溶剂包括芳香烃类,如苯、甲苯和二甲苯;卤代烃,如二氯甲烷、氯仿和四氯化碳;醚,如二噁烷、四氢呋喃和二***;N,N-二甲基甲酰胺(DMF);和二甲基亚砜(DMSO)等。所述卤化剂可以是任何常规的可将羧基中的羟基转换成卤素原子的卤化剂,且包括例如亚硫酰氯、三氯氧化磷、三溴氧化磷、五氯化磷、和五溴化磷等。化合物(1)和卤化剂的量没有特别的限制,但是,在不使用溶剂的情况下,卤化剂通常以大过量使用,和在使用溶剂的情况下,卤化剂通常以每1摩尔化合物(1)使用至少1摩尔、优选2~4摩尔的量。反应温度和反应时期没有特别的限制,但是反应通常在室温至约100℃的温度下进行约30分钟至约6小时。
将得到的酰基卤与丙二酸单烷基酯的镁盐反应,得到化合物(2)。丙二酸单烷基酯的镁盐可以在氯化镁和碱性化合物如三乙胺的存在下由丙二酸单烷基酯的钾盐如丙二酸乙酯钾在原位制得。该反应可以在适当的溶剂中进行。在反应中所用的溶剂,除非它们对反应产生任何不良的影响,可以是任何常规的溶剂,且包括例如,酯如乙酸乙酯;醚类如二***、二噁烷、四氢呋喃、甘醇二甲醚和二甘醇二甲醚;醇如甲醇、乙醇和异丙醇;芳族烃类如苯、甲苯和二甲苯;脂族烃如正己烷、庚烷、环己烷和石油醚(ligroin);胺如吡啶和N,N-二甲基苯胺;卤代烃如氯仿、二氯甲烷和四氯化碳;非质子极性溶剂如DMF、DMSO和六甲基磷酰三胺(HMPA);以及这些溶剂的混合物。反应通常在温度为约0℃至约150℃、优选约0℃至约120℃下进行约0.5至约20小时。丙二酸单烷基酯的钾盐通常以每1摩尔化合物(1)使用至少1摩尔、优选1~2摩尔的量。氯化镁和碱性化合物通常以每1摩尔化合物(1)使用至少1摩尔、优选1~2摩尔的量。
步骤b
通过化合物(2)与原甲酸三烷基酯如原甲酸三甲酯和原甲酸三乙酯在乙酸酐中反应,可以制得化合物(3)。该反应通常在温度为约0℃至约200℃、优选在约0℃至约150℃下进行约0.5至约20小时。原甲酸三烷基酯通常以每1摩尔化合物(2)使用至少1摩尔、优选1~10摩尔的量。
步骤c
化合物(4)可以通过化合物(3)与化合物(6)起反应制得。
化合物(3)与化合物(6)之间的反应可以在适当的溶剂中进行。在反应中所用的溶剂,除非它们对反应产生任何不良的影响,可以是任何常规的溶剂,且包括例如,醇如甲醇、乙醇和异丙醇;醚类如二***、二噁烷、四氢呋喃、甘醇二甲醚和二甘醇二甲醚;芳族烃类如苯、甲苯和二甲苯;脂族烃如正己烷、庚烷、环己烷和石油醚;卤代烃如氯仿、二氯甲烷和四氯化碳;非质子极性溶剂如DMF、DMSO和HMPA;等。反应通常在温度为约0℃至约150℃、优选室温至约100℃下进行约0.1至约15小时。化合物(6)通常以每1摩尔化合物(3)使用至少1摩尔、优选1~2摩尔的量。
步骤d
化合物(5)可通过化合物(4)的环化反应制得。
化合物的(4)环化反应可以在碱性化合物存在下在适当的溶剂中进行。在反应中所用的溶剂,除非它们对反应产生任何不良的影响,可以是任何常规的溶剂,且包括例如,醚类如二***、二噁烷、四氢呋喃、甘醇二甲醚和二甘醇二甲醚;脂族烃如正己烷、庚烷和石油醚;卤代烃如氯仿、二氯甲烷和四氯化碳;非质子极性溶剂如DMF、DMSO和HMPA;等。在反应中所用的碱性化合物包括无机碱如金属钠、金属钾、氢化钠、氨基钠、氢氧化钠、氢氧化钾、碳酸钠和碳酸钾,金属醇化物如甲醇钠和乙醇钠,有机碱如1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、N-苄基三甲基氢氧化铵和四丁基氢氧化铵,等。反应通常在温度为约0℃至约200℃、优选室温至约150℃下进行约0.5至约15小时。碱性化合物通常以每1摩尔化合物(4)使用至少1摩尔、优选1~2摩尔的量。
反应方案II
其中X、R1、R2、R3和R32定义如上。
步骤a
通过在存在或缺失碱性化合物下,在钯催化剂的存在下,在惰性溶剂中或不使用任何溶剂,使化合物(5)和化合物(7)或化合物(8)起反应,可以制备化合物(Ia)。
惰性溶剂的实例包括水;醚如二噁烷、四氢呋喃、二***、1,2-二甲氧基乙烷、二乙二醇二甲基醚和乙二醇二甲基醚;芳香烃类如苯、甲苯和二甲苯;醇如甲醇、乙醇和异丙醇;酮如丙酮和甲基乙基甲酮;和非质子极性溶剂如DMF、DMSO、HMPA和乙腈。这些惰性溶剂可以单独使用,或两种或两种以上的组合使用。
在反应中所用的钯催化剂没有特别的限定,但包括例如4价的钯催化剂,如六氯钯(IV)酸钠四水合物和六氯钯(IV)酸钾;二价钯催化剂,如氯化钯(II)、溴化钯(II)、醋酸钯(II)、乙酰丙酮酸钯(II)、双(苄腈)二氯化钯(II)、双(乙腈)二氯化钯(II)、双(三苯基膦)二氯化钯(II)、二氯四氨钯(II)(dichlorotetramine palladium(II))、(1,5-环辛二烯)二氯化钯(II)、三氟乙酸钯(II)、和1,1'-双(二苯基膦基)二茂铁二氯化钯(II)二氯甲烷复合物(Pd(dppf)Cl2·CH2C12);零价的钯催化剂,如三(二亚苄基丙酮)二钯(0)、三(二亚苄基丙酮)二钯(0)氯仿加合物和四(三苯基膦)钯(0)等。这些钯催化剂可以单独使用或者两种或两种以上的组合使用。
在该反应中,钯催化剂的量没有特别的限制,但以相对于1摩尔化合物(5)而言通常为0.000001至20摩尔的钯。优选地,钯催化剂的量以相对于1摩尔化合物(5)而言为0.0001至5摩尔的钯。
该反应在合适的配体存在下有利地进行。钯催化剂配体的实例包括,例如,2,2'-双(二苯基膦基)-1,1'-联萘(BINAP)、三-邻-甲苯基膦、双(二苯基膦基)二茂铁、三苯基膦、三-叔丁基膦和4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(Xantphos)。这些配体单独或者两种或两种以上的组合使用。
钯催化剂和配体的比例没有特别的限制。配体的量相对每1摩尔钯催化剂为约0.1至约100摩尔,优选每1摩尔钯催化剂为约0.5至约15摩尔。
作为碱性化合物,可以使用公知的各种无机和有机碱。
无机碱包括,例如,碱金属氢氧化物如氢氧化钠、氢氧化钾、氢氧化铯和氢氧化锂;碱金属碳酸盐如碳酸钠、碳酸钾、碳酸铯和碳酸锂;碱金属碳酸氢盐如碳酸氢锂、碳酸氢钠和碳酸氢钾;碱金属如钠和钾;磷酸盐如磷酸钠和磷酸钾;酰胺如氨基钠;和碱金属氢化物如氢化钠和氢化钾。
有机碱包括,例如,低级醇碱金属盐如甲醇钠、乙醇钠、叔丁醇钠、甲醇钾、乙醇钾和叔丁醇钾,和胺如三乙胺、三丙胺、吡啶、喹啉、哌啶、咪唑、N-乙基二异丙胺、二甲基氨基吡啶、三甲胺、二甲基苯胺、N-甲基吗啉、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)等。
这样的碱性化合物可以单独使用,或两种或两种以上的组合使用。更优选地,在反应中所用的碱性化合物包括碱金属碳酸盐如碳酸钠、碳酸钾、碳酸铯和碳酸锂。
碱性化合物的量通常以每1摩尔化合物(5)使用0.5至10摩尔,且优选以每1摩尔化合物(5)使用0.5至6摩尔。
化合物(7)或化合物(8)的量通常以每1摩尔化合物(5)使用至少1摩尔,且优选以每1摩尔化合物(5)使用约1至约5摩尔。
该反应可以在标准压力下,在惰性气体气氛包括氮气、氩气等下,或在增加的压力下进行。
反应通常在室温至约200℃、优选室温至约150℃进行,且通常在约1至约30小时内完成。通过使用微波反应器在约100℃至约200℃加热约5分钟至约1小时,也实现了反应。
步骤b
化合物(Ib)通过化合物(Ia)的水解可以制得。
化合物(Ia)的水解可以在常规水解条件下,例如,在碱性化合物如氢氧化钠、氢氧化钾、氢氧化钡或碳酸钾;矿物酸如硫酸、盐酸或硝酸;或有机酸如乙酸或芳族磺酸存在下,在溶剂包括水,醇如甲醇、乙醇和异丙醇;酮如丙酮、甲基乙基甲酮;醚如二噁烷和乙二醇二***;或它们的混合物中进行。该反应通常在温度为室温至约200℃、优选室温至约150℃进行约0.1至约30小时。
反应方案III
硼酸酯和硼酸的制备
其中R3定义如上,和Z是溴原子或碘原子。
步骤a
通过在钯催化剂和碱性化合物存在下将化合物(9)与双(频哪醇合(pinacolato))二硼(10)在惰性溶剂中反应,可以制备化合物(7)。
惰性溶剂和钯催化剂的实例与反应方案II步骤a中所述的那些相同。
反应中所用的碱性化合物包括乙酸钾、三乙胺、N-甲基吗啉、碳酸钠、碳酸钾、碳酸铯、碳酸锂、磷酸钾和碳酸氢钠。
在该反应中,钯催化剂的量没有特别的限制,但以相对于1摩尔化合物(9)而言通常为0.000001至20摩尔的钯。优选地,钯催化剂的量以相对于1摩尔化合物(9)而言为0.0001至5摩尔的钯。
碱性化合物的量通常以每1摩尔化合物(9)使用0.5至10摩尔,且优选以每1摩尔化合物(9)使用0.5至6摩尔。
双(频哪醇合)二硼(10)的量通常以每1摩尔化合物(9)使用至少1摩尔,且优选以每1摩尔化合物(9)使用约1至约5摩尔。
该反应可以在标准压力下,在惰性气体气氛包括氮气、氩气等下,或在增加的压力下进行。
反应通常在室温至约200℃、优选室温至约150℃进行,且通常在约1至约30小时内完成。
步骤b
通过在正丁基锂或二异丙基氨基锂的存在下,将化合物(9)与硼酸三烷基酯如硼酸三甲酯、硼酸三乙酯、硼酸三(异丙基)酯和硼酸三(正丁基)酯在惰性溶剂中反应,可制得化合物(8)。
惰性溶剂的实例与反应方案II步骤a中所述的那些相同。
硼酸三烷基酯的量通常以每1摩尔化合物(9)使用至少1摩尔,且优选以每1摩尔化合物(9)使用约1至约5摩尔。
正丁基锂或二异丙基氨基锂的量通常以每1摩尔化合物(9)使用至少1摩尔,且优选以每1摩尔化合物(9)使用约1至约5摩尔。
该反应通常在约-70℃至约0℃的温度下进行约0.1至约15小时。
本发明的化合物(I)通过用药学上可接受的酸或碱处理可以容易地转化成其盐。所述酸包括无机酸如盐酸、硫酸、磷酸、和氢溴酸,以及有机酸如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、乳酸、甲磺酸和丙酸。所述碱包括氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠、和碳酸氢钾等。
由此得到的化合物通过常规的方法,例如,溶剂提取、稀释法、重结晶、柱色谱法和制备薄层色谱法,可以容易地分离和纯化。
化合物(I)对支原体、铜绿假单胞菌(Pseudomonas aeruginosa)、厌氧菌、耐受多种抗微生物剂的细胞(cells)、临床分离细菌、和革兰氏阴性和革兰氏阳性菌如难辨梭菌、粪肠球菌(Enterococcus faecalis)和酿脓葡萄球菌(Staphylococcus pyogenes)显示出优异的抗微生物活性,因此作为抗微生物剂用于治疗这些微生物引起的疾病。化合物(I)也显示出低毒性和更少的副作用,且特有好的吸收性和持续的活性。
由于化合物(I)显示出抗难辨梭菌优异的抗微生物活性,它有用于预防或治疗肠道感染,包括抗生素相关性腹泻(AAD)如难辨梭菌-相关性腹泻(CDAD)。
本发明化合物通常以常用的药物制剂的形式使用。与常规的药学上可接受的稀释剂或载体,如填充剂、增量剂(bulking agents)、粘合剂、润湿剂、崩解剂、表面活性剂和润滑剂混合,可以制备该药物制剂。所述药物制剂包括适于治疗所述疾病的多种制剂,例如片剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、胶囊剂、栓剂、和如溶液和悬浮液的注射剂等。在制备片剂时,可以使用任何常规载体,例如,赋形剂如乳糖、精制糖(white sugar)、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、微晶纤维素和硅酸盐,粘合剂例如水、乙醇、丙醇、单糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、虫胶、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮,崩解剂如干淀粉、藻酸钠、琼脂粉、昆布糖粉(laminaran powder)、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇脂肪酸酯、月桂基硫酸钠、硬脂酸单甘油酯、淀粉和乳糖,崩解抑制剂如精制糖、硬脂、可可豆脂和氢化油,吸收促进剂如季铵盐和月桂基硫酸钠,润湿剂如甘油和淀粉,吸附剂如淀粉、乳糖、高岭土、膨润土和胶态硅酸盐,润滑剂如精制滑石、硬脂酸盐、硼酸粉和聚乙二醇等。片剂也可以用常规的包衣剂包衣,例如,可以是糖包衣片剂、明胶包衣片剂、肠溶包衣片剂、薄膜包衣片剂、或双或多层片剂的形式。在制备丸剂时,可以使用常规载体,其包括赋形剂如葡萄糖、乳糖、淀粉、可可豆脂、氢化的蔬菜油、高岭土和滑石,粘合剂如***胶粉、黄蓍胶粉、明胶和乙醇,崩解剂如昆布多糖和琼脂等。在制备栓剂时,可以使用常规载体,例如,聚乙二醇、可可豆脂,高级醇、高级醇酯、明胶和半合成甘油酯。在制备注射剂时,所述化合物的溶液、乳剂或悬浮液是灭菌的,且优选被制成与体液等渗。通过将活性化合物与常规的稀释剂如水、乳酸水溶液、乙醇、丙二醇、乙氧基化异硬脂醇、聚氧化异硬脂醇或聚氧乙烯脱水山梨糖醇脂肪酸酯混合,制备这些溶液剂、乳剂和悬浮液。所述制剂也可掺入足够量的氯化钠、葡萄糖或甘油,以使它们与体液等渗。所述制剂也可掺入常规的增溶剂、缓冲剂、麻醉剂,和进一步掺入着色剂、防腐剂、香料、矫味剂、甜味剂和其它药物。使用作为稀释剂如白凡士林、石蜡、甘油、纤维素衍生物、聚乙二醇、硅酮、或膨润土等,可以制备糊剂、霜剂或凝胶形式的制剂。当活性成分的化合物在注射剂中沉淀时,酸例如甲磺酸、丙酸、盐酸、琥珀酸或乳酸可按需要添加到注射剂中,以保持注射稳定的溶液。
制剂中可以包含任何量的化合物(I),通常包含基于制剂的总重量的1~70%的量。
本发明的药物制剂可以以任何方法施用。施用的合适方法可以根据制剂的形式、患者的年龄和性别、和疾病的严重程度等进行选择。例如,片剂、丸剂、溶液、悬浮液、乳剂、颗粒剂和胶囊剂是口服途径施用的。在注射情况下,以单一形式或连同辅助液体如葡萄糖或氨基酸溶液经静脉内施用。注射也可以经肌内、皮内、皮下、或腹膜内途径施用。栓剂在直肠内途径施用。
本发明药物制剂的剂量可根据施用方法、患者的年龄和性别、和疾病的严重程度等而变化,对于每天每1kg患者体重,通常为在约0.1至约100mg,更优选为约0.1至约50mg的化合物(I)。制剂通常分成每天2~4次施用。
本发明由下面的实施例、实验实施例和制备实施例举例说明。应当理解,本发明并不限于这些实施例、实验实施例或制备实施例,且可以在不脱离本发明的范围和精神下作出各种变化和修改。
实施例
一般方案I.中间体的合成
在我们的工作中,应用了铃木偶联反应作为关键反应,以构建我们的最终产品。至于偶联反应,通过众所周知的以前广泛用于合成喹诺酮类的方法,可以制备相应的碘代-中间体(一般方案I)。
实施例1:中间体5a(R2=Me)的合成
1.1.化合物2:将化合物1(2g,6.71mmol)和亚硫酰氯(9.8mL)的混合物回流3小时,然后浓缩,得到酰氯。向剩余物中加入无水EtOAc(10mL),然后浓缩混合物。
在50℃以下将丙二酸单乙酯钾(1.6g,9.40mmol)和MgCl2(1.91g,20.13mmol)于无水EtOAc的混合物搅拌30分钟。在50℃以下向混合物中加入Et3N(2.83mL,20.13mmol)。然后,将混合物回流1小时。在50-70℃,向混合物中逐滴加入所述酰氯的无水EtOAc(10mL)溶液,然后将混合物回流1.5小时。在冰冷却下,向反应混合物中加入水(30mL)和5N HC1(30mL)。将EtOAc溶液用水洗涤,干燥并浓缩,得到为黄色油的化合物2,其无需纯化用于下一步骤。
1.2.化合物3:将化合物2(11g,29.88mmol)、原甲酸三乙酯(7.47mL,44.82mmol)和乙酸酐(6.77mL,71.72mmol)的混合物在150℃加热1小时,然后浓缩,得到化合物3,其无需纯化用于下一步骤。
1.3.化合物4:向化合物3(上面获得的)中加入EtOH(50mL)和环丙胺(2.48mL,35.86mmol)。将混合物搅拌30分钟并浓缩,得到化合物4,其无需纯化用于下一步骤。
1.4.中间体5a:将化合物4(上面获得的)溶于无水DMSO(100mL)。将K2CO3(16.52g,119.53mmol)加入到该溶液中。反应混合物在100℃搅拌1小时。当TLC(EtOAc/二丙醚=1/1)指示反应完成后,将混合物冷却至室温,倒入水中,用EtOAc萃取。将有机层用盐水洗涤,干燥并浓缩,得到黄色固体,将其从EtOAc中重结晶。得到为白色固体的中间体5a,总产率75%。1H NMR(400MHz,DMSO)δ8.60(s,1H),7.70(d,J=7.8Hz,1H),4.29-4.14(m,3H),2.96(s,3H),1.28(t,J=7.1Hz,3H),1.14(q,J=7.0Hz,2H),0.87-0.76(m,2H)。
下列化合物根据一般方案I得到合成。
实施例2:中间体5b(R2=OMe):1H NMR(400MHz,DMSO)δ8.51(s,1H),7.69(d,J=7.7Hz,1H),4.23(dd,J=14.0,6.9Hz,2H),4.03(s,1H),3.80(s,3H),1.28(t,J=7.0Hz,3H),1.09(d,J=6.2Hz,2H),0.97(m,2H)。
实施例3:中间体5c(R2=C1):1HNMR(400MHz,DMSO)δ8.61(s,1H),7.81(d,J=7.6Hz,1H),4.23(m,3H),1.28(t,J=7.1Hz,3H),1.21-1.08(dd,J=7.1,2.2Hz,2H),0.99-0.92(m,2H)。
实施例4:中间体5d:1H NMR(400MHz,CDC13)δ8.59-8.51(d,J=3.1Hz,1H),8.03-7.92(d,J=7.5Hz,1H),4.98-4.73(dddd,J=62.9,6.3,4.9,3.4Hz,1H),4.44-4.34(q,J=7.1Hz,2H),3.91-3.83(dt,J=8.6,5.4Hz,1H),2.95-2.88(s,3H),1.59-1.48(m,1H),1.45-1.38(t,J=7.1Hz,3H),1.35-1.18(m,1H)。
实施例5:中间体5e:1H NMR(400MHz,CDC13)δ8.51-8.43(d,J=2.0Hz,1H),7.94-7.86(d,J=7.6Hz,1H),4.90-4.65(dddd,J=62.7,6.0,5.1,3.3Hz,1H),4.37-4.28(q,J=7.1Hz,2H),3.80-3.76(s,3H),3.75-3.69(dt,J=8.7,5.5Hz,1H),1.61-1.47(m,2H),1.46-1.30(m,4H)。
实施例6:中间体5f:1H NMR(400MHz,DMSO)δ8.65(s,1H),7.48(d,J=8.16Hz,1H),4.79(q,J=6.65Hz,1H),4.62(dd,J=1.82,11.36Hz,1H),4.44(dd,J=2.20,11.36Hz,1H),4.23(qd,J=2.95,7.09Hz,2H),1.40(d,J=6.65Hz,3H),1.28(t,J=7.09Hz,3H)。
一般方案II.硼酸酯和硼酸的制备
反应试剂和条件:a.Pd(dppf)C12.CH2C12(5%mol),KOAc,二噁烷,80℃;b.nBuLi(或LDA),B(OiPr)3,THF。
一般方案II概述了所需的硼酸和硼酸酯的制备。他们通过一般方法容易制得。
实施例7硼酸7的合成
反应试剂和条件:a.1)NaH,THF,r.t.;2)nBuLi,B(OiPr)3,-70℃~0℃。
7.1硼酸7:在0℃向化合物6(10g,44.44mmol)于无水四氢呋喃(350mL)的溶液中,加入氢化钠(2g,66.66mmol,80%分散液)。该混合物在室温搅拌30分钟后,将混合物在干冰/丙酮浴中冷却到-60℃以下,在30分钟内加入正丁基锂(70mL,112mmol,1.6M己烷溶液)。继续搅拌该混合物另一个30分钟,然后滴加入硼酸三异丙酯(40mL,177mmol)。将反应混合物搅拌10分钟,然后在冰浴中慢慢地升温至0℃。将HC1(5N)加入到该混合物中以调节pH=3-4,并搅拌混合物20分钟。将NaOH水溶液加入到混合物中,以调节pH=10。过滤后,分离有机层。将水层用乙酸乙酯/THF(4/1;2x 120mL)的混合物和EtOAc(100mL)萃取。水层用盐酸调节至pH=5-6。通过过滤收集如此形成的沉淀物,干燥得到硼酸7(3.5g,41%),为白色固体。
实施例8硼酸酯8的合成
8.1化合物9:将2-氨基烟腈8(100g,0.839mol)溶于HOAc(800mL)。向该溶液中加入Na2CO3(88.97g,0.839mol)。然后,逐滴加入Br2(46.4mL,0.923mol)。反应混合物在室温搅拌50分钟。向混合物中加入水(600mL)。将混合物冷却至约5℃。通过过滤收集如此形成的沉淀,干燥得到化合物9(207g,96%)。
8.2硼酸酯10:将化合物9(50g,0.224mol)、双(频哪醇合)二硼(85.6g,0.337mol)、KOAc(44.1g,0.449mol)和Pd(dppf)Cl2.CH2C12(2.77g,3.4mmol)装入烧瓶中。加入二噁烷(400mL)。该反应混合物在氩气氛下100℃搅拌2小时。当LC-MS表明反应完成后,将混合物冷却至室温。该混合物通过硅藻土过滤,浓缩,用乙酸乙酯和己烷的3/1比例的混合物(1000mL)稀释,通过硅胶(300-400目)过滤,浓缩,结晶,干燥得到硼酸酯10(32g,66%),为白色固体。
实施例9硼酸酯13的合成
9.1化合物12:将3-氯吡啶-2-胺(100g,0.778mol)溶于乙酸(1200mL)。向该溶液中加入Na2CO3(82.4g,0.778mol)。然后,滴加入Br2(39.1mL,0.856mmol)。加完后,将反应混合物在室温搅拌30分钟。向混合物中加入水(800mL)。将混合物冷却至约5℃。将所得到的固体通过过滤收集并干燥,得到化合物12(147g,91%),为白色固体。
9.2硼酸酯13:将化合物12(4g,17.2mmol)、双(频哪醇合)二硼(4.79g,18.8mmol)、KOAc(3.37g,34.2mmol)和Pd(dppf)Cl2·CH2C12(0.210g,0.25mmol)装入烧瓶中。加入二噁烷(80mL)。该混合物在氩气氛下85℃搅拌2小时。当LC-MS表明反应完成后,将混合物冷却至室温。该混合物通过硅藻土过滤和浓缩。剩余物用乙酸乙酯和己烷(3/1,100mL)稀释,通过硅胶(300-400目)过滤,浓缩,通过正己烷结晶,得到硼酸酯13(3.4g,78%),为白色固体。
一般方案III
反应试剂和条件:a.Pd(dppf)C12.CH2C12(5%mol),K2CO3,二噁烷,80℃;b.NaOH,EtOH。
实施例10化合物1-2的合成
10.1化合物16:将中间体5a(30g,65mmol)、硼酸7(17g,71.6mmol)和K2CO3(27,195mmol)装入烧瓶中。加入二噁烷(600mL)和水(60mL)。溶液用N2脱氧15分钟。向混合物中加入Pd(dppf)C12.CH2C12(2.8g,3.24mmol)。反应混合物在85℃搅拌过夜。当反应完成后,将反应混合物冷却至室温。将沉淀物滤出,溶于水中,过滤,用EtOH研磨,过滤并干燥,得到化合物16(16g,57%),为灰白色固体。至于使用,所得化合物是足够纯的。
浓缩有机滤液。向剩余物中加入水、二氯甲烷和EtOAc。将这样形成的沉淀物通过过滤收集,并溶于HC1(5N)。在过滤除去钯剩余物后,将滤液用NaOH水溶液碱化(pH=7-8)。通过过滤收集沉淀物,干燥得到化合物16(3g,11%),为灰白色固体。
10.2化合物1-2:将化合物16(33g,76.1mmol)悬浮于EtOH(300mL)。向悬浮液中加入NaOH水溶液(4N,100mL),并将该混合物在60℃搅拌2小时。在减压下蒸发200mLEtOH。向剩余物中加入HC1(5N)以调节pH=4。将所得沉淀物滤出,用EtOH研磨,过滤并干燥,得到化合物1-2(30g,97%),为灰白色固体。熔点:>300℃。1H NMR(400MHz,DMSO)δ14.64(s,1H),12.39(s,1H),8.92(s,1H),8.58(s,1H),8.28(s,1H),8.01(m,2H),6.67(d,J=9.4Hz,1H),4.42(s,1H),2.68(s,3H),1.27(d,J=6.4Hz,2H),1.12-1.03(m,2H)。13C NMR(101MHz,DMSO)δ176.92,165.25,162.85,158.16,155.72,152.71,150.92,149.62,139.29,138.79,137.62,133.70,133.52,131.80,127.47,127.38,123.75,123.42,113.89,108.05,107.81,107.29,41.29,20.64,20.62,10.62。HPLC-MS m/z 406(MH+)。分析.C22H16FN3O4的计算值:C,65.18,H,3.98,N,10.37。实测值:C,63.50,H,4.00,N,9.91。
实施例11化合物2-18的合成
11.1化合物17:将硼酸酯10(14g,56.1mmol)、中间体5a(20g,46.7mmol)、Cs2CO3(15.22g,46.7mmol)和Pd(dppf)C12.CH2C12(0.98g,1.2mmol)装入烧瓶中。加入二噁烷(500mL)和水(5mL)。该混合物在氩气氛下110℃搅拌过夜。混合物冷却至室温。将混合物过滤,用二噁烷和乙酸乙酯洗涤固体。将固体溶于热CH2C12(1200mL),并通过硅藻土过滤该溶液。该操作被重复两次。将有机层合并,浓缩。向剩余物中加入乙酸乙酯(200mL)。固体通过过滤收集,用乙酸乙酯(60mL)洗涤,干燥得到化合物17(17.6g,90%),为白色固体。
11.2化合物2-18:将化合物17(43g,0.101mol)溶于THF和EtOH(1/1,500mL)。向该溶液中加入NaOH(60mL,4N)。混合物在室温搅拌2小时。加入HC1(63mL,4N)以酸化混合物(pH=3-4)。固体通过过滤收集,用EtOH(100mL)洗涤,干燥得到化合物2-18(35.7g,99%),为白色固体。熔点>300℃。1H NMR(400MHz,DMSO)δ14.65(s,1H),8.89(s,1H),8.32-8.23(m,1H),8.08(d,J=2.09Hz,1H),7.94(d,J=8.87Hz,1H),7.28(s,2H),4.40(tt,J=3.74,7.17Hz,1H),2.67(s,3H),1.31-1.19(m,2H),1.10-0.99(m,2H)。13C NMR(101MHz,DMSO)δ176.95,176.92,165.32,159.60,158.29,155.86,154.07,152.67,143.59,139.32,133.39,133.22,131.73,127.13,127.05,116.93,116.52,107.96,107.71,107.27,89.15,41.32,20.64,20.62,10.65。HPLC-MS m/z 379(MH+)。分析.C20H15FN4O3的计算值:C,63.49,H,4.00,N,14.81。实测值:C,62.04,H,4.20,N,13.97。
实施例12化合物3-11的合成
12.1化合物18:将硼酸酯13(20g,75.4mmol)、中间体5a(24.1g,58.03mmol),Cs2CO3(26.5g,81.2mmol)和Pd(dppf)C12.CH2C12(1.42g,1.7mmol)装入烧瓶中。加入二噁烷(400mL)和水(4mL)。该混合物在氩气氛下100℃搅拌过夜。混合物冷却至室温。将混合物过滤,用二噁烷和乙酸乙酯洗涤固体。将固体溶于热CH2C12(1200mL),并通过硅藻土过滤该溶液。该操作被重复两次。将有机层合并,浓缩。向剩余物中加入乙酸乙酯(200mL)。固体通过过滤收集,用乙酸乙酯(60mL)洗涤,干燥得到化合物18(21g,85%),为白色固体。
12.2化合物19:将化合物18(39g,91.91mmol)溶于THF和EtOH(1/1,600mL)。向该混合物中加入NaOH(4N,60mL)。混合物在室温搅拌2小时。加入HC1(4N,62mL)以酸化溶液(pH=3-4)。固体通过过滤收集,用EtOH(100mL)洗涤,干燥得到化合物19(34g,98%),为白色固体。
12.3化合物3-11:将氯乙醛(40%水溶液,80mL)加入到化合物19(34g,91.9mmol)的EtOH(600mL)溶液中。将混合物回流3小时。当LC-MS表明反应完成后,将混合物冷却至5℃,过滤。将固体干燥得到化合物3-11(21g)。母液用NaOH水溶液碱化(pH=7-8)。将沉淀物通过过滤收集,用EtOH洗涤并干燥,得到化合物3-11(11.5g),为白色固体。总共得到了32.5g化合物3-11,产率93%,熔点:307-311℃。1HNMR(400MHz,DMSO)δ14.53(s,1H),8.98-8.84(m,2H),8.28(d,J=1.16Hz,1H),7.98(d,J=8.83Hz,1H),7.90(d,J=0.89Hz,1H),7.77(s,1H),4.43(tt,J=3.70,7.10Hz,1H),3.50-3.36(m,1H),2.72(s,3H),1.26(d,J=6.80Hz,2H),1.07(d,J=18.24Hz,2H)。13C NMR(101MHz,DMSO)δ176.91,176.88,165.23,158.22,155.77,152.84,139.98,139.17,139.16,132.44,132.15,131.98,131.54,127.86,127.78,127.38,120.72,118.97,116.37,108.15,107.91,107.37,41.38,20.54,20.52,10.72。HPLC-MS:m/z 412(MH+)。分析.C21H15ClF3O3的计算值:C,61.25,H,3.67,N,10.20。实测值:C,58.59,H,3.86,N,9.76。
在下述表中列出的化合物根据一般方案III得到合成。
表8-1
表8-2
表9
实验实施例1
体外抗菌活性
将所有化合物溶于二甲基亚砜(DMSO,Merck,纯度>99.9%),以达到最终1mg/ml的所需浓度。
通过肉汤微量稀释技术,用96孔微量稀释板测定了MIC(最小抑菌浓度)。抗微生物剂使用下面的MIC范围:0.008~8μg/ml进行了测试。将板填满100μl强化的梭状芽胞杆菌培养基(Oxoid;Unipath Ltd.,Basingstoke,United Kingdom),每孔包含最终的抗生素浓度。将板解冻并在包含80%N2、15%CO2、和5%H2气氛的厌氧培养室(Thermal,USA)中预孵育3小时。通过从48小时强化的梭状芽胞杆菌培养基培养中暂停生长,制备了细菌接种物。最终接种物是约1.0x 105-6CFU/孔。将板在厌氧培养室中37℃孵育48小时。MIC定义为抑制可见生长的最低抗生素浓度。环丙沙星、万古霉素和甲硝唑用作阳性对照。其结果示于表10中。
表10:实施例化合物抗难辨梭菌的MIC(μg/mL)
实验实施例2
体内抗菌功效
在仓鼠肠道感染的治疗模型中,评估了体内功效。雄性叙利亚金色仓鼠购自CharlesRiver Laboratories(Kingston,NY,USA),且为约6周龄,在研究开始时重量为80至100g。将动物单独安置在滤过性聚碳酸酯动物箱式笼中,并配有水瓶,且Harlan Teklab GlobalDiet 2016经由食物储料漏斗可随意食用。在第0天将仓鼠预先用配制在***胶中的克林霉素(1mg/kg,p.o.)和万古霉素(50mg/kg,p.o.)治疗。在第7天,每只仓鼠通过口服管饲法接种0.5mL难辨梭菌ATCC 43255悬浮液(105CFU/躯体,p.o.)。为了准备此接种,将难辨梭菌在GAM琼脂(Japan)中37℃生长5天,通过离心收集细菌,用***胶清洗两次,再悬浮在***胶中,并使用稀释平板计数法测定了准确的细菌密度。在随后一天(第8天)开始化合物口服给药,所述化合物粉碎并配制在***胶中。每天一次,连续5天以指定的剂量(10、2、和0.4mg/kg)对每组五只仓鼠给药治疗。对照包括未感染组和感染但未治疗组,和万古霉素用作阳性对照。每天观察仓鼠,记录临床体征(持续时间、发病时间、恢复或死亡时间),并对昏睡的明确垂死状态的动物实施安乐死。对发现死亡或在研究结束时(第37天)实施安乐死的动物进行剖检。其结果示于图1和图2中。
制备实施例1
注射制剂由下列组分制得。
将化合物1-2和葡萄糖溶于注射用蒸馏水中,并将该溶液加入到5ml的安瓿中,所述安瓿用氮气吹洗,然后在121℃灭菌15分钟,得到注射制剂。
制备实施例2
薄膜包衣片由下列组分制得。
将化合物2-18、Avicel(注册商标的微晶纤维素,AsahiKasei Corporation,Japan制造)、玉米淀粉和硬脂酸镁混和并捏合,为糖包衣使用常规捣杵(R 10mm)(KikusuiSeisakusho Ltd.,Japan制造)将混合物制片。将这样得到的片剂涂布薄膜包衣剂,得到薄膜包衣片,其中所述薄膜包衣剂由TC-5(注册商标的羟丙基甲基纤维素,Shin-EtsuChemical Co.,Ltd.,Japan制造)、聚乙二醇6000、蓖麻油和乙醇组成。
制备实施例3
软膏由下列组分制备。
将白蜂蜡加热制成液体,向其中加入化合物3-11、纯羊毛脂和白凡士林,将混合物加热,直到它变成液体。将混合物搅拌,直到它固化,得到软膏。
Claims (23)
1.由式(I)表示的化合物或其盐
其中
X是氢原子或氟原子;
R是氢原子或烷基;
R1是(1)任选被1至3个卤素原子取代的环丙基或(2)任选被1至3个卤素原子取代的苯基;
R2是氢原子;任选被1或2个选自卤素原子和羟基的取代基取代的烷基;烷氧基;卤代烷氧基;卤素原子;氰基;环丙基;硝基;氨基;甲酰基;链烯基或炔基;或
R1和R2键合以形成任选被烷基取代的5-或6-元的环;
R3是
(3)下式的基团
其中
X3和X4是N,或
X3是N和X4是CR",其中R"是氢原子、氨基、羟基、任选被1至3个选自烷氧基和二甲基氨基的取代基取代的烷基、或巯基,或
X3是CH和X4是N,
R'是氢原子或任选被1至3个选自取代的羟基和氨基的取代基取代的烷基,和
R6定义如上,
(4)下式的基团
其中
表示单键或双键,和R6定义如上,
(5)下式的基团
(d)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代,
(6)任选被卤素原子取代的4-吡啶基,
(8)2-吲哚基、3-吲哚基、5-吲哚基、6-吲哚基、苯并呋喃基、苯并噻吩基、苯并噁唑基或苯并噻唑基,各自任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,和
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基,和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基,所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)环烷基烷基磺酰基,其任选被1至3个选自烷基和氧代的取代基取代,
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基,和
(x)-C(=N-CN)-SR9,其中R9是烷基,
(9)下式的基团
其中
Y1、Y2、Y3和Y4之一是N或N+(-O-),和其余三个各自是C(R25)、C(R26)和C(R27),
W是O、S、NH或N(R23)
R23是氢原子或烷基,和
R24、R25、R26和R27各自独立地为,
(a)氢原子,
(b)氰基,或
(c)硝基,
(10)下式的基团
其中
R28是氢原子或羟基,和
R29是氢原子或烷基,
(12)下式的基团
其中R16是
(a)氢原子,
(b)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(c)任选被羧基取代的链烯基,
(d)甲酰基,
(e)羧基,
(f)氨基甲酰基,
(g)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,
(h)5-至10-元的芳香族杂环基,其任选被烷基、烷氧基羰基、羧基或苯基取代,或
(i)氰基,
(13)下式的基团
其中
R18是氢原子或任选被1至3个选自卤素原子和苯基的取代基取代的烷基,
n是0或1,
R19、R20和R33各自独立地为,
(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基,
(e)烷氧基,
(f)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基取代的烷基羰基,
(ii)烷基磺酰基,
(iii)氨基甲酰基,
(iv)烷基、环烷基或环烷基烷基,和
(v)5-至10-元的饱和杂环基,
(g)羧基,
(h)烷氧基羰基,
(i)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(j)甲酰基,
(k)任选被烷基取代的5-至10-元的芳香族杂环基,
(1)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基,
(m)硝基,
(n)任选被氨基取代的5-至10-元的饱和杂环基,
(o)苯基,或
(P)-NHC(SMe)=CHCN,
(14)下式的基团
其中
R30是(a)氢原子,
(b)卤素原子,
(c)氰基,
(d)任选被1至3个选自卤素原子和羟基的取代基取代的烷基,
(e)链烯基,
(f)炔基,
(g)烷氧基,
(h)甲酰基,
(i)-CH=N-OH,或
(j)氨基甲酰基,
(15)萘基或异色烯基,
(16)喹啉基或异喹啉基、或它们的氧化物衍生物,
(17)下式的基团
(18)下式的基团
其中
U是0或S,和
R31是(a)氢原子,
(b)卤素原子,
(c)任选被1至3个卤素原子取代的烷基,
(d)羧基,
(e)硝基,
(f)氰基,或
(g)氨基,
(19)下式的基团
其中
R32是(a)卤素原子,
(b)苯基,或
(c)下式的基团
(20)下式的基团
其中
R34和R35各自独立地为,
(a)氢原子,或
(b)氨基烷基,
或
R34和R35键合以形成任选被氨基或氧代取代的6-元环,
(21)下式的基团
其中R36是
(a)氢原子,
(b)卤素原子,
(c)硝基,或
(d)噻吩基,或
(22)下式的基团
2.权利要求1的化合物或其盐,其中X是氟原子。
其中X2、R6和R7如权利要求1中所定义。
3.权利要求1的化合物或其盐,其中R3是下式的基团
其中X3、X4、R6和R'如权利要求1中所定义。
4.权利要求1的化合物或其盐,其中R3是下式的基团
其中和R6权利要求项1中所定义。
5.权利要求1的化合物或其盐,其中R3是下式的基团
其中R22是
(d)烷基,其任选被1至3个选自卤素原子、烷基氨基、二烷基氨基和羟基的取代基取代。
6.权利要求1的化合物或其盐,其中R3是2-吲哚基,其任选被1或2个选自下列的取代基取代
(a)卤素原子,
(b)氰基,
(c)硝基,
(d)羟基,
(e)烷基,其任选被1至3个选自氨基、烷氧基羰基氨基、烷基氨基和二烷基氨基的取代基取代,
(f)烷氧基,
(g)甲酰基,
(h)羧基,或
(j)任选被1或2个选自下列的取代基取代的氨基
(i)烷氧基羰基,
(ii)任选被选自下列的取代基取代的烷基羰基
(A)任选被1至3个烷基取代的环烷基氧基,
(B)烷基氨基,
(C)二烷基氨基,
(D)任选被烷氧基羰基取代的环状氨基,和
(E)卤素原子,
(iii)任选被1至3个选自烷基和烷氧基的取代基取代的苯基羰基,
(iv)环烷基羰基,
(v)任选被烷基取代的5-至10-元的芳香族杂环基羰基,所述烷基任选被1至3个卤素原子取代,
(vi)苄基羰基,其任选被1至3个选自卤素原子和烷氧基的取代基取代,
(vii)任选被烷氧基取代的芳基磺酰基,
(viii)环烷基烷基磺酰基,其任选被1至3个选自烷基和氧代的取代基取代,
(ix)任选被1至3个烷基取代的5-至10-元的芳香族杂环基磺酰基,和
(x)-C(=N-CN)-SR9,其中R9是烷基。
7.权利要求1的化合物或其盐,其中R3是下式的基团
其中Y1、Y2、Y3、Y4、W和R24如权利要求1中所定义。
8.权利要求1的化合物或其盐,其中R3是下式的基团
其中R28和R29如权利要求1中所定义。
9.权利要求1的化合物或其盐,其中R3是下式的基团
其中R16a是
(a)烷基,其任选被1至3个选自氰基、烷基氨基和二烷基氨基的取代基取代,
(b)任选被羧基取代的链烯基,
(c)甲酰基,
(d)羧基,
(e)氨基甲酰基,
(f)-C(R17)=N-OH,其中R17是氢原子、氰基或羟基,
(g)5-至10-元的芳香族杂环基,其任选被烷基、烷氧基羰基、羧基或苯基取代,或
(h)氰基。
10.权利要求1的化合物或其盐,其中R3是下式的基团
其中
R18a是烷基,和
R19a是(a)卤素原子,
(b)氰基,
(c)任选被1至3个选自下列的取代基取代的烷基
(i)卤素原子,
(ii)氰基,
(iii)羟基,
(iv)氨基,
(v)烷基氨基,
(vi)二烷基氨基,和
(vii)任选被烷基取代的环状氨基,
(d)烷氧基,
(e)任选被1或2个选自下列的取代基取代的氨基
(i)任选被环状氨基取代的烷基羰基,
(ii)烷基磺酰基,
(iii)氨基甲酰基,和
(iv)烷基或环烷基,
(f)羧基,
(g)烷氧基羰基,
(h)任选被烷基取代的氨基甲酰基,所述烷基任选被氨基、烷基氨基、二烷基氨基或烷氧基羰基氨基取代,
(i)甲酰基,
(j)任选被烷基取代的5-至10-元的芳香族杂环基,
(k)-CH=N-OR21,其中R21是氢原子或任选被烷基氨基或二烷基氨基取代的烷基,或
(1)硝基。
11.权利要求1的化合物或其盐,其中R3是下式的基团
其中R30如权利要求1中所定义盐。
12.权利要求1的化合物或其盐,其中R3是萘基或异色烯基。
13.权利要求1的化合物或其盐,其中R3是喹啉基或异喹啉基、或它们的氧化物衍生物。
14.权利要求1的化合物或其盐,其中R是氢原子。
15.权利要求1的化合物或其盐,其中R1是环丙基、2-氟环丙基或2,4-二氟苯基。
16.权利要求1的化合物或其盐,其中R2是甲基、甲氧基或氯原子。
17.药物组合物,其包括权利要求1的化合物或其盐和药学上可接受的载体。
18.抗微生物剂,其包括权利要求1的化合物或其盐。
19.权利要求1的化合物或其盐,其用作药物。
20.权利要求1的化合物或其盐,其用作抗微生物剂。
21.权利要求1的化合物或其盐,其在预防或治疗细菌感染中的用途。
22.权利要求1的化合物或其盐在制备用于预防或治疗细菌感染的药物中的用途。
23.预防或治疗细菌感染的方法,其包括给人类或动物施用有效量的权利要求1的化合物或其盐。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110724097A (zh) * | 2019-11-11 | 2020-01-24 | 山东畜牧兽医职业学院 | 一种治疗耐药性微生物菌的化合物及其制备方法 |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3476844B1 (en) * | 2011-02-01 | 2020-11-11 | Emergent Product Development Gaithersburg Inc. | Antimicrobial 4-oxoquinolizines |
EP3318557A3 (en) * | 2011-08-31 | 2018-07-11 | Otsuka Pharmaceutical Co., Ltd. | Quinolone compound |
EA038494B1 (ru) * | 2013-03-15 | 2021-09-07 | Инсайт Холдингс Корпорейшн | Трициклические гетероциклы как ингибиторы белков бэт |
AR096135A1 (es) | 2013-05-02 | 2015-12-09 | Actelion Pharmaceuticals Ltd | Derivados de la quinolona |
US9290514B2 (en) | 2013-07-08 | 2016-03-22 | Incyte Holdings Corporation | Tricyclic heterocycles as BET protein inhibitors |
CN104513253A (zh) | 2013-10-01 | 2015-04-15 | 南京波尔泰药业科技有限公司 | 用于治疗增殖性疾病的大环化合物 |
WO2015081203A1 (en) | 2013-11-26 | 2015-06-04 | Incyte Corporation | Bicyclic heterocycles as bet protein inhibitors |
US9315501B2 (en) | 2013-11-26 | 2016-04-19 | Incyte Corporation | Bicyclic heterocycles as BET protein inhibitors |
US9309246B2 (en) | 2013-12-19 | 2016-04-12 | Incyte Corporation | Tricyclic heterocycles as BET protein inhibitors |
SI3674302T1 (sl) | 2014-04-23 | 2023-07-31 | Incyte Holdings Corporation | 1h-pirolo(2,3-c)piridin-7(6h)-oni in pirazolo(3,4-c)piridin-7(6h)-oni kot zaviralci proteinov bet |
EP3194406B8 (en) | 2014-09-15 | 2021-03-31 | Incyte Corporation | Tricyclic heterocycles for use as bet protein inhibitors |
SI3226858T1 (sl) | 2014-12-04 | 2021-07-30 | Procomcure Biotech Gmbh | Protimikrobna sredstva na osnovi imidazola |
US10314820B2 (en) | 2014-12-04 | 2019-06-11 | Procomcure Biotech Gmbh | Imidazole-based heterocyclic compounds |
CN108349968A (zh) * | 2015-07-28 | 2018-07-31 | 维奥梅生物科学私人有限公司 | 抗菌治疗剂和预防剂 |
US20170121347A1 (en) | 2015-10-29 | 2017-05-04 | Incyte Corporation | Amorphous solid form of a bet protein inhibitor |
US10226464B2 (en) * | 2015-12-29 | 2019-03-12 | ImmuneTarget, Inc. | Small molecule NF-κB inhibitors |
UA125476C2 (uk) | 2016-06-20 | 2022-03-23 | Інсайт Корпорейшн | Спосіб отримання 2,2,4-триметил-8-(6-метил-7-оксо-6,7-дигідро-1н-піроло[2,3-c]піридин-4-іл)-6-(метилсульфоніл)-2н-бензо[b][1,4]оксазин-3(4н)-ону і проміжних сполук |
WO2018013430A2 (en) | 2016-07-12 | 2018-01-18 | Arisan Therapeutics Inc. | Heterocyclic compounds for the treatment of arenavirus infection |
KR102537749B1 (ko) | 2017-06-14 | 2023-05-26 | 산요 시키소 가부시키가이샤 | 안료 분산체 및 그것을 포함하는 착색 조성물 |
CN108191889B (zh) * | 2018-01-11 | 2019-06-07 | 河南大学 | 1-(n-氧氟沙星酰胺基)-6-氟-7-哌嗪萘啶酮酸化合物及其制备方法和应用 |
CN107964020B (zh) * | 2018-01-11 | 2019-07-05 | 河南大学 | 1-(n-左氧氟沙星酰胺基)-6-氟-7-哌嗪萘啶酮酸化合物及其制备方法和应用 |
SG11202101335WA (en) * | 2018-08-13 | 2021-03-30 | Otsuka Pharma Co Ltd | Novel medicament for treating inflammatory bowel disease |
AU2020218557A1 (en) * | 2019-02-08 | 2021-08-12 | Frequency Therapeutics, Inc. | Quinolin-4-one and 4(1H)-cinnolinone compounds and methods of using same |
CN110563645B (zh) * | 2019-06-14 | 2021-03-30 | 山东省联合农药工业有限公司 | 一种喹诺酮类化合物及其制备方法和应用 |
CN112624970B (zh) * | 2019-09-24 | 2022-10-28 | 南开大学 | 8位芳基取代喹啉氮氧化物在抗植物病毒及杀菌方面的应用 |
JP2023012558A (ja) | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 腸内細菌叢構成比率調整剤 |
JP2023012559A (ja) | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 新規炎症性疾患治療剤 |
JP2023012557A (ja) | 2020-02-10 | 2023-01-26 | 大塚製薬株式会社 | 新規肝性脳症治療剤 |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
WO2023208172A1 (en) * | 2022-04-29 | 2023-11-02 | Beigene , Ltd. | Substituted 7- (pyrimidin-4-yl) quinolin-4 (1h) -one compounds as cyclin dependent kinase inhibitors |
TW202402287A (zh) * | 2022-07-11 | 2024-01-16 | 日商大塚製藥股份有限公司 | 包含喹諾酮類化合物的腸易激綜合症用醫藥組成物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4797490A (en) * | 1984-12-06 | 1989-01-10 | Pfizer Inc. | Process for the preparation of 3-(2'-fluorophenyl)pyridine |
EP0343398A2 (de) * | 1988-05-11 | 1989-11-29 | Bayer Ag | 7-Substituierte Chinolon- und Naphthyridoncarbonsäure-Derivate |
WO1999007682A1 (fr) * | 1997-08-08 | 1999-02-18 | Toyama Chemical Co., Ltd. | Derives d'acide quinolonecarboxylique ou sels de ces derives |
EP1160241A2 (de) * | 2000-06-03 | 2001-12-05 | CPC Cellular Process Chemistry Systems GmbH | Verfahren zur Herstellung von Chinolon-3-carbonsäuren |
CN1299356C (zh) * | 2002-06-28 | 2007-02-07 | 株式会社日立制作所 | 电子设备 |
Family Cites Families (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5781486A (en) * | 1980-11-10 | 1982-05-21 | Otsuka Pharmaceut Co Ltd | Benzo(ij)quinolidine-2-carboxylic acid derivative |
JPS5872589A (ja) * | 1981-10-28 | 1983-04-30 | Dai Ichi Seiyaku Co Ltd | ピリド〔1,2,3−de〕〔1,4〕ベンゾオキサジン誘導体 |
US4443447A (en) | 1982-10-25 | 1984-04-17 | Riker Laboratories, Inc. | Phenyl-substituted tricyclic antibacterial agents |
ZA859283B (en) | 1984-12-06 | 1987-07-29 | Pfizer | Substituted dihydroquinolone carboxylic acids and anti-bacterial compositions containing them |
US4636506A (en) * | 1984-12-06 | 1987-01-13 | Pfizer, Inc. | 7-heterocyclic-1,4-dihydroquinolones |
US4623650A (en) * | 1984-12-06 | 1986-11-18 | Pfizer Inc. | Antibiotic derivatives of 7-phenyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
JPS62228063A (ja) * | 1985-12-27 | 1987-10-06 | Sankyo Co Ltd | キノリンカルボン酸誘導体 |
IT1197841B (it) * | 1986-10-14 | 1988-12-06 | Mediolanum Farmaceutici Srl | Derivati pirido-benzotiazinici ad attivita' antibatterica ed a lunga durata di azione |
US4929613A (en) | 1987-08-26 | 1990-05-29 | Warner-Lambert Company | Antibacterial agents |
US5081254A (en) | 1987-08-26 | 1992-01-14 | Warner-Lambert Company | Antibacterial agents |
US5075319A (en) * | 1987-09-08 | 1991-12-24 | Sterling Drug Inc. | Pyridinyl-quinolone compounds, their preparation and use |
US4839355A (en) * | 1987-09-09 | 1989-06-13 | Sterling Drug Inc. | Tricyclic-pyridinylquinoline compounds, their preparation and use |
WO1989005643A1 (en) * | 1987-12-18 | 1989-06-29 | Pfizer Inc. | Heterocyclic-substituted quinoline-carboxylic acids |
JPH0366301A (ja) | 1989-08-03 | 1991-03-22 | Asahi Corp | 靴底射出成形金型 |
KR910009333B1 (ko) * | 1989-10-23 | 1991-11-11 | 재단법인 한국화학연구소 | 항균작용을 갖는 퀴놀린계 화합물과 그의 제조방법 |
JP2613139B2 (ja) * | 1990-07-19 | 1997-05-21 | エスエス製薬 株式会社 | キノロンカルボン酸誘導体 |
US5308843A (en) * | 1990-09-11 | 1994-05-03 | Sterling Drug Inc. | Method of inhibiting mammalian topoisomerase II and malignant cell growth in mammals, with substituted (S)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4 ]-benzoxazine(and-benzothiazine)-6-carboxylic acids |
JPH06507149A (ja) | 1990-12-05 | 1994-08-11 | シンファー ラボラトリーズ,インコーポレーティッド | 抗菌剤として有用な7−置換−6−フルオロ−1,4−ジヒドロ−4−オキソ−キノリン−3−カルボン酸化合物 |
CA2196271C (en) | 1994-08-12 | 2007-01-09 | Yozo Todo | Quinolone- or naphthyridonecarboxylic acid derivative or salt thereof |
AU7940598A (en) | 1997-06-26 | 1999-01-19 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Quinolone carboxylic acid derivatives |
AU8128898A (en) | 1997-07-16 | 1999-02-10 | Eisai Co. Ltd. | Antibiotics containing indole derivatives |
CA2307824C (en) | 1997-10-27 | 2008-02-19 | Toyama Chemical Co., Ltd. | Processes for producing 7-isoindolinequinolonecarboxylic acid derivatives and intermediates therefor,salts of 7-isoindolinequinolonecarboxylic acids, hydrates thereof, and compositions containing the same as active ingredient. |
CA2327328C (en) | 1998-04-06 | 2007-11-13 | Toyama Chemical Co., Ltd. | Quinolonecarboxylic acid derivatives or salts thereof |
JP2000229946A (ja) * | 1998-12-10 | 2000-08-22 | Toyama Chem Co Ltd | キノロンカルボン酸の製造法およびその中間体 |
AU2325300A (en) * | 1999-02-05 | 2000-08-25 | Toyama Chemical Co. Ltd. | Tricyclic quinolonecarboxylic acid derivatives or salts thereof |
US20020049223A1 (en) * | 1999-11-05 | 2002-04-25 | Elmore Steven W. | Quinoline and naphthyridine carboxylic acid antibacterials |
CA2417799A1 (en) * | 2000-08-01 | 2002-02-07 | Wockhardt Limited | Inhibitors of cellular efflux pumps of microbes |
JP2003104988A (ja) * | 2001-09-28 | 2003-04-09 | Sato Pharmaceutical Co Ltd | 抗菌剤として有用なキノロン誘導体 |
US7012144B2 (en) | 2001-12-31 | 2006-03-14 | Korea Research Institute Of Chemical Technology | Quinolone carboxylic acid derivatives |
US20070224282A1 (en) * | 2005-03-28 | 2007-09-27 | Toyama Chemical Co., Ltd. | Fine Dispersion of Sparingly Soluble Drug and Process for Producing the Same |
CN101341249B (zh) * | 2006-02-17 | 2013-07-24 | 森永乳业株式会社 | 用于检测微生物的方法和用于检测微生物的试剂盒 |
CN101168541A (zh) * | 2006-10-26 | 2008-04-30 | 孙飘扬 | 喹诺酮羧酸类衍生物及其制备方法和药物用途 |
US8124623B2 (en) * | 2006-11-10 | 2012-02-28 | Actelion Pharmaceuticals Ltd. | 5-hydroxymethyl-oxazolidin-2-one-derivatives and their uses as antibacterials |
US20090270379A1 (en) * | 2008-04-23 | 2009-10-29 | Macielag Mark J | Quinolone derivatives useful as antibacterial agents |
EP2177214A1 (en) * | 2008-10-17 | 2010-04-21 | Ferrer Internacional, S.A. | Solid Oral Dosage Forms and Uses |
EP3318557A3 (en) * | 2011-08-31 | 2018-07-11 | Otsuka Pharmaceutical Co., Ltd. | Quinolone compound |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4797490A (en) * | 1984-12-06 | 1989-01-10 | Pfizer Inc. | Process for the preparation of 3-(2'-fluorophenyl)pyridine |
EP0343398A2 (de) * | 1988-05-11 | 1989-11-29 | Bayer Ag | 7-Substituierte Chinolon- und Naphthyridoncarbonsäure-Derivate |
WO1999007682A1 (fr) * | 1997-08-08 | 1999-02-18 | Toyama Chemical Co., Ltd. | Derives d'acide quinolonecarboxylique ou sels de ces derives |
EP1160241A2 (de) * | 2000-06-03 | 2001-12-05 | CPC Cellular Process Chemistry Systems GmbH | Verfahren zur Herstellung von Chinolon-3-carbonsäuren |
CN1299356C (zh) * | 2002-06-28 | 2007-02-07 | 株式会社日立制作所 | 电子设备 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN110724097B (zh) * | 2019-11-11 | 2021-03-09 | 山东畜牧兽医职业学院 | 一种治疗耐药性微生物菌的化合物及其制备方法 |
CN112939860A (zh) * | 2019-11-11 | 2021-06-11 | 山东畜牧兽医职业学院 | 一种治疗耐药性革兰阴阳性菌的化合物及其制备方法 |
CN112939860B (zh) * | 2019-11-11 | 2022-11-11 | 山东畜牧兽医职业学院 | 一种治疗耐药性革兰阴阳性菌的化合物及其制备方法 |
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