CN86104256A - 1,8-桥连 4-喹诺酮-3-羧酸类的制备方法 - Google Patents
1,8-桥连 4-喹诺酮-3-羧酸类的制备方法 Download PDFInfo
- Publication number
- CN86104256A CN86104256A CN198686104256A CN86104256A CN86104256A CN 86104256 A CN86104256 A CN 86104256A CN 198686104256 A CN198686104256 A CN 198686104256A CN 86104256 A CN86104256 A CN 86104256A CN 86104256 A CN86104256 A CN 86104256A
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- China
- Prior art keywords
- carbon atom
- alkyl
- phenyl
- represent hydrogen
- group
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 11
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 title claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- -1 alkali metal salt Chemical class 0.000 claims abstract description 44
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 10
- 241001465754 Metazoa Species 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 3
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 127
- 229910052799 carbon Inorganic materials 0.000 claims description 125
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 76
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
- 150000002431 hydrogen Chemical class 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 239000011737 fluorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000003158 alcohol group Chemical group 0.000 claims description 5
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005188 oxoalkyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000370 acceptor Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 238000010572 single replacement reaction Methods 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 3
- 239000007952 growth promoter Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
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- 239000000203 mixture Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
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- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 5
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- WWYFHDNQGVTJJJ-UHFFFAOYSA-N 2-cyclohexylpiperazine Chemical class C1CCCCC1C1NCCNC1 WWYFHDNQGVTJJJ-UHFFFAOYSA-N 0.000 description 3
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- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 3
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical class [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
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- 206010034674 peritonitis Diseases 0.000 description 1
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Classifications
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- 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
- C07D487/06—Peri-condensed systems
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D471/06—Peri-condensed systems
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Abstract
本文叙述了具有上式化合物和它的药学上可以接受的水合物、碱金属盐、碱土金属盐、银盐或盐以及它的酯,可以作为抗菌剂或动物生长促进剂,其中Y是-COOH,-COOR7或-CONR8,R9,X1是H,硝基,烷基或卤素,R10和R11最好与相连的氮原子共同形成哌嗪环,Z是氧或NR15,n是0或1,并且其它可代表不同的意义。
Description
本发明是关于新的1,8-桥连4喹诺酮-3-羧酸类,它们的制备方法和它们作为药物的效用,特别是在人用药和兽药中可作为抗菌剂。
本发明是关于具有式(Ⅰ)的新的1,8-桥连4-喹诺酮-3-羧酸及其衍生物,药学上用的水合物,它的碱金属盐、碱土金属盐、银盐、鈲盐及它的酯,它们均具有很强的抗菌作用。
Y代表羧基、腈基、酯基-COOR7或酰胺基-COOR8R9其中
R7代表C1-C4烷基;
R8和R9代表氢或C1-C4烷基,并具有R9还可以是有选择取代的苯基;
X1代表氢、硝基、带有1至3个碳原子的烷基或卤素,最好是氟;
X5可以是氢、卤素或甲基;
R10和R11可与它们所连接的氮原子一起形成五元或六元杂环,该杂环可带有另外的原子或基团-O-,-S-,-SO-,-SO2-,>N-R12或-CO-N1-R12,并且在碳原子上可有选择地由C1-C4烷基、苯基或环己基(它们可以有选择的由氯、氟、溴、甲基、苯基、羟基、甲氧基、苄氧基、硝基或哌啶子基单取代、双取代或三取代)、2-噻吩基、羟基、带有1至3个碳原子的烷氧基、氨基、甲氨基、乙氨基、氨甲基、甲基氨甲基或乙基氨甲基单取代、双取代或三取代,其中
R12代表氢,有1至6个碳原子的直链或带支链的烷基、链烯基或链炔基并且可以被1个或2个羟基、带有1至3碳原子烷基的二烷氨基、烷氨基或烷氧基有选择地取代,氰基或在醇部分有1至4个碳原子的烷氧羰基,在脂肪族部分至多含有4个碳原子而苯基可有选择取代的苯基烷基,由羟基、甲氧基、氯或氟选择性单或双取代的苯甲酰甲基,至多有6个碳原子的氧代烷基,此外还可以为COR13或SO2R14;
R13代表氢,带有1至4个碳原子的直链或带支链的烷基,并且该烷基可由氨基、在烷基部分带有1至3个碳原子的烷氧羰基、羧基和带有1至3个碳原子的烷氧基以及卤素、(例如氯、溴和氟)一组取代基中的一个或2个有选择地取代或者代表有1至4个碳原子的烷氧基、氨基,在烷基部分含有1至5个碳原子的二烷氨基或烷氨基,并且R14代表带有1至3个碳原子的直链或带支链的烷基,2代表氧或胺基NR15;
R15代表氢,带有1至6个碳原子的烷基,并且该烷基可由卤素、三氟甲基、硝基、氰基、羟基、烷氧基、带有1至3个碳原子的烷巯基芳氧基、芳硫基或在醇部分带有1至3个碳原子的酯基选择性取代,或者是由卤素、硝基、带有1至3个碳原子的烷基或带有1至3个碳原子的烷氧基或烷巯基选择性取代的苯基,此外R15还可代表酰基R16CO-或R17SO2-;
R16和R17代表有1至6个碳原子的烷基或有选择取代的苯基或R15为
,其中R18至R21代表氢、带有1至6个碳原子的烷基或有选择取代的苯基;并且
A.如果n为0,
a)R1、R2和R3代表氢、带有1至2个碳原子的烷基或苯基,并且R4代表CH2X;
其中X代表卤素、氰基、羟基、烷基或带有1至3个碳原子并被苯基有选择取代的烷巯基;
b)R1是氢、带有1至2个碳原子的烷基或苯基,R2代表CH2X,
其中X代表卤素、氰基、羟基、烷基或带有1至3个碳原子并被苯基有选择取代的烷巯基;R3代表氢、带有1至3个碳原子的烷基或苯基,R4代表苯基;
c)R1和R2代表带有1至2个碳原子的烷基,R3和R4代表氢或有1至6个碳原子并被苯基有选择取代的烷基、或代表苯基;
d)R1代表氢,R2代表氢或带有1至2个碳原子的烷基,R3代表氢、带有1至3个碳原子并可被苯有选择取代的烷基或苯基,R4代表苯基;
e)R1代表氢,R2代表芳基,并且R3和R4代表氢,烷基或苯基;
f)R1和R2代表氢或带有1至2个碳原子的烷基,并且R3和R4与它们所连接的碳原子共同形成三至七元的螺环;
g)R1和R2与它们所连接的碳原子共同形成三至七元环的螺环,并且R3和R4代表氢、有1至6个碳原子并被苯有选择取代的烷基或苯基;
h)R2和R4代表氢、带有1至6个碳原子的烷基或苯基,并且
R1和R3与它们所连接的碳原子共同形成三至七个元环;
B.如果n是1
Ⅰ.R1和R2代表氢或带有1至2个碳原子的烷基,并且
a)R3和R4代表氢,R5和R6代表有1至6个碳原子并被苯基有选择取代的烷基;
b)R3和R4代表有1至6个碳原子并被苯基有选择取代的烷基,R5和R6代表氢;
c)R3和R4和R5代表有1至6个碳原子并被苯基有选择取代的烷基,R6代表氢;
d)R4、R5和R6代表有1至6个碳原子并被苯基有选择取代的烷基,R3代表氢;
e)R3至R6代表有1至6碳原子并被苯基有选择取代的烷基;
f)R3代表有选择取代的苯基,R4、R5和R6代表氢;
g)R5代表有选择取代的苯基,R3、R4、和R6代表氢;
h)R3和R6代表氢,R4和R5与它们所连接的碳原子共同形成三至七个元环;
i)R3和R4与它们所连接的碳原子共同形成三至七元的螺环,R5和R6代表氢,带有1至3个碳原子的烷基或苯基;
j)R5和R6与它们所连接的碳原子共同形成三至七元的螺环,R3和R4代表氢,带有1至3个碳原子的烷基的或苯基;
k)R3和R4、R5和R6与它们所连接的特定碳原子共同形成三至七元螺环,
Ⅱ、R1代表氢,R2和R3与它们所连接碳原子共同形成三至七元环,R4、R5和R6代表氢,且有1至6个碳原子的烷基或苯基。
Ⅲ、R1和R6代表氢,R2和R3、R4和R5分别与它们所连接的碳原子共同形成三至七元环。
Ⅳ、R1和R2与它们所连接的碳原子共同形成三至七元螺环,R3和R5与它们所连接的碳原子共同形成三至七元环,R4和R6代表氢或烷基。
Ⅴ、R1和R4代表氢或带有1至2个碳原子的烷基,R2和R3与它们所连接的碳原子共同形成三至七个元环,R5和R6与它们所连接的碳原子共同形成三至七元螺环。
因此,它们适宜用作人类医疗和兽医的有效药物,并且上述化合物均可用作为该杀茵剂的中间产品。
优先选用的Ⅰ式化合物是其中Y代表羧基、腈基或脂基-COOR7,这里R7可是甲基或乙基,X1是氟,X5是氢,R10和R11与它们所连接的氮原子共同形成五元或六元杂环,该杂环可另外含有氧原子或N-R12、-CO-
-R12基团作为环上原子,并且在该杂环的碳原子上可有选择地由C1-C2烷基,环己基,被氯、氟、甲基、苯基、羟基、甲氧基、苄氧基、硝基或哌啶子基取代的苯基,2-噻吩基或羟基单取代或双取代;
R12代表氢,带有1至3个碳原子并被1个或2个羟基有选择取代的直链或带支链的烷基,苯甲酰甲基和最多4个碳原子的氧代烷基或COR13;
R13代表氢或带有1个或2个碳原子的烷基,Z代表氧或胺基NR15;
R15代表带有1至4个碳原子的烷基或被卤素、甲基或硝基有选择取代的苯基。
如果n等于0或1,上述的定义适用于R1至R6。
苯基可被卤素、带有1至3个碳原子的烷基、硝基、氰基、烷氧基或有1至3个碳原子的烷巯基、苯氧基、苯硫基或在醇部分带有1至3个碳原子的酯基所取代。
由R1至R6形成的三至七元环可被有1至3个碳原子的烷基或苯基取代。
此外还发现,式Ⅰ化合物可用式(Ⅱ)的喹诺酮羧酸衍生物。
其中X1、X5、R1至R6、Z和n的定义同前。
X2最好是氯或氟,
在酸结合剂存在下与Ⅲ胺反应的方法制得(方法A)。
其中R10和R11的定义同前(方法A)。
根据本发明、式(Ⅰ)化合物还可由10-(1-哌嗪基)-化合物(其中n=0)或11-(1-哌嗪基)-化合物(其中n=1)(Ⅳ式)
其中X1、X5、R1至R6、Z、Y和n的定义同前。并且哌嗪基的碳原子上可被C1-C4烷基、2-噻吩基、或被有选择取代的环己基或苯基单取代、双取代或三取代,在酸结合剂存在下与式(Ⅴ)化合物反应制得(方法B)
其中R12的定义同前,但不能是氢,并且X代表氟、氯、溴、碘、羟基、酰氧基、乙氧基、苯氧基或4-硝基苯氧基。
根据本发明,式(Ⅰ)的化合物还可由10(1-哌嗪基)-喹诺酮羧酸衍生物(n=0)或11-(1-哌嗪基)喹诺酮羧酸衍生物(n=1)(式Ⅳ),其中哌嗪基的碳原子上可被C1-C4烷基、2-噻吩基或者被有选择取代的环己基或苯基单取代、双取代或三取代,与式(Ⅵ)的迈克尔接受体(Michael acceptors)(Ⅵ)反应而制备(方法c)。
其中B代表CN,CO-R22或COOR23
R22代表甲基或乙基,R23代表甲基、乙基、正-或异丙基。
在方法A的反应中,如果应用1-甲基-哌嗪和9,10-二氟代-2,3-二氢-7-氧代-2-苯基-7H-吡啶并〔1,2,3-de〕〔1,4〕-苯并噁嗪-6-羧酸作为起始物质,那么可用下列反应式表示反应的过程:
在方法B的反应中,如果应用碘乙烷和9-氟代-2,3-二氢-7-氧代-2-苯基-10(1-哌嗪基)-7H-吡啶并〔1,2,3-de〕〔1,4〕-苯并噁嗪-6-羧酸作为起始物质,那么可用下列反应式表示反应的过程:
在方法C的反应中,如果应用9-氟代-2,3-二氢-7-氧代-2-苯基-10(1-哌嗪基)-7H-吡啶并〔1,2,3-de〕〔1,4〕-苯并噁嗪-6-羧酸和甲基乙稀基酮作为起始物质,那么可用下列反应式表示反应的过程:
根据方法A,可以用作为起始物质的喹诺酮羧酸(式Ⅱ)可按下述反应式制备:
根据该反应式,丙二酸二乙酯(2)在乙醇镁存在用合适苯甲酰氟或苯甲酰氯(1)酰化,可得到苯甲酰丙二酸二乙酯(3)。(Organicum.第3版,1964年,438页)。
在水介质中,用催化量的硫酸或对-甲苯磺酸使(3)进行部分水解和脱羧,可以高产率得到苯甲酰基乙酸乙酯(4),(4)可用原甲酸三乙酯/乙酐转化成3-乙氧基丙烯酸乙酯(5)。(5)与相应的胺(6)在溶剂(例如二氯甲烷、乙醇、氯仿、环己烷或甲苯)中,以轻微的放热反应生成了所需要的中间产物(7)。
成环反应(7)→(9)和(8)→(9)是在约60至300℃的高温范围内进行的,最好是80至180℃。
可用的稀释剂是二噁烷、二甲基亚砜、N-甲基吡咯烷酮、四氢噻吩砜、六甲基磷酸三酰胺,最好是N,N-二甲基甲酰胺。
在该反应阶段可用的酸结合剂是:叔丁醇钾盐、丁基-锂、锂-苯、苯基-溴化镁、甲酵钠、氢化钠、碳酸钠或钾,最好是氟化钾或钠。
为完成第一步环化(7)→(8)和第二步环化(8)→(9),一般每步使用1当量的碱。
如果两步环化合并成“一步反应”(7)→(9),必须使用2当量上述的碱。在成环缩合反应(7)→(9)和(8)→(9)中,使用过量约10摩尔%的碱是有益的。
为了得到相应的羧酸,最后一步酯(9)的水解反应可在通常已知的酸或碱的条件下进行。
作为起始物质用于该合成路线中的2,3,4,5-四氢代苯甲酰氯成五氟代苯甲酰氯是已知化合物。
当四氯代苯甲酰氯与氟化钾在四氢噻吩砜中被加热升温时,可以同时得到3,5-二氯代-2,4-二氟代-苯甲酰氟(沸点97°/20毫巴,n20 D=1.5148)和5-氯代-2,3,4-三氟代苯甲酰氟(沸点66-70°/20毫巴;n20 D=1.4764)。
在氯代磺酸存在下,使2,4,5-三氟代苯甲酸氯化生成3-氯代-2,4,5-三氟代-苯甲酸,该化合物作为粗产物与亚硫酰氯反应,得到3-氯代-2,4,5-三氟代苯甲酰氯(沸点94°/18毫巴;n20 D=1.5164);
将已知的2,4-二氯代-5-氟代-苯甲酸硝化生成2,4-二氯代-5-氟代-3-硝基-苯甲酸,而该化合物与亚硫酰氯反应可得到2,4-二氯代-5-氟代-3-硝基-苯甲酰氯。
作为起始物质的胺(式6)是已知的。可应用的例子有:2-氨基环戊醇、2-氨基环己醇、2-(2-氨基乙氨基)-乙醇、2-氨基-2-苯基乙醇、1-氨基-2,3-丙二醇、2-氨基-3-苯基丙醇、2-氨基-1-苯基-1,3-丙二醇、N-苯基-亚乙基-二胺、N-苄基-亚乙基-二胺和2-氨基甲基环己醇。
用作起始物质的胺(Ⅲ)是已知的或它可按文献〔美国专利4166180和J.Med,chem.26 1116(1983)〕中已知的方法制得。2-芳基-哌嗪的催化氢化,可得到相应的2-环己基-哌嗪类。例如可得到2-环己基-哌嗪(蜡状,熔点:71-73℃)。可用的例子有:吗啉、哌啶、硫代吗啉、吡啶烷、哌嗪、N-甲基哌嗪、N-乙基哌嗪、N-(2-羟乙基)-哌嗪、N-甲酰基哌嗪、2-甲基哌嗪、1,2-二甲基哌嗪、顺和反-2,5-二甲基哌嗪、顺和反-2,6-二甲基哌嗪、2-乙基哌嗪、2-丙基哌嗪、2-异丙基哌嗪、2-异丁基哌嗪、2-哌嗪酮、1-甲基-2-哌嗪酮。1-乙基-2-哌嗪酮、2-环己基哌嗪、2-苯基哌嗪、2-(4-氯代苯基)-哌嗪、2-(4-氟代苯基)-哌嗪、2-(4-溴代苯基-哌嗪、2-(4-甲基苯基)-哌嗪、2-(4-联苯基)-哌嗪、2-(4-甲氧基苯基)-哌嗪、2-(4-苄氧基苯基)-哌嗪、2-(4-羟基苯基)-哌嗪、2-(4-硝基苯基)-哌嗪、2-(3-硝基苯基)-哌嗪、2-(4-哌啶子基苯基)-哌嗪、2-(3,4-二甲氧基苯基)-哌嗪、2-(3,4,5-三甲氧基苯基)-哌基、2-(3,4-二甲氧基-6-甲基)-哌嗪、2-(2-噻吩基)-哌嗪和3-氨基-吡啶烷。
用作为起始物质的式(Ⅴ)化合物是已知的。可用的例子有:碘代甲烷、溴代甲烷、碘代乙烷、溴代乙烷、氯代乙烷、2-羟基乙基氯、3-羟基丙基氯、4-羟基丁基氯、溴代正-丙烷、碘代异-丙烷、溴代正丁烷、溴代异丁烷、氯代仲丁烷、氯代正戊烷、3-甲基丁基氯和溴代正己烷。
甲酸/乙酐、乙酐、丙酸酐、乙酰氯、氯乙酰氯、二氯乙酰氯、溴乙酰溴、丁酰氯、4-氯丁酰氯、异丁酰氮、N-(叔-丁氧基羰基)甘氨酸4-硝基苯酯、N-(叔-丁氧基羰基)-L-丙氨酸 4-硝基苯酯、N-(叔-丁氧基羰基)-L-亮氨酸 4-硝基苯酯N-(叔-丁氧基羰基)-L-缬氨酸4-硝基苯酯、3-甲氧基丙酰氯、氯甲酸甲酯、氯甲酸乙酯、氯甲酸正丁酯、碳酸二乙酯、氯化氰、碳酸二苯酯、溴化氰、二甲基氨基甲酰氯、甲磺酰氯、乙磺酰氯、丙烷-1-碳酰氯和甲酸。
本发明所用的式(Ⅶ)化合物是已知的,可应用的例子有:丙烯腈、甲基乙烯酮、丙烯酸甲酯和丙烯酸乙酯。
根据方法A,(Ⅲ)与(Ⅱ)的反应最好是在稀释剂中进行,可以应用的稀释剂有二甲基亚砜、N、N-二甲基甲酰胺、六甲基-磷酸三酰胺、四氢噻吩砜、水及醇类(如甲醇、乙醇、正丙醇、异丙醇或乙二醇-甲醚)或吡啶。也可使用上述稀释剂的混合物。
所有常用的无机和有机酸结合剂都可用作为酸结合剂。酸结合剂包括:碱金属氢氧化物、碱金属碳酸盐、有机胺类和脒类。特别适用的是如下化合物:三乙胺、1,4-二氮杂-二环〔2,2,2〕-辛烷(DABCO)、1,8-二氮杂-二环〔5,4,0〕-十-碳-7-烯(DBu)或过量的胺(Ⅲ)。
反应温度可在一相当大的范围内变化。反应一般在约20℃至200℃下进行,最好在80℃-180℃下。
反应可在常压下进行,但也可在加压下进行。一般压力范围约为1至100巴,最好在1至10巴之间进行。
根据本发明的工艺过程,每摩尔的羧酸(Ⅱ)需用1至15摩尔,最好为1至6摩尔的胺(Ⅲ)。
(Ⅴ)与(Ⅳ)的反应最好是石稀释剂中进行,稀释剂有二甲基亚砜、二噁烷、N、N-二甲基甲酰胺、六甲基-磷酸三酰胺、四氢噻吩砜、水、醇(例如:甲醇、乙醇、正丙醇、异丙醇或乙二醇-甲醚)或吡啶。也可使用这些稀释剂的混合物。
所有通用无机和有机酸结合剂可用作为酸结合剂。酸结合剂包括:碱金属氢氧化物、碱金属碳酸盐、有机胺和脒类。特别适用的是如下化合物:三乙胺、1,4-二氮杂-二环〔2,2,2〕-辛烷(DABCD)或1,8-二氮杂-二环-〔5,4,0〕-十-碳-7-烯(DBu)。
反应温度可在相当大的范围内变化。一般反应温度为约20℃至180℃,最好40℃至110℃。
反应可在常压下进行,但也可在加下进行。一般压力范围约为1至100巴,最好在1至10巴。
根据本发明方法B进行的工艺过程,每摩尔化合物(Ⅳ)需用1至4摩尔,最好是1至1.5摩尔的化合物(Ⅴ)。
(Ⅵ)与(Ⅳ)的反应(方法C)最好是在稀释剂中进行,稀释剂有二噁烷、二甲基亚砜、N,N-二甲基甲酰胺、甲醇、乙醇、异丙醇、正丙醇或乙二醇-甲醚,或在上述稀释剂的混合物中进行反应。
反应温度可在相当大的范围内变化。反应通常在约20℃至150℃,最好在50℃至100℃下进行。
反应可在常压下进行,也可在加压下进行。一般反应压力为约1至100巴,最好为1至10巴。
根据本发明方法C进行的工艺过程,每摩尔化合物(Ⅳ)需用1至5摩尔,最好为1至2摩尔化合物(Ⅵ)。
除在实例中列举的化合物外,下列化合物是新的有效化合物:9-氟代-2,3-二氢-10-(4-甲基-1-哌嗪基)-7-氧代-3-苯基-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氟代-2,3-二氢-7-氧代-3-苯基-10-(1-哌嗪基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氟代-2,3-二氢-2-羟甲基-10-(4-甲基-1-哌嗪基)-7-氧代-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氯代-2,3-二氢-2-羟甲基-10-(4-甲基-1-哌嗪基)-7-氧代-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氯代-2,3-二氢-7-氧代-2-苯基-10-(1-吡咯烷基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氟代-2,3-二氢-7-氧代-2-苯基-10-(1-吡咯烷基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、6-氟代-3a,11a-二氢-8-氧代-5-(1-吡咯烷基)-8H-环戊二烯并〔1,2-6〕吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-9-羧酸、6-氯代-3a,11a-二氢-8-氧代-5-(1-吡咯烷基)-8H-环戊二烯并〔1,2-6〕吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-9-羧酸、9-氯代-2,3-二氢-3,3-二甲基-7-氧代-10(1-吡咯烷基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氯代-2,3-二氢-3,3-二甲基-7-氧代-10(1-吡啶烷基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、9-氯代-2,3-二氢-3,3-二甲基-7-氧代-10(3-苯基-1-哌嗪)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸、6-氟代-3a,11a-二氢-8-氧代-5(3-苯基-1-哌嗪基)-8H-环戊二烯并〔1,2-b〕吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-9-羧酸和9-氟代-2-氟甲基-2,3-二氢-7-氧代-10(1-吡咯烷基)-7H-吡啶并〔1,2,3-de〕〔1,4〕苯并噁嗪-6-羧酸。
本发明片剂的实例
每片包含:
实例1的化合物 583.0毫克
微晶纤维素 55.0毫克
玉米淀粉 72.0毫克
不溶性聚(1-乙烯基-2-吡咯烷酮) 30.0毫克
高分散的二氧化硅 5.0毫克
硬脂酸镁 5.0毫克
750.0毫克
胶膜壳含有:
聚(0-羟丙基-0-甲基)-纤维素15CP 6.0毫克
Macrogol 400 推荐的INN
聚乙二醇(DAB) 2.0毫克
氧化钛-(Ⅳ) 2.0毫克
10.0毫克
本发明的化合物显示出具有抗革兰氏阳性和革兰氏阴性病菌的广抗菌谱,特别是可以抗肠杆菌科,本发明化合物尤其可用于对各种抗菌剂(例如青霉素类、头孢菌素类、氨基糖苷类、磺胺类药物和四环素类)已产生了抗性的病菌,并且本发明化合物还是低毒的。
这些有用的特性使它们在医学上可用做为化学治疗剂的有效化合物,并且可以用来保护有机和无机材料,特别是所有类型的有机材料,如聚合物、润滑剂、油漆、纤维、皮革、纸张和木材、食品和水。
本发明的化合物具有广谱的抗菌作用。本发明的化合物对革兰氏阴性和革兰氏阳性细菌以及类似细菌的微生物均有效,并且可以预防、减轻和/或治愈上述病原体所引起的疾病。
本发明的化合物对细菌和类似细菌的微生物尤其有效。因此它们特别适用于人类和兽医预防和化学治疗由于上述病原体所引起的局部和全身感染。
例如,本发明化合物可以治疗和/或预防由下述病原体或病原体的混合物所引起的局部和/或全身疾病。
革兰氏阳性球菌,例如葡萄球菌属(金黄色葡萄球菌和表皮葡萄球菌)和链球菌属(无乳链球菌、粪链球菌、肺炎链球菌和酿脓链球菌);革兰氏阴性球菌(淋病奈瑟氏球菌)和革兰氏阴性棒状球菌,例如肠杆菌科,如大肠埃希氏菌、流感嗜血菌、柠檬酸细菌属(弗氏柠檬酸细菌和divernis柠檬酸细菌)、沙门氏菌属和志贺氏菌属;还有克雷伯氏杆菌属(肺炎克雷伯氏菌和oxytoca克雷伯氏菌)、肠杆菌属(产气肠杆菌和agglomerans肠杆菌)、哈夫尼菌属、沙雷氏菌属(粘质沙雷氏菌)、变形杆菌属(奇异变形菌、雷氏变形菌和普通变形菌)、普罗威登斯菌属、耶尔森氏菌属,以及不动杆菌属。但是抗菌谱还包括假单胞菌属(铜绿假单胞菌和嗜麦芽假单胞菌)以及压氧细菌,例如脆弱拟杆菌多形亚种,还有球菌属、消化链球菌属和梭状芽孢杆菌属,另外还有支原体属(肺炎枝原体、人型枝原体和urealyticum枝原体)和分支杆菌,例如结核分支杆菌。
上述所列的病原体仅仅是为了举例,决不能解释为限定范围。本发明化合物能够预防、减轻和/或治愈的疾病的实例有:耳炎、咽炎、肺炎、腹膜炎、肾盂肾炎、膀胱炎、心内膜炎、全身感染、支气管炎、关节炎、局部感染和脓毒性的疾病。
本发明包括药用配方,该配方除了含有适用于药用的无毒的惰性赋形剂以外,还含有一个或一个以上本发明的化合物,该配方也可由一个或一个以上本发明的化合物组成,本发明还包括配制这些配方的方法。
本发明还包括按剂量单位的药物配方,这意指该配方可以是单独部分的形式,例如片剂、糖衣丸、胶囊剂丸剂、栓剂和安瓿,配方中有效化合物的含量相当于单个剂量的几分之一或多倍。例如剂量单位可包含1、2、3或4倍的单个剂量或单个剂量的1,/2、1/3或1/4。单个剂量最好含有有效化合物的一次服用量,并且有效化合物的含量通常相当于一天的全部剂量或相当于一天剂量的1/2、1/3、1/4。
适用于药用的无毒的惰性赋形剂可以是固体的、半固体的或液体稀释剂、填料和所有类型的配方辅助剂。
可以提到的最好药用配方有片剂、糖衣剂、胶囊剂、丸剂、颗粒剂、栓剂、溶液剂。悬浮液剂和乳剂、糊剂、软膏剂、凝胶、乳羔、洗剂、粉剂和喷雾剂。
片剂、糖衣剂、胶囊剂、丸剂和颗粒剂可含有有效化合物或化合物组和普通的赋形剂,如(a)填料和补充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸,(b)粘合剂,例如羟甲基纤维素,藻酸盐、明胶和聚乙烯吡咯烷酮,(c)湿润剂(humectants),例如甘油,(d)崩解剂,例如琼脂、碳酸钙和碳酸钠,(e)溶液阻滞剂,例如石蜡,(f)吸收加速剂,例如季铵化合物,(g)浸润剂(Wettingagent),例如十六烷醇和甘油单硬脂酸,(h)吸附剂,例如高岭土和膨润土,和(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁和固态聚乙二醇、或(a)至(i)所列物质的混合物。
片剂、糖衣剂、胶囊剂、丸剂和颗粒剂可带有普通的色衣和外壳,并可有选择地带有不透明剂,也可以配制成这样组分,这种组份只释放有效化合物或化合物组,或者最好能在肠道的某一部位释放出有效化合物,并且具有选择性的延效作用,例如植入配方,聚合物和蜡可用于该植入配方。
可以有选择地带有一种或多种上述赋形剂的有效化合物或化合物组,也可以制成微型胶囊形式。
除了含有效化合物或化合物组外,栓剂可含有通常的水溶性或水不溶性赋形剂,例如聚乙二醇、脂肪(如可可脂)和高级酯(如C16脂肪酸和C14醇生成的酯),或这些物质的混合物。
软膏、糊剂、乳羔和凝胶除了含有有效化合物或化合物组以外还可含有普通的赋形剂,例如动物或植物脂肪、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石和氧化锌,或这些物质的混合物。
除了含有有效化合物或化合物组外,粉末和喷雾剂还可含有普通的赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。此外,喷雾剂还含有普通的推进剂如氯化氟代烃类。
除了含有有效化合物和化合物组外,溶液剂和乳剂可含有普通的赋形剂,例如溶剂、加溶剂和乳化剂,如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺,油类特别是棉子油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油、甘油、甲醛缩甘油(glycerol formall)、四氢糠醇、聚乙二醇类和脱水山梨(糖)醇的脂肪酸酯,或这些物质的混合物。
对于胃肠外给药,溶液剂和乳剂可以制成无菌的液体制剂形式,并且该液体制剂要与血液等渗。
除了含有有效化合物或化合物组外,悬浮液可含有普通的赋形剂,例如液体稀释剂,如水、乙醇和丙二醇,悬浮剂如乙氧基异十八烷醇、聚氧乙烯山梨(糖)醇和脱水山梨(糖)醇酯类、微晶纤维素、偏氢氧化铝、膨润土、琼脂和西黄蓍胶,或上述化合物的混合物。
所述的配方还包含有着色剂、防腐剂和可改进气味和味道的添加剂,如薄荷油和桉树油或坛甜剂,如糖精。
在上述药物配方中,有治疗作用的有效组份应占混合物总量的0.1-99.5%,最好为约0.5-95%(按重量计)。
上述药用配方中,除了含有本发明的化合物外,还可含有其他药用的有效化合物。
上述药用配方可按常规用已知方法制备,例如用赋形剂或赋形剂组合物与有效化合物或化合物组混合的方法进行制备。
有效化合物或其药用配方的给药方法有:局部给药、口服给药、胃肠外给药、腹膜内给药和/或直肠给药,以口服或胃肠外给药(例如静脉内或肌肉给药)为最好。
通常,为了得到所希望的结果在临床医疗和兽医中本发明有效化合物或化合物组的施用量,每公斤体重按每24小时总量为0.5-500,最好5-100毫克,如果需要可以均分剂量的形式给药。每次剂量最好含有约1-250,更好是3-60毫克/公斤体重的有效化合物或化合物组。但是,它不可避免的会与上述剂量有差异,特别是由于授受治疗的对象的体重和性情作用、疾病的性质和严重的程度、施用的对象药用配方性质和服用的方法、时间或间隔不同时,剂量必需要改变。
于是,在某些情况下可用少于上述剂量的有效化合物,而在另外情况下必须用大于上述剂量的有效化合物。所需有效化合物特定的适宜剂量和服用方式可由有经验的专家很容易地确定。
新化合物可以普通浓度与食品或食品组成物一起组成配方服用,或与饮用水一起组成配方服用。因此,革兰氏阴性或革兰氏阳性细菌的感染病可被预防、减轻和/或治愈并且可促进机体生长并在食品利用上会有所改进。
本发明的一些化合物的MIC值列于下表
MIC(毫克/毫升)
品系 实例7 实例3
大肠埃希氏杆菌 1 2
大肠埃希氏杆菌T7 0.5 2
大肠埃希氏杆菌A261 0.125 2
克雷伯氏杆菌8085 0.25 2
琼脂稀释试验(相同敏感试验培养基);Denley多点接种器。
下面实例举例说明本发明。
实例1:
a)将6.4克3-乙氧基-2-(2,3,4,5-四氟苯甲酰基)-丙烯酸乙酯首先加入到8毫升的乙醇中。将2.5克2-氨基环戊醇的15毫升乙醇溶液滴入,同时用冰冷却。混合物在室温下搅拌2小时,然后真空浓缩。得到8.3克2-(2,3,4,5-四氟苯甲酰基)-3-(2-羟基环戊基)-氨基丙稀酸乙酯,为粗油状物。
b)8克(a)产物与3.3克碳酸钾和40毫升二甲基甲酰胺于140℃-145℃加热4小时。冷却到室温后,混合物用水稀释并冷却。分出沉淀物,可用乙二醇-甲醚重结晶,得到5.4克5,6-二氟代-3a、11a-二氢-8-氧代-8H-环戊并〔1,2-b〕吡啶并〔1,2,3-d,e〕-〔1,4〕-苯并噁嗪-9-羧酸乙酯。熔点:255-58°
c)5.4克(b)产物在17毫升乙酸、16毫升水和1.6毫升浓硫酸的混合物中于140℃(浴温)加热4小时。混合物冷却并且用水稀释,分离出固体。得到4.4克5,6-二氟-3a,11a-二氢-8-氧代-8H-环戊并〔1,2-b〕-吡啶〔1,2,3-d,e〕〔1,4〕-苯并噁嗪-9-羧酸熔点:270°(分解)
实例2
1.4克实例1产物和1.94克哌嗪在14毫升二甲基亚砜(DMSO)中于140℃加热2.5小时。然后,在高真空下将溶剂蒸出。残余物用乙醇煮沸出并将固体分出。得到1.6克6-氟代-3a、11a-二氢-8-氧代-5-(1-哌嗪基)-8H-环戊并〔1,2-b〕-吡啶〔1,2,3-d,e〕-〔1,4〕-苯并噁嗪-9-羧酸。熔点:252-4°
式(Ⅰ)的喹诺酮羧酸可由实例2类似的方法得到(见表1)。
表(Ⅰ)喹诺酮羧酸
Z=O,X1=F,X5=H,Y=COOH
Claims (5)
1、制备1,8-桥连4-喹诺酮-3-羧酸及其衍生物式(Ⅰ),其药学上有用的水合物,它的碱金属盐、碱土金属盐、银盐、鈲盐及它的酯之方法。
其中:Y代表羰基、腈基、酯基-COOR7或酰胺基-CONR8R9;
R7代表C1-C4烷基;
R8和R9代表氢或C1-C4烷基,并且R9也可以是有选择取代的苯基;
X1代表氢、硝基、带有1至3个碳原子的烷基或卤素,最好是氟;
X5可以是氢、卤素或甲基;
R10和R11可与它们连接的碳原子一起形成五元或六元杂环,该杂环可带有另外的原子或基团;-O-、-S-、-SO-、-SO2-、>N-R12或
,并且在碳原子上可选择性地有单取代、双取代或三取代,取代基有C1-C4烷基、苯基或环己基(可由氟、氯、溴、甲基、苯基、羟基、甲氧基、苄氧基、硝基或哌啶子基有选择地单取代、双取代或三取代)、或2-噻吩基、羟基、带有1至3个碳原子的烷氧基、氨基、甲氨基、乙氨基、氨甲基、甲基氨甲基或乙基氨甲基;其中:
R12代表氢、有1至6个碳原子的直链或带支链的烷基、链烯基或链炔基,并且可以被一个或两个羟基、烷氧基或带有1至3个碳原子烷基的二烷氨基或烷氨基有选择地取代,氰基或在醇部分有1至4个碳原子的烷氧羰基,在脂肪族部分至多含有4个碳原子而苯基可以有选择地取代的苯基烷基,由羟基、甲氧基、氯或氟有选择单取代或双取代的苯甲酰甲基,至多有6个碳原子的氧代烷基,此外还可以为COR13或SO2R14;
R13代表氢,带有1至4个碳原子的直链或带支链烷基,并且该烷基可由氨基、在烷基部分带有1至3个碳原子的烷氧羰基、羧基和带有1至3个碳原子的烷氧基以及卤素(例如氯、溴和氟)一组取代基中的1个或2个有选择地取代,或者代表带有1至4个碳原子的烷氧基、氨基,在烷基部分含有1至5个碳原子的二烷氨基或烷氨基,并且R14代表带有1至3个碳原子的直链或带支链的烷基,Z代表氧或胺基NR15;
R15代表氢,带有1至6个碳原子的烷基,并且该烷基可由卤素、三氟甲基、硝基、氰基、羟基、烷氧基、带有1至3个碳原子的烷巯基、芳氧基、芳硫基或在醇部分上带有1至3个碳原子的酯基选择性取代,或者是由卤素、硝基、带有1至3个碳原子的烷基或带有1至3个碳原子的烷氧基或烷巯基选择性取代的苯基,此外R15还可代表酰基R16CO-或R17SO2-;
A、如果n为0
a)R1、R2和R3代表氢,带有1至2个碳原子的烷基或苯基,并且R4代表CH2X;
其中X代表卤素、氰基、羟基或烷氧基、或带有1至3个碳原子并被苯基有选择取代的烷巯基;
b)R1是氢、带有1至2个碳原子的烷基或苯基,R2代表CH2X;
其中X代表卤素、氰基、羟基、烷氧基或带有1至3个碳原子并被苯基有选择取代的烷巯基,R3代表氢、带有1至3个碳原子的烷基或苯基;R4代表苯基;
c)R1和R2代表带有1至2个碳原子的烷基,R3和R4代表氢或有1至6个碳原子并被苯基有选择取代的烷基,或代表苯基;
d)R1代表氢,R2代表氢或带有1至2个碳原子的烷基,R3代表氢、带有1至3个碳原子并被苯有选择取代的烷基或苯基,R4代表苯基;
e)R1代表氢,R2代表芳基,R3和R4代表氢、烷基或苯基;
f)R1和R2代表氢或带有1至2个碳原子的烷基,并且R3和R4代表的是与它们所连接的碳原子共同形成三至七元的螺环;
g)R1和R2与它们所连接的碳原子共同形成三至七元环的螺环,并且R3和R4代表氢,有1至6个碳原子并被苯有选择取代的烷基或苯基;此外
h)R2和R4代表氢、带有1至6个碳原子的烷基或苯基,并且R1和R3与它们所连接的碳原子共同形成三至七元环;
B、如果n是1
I、R1和R2代表氢或带有1至2个碳原子的烷基,并且
a)R3和R4代表氢,R5和R6代表有1至6个碳原子并可被苯基有选择取代的烷基;
b)R3和R4代表有1至6个碳原子并被苯基有选择取代的烷基,R5和R6代表氢;
c)R3、R4和R5代表有1至6个碳原子并被苯基有选择取代的烷基,R6代表氢;
d)R4、R5和R6代表有1至6个碳原子并被苯基有选择取代的烷基,R3代表氢;
e)R3和R6代表有1至6个碳原子并被苯基有选择取代的烷基;
f)R3代表有选择取代的苯基,R4、R5和R6代表氢;
g)R5代表有选择取代的苯基,R3和R4和R6代表氢;
h)R3和R6代表氢,R4和R5与它们所连接的碳原子共同形成三元至七元环;
i)R3和R4与它们所连接的碳原子共同形成三至七元的螺环,R5和R6代表氢,带有1至3个碳原子的烷基或苯基;
j)R5和R6与它们所连接的碳原子共同形成三至七元的螺环,R3和R4代表氢,带有1至3个碳原子的烷基或苯基;
k)R3和R4,R5和R6与它们所连接的特定的碳原子共同形成三至七元螺环;
Ⅱ、R1代表氢,R2和R3与它们所连接的碳原子共同形成三至七元环,R4、R5和R6代表氢,具有1至6个碳原子的烷基或苯基;
Ⅲ、R1和R6代表氢,R2、和R3、R4和R5分别与它们所连接的碳原子共同形成三至七元环;
Ⅳ、R1和R2与它们所连接的碳原子共同形成三至七元螺环,R3和R5与它们所连接的碳原子共同形成三至七元环,R4和R6代表氢或烷基;
Ⅴ、R1和R4代表氢或带有1至2个碳原子的烷基,R2和R3与它们所连接的碳原子共同形成三至七元环,R5和R6与它们所连接的碳原子共同形成三至七元螺环,
其特征在于使喹诺酮羧酸衍生物(Ⅱ),
(Ⅱ)其中X1、X5、R1至R6、Z和n与上述的定义相同,
X2最好是氯或氟,
与式(Ⅲ)的胺反应,妲果需要,可在酸结合剂存在下进行反应,
其中R10和R11与上述的定义相同。
2、按照权利要求1所述的制备方法,其中在制备的化合物中Y代表羧基、腈基或酯基-COOR7,
R7可以是甲基或乙基,X1是氟,X5是氢,R10和R11代表与它们所连接的氨原子共同形成五元或六元杂环,该杂环还可带有另外的氧原子或N-R12、-CO-
-R12基团,并且在碳原子上可选择地有单取代或双取代,取代基有C1-C3烷基、环己基、被氯、氟、甲基、苯基、羟基、甲氧基、苄氧基、硝基或哌啶子基有选择取代的苯基,2-噻吩基或羟基;
R12代表氢,带有1至3个碳原子并被1个或2个羟基有选择地取代的直链或支链的烷基,苯甲酰甲基和最多有4个碳原子的氧代烷基或COR13;
R13代表氢或带有1个或2个碳原子的烷基,Z代表氧或胺基NR15;
R15代表带有1至4个碳原子的烷基或被卤素、甲基或硝基有选择地取代的苯基,并且
如果n等于0或n等于1,权利要求1中给出的定义可应用于R1至R6。
4、制备按照权利要求1所述的1,8-桥连4-喹诺酮-3-羧酸或它的衍生物(式Ⅰ)的方法,其特征在于使权利要求4式(Ⅳ)的10-(1-哌嗪基)-喹诺酮羧酸衍生物(n=0)或11-(1-哌嗪基)喹诺酮羧酸衍生物(n=1),其中哌嗪基的碳原子上可被单取代、双取代或三取代,取代基有C1-C4烷基、2-噻吩基或有选择取代的环己基苯基,与式(Ⅵ)的迈克尔接受体(Michael acceptors)进行反应,
其中B代表CN、CO-R22或COOR23,
R22代表甲基或乙基,R23代表甲基、乙基、正-或异-丙基。
5、含有权利要求1所述的1,8-桥连4-喹诺酮-3-羧酸及其衍生物(式Ⅰ)的动物食物或动物食物添加剂。
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US4771054A (en) * | 1985-01-23 | 1988-09-13 | Warner-Lambert Company | Antibacterial agents |
DE3522406A1 (de) * | 1985-06-22 | 1987-01-02 | Bayer Ag | Verfahren zur herstellung von 1,8-verbrueckten 4-chinolon-3-carbonsaeuren |
DE3600891A1 (de) * | 1986-01-15 | 1987-07-16 | Bayer Ag | 1,8-verbrueckte 4-chinolon-3-carbonsaeuren und diese enthaltende arzneimittel |
-
1985
- 1985-06-22 DE DE19853522405 patent/DE3522405A1/de not_active Withdrawn
-
1986
- 1986-06-03 NO NO862198A patent/NO862198L/no unknown
- 1986-06-09 EP EP86107840A patent/EP0206076A3/de not_active Withdrawn
- 1986-06-13 US US06/874,249 patent/US4847375A/en not_active Expired - Fee Related
- 1986-06-19 NZ NZ216598A patent/NZ216598A/xx unknown
- 1986-06-19 FI FI862640A patent/FI862640A/fi not_active Application Discontinuation
- 1986-06-19 IL IL79163A patent/IL79163A0/xx unknown
- 1986-06-20 DK DK291886A patent/DK291886A/da unknown
- 1986-06-20 ZA ZA864604A patent/ZA864604B/xx unknown
- 1986-06-20 ES ES556369A patent/ES8802301A1/es not_active Expired
- 1986-06-20 JP JP61143149A patent/JPS62490A/ja active Pending
- 1986-06-20 PT PT82802A patent/PT82802B/pt unknown
- 1986-06-20 HU HU862603A patent/HU195662B/hu not_active IP Right Cessation
- 1986-06-20 GR GR861602A patent/GR861602B/el unknown
- 1986-06-21 KR KR1019860004971A patent/KR870000337A/ko not_active Application Discontinuation
- 1986-06-21 CN CN198686104256A patent/CN86104256A/zh active Pending
- 1986-06-23 AU AU59207/86A patent/AU564013B2/en not_active Ceased
-
1987
- 1987-09-15 ES ES557727A patent/ES8802050A1/es not_active Expired
- 1987-09-15 ES ES557728A patent/ES8801921A1/es not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ES557728A0 (es) | 1988-03-01 |
FI862640A0 (fi) | 1986-06-19 |
DE3522405A1 (de) | 1987-01-02 |
AU564013B2 (en) | 1987-07-30 |
ES8802301A1 (es) | 1988-05-01 |
IL79163A0 (en) | 1986-09-30 |
NZ216598A (en) | 1989-07-27 |
US4847375A (en) | 1989-07-11 |
NO862198D0 (no) | 1986-06-03 |
NO862198L (no) | 1986-12-23 |
GR861602B (en) | 1986-10-20 |
HUT44256A (en) | 1988-02-29 |
FI862640A (fi) | 1986-12-23 |
AU5920786A (en) | 1987-02-05 |
DK291886D0 (da) | 1986-06-20 |
EP0206076A2 (de) | 1986-12-30 |
PT82802B (en) | 1988-05-23 |
EP0206076A3 (de) | 1988-07-27 |
DK291886A (da) | 1986-12-23 |
ES556369A0 (es) | 1988-05-01 |
PT82802A (en) | 1986-07-01 |
ES557727A0 (es) | 1988-03-16 |
JPS62490A (ja) | 1987-01-06 |
KR870000337A (ko) | 1987-02-17 |
HU195662B (en) | 1988-06-28 |
ES8802050A1 (es) | 1988-03-16 |
ES8801921A1 (es) | 1988-03-01 |
ZA864604B (en) | 1987-02-25 |
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