CN86102683A - 抗菌药的制备方法 - Google Patents
抗菌药的制备方法 Download PDFInfo
- Publication number
- CN86102683A CN86102683A CN86102683.7A CN86102683A CN86102683A CN 86102683 A CN86102683 A CN 86102683A CN 86102683 A CN86102683 A CN 86102683A CN 86102683 A CN86102683 A CN 86102683A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- dihydro
- carboxylic acid
- oxo
- pyrrolidyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000004599 antimicrobial Substances 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 70
- HJZQMXIVAIMIQA-UHFFFAOYSA-N 1-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)=CN(F)C2=C1 HJZQMXIVAIMIQA-UHFFFAOYSA-N 0.000 claims description 22
- -1 4Be hydrogen Chemical class 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 150000001447 alkali salts Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
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- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
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- 208000022362 bacterial infectious disease Diseases 0.000 abstract description 3
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- 239000000203 mixture Substances 0.000 description 27
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- 230000033228 biological regulation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- SOZFIIXUNAKEJP-UHFFFAOYSA-N 1,2,3,4-tetrafluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1F SOZFIIXUNAKEJP-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 238000002512 chemotherapy Methods 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SKQYNBDFFGITQV-UHFFFAOYSA-N ethyl 1-ethyl-5,6,7,8-tetrafluoro-4-oxoquinoline-3-carboxylate Chemical compound FC1=C(F)C(F)=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C1F SKQYNBDFFGITQV-UHFFFAOYSA-N 0.000 description 1
- XTFNCVOVZYMQOO-UHFFFAOYSA-N ethyl 5,6,7,8-tetrafluoro-4-oxo-1h-quinoline-3-carboxylate Chemical compound FC1=C(F)C(F)=C(F)C2=C(O)C(C(=O)OCC)=CN=C21 XTFNCVOVZYMQOO-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical class ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- YZERDTREOUSUHF-UHFFFAOYSA-N pentafluorobenzoic acid Chemical class OC(=O)C1=C(F)C(F)=C(F)C(F)=C1F YZERDTREOUSUHF-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical class C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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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
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/04—Antibacterial agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
叙述了新型二氟-萘啶和三氟-喹啉-羧酸作为抗菌药及其制造、配制的方法,并在治疗细菌性传染病中应用,还叙述了在抗菌药制造中所用的某些新型中间体。
Description
欧洲专利公布号106,489公开了,把6-氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸和6,8-二氟-1,4-二氢-4-氧代喹啉-3-羧酸作为抗菌药。
本发明涉及有抗菌性价值的相应的5,6-二氟萘啶和5,6,8-三氟喹啉。
因此,本发明涉及分子式为Ⅰ的化合物
其中Z是
n和n′分别是任意的1、2、3或4,其中n+n′的总数是2、3、4或5;n″是0、1或2;n′″是0、1或2;和nⅳ是1到5;R1是氢、有1到6个碳原子的烷基或一个阳离子;R2是1到4个碳原子的烷基、乙烯基、卤代烷基或2到4个碳原子的羟烷基或3到6个碳原子的环烷基;R3是氢、有1到4个碳原子的烷基或3到6个碳原子的环烷基;R4是氢、有1到4个碳原子的烷基、有2到4个碳原子的羟烷基、三氟乙基或R7CO,式中R7是有1到4个碳原子的烷基或有1到4个碳原子的烷氧基;R5是氢或有1到3个碳原子的烷基;R6是氢或1到3个碳原子的烷基;
本发明中最好的化合物是式中的R1为氢或药用合格的盐基盐,例如,金属盐或胺盐。
本发明另一个最好的化合物是分子式中的R2是乙基、乙烯基、2-氟乙基或是环丙基。
本发明另一个最好的化合物是分子式中的R3是氢、甲基、乙基或正丙基,和R4、R5和R6都是氢。
非常好的化合物是式中的X是CF,Z是
n″是0或1;R1是氢,R2是乙基、乙烯基、2-氟乙基或环丙基,和R3是氢、甲基、乙基、1-或2-丙基,或药用合格的酸加合盐或其盐基盐。
本发明特别好的一类化合物,其名称为:
7-〔3-(氨甲基)-1-吡咯烷基〕-1-乙基-5,6-二氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸;
7-〔3-(氨甲基)-1-吡咯烷基〕-1-乙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
7-〔3-(氨甲基)-1-吡咯烷基〕-5,6,8-三氟-1-(2-氟乙基)-1,4-二氢-4-氧代-3-喹啉羧酸;
7-〔3-(氨甲基)-1-吡咯烷基〕-5,6,8-三氟-1-乙烯基-1,4-二氢-4-氧代-3-喹啉羧酸;
1-乙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6-二氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸;
1-乙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1-(2-氟乙基)-1,4-二氢-4-氧代-3-喹啉羧酸;
1-乙烯基-7-〔3-〔(乙氨基)甲基-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-乙基-5,6-二氟-1,4-二氢-7-〔3-〔〔(1-甲基乙基)氨基〕甲基〕-1-吡咯烷基〕-4-氧代-1,8-萘啶-3-羧酸;
1-乙基-7-〔3-〔〔(1-甲基乙基)氨基〕甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-乙基-5,6-二氟-1,4-二氢-7-(7-甲基-2,7-二氮螺〔4.4〕壬烷基-2)-4-氧代-1,8-萘啶-3-羧酸;
1-乙基-5,6,8-三氟-1,4-二氢-7-(7-乙基-2,7-二氮螺〔4.4〕壬基-2)-4-氧代-3-喹啉羧酸;
1-乙基-5,6,8-三氟-1,4-二氢-7-(7-甲基-2,7-二氮螺〔4.4〕壬基-2)-4-氧代-3-喹啉羧酸;
7-(3-氨基-1-吡咯烷基)-1-乙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
7-〔3-(氨乙基)-1-吡咯烷基〕-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-环丙基-7-〔3-(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-喹啉羧酸;
7-〔3-氨基-1-吡咯烷基〕-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-环丙基-7-〔3-〔(甲氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-环丙基-7-〔3-(乙氨基)-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸;
1-环丙基-5,6,8-三氟-1,4-二氢-7-〔3-〔〔(1-甲基-乙基)氨基〕甲基〕-1-吡咯烷基〕-4-氧代-3-喹啉羧酸;
7-〔3-(氨甲基)-1-吡咯烷基〕-1-环丙基-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸;
1-环丙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸;
7-〔3-氨基-1-吡咯烷基〕-1-环丙基-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸;
以及药用合格的酸加合盐或其盐基盐。
制备下列分子式化合物的方法:
式中R1、R2、X、Y和Z,在分子式Ⅰ中已经确定,它含有下下列结构式的化合物与相
当于基团Z的胺反应。式中的Z是有下列结构的化合物
式中所有的上述符号在分子式Ⅰ中都已确定,而L是一个离去基团,最好是氟或氯。
本发明也包括一种药物组分,它是含有结构式为Ⅰ并有抗菌有效剂量的化合物和与载体结合的药用合格的盐基盐。
本发明还包括治疗哺乳动物细菌性传染病的方法,其方法是按需要,将上述药物组分的抗菌有效剂量给予哺乳动物。
本发明中结构式为Ⅲ的化合物,是很容易由结构式为Ⅳ的相应化合物与所要求的环胺Ⅴa或Ⅴb制取。为此,化合物Ⅴa或Ⅴb的烷基胺取代基,如果需要,就可由基团来保护,使之在该反应条件下,基本不起化学反应。因此,可以利用如下的保护基:羧酸酰基,例如甲酰、乙酰、三氟乙酰;烷氧羰基有乙氧羰基、叔丁氧羰基、β,β,β-三氯乙氧羰基、β-碘乙氧羰基;芳氧羰基有苄氧羰基、对甲氧基苄氧羰基、苯氧羰基;甲硅烷基有三甲基甲硅烷基;和一些其他基团,例如三苯甲基、四氢吡喃基、乙烯氧羰基、阴硝基苯亚磺酰基、二苯氧膦基、对甲苯磺酰基和苄基都可以利用。在化合物Ⅳ和化合物Ⅴa或Ⅴb反应之后,如果需要,保护基可以用精通这类技术者熟知的方法把它除掉。例如,乙氧羰基可以在酸或碱中水解除去而三苯甲基可以用氢解法除去。
结构式为Ⅳ的化合物和作了适当保护的分子式为Ⅴa和Ⅴb的化合物之间的反应,可以在溶剂中进行,也可以不用溶剂,而最好是在高温下反应足够的时间以使反应基本上完全。反应最好是有酸性接受体存在的情况下进行,酸性接受体是一种碱金属或碱土金属的碳酸盐或碳酸氢盐、一种叔胺如三乙胺、吡啶或甲基吡啶。也可用另一种方法,即利用过量的分子式为Ⅴ的化合物作酸性接受体。
适合该反应的溶剂是非活性的溶剂,例如乙腈、四氢呋喃、乙醇、氯仿、二甲亚砜、二甲替甲酰胺、吡啶、甲基吡啶、水等。混合溶剂也可以利用。
合适的反应温度在约20℃到约150℃范围之内。通常温度愈高,要求的反应时间愈短。
除去保护基R4,可以在分离产品Ⅲ之前或之后进行。用另一种方法,保护基可以不必除去。
结构式为Ⅳ的原料化合物是本工艺已知的,如果是新的,则可以从已知的原料用标准方法或用其变更的方法来制取。
例如,在分子式为Ⅳ的化合物中,除R2是环烷基外,都可以从市场上买得到的四氟苯制取。
四氟苯先硝化,而后硝基还原成氨基,不必分离,再与乙氧亚甲基丙二酸二乙酯反应得到2,3,4,5-四氟苯胺基亚甲基丙二酸二乙酯,加热环化形成5,6,7,8四氟-1,4-二氢-4-氧代-3-喹啉羧酸,乙基酯。如果需要,酯烷基化并水解得到分子式为Ⅳ的适当的中间体。上述步骤在实施例中提供说明。
另一方面,特别是当R2为环烷基时,分子式为Ⅳ的化合物,可以从市场买得到的五氟代苯甲酸来制备。这种酸是通过酰氯转化成苯甲酰乙酸乙酯。中间体(2)与乙酸酐和原甲酸三乙酯反应,随后与适当的环烷基胺,例如环丙基胺,反应,得到(3),与碱共热闭环。如果需要,水解后得到分子式为Ⅳ的游离酸。这种方法在实施例中要作更具体的叙述,同时也用下列流程图说明。
(图见下页)
本发明中,具有结构式Ⅴa或Ⅴb的化合物是已知的化合物,可以按照欧州专利公开号106,489的叙述的来制备。
本发明的化合物,用微量滴定稀释法测试时显示出抗菌活性。这一方法是海费兹(Heifetz)等人发表在“杀菌剂和化学疗法”,
6,124(1974)上。这里引入,以供参考。
使用上述的参考方法,下面得到的是本发明有代表性的化合物最小的抑制浓度值,(MICS以微克/毫升计)。
(见下页表)
本发明的这些化合物都能形成药用合格的酸加合盐和/或盐基盐。盐基盐是用金属或胺,例如碱和碱土金属或有机胺形成。用作阳离子的金属,其实例为钠、钾、镁、钙等离子。适用的胺,其实例如N,N-二苄基乙二胺、氯普鲁卡因,胆碱、二乙醇胺、乙二胺、N-甲基还原葡糖胺和普鲁卡因。
药用合格的酸加合盐是用有机和无机酸生成的。
适合生成盐的酸,其例子是盐酸、硫酸、磷酸、醋酸、柠檬酸、草酸、丙二酸、水杨酸、苹果酸、葡糖酸、富马酸、琥珀酸、抗坏血酸、马来酸、甲磺酸等。制备这些盐是游离形式的碱与足够量理想的酸以一般的方式接触得到了不是一元就是二元等的盐。多种形式的游
离碱可以用碱处理盐而再生。例如,可利用稀的碱水溶液。为此,稀的氢氧化钠、碳酸钾、氨和碳酸氢钠的水溶液都是适用的。许多游离碱,与其各自的盐相比,在某些物性方面稍有不同,例如,在极性溶剂中的溶解度。不过盐的其他性质是与本发明所用的游离碱形式是一样的。利用碱中,R′是氢的过量碱,得到相应的盐基盐。
本发明的各化合物,可以以非溶剂化以及溶剂化的形式存在,包括水合的形式。一般来说,溶剂化形式,包括水合形式等都与本发明所用的非溶剂化形式是一样的。
本发明所考虑的烷基基团包含1到大约3个碳原子的直碳链和支碳链,除有具体说明外,可以超过3个碳原子。这些基团的代表是甲基、乙基、丙基、异丙基等。
本发明所考虑的环烷基团包含有3个到6个碳原子的这些基团,例如环丙基、环丁基、环戊基和环己基。
本发明所考虑的烷氧基团包含1到大约4个碳原子的直碳链和支碳链,除非另有规定这些基团的代表是,甲氧基、乙氧基、丙氧基、异-丙氧基、叔-丁氧基等基团。
卤代烷基这个专门名词是规定2到4个碳原子的直碳链和支碳链上卤素取代的基团。那些精通技术的人能够识别出卤素取代基,可以不在链的α-碳原子上。这些基团的代表是β-氟乙基、β-氯乙基、β,β-二氯乙基、β-氯丙基、β-氯-2-丙基、r-碘丁基等。
卤素这个专门名词规定包括氟、氯、溴、和碘,除非另有规定。
本发明的某些化合物,可以以旋光性的形式存在,纯D异构体、纯L异构体以及它们的混合物;包括外淆旋混合物都为本发明所考虑。
外加的不对称碳原子可在取代基中出现,例如烷基。并规定所有这些异构体以及它们的混合物,都将包括在本发明的范围内。
本发明中的各化合物可以各种各样的口服和肠送外给药的形式制备和供给。对于那些精通工艺的人,显然是下列给药的形式,作为活性部分,可以是分子式Ⅰ的化合物,也可以是相当于分子式为Ⅰ的化合物,它的药理盐。
由本发明所叙述的化合物来配制药物组成,所用的药用合格的载体,可以是固体也可以是液体。固体制剂包括粉剂、片剂、可分散的小颗粒、胶囊、扁囊和栓剂。固体载体可以是一种也可以是多种物质并可作稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、药片崩解剂;它也可以是一种胶囊材料。在药粉中,载体是细碎的固体,它与细碎的活性化合物混和。在药片中,活性化合物与必需要有胶粘性的载体以适当比例混和,并压紧做成所要求的一定形式和大小。药粉和药片中含的活性成分最好是5或10到大约70%。适用的固体载体是碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍股、甲基纤维素、羧甲基纤维素钠、低熔点蜡、椰子油等。
制剂这个专门名词规定包含活性组分用作为载体的胶囊材料来配方,提供一种胶囊,在胶囊中活性组分(有或没有其他载体)的周围都是载体,这样它们之间就结合在一起。类似的,也包含扁囊剂。药片药粉、扁囊和胶囊都能以适于口服的固体剂量形式加以应用。
液体制剂,包括悬浮剂和乳剂。可以作为例子来叙述的有肠胃外注射用水溶液或水-丙二醇溶液。制备这些溶液,以便生物系统接受(等渗性、PH等)。液体制剂必可配成聚乙二醇的水溶液。水溶液适合口服,是将活性成分溶于水中加上适当的着色剂,调味剂、稳定剂和增稠剂就能制得。适用于口服的水悬液,是将细粉状的活性成分用粘性料悬浮于水中而制成的。粘性料为天然的或合成的胶、树脂、甲基纤维素、羧甲基纤维素钠、以及其他熟知的悬浮剂。
制剂最好是以单位剂量的形式。在这种形式中,制剂再分成含适当量活性成分的单位剂量。这种单位剂量形式可以是封装制剂,这种封装包含不连续量的制剂,例如一小包药片,胶囊和小并或安瓿中的药粉。单位剂量形式也可以是胶囊、扁囊或药片本身或可能是这些包装形式中任何适宜的几种。
在制剂的单位剂量中活性化合物的量可以按特殊应用和活性成分的效力从1毫克变动或调节到100毫克。
用作治疗细菌性传染病的药剂时,本发明的药物方法中所用的化合物,每天服用的起始剂量是约3毫克到约40毫克/千克。最好是6毫克到约14毫克/千克。然而,这一剂量可以根据病人的需要量、治疗情况的难度以及所用的化合物而变动。
确定特殊情况下的恰当剂量,是属本熟练技术范围之内的。一般来说,开始治疗时,用较小的剂量,该剂量是比化合物的最佳用量要小些。其后,在达到最佳效果之前,一直用很小的增量来增加剂量。为方便起见,如果有必要,可将一天中总用药量分开,按份服用。
下面是不受限制的举例,来说明发明者用的制备本发明化合物的最好方法。
实施例1
7-〔3-(氨甲基)-1-吡咯烷基〕-1-乙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸(A)
向1.0克(3.5毫摩尔)1-乙基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸的20毫升乙腈液中加入1.05克(6.9毫摩尔)1,8-重氮双环-〔5.4.0〕+-碳烯-7和0.35克(3.5毫摩尔)3-吡咯烷甲胺,混合物在45℃搅拌18小时,然后迴流1小时。混合物冷却,用50毫升乙醚稀释,并过滤。所得固体先用乙醇再用乙醚洗涤,得到1.04克(82%)标题化合物。熔点大于170℃(分解)。
用类似的方法制备下列化合物。
(B)1-乙基-5,6,8-三氟-1,4-二氢-7-(7-甲基2,7-二氮螺〔4.4〕壬烷基-2)-4-氧代-3-喹啉羧酸,熔点253-255℃。
(C)1-乙基-5,6,8-三氟-1,4-二氢-7-〔3-〔(甲氨基)甲基〕-1-吡咯烷基〕-4-氧代-3-喹啉羧酸,熔点225-227℃和
(D)1-乙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸,熔点224-227℃。
实施例2
1-环丙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸(A)
向1.0克(3.32毫摩尔)1-环丙烷基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸的9毫升乙腈液中加入0.5克(1当量)1,8-二氮双环〔5.4.0〕+-碳烯-7和0.42克N-乙基-3-吡咯烷甲胺两者的另外3毫升乙腈液。混合物在60℃加热4小时并在25℃搅拌18小时。混合物过滤并用乙醚洗涤固体,得到1.12克标题化合物,熔点247-248℃。
用类似方式,制备下列化合物
(B)1-环丙烷基-5,6,8-三氟-1,4-二氢-7-〔3-〔(甲氨基)甲基〕-1-吡咯烷基〕-4-氧代-3-喹啉羧酸;和
(C)7-〔3-(氨甲基)-1-吡咯烷基〕-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
实施例3
7-〔3-氨基-1-吡咯烷基〕-1-环丙烷基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸
向2.0克(6.64毫摩尔)1-环丙烷基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸的10毫升乙腈液中加入1.5克(8.3毫摩尔)3-叔-丁氧羰基氨基吡咯烷和1.01克(6.64毫摩尔)1,8-二氮双环〔5.4.0〕+-碳烯-7。混合物搅拌过夜,再迴流2小时。过滤得到的固体用醚洗涤。然后用5毫升三氟乙酸处理并在25℃搅拌1小时半后。将三氟乙酸除去并使混合物溶于水。将PH调至7.0,过滤后得到固体,然后干燥得到2.0克标题化合物,熔点290-292℃。
原料的制备
实施例A
2,3,4,5-四氟-1-硝基苯
向1升浓硫酸中,温度为5℃时加入100毫升1,2,3,4四氟等。然后慢慢加入100毫升70%的硝酸与200毫升浓硫酸在0℃予先混合的混合物。在0℃搅拌下,反应1小时,然后在25℃反应1小时。混合物注入冰上并用二氯甲烷萃取。萃取液干燥后浓缩,在斑点薄层层析上得到120克的浓稠残余物。该产品下步使用,不必提纯。
实施例B
2,3,4,5-四氟苯胺基亚甲基-丙二酸二乙酯
向48.6克(0.25摩尔)2,3,4,5-四氟-1-硝基苯的500毫升2-丙醇液中加入3.0克拉内镍并以20磅/英寸的压力通入氢气。19小时后,混合物放出并直接过滤到58毫升二乙基乙氧基亚甲基丙二酸酯和500毫升甲苯混合物中。三小时内蒸完甲苯,残余物用戊烷处理,过滤得到62.5克标题化合物,熔点115-116℃。
实施例C
5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯
向700毫升迴流道氏热载体中分三次加入62.5克(187毫摩尔)的2,3,4,5-四氟苯胺基亚甲基丙二酸二乙酯。30分钟后,混合物冷却,用乙醚稀释,并过滤。所得固体用乙醚洗涤,得到标题化合物40.0克(74%),熔点282-283℃。
实施例D
1-乙基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯
向38.5克(134毫摩尔)5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯的700毫升N,N-二甲基甲酰胺液中加入37.15克(2当量)的碳酸钾和50毫升(5当量)的碘乙烷。混合物加热至50℃并剧烈搅拌至过夜。除去溶剂,残余物在水和二氯甲烷之间进行分配。将二氯甲烷干燥(硫酸镁)并浓缩。残余物在乙醚中研碎,得到30.5克原料,再用乙醇重结晶,过滤得到标题化合物23.5克,熔点217-220℃。
实施例E
1-乙基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸
向20.0克(63毫摩尔)1-乙基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸,乙酯中加入200毫升乙酸和150毫升6N盐酸的70毫升水液。混合物在100℃维持2小时。然后冷却、过滤和用乙醚洗涤,得到17克标题化合物,熔点229-230℃。
实施例F
五氟苯甲酰乙酸乙酯
向20.0克(0.094毫摩尔)五氟苯甲酸和175毫升二氯甲烷中加入9.0毫升(1.1当量)草酰氯和三滴N,N-二甲基甲酰胺。混合物静置过夜而后浓缩。残余物溶于100毫升四氢呋喃中。不用提纯,下一步就能使用。
向26克(2当量)丙二酸半乙酯的600毫升四氢呋喃液中,在-10-0℃时加入179毫升(4当量)的2.2Nn-丁基锂。当完全形成双阴离子时。混合物冷至-78℃并将上述制得的酰基氯慢慢加入。加完后,混合物温度升至-35℃并搅拌1小时。然后将混合物注入94毫升2N盐酸和200克冰中。全部混合物用二氯甲烷萃取,该溶液再用碳酸氢钠的饱和溶液萃取。二氯甲烷干燥并浓缩,色谱柱分离出一种亮黄色油状的标题化合物14.3克。(甲苯∶乙烷∶醚=6∶3∶1)
实施例G
2-(五氟苯甲酰)-3-环丙基氨基丙烯酸乙酯
向14.0克(49.6毫摩尔)五氟苯甲酰乙酸,乙酯中加入12.1克乙酸酐和10.9克原甲酸三乙酯。混合物在150℃迴流2.2小时,然后冷却到80℃并浓缩1个半小时。混合物继续冷却至45℃并与100毫升2-丙醇中的2.83克环丙基胺反应。混合物搅拌过夜再浓缩。残余物用戊烷处理,过滤出固体,得到11.36克苍黄色粉末状的标题化合物,熔点85-86℃。
实施例H
1-环丙基-5,6,7,8-四氟-1,4-二氢-4-
氧代-3-喹啉羧酸
向11.43克(32.75毫摩尔)2-(五氟苯甲酰)-3-环丙基氨基丙烯酸,乙酯的250毫升二噁烷液中85℃时加入4.99克1,8-二氮双环〔5.4.0〕+-碳烯-7。混合物搅拌2小时,生成物在水和二氯甲烷之间进行分配。反应结束后,二氯甲烷用1N盐酸洗涤,然后干燥并加活性炭。混合物过滤,浓缩并用柱色谱柱提纯(氯仿∶乙烷∶2-丙醇=6∶3∶1),得到2.75克产物,将该产物溶于40毫升醋酸和8毫升2N盐酸中,在100℃保持2小时,然后加入20毫升水。混合物冷却,过滤出固体,得到2.5克标题化合物,熔点179-180℃。
勘误表
Claims (23)
1、制备下述分子式的化合物或其药用合格的酸加成盐或盐基盐的方法,
X是CF或N;
n和n′分别是任意的1、2、3、或4,其中
n+N′的总数是2、3、4或5;
n″是0、1或2;
n′″是0、1或2;
niv是1到5;
R1是氢、有1到6个碳原子的烷基或阳离子;
R2是有1到4个碳原子的烷基、乙烯基、囟代烷基、有2到4个碳原子的羟烷基或有3到6个碳原子的环烷基;
R3是氢、有1到4个碳原子的烷基或有3到6个碳原子的环烷基;
R4是氢、有1到4个碳原子的烷基、有2到4个碳原子的羟烷基、三氟乙基、或R7CO,其中R7是有1到4个碳原子的烷基或有1到4个碳原子的烷氧基;
R5是氢或有1到3个碳原子的烷基;
R6是氢或有1到3个碳原子的烷基;
制备方法包括,使下式(Ⅳ)的化合物与对应于基团Z的胺反应,
Z是有下列结构的化合物
式中所有符号如上所述,而L是一个离去基团,最好是氟或氯。
2、根据权利要求1的方法,其中R2是乙基、乙烯基、2-氟乙基或环丙基。
3、根据权利要求2的方法,其中R1是氢或药用合格的盐基盐。
6、根据权利要求4的方法,其中所制备的化合物是7-〔3-(氨甲基)-1-吡咯烷基〕-1-乙基-5,6-二氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸。
7、根据权利要求4的方法,其中所制备的化合物是7-〔3-(氨甲基)-1-吡咯烷基〕-1-乙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
8、根据权利要求4的方法,其中所制备的化合物是1-乙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6-二氟-1,4-二氢-4-氧代-1,8-萘啶-3-羧酸。
9、根据权利要求4的方法,其中所制备的化合物是1-乙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4二氢-4-氧代-喹啉羧酸。
10、根据权利要求4的方法,其中所制备的化合物是1-乙基-5,6-二氢-1,4-二氢-7-〔3-〔〔(1-甲基-乙基)氨基〕甲基〕-1-吡咯烷基〕-4-氧代-1,8-萘啶-3-羧酸。
11、根据权利要求4的方法,其中所制备的化合物是1-乙基-7-〔3-〔(1-甲基-乙基)氨基〕甲基〕-1-吡咯烷基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
12、根据权利要求5的方法,其中所制备的化合物是1-乙基-5,6-二氟-1,4-二氢-7-(7-甲基-2,7-二氮螺〔4.4〕壬基-2〕-4-氧代-1,8-萘啶-3-羧酸。
13、根据权利要求5的方法,其中所制备的化合物是1-乙基-5,6,8-三氟-1,4-二氢-7-(7-甲基-2,7-二氮螺〔4.4〕壬基-2〕-4-氧代-3-喹啉羧酸。
14、根据权利要求4的方法,其中所制备的化合物是7-〔3-(氨甲基)-1-吡咯烷基〕-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
15、根据权利要求4的方法,其中所制备的化合物是1-环丙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
16、根据权利要求4的方法,其中所制备的化合物是7-〔3-氨基-1-吡咯烷基〕-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
17、根据权利要求4的方法,其中所制备的化合物是7-〔3-(氨甲基)-1-吡咯烷基〕-1-环丙基-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸。
18、根据权利要求4的方法,其中所制备的化合物是1-环丙基-7-〔3-〔(乙氨基)甲基〕-1-吡咯烷基〕-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸。
19、根据权利要求4的方法,其中所制备的化合物是7-〔3-氨基-1-吡咯烷基〕-1-环丙基-1,4-二氢-5,6-二氟-4-氧代-1,8-萘啶-3-羧酸。
20、根据权利要求4的方法,其中所制备的化合物是1-环丙基-7-〔3-〔(甲氨基)甲基〕-1-吡咯烷基〕-5,6,8-三氟-1.4-二氢-4-氧代-3-喹啉羧酸。
21、根据权利要求4的方法,其中所制备的化合物是1-环丙基-7-3-(乙氨基)-1-吡咯烷基〕-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸。
22、根据权利要求4的方法,其中所制备的化合物是1-环丙基-5,6,8-三氟-1,4-二氢-7-〔3-〔〔(1-甲基乙基)氨基〕甲基〕-1-吡咯烷基〕-4-氧代-3-喹啉羧酸。
23、根据权利要求4的方法,其中所制备的化合物是7-(3-氨基-1-吡咯烷基)-1-乙基-5,6,8-三氟-1,4-二氢-4-氧代-3喹啉羧酸。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US724,442 | 1985-04-18 | ||
US06/724,442 US4657913A (en) | 1985-04-18 | 1985-04-18 | Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents |
Publications (2)
Publication Number | Publication Date |
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CN86102683A true CN86102683A (zh) | 1986-12-03 |
CN1012064B CN1012064B (zh) | 1991-03-20 |
Family
ID=24910460
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86102683A Expired CN1012064B (zh) | 1985-04-18 | 1986-04-18 | 喹啉羟酸衍生物的制备方法 |
Country Status (22)
Country | Link |
---|---|
US (1) | US4657913A (zh) |
EP (1) | EP0202763B1 (zh) |
JP (1) | JPS61243077A (zh) |
KR (1) | KR890005199B1 (zh) |
CN (1) | CN1012064B (zh) |
AR (1) | AR240458A1 (zh) |
AT (1) | ATE47853T1 (zh) |
AU (1) | AU587811B2 (zh) |
DD (1) | DD244553A5 (zh) |
DE (1) | DE3666820D1 (zh) |
DK (1) | DK172786A (zh) |
ES (1) | ES8800160A1 (zh) |
FI (1) | FI861574A (zh) |
GR (1) | GR860998B (zh) |
HU (1) | HU195498B (zh) |
IL (1) | IL78528A (zh) |
NO (1) | NO166080C (zh) |
NZ (1) | NZ215868A (zh) |
OA (1) | OA08236A (zh) |
PH (1) | PH23770A (zh) |
PT (1) | PT82414B (zh) |
ZA (1) | ZA862388B (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE58742B1 (en) * | 1984-07-20 | 1993-11-05 | Warner Lambert Co | Substituted-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de] [1,4]benzoxauine-6-carboxylic acids; sibstituted-5-amino-6-6fluoro-4-oxo.1,4-dihydroquinoline-3 carboxylic acids; substituted-5-amino-6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acids; derivatives thereof; pharmaceutical compositions comprising the compounds; and processes for producing the compounds |
ATE75740T1 (de) * | 1985-06-26 | 1992-05-15 | Daiichi Seiyaku Co | Pyridoncarbonsaeurederivate. |
AU594983B2 (en) * | 1985-10-29 | 1990-03-22 | Dainippon Pharmaceutical Co. Ltd. | Novel quinoline derivatives and processes for preparation thereof |
DE3705621C2 (de) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclisch substituierte Chinoloncarbonsäurederivate |
EP0242789A3 (en) * | 1986-04-25 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | Novel quinoline derivates and processes for preparation thereof |
GB8612137D0 (en) * | 1986-05-19 | 1986-06-25 | Fujisawa Pharmaceutical Co | Quinolone compounds |
FR2607503B1 (fr) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2607504B1 (fr) * | 1986-12-02 | 1989-01-27 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2607506B1 (fr) * | 1986-12-02 | 1989-01-06 | Rhone Poulenc Sante | Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent |
DE3711193A1 (de) * | 1987-04-02 | 1988-10-13 | Bayer Ag | 5-substituierte chinolon- und naphthyridoncarbonsaeure-derivate |
US5591744A (en) * | 1987-04-16 | 1997-01-07 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
US5290934A (en) * | 1987-04-16 | 1994-03-01 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
US4851418A (en) * | 1987-08-21 | 1989-07-25 | Warner-Lambert Company | Naphthyridine antibacterial agents containing an α-amino acid in the side chain of the 7-substituent |
JPH0794452B2 (ja) * | 1987-10-16 | 1995-10-11 | 大日本製薬株式会社 | 新規ピリドンカルボン酸誘導体、そのエステルおよびその塩 |
WO1989005643A1 (en) * | 1987-12-18 | 1989-06-29 | Pfizer Inc. | Heterocyclic-substituted quinoline-carboxylic acids |
DE3814517A1 (de) * | 1988-02-05 | 1989-08-17 | Bayer Ag | Chinolon- und naphthyridoncarbonsaeurederivate, verfahren zu ihrer herstellung und sie enthaltende antibakterielle mittel und futterzusatzstoffe |
IL90062A (en) | 1988-04-27 | 1994-10-07 | Daiichi Seiyaku Co | History of pyridonecarboxylic acid, their preparation and pharmaceutical preparations containing them |
DE3906365A1 (de) * | 1988-07-15 | 1990-01-18 | Bayer Ag | 7-(1-pyrrolidinyl)-3-chinolon- und -naphthyridoncarbonsaeure-derivate, verfahren sowie substituierte (oxa)diazabicyclooctane und -nonane als zwischenprodukte zu ihrer herstellung, und sie enthaltende antibakterielle mittel und futterzusatzstoffe |
US4992449A (en) * | 1990-02-01 | 1991-02-12 | American Cyanamid Company | 7-(substituted)cycloalkylamino-1-(substituted)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
FR2692577B1 (fr) * | 1992-05-26 | 1996-02-02 | Bouchara Sa | Nouvelles quinolones fluorees, leur procede de preparation et les compositions pharmaceutiques en renfermant. |
TW425394B (en) * | 1996-04-24 | 2001-03-11 | Daiichi Seiyaku Co | Antimicrobial quinolone derivatives having 3-(N-cycloalkyl) aminomethylpyrrolidine group |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
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US3963736A (en) * | 1970-01-28 | 1976-06-15 | Sumitomo Chemical Company, Limited | Preparation of 1-(lower alkyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acids |
US3907808A (en) * | 1971-05-17 | 1975-09-23 | Sterling Drug Inc | 1,4-Dihydro-4-oxo-7-pyridyl-3-quinolinecarboxylic acid derivatives |
US4292317A (en) * | 1977-09-20 | 1981-09-29 | Laboratorie Roger Bellon | 1,4-Dihydro-quinoline-3-carboxylic acid derivatives, process for their preparation and compositions containing them |
JPS5845426B2 (ja) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | 置換キノリンカルボン酸誘導体 |
SE440354B (sv) * | 1981-02-19 | 1985-07-29 | Kyorin Seiyaku Kk | Kinolinkarboxylsyraderivat |
HU188181B (en) * | 1981-06-11 | 1986-03-28 | Warner-Lambert Co,Us | Process for producing salts of naphtiridine and quinoline compounds of antimicrobial activity |
US4477449A (en) * | 1982-04-19 | 1984-10-16 | Warner-Lambert Company | Certain 1,8-naphthyridine compounds useful as antibacterial agents |
IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
IE58742B1 (en) * | 1984-07-20 | 1993-11-05 | Warner Lambert Co | Substituted-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de] [1,4]benzoxauine-6-carboxylic acids; sibstituted-5-amino-6-6fluoro-4-oxo.1,4-dihydroquinoline-3 carboxylic acids; substituted-5-amino-6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acids; derivatives thereof; pharmaceutical compositions comprising the compounds; and processes for producing the compounds |
AU4042085A (en) * | 1985-03-27 | 1986-10-02 | Brugnoli, Angelo | Energy system using hydrostatic pressure air compressor |
-
1985
- 1985-04-18 US US06/724,442 patent/US4657913A/en not_active Expired - Fee Related
-
1986
- 1986-04-01 ZA ZA862388A patent/ZA862388B/xx unknown
- 1986-04-03 AU AU55615/86A patent/AU587811B2/en not_active Ceased
- 1986-04-14 FI FI861574A patent/FI861574A/fi not_active Application Discontinuation
- 1986-04-15 AT AT86302812T patent/ATE47853T1/de not_active IP Right Cessation
- 1986-04-15 DD DD86289148A patent/DD244553A5/de not_active IP Right Cessation
- 1986-04-15 GR GR860998A patent/GR860998B/el unknown
- 1986-04-15 EP EP86302812A patent/EP0202763B1/en not_active Expired
- 1986-04-15 DE DE8686302812T patent/DE3666820D1/de not_active Expired
- 1986-04-16 DK DK172786A patent/DK172786A/da active IP Right Grant
- 1986-04-16 IL IL78528A patent/IL78528A/xx unknown
- 1986-04-17 NZ NZ215868A patent/NZ215868A/xx unknown
- 1986-04-17 NO NO861509A patent/NO166080C/no unknown
- 1986-04-17 OA OA58838A patent/OA08236A/xx unknown
- 1986-04-17 HU HU861617A patent/HU195498B/hu not_active IP Right Cessation
- 1986-04-17 PT PT82414A patent/PT82414B/pt not_active IP Right Cessation
- 1986-04-17 JP JP61087237A patent/JPS61243077A/ja active Pending
- 1986-04-17 AR AR303682A patent/AR240458A1/es active
- 1986-04-17 PH PH33665A patent/PH23770A/en unknown
- 1986-04-18 KR KR1019860002997A patent/KR890005199B1/ko not_active IP Right Cessation
- 1986-04-18 ES ES554142A patent/ES8800160A1/es not_active Expired
- 1986-04-18 CN CN86102683A patent/CN1012064B/zh not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DK172786A (da) | 1986-10-19 |
HU195498B (en) | 1988-05-30 |
IL78528A (en) | 1990-09-17 |
PH23770A (en) | 1989-11-03 |
HUT41020A (en) | 1987-03-30 |
ES8800160A1 (es) | 1987-10-16 |
KR890005199B1 (ko) | 1989-12-18 |
DK172786D0 (da) | 1986-04-16 |
OA08236A (en) | 1987-10-30 |
GR860998B (en) | 1986-08-12 |
CN1012064B (zh) | 1991-03-20 |
ATE47853T1 (de) | 1989-11-15 |
PT82414A (en) | 1986-05-01 |
DD244553A5 (de) | 1987-04-08 |
NO861509L (no) | 1986-10-20 |
EP0202763A1 (en) | 1986-11-26 |
AU587811B2 (en) | 1989-08-31 |
JPS61243077A (ja) | 1986-10-29 |
KR860008164A (ko) | 1986-11-12 |
ES554142A0 (es) | 1987-10-16 |
AU5561586A (en) | 1986-10-23 |
NO166080C (no) | 1991-05-29 |
DE3666820D1 (en) | 1989-12-14 |
IL78528A0 (en) | 1986-08-31 |
AR240458A1 (es) | 1990-04-30 |
PT82414B (pt) | 1988-05-27 |
FI861574A0 (fi) | 1986-04-14 |
US4657913A (en) | 1987-04-14 |
ZA862388B (en) | 1987-11-25 |
NO166080B (no) | 1991-02-18 |
FI861574A (fi) | 1986-10-19 |
EP0202763B1 (en) | 1989-11-08 |
NZ215868A (en) | 1988-08-30 |
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