CN1046162A - 5-烷基喹诺酮羧酸 - Google Patents
5-烷基喹诺酮羧酸 Download PDFInfo
- Publication number
- CN1046162A CN1046162A CN90101902A CN90101902A CN1046162A CN 1046162 A CN1046162 A CN 1046162A CN 90101902 A CN90101902 A CN 90101902A CN 90101902 A CN90101902 A CN 90101902A CN 1046162 A CN1046162 A CN 1046162A
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- Prior art keywords
- alkyl
- methyl
- group
- hydrogen
- formula
- Prior art date
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- Granted
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- 239000002253 acid Substances 0.000 title claims abstract description 22
- 150000007513 acids Chemical class 0.000 title abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 74
- 239000001257 hydrogen Substances 0.000 claims abstract description 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 34
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- -1 alkali metal salt Chemical class 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- NAJSFTMUIDDRNA-UHFFFAOYSA-N 1-fluoro-5-methyl-4-oxoquinoline-3-carboxylic acid Chemical compound FN1C=C(C(O)=O)C(=O)C2=C1C=CC=C2C NAJSFTMUIDDRNA-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
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- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 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 description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 claims description 4
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical group FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
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- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 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 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims description 2
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- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 6
- 230000000845 anti-microbial effect Effects 0.000 abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000003282 alkyl amino group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 11
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- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
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- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000019721 spearmint oil Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 206010044008 tonsillitis Diseases 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
- 206010061393 typhus Diseases 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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- 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
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Abstract
按下式的具抗菌作用的5-烷基喹诺酮羧酸及其水合物及盐,基中:R3是C1-C4烷基;R1是任选取代的烷基或环烷基、链烯基、烷氧基、氨基或烷氨基,或任选取代的苯基;R2是氢或任选取代的烷基;R4是含氮的杂环基;A是氢、卤素、甲基、氰基或硝基,或与R1形成桥。
Description
本发明涉及带有一个烷基的新的喹诺酮羧酸衍生物,其制备方法以及含有这些衍生物的抗菌剂及食品添加剂。
业已发现,具有式(Ⅰ)的喹诺酮羧酸衍生物,以及其适于用作药物的水合物及酸加合盐以及其基础羧酸的碱金属盐、碱土金属盐、银盐、鈲盐,都具有很高的抗菌作用,尤其是对革兰氏阳性菌类:
其中:
R1是直链或支链C1-C4烷基,并可任选由羟基、卤素、C1-C3烷氧基或C1-C3烷硫基、C3-C9环烷基所取代,该C3-C9环烷基又可任选由卤素、C1-C3烷基、C1-C4链烯基所取代,还包括C1-C3烷氧基、氨基、C1-C3单烷基氨基、C2-C6二烷基氨基、苯基,该苯基还可任选由卤素取代;
R2是氢、C1-C4烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R3是C1-C4烷基;
R4是如下列的基团,并在环系中任选由羟基或甲基所取代:
其中:
E是R5-N、O或S;
G是
j是1、2或3;
R5是氢、C1-C4烷基、链烯基或链炔基并任选由羟基、苄基所取代,该苄基又可任选由硝基或氨基、C2-C4氧代烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基所取代;
R6是氢或甲基;
R4还可以是如下式所表示的基团:
其中:
l是0、1或2;
m是1或2,其中p+m可以是1、2或3;
n是1或2;
W是
、OR9、SR9、卤素或氢;
X2和X3可以相同或不同,并且是氧或N-CH3;
R7是氢、C1-C3烷基、烯丙基或炔丙基;
R8是氢、C1-C3烷基或C3-C6环烷基,其中R7+R8一起可以成为-CH2CH2-O-CH2CH2-或-(CH2)k-,其中k可以是3、4或5;
R9是氢、C1-C3烷基或C1-C3酰基;
R10是氢或C1-C3烷基;
R4还可以是如下式的结构:
其中:
R11可以是H、C1-C3烷基或C1-C2酰基;
R12可以是H、C1-C3烷基、OH或OCH3,其中R11和R12一起也可以成为C1-C2亚烷基桥,并可任选由甲基单取代或二取代;
R13可以是H、C1-C3烷基、芳基、杂环芳基、苄基、C1-C4烷氧羰基、C1-C4酰基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R14可以是H或C1-C4烷基;
R15可以是H或CH3或苯基;
R16可以是H或CH3或苯基;
R17可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O,也可通过CH2;
Z可以是O或S;
A是氢、卤素、甲基、氰基、硝基,或与R1一起形成如下结构的桥:
可以是R-或S-构型。
这些化合物适于作为人类药物及兽药的活性化合物,所述兽药包括医治或预防鱼类的细菌感染的药物。
式(Ⅰ)的优选化合物为:其中:
R1是乙基、异丙基、环丙基、乙烯基、叔丁基、2-羟乙基、2-氟乙基、氨基、甲基氨基、苯基、4-氟苯基或2,4-二氟苯基;
R2是氢、C1-C3烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R3是C1-C3烷基;
R4是如下式的取代的基团,并且在其环系中任选由甲基所取代:
其中:
E是R5-N、O或S;
G是
j是1、2或3;
R5是氢、C1-C3烷基、链烯基或链炔基,并且任选由羟基、苄基所取代,该苄基又任选由硝基、氨基或C2-C4氧代烷基所取代;
R6是氢或甲基;
R4还可以是如下式的基团:
其中:
l是0、1或2;
m是1或2,其中p+m一起可以是1、2或3;
n是1或2;
X1是
、OR9、氟、氯或C1-C2烷基;
X2和X3可以相同或不同,并且是氧、硫或N-CH3;
R7是氢、C1-C2烷基或乙酰基;
R8是氢或C1-C2烷基;
其中R7+R8一起还可以是如下基团:-CH2CH2-O-、-CH2CH2-或-(CH2)k-,其中k可以是3、4或5;
R9是氢、C1-C2烷基或乙酰基;
R10是氢或C1-C2烷基;
R4还可以是如下结构的基团:
其中:
R11可以是H、C1-C3烷基或C1-C2酰基;
R12可以是H、C1-C3烷基、OH或OCH3,其中R11和R12一起也可以成为C1-C2亚烷基桥,并可任选由甲基单取代或二取代;
R13可以是H、C1-C3烷基、苯基、苄基、C1-C4烷氧羰基、C1-C2酰基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R14可以是H或C1-C2烷基;
R15可以是H或CH3;
R16可以是H或CH3;
R17可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O或者通过CH2;
Z是O;
A是H、氟、氯、甲基、氰基或硝基,或者可与R1形成如下结构的桥:
包括R-或S-构型。
按式(Ⅰ)特别优选的化合物为:
其中:
R1是乙基、乙烯基、叔丁基、环丙基、2-羟乙基、2-氟乙基、甲基氨基、4-氟苯基或2,4-二氟苯基;
R2是氢或C1-C2烷基;
R3是C1-C3烷基;
R4是如下式的基团,并且任选在环系中由甲基取代:
其中:
E是R5-N;
G是-(CH2)j-;
j是1或2;
R5是氢、C1-C3烷基、链烯基或链炔基,并任选由羟基、苄基所取代,该苄基又任选由硝基、氨基或C2-C4氧代烷基所取代;
R6是氢或甲基;
R4还可以是如下式的基团:
其中:
l是0、1或2;
m是1或2,其中p+m一起可以是1、2或3;
n是1;
X1是
、OR9、氯或甲基;
X2和X3可以相同或不同,并且是氧或N-CH3;
R7是氢或甲基;
R8是氢或甲基;
R9是氢或甲基;
R10是氢或甲基;
R4还可以是如下结构的基团:
其中:
R11可以是H、C1-C2烷基或乙酰基;
R12可以是H或C1-C2烷基,其中R11和R12还可以一起成为C1-C2亚烷基桥,并可任选由甲基所取代;
R13可以是H、C1-C2烷基、羟乙基、苄基、C1-C4烷氧羰基或C1-C2酰基;
R14可以是H或CH3;
R15可以是H或CH3;
R16可以是H或CH3;
R17可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O或通过CH2;
Z可以是O,
A是H、氟或氯,或与R1一起而成为如下结构的桥
包括R-或S-构型。
此外,进一步发现当将式(Ⅱ)化合物与式(Ⅲ)化合物反应,并在适当的酸清除剂存在下并将在R4处所含的适当保护基除去后,可得到式(Ⅰ)化合物
其中:
R1、R2、R3和A如前述定义;
X4是卤素,特别是氟或氯,
R4如前述定义。
例如,若使用1-环丙基-6,7,8-三氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸以及1-甲基-八氢吡咯并〔3,4-b〕吡啶作为起始物质,则反应历程可由以下反应式表示:
例如,若使用8-氯-1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸以及3-乙基氨基甲基-3-羟基吡咯烷酮作为起始物质,则反应历程可由以下反应式表示:
例如,若使用1-环丙基-7-(2,7-二氮杂二环〔3.3.0〕辛-7-基)-6-氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸以及乙醇/氯化氢作为起始物质,则反应历程可由以下反应式表示:
用作为起始物质的式(Ⅱ)化合物为已知化合物,或可由已知方法制备。可提出的实例如下:
1-环丙基-6,7,8-三氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸;8-氯-1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸;1-环丙基-6,7-二氟-1,4-二氢-5,8-二甲基-4-氧代-3-喹啉羧酸;1-乙基-6,7,8-三氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸;1-环丙基-6,7,8-三氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸乙酯;8-氯-1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸乙酯;
6,7-二氟-1-(4-氟苯基)-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸;
6,7-二氟-1-(2,4-二氟苯基)-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸。
7-氯-1-环丙基-6,8-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸是未知物质,它可以按下述路线制备:
DABCO=1,4-二氮杂二环〔2.2.2〕辛烷
具下式结构的式Ⅲ化合物为已知物质(EP-PS 230274):
有一些用作为起始物质并具以下结构的式Ⅲ化合物是新的化合物:
它们可以通过多种方法制备:
1.将氮原子被保护的螺-环氧乙烷(1)〔J.Med.Chem.30,222(1987);USP 4508724;EP-PS 189370〕与胺(2)反应,发生开环作用而得羟胺(3)。除掉保护基得到式(Ⅲa)的起始化合物:
R18=COO烷基或CH2C6H5
2.该琥珀酸酯(4)〔Tetrahedron Letters 46,4561(1973)〕与苄胺的环化作用,得到1-苄基-3-羟基-5-氧代-吡咯烷-3-羧酸烷基酯(5),然后与胺(2)反应,得到酰胺(6)。然后用LiAlH4还原,然后用氢解断开该苄基,得到如式(Ⅲb)的起始物质:
3.(1-苄基-3-羟基-2,5-二氧代-吡咯烷-3-基)-乙酸(7)〔Gazz.Chim.Ital.24,226(1894)〕经反应后得到酰胺(8),然后用LiAlH4还原并除去苄基,得到如式(Ⅲc)的起始物质:
4.3-羟基-3-甲基吡咯烷可由LiAlH4还原4-羟基-4-甲基-吡咯烷-2-酮〔Zh.Org.Khim.14,7,p.1420(1978)〕来制备,或通过1-苄基-3-羟基-3-甲基吡咯烷(EP 132845)脱苄基来制备。
5.从环状氧代胺(9)(在氮处用保护基封闭)起始,可以合成得到式(Ⅲd)、(Ⅲe)、(Ⅲf)的起始物质〔Acta Chem.Scand.B 34,319(1980)〕。
6.可将羟基胺(Ⅲa)-(Ⅲe)的羟基进行烷基化或卤化。
7.从环状氧代胺(9)可以制备酮缩醇、硫代酮缩醇或胺醛〔Helv.Chim.Acta 50,1289(1967)〕。
由螺环氧乙烷(氮原子被保护)(1)与氰化三甲基甲硅烷反应〔J.Amer.Chem.Soc.104,5849(1982)〕,可制备异腈(14),经水解并除去保护基,可得式(Ⅲg)的起始化合物:
可以提出的式(Ⅲ)起始化合物实例如下,可以使用其手性化合物,可以是外消旋物或纯的对映体物质:
3-氨甲基-3-羟基-吡咯烷;
3-乙酰基氨甲基-3-羟基-吡咯烷;
3-叔丁氧羰基氨甲基-3-羟基-吡咯烷;
3-羟基-3-甲基氨甲基-吡咯烷;
3-乙基氨甲基-3-羟基-吡咯烷;
3-羟基-3-丙基氨甲基-吡咯烷;
3-乙基氨甲基-3-甲氧基-吡咯烷;
3-乙氧基-3-乙基氨甲基-吡咯烷;
3-氯-3-乙基氨甲基-吡咯烷;
3-乙基氨甲基-3-氟-吡咯烷;
3-乙基氨甲基-3-甲基-吡咯烷;
3-乙基氨甲基-3-巯基-吡咯烷;
3-乙基氨甲基-3-甲硫基-吡咯烷;
3-乙酰氧基-3-乙基氨甲基-吡咯烷;
3-二甲基氨甲基-3-羟基-吡咯烷;
3-羟基-3-吡咯烷子基甲基-吡咯烷;
3-羟基-3-吗啉代甲基-吡咯烷;
3-氨基-3-乙基氨甲基-吡咯烷;
3-乙酰氨基-3-乙基氨甲基-吡咯烷;
3-二甲基氨基-3-乙基氨甲基-吡咯烷;
3-氨基-3-羟甲基-吡咯烷;
3-乙酰氨基-3-羟甲基-吡咯烷;
3-氨基-3-甲氧基甲基-吡咯烷;
3-叔丁氧羰基氨基-3-甲氧基甲基-吡咯烷;
3-氨基-3-甲硫基甲基-吡咯烷;
3-氨基-3-巯基甲基-吡咯烷;
3-环丙基氨甲基-3-羟基-吡咯烷;
3-异丙基氨甲基-3-羟基-吡咯烷;
1,4-二氧杂-7-氮杂螺〔4.4〕壬烷;
1-氧杂-4,7-二氧杂螺〔4.4〕壬烷;
4-甲基-1-氧杂-4,7-二氮杂螺〔4.4〕壬烷;
1-硫杂-4,7-二氮杂螺〔4.4〕壬烷;
1,4,7-三氮杂螺〔4.4〕壬烷;
1,4-二甲基-1,4,7-三氮杂〔4.4〕壬烷。
有些用作为起始物质并具有如下结构的式Ⅲ化合物也是新的。它们可按下述方法制备:
1.从N-被护的3,4-环氧吡咯烷(1)起始(German Offenlegungsschrift 1929237,USP 4254135),其中可任选带有一或二个甲基或苯基,从而制得式(Ⅲa)-(Ⅲe)的起始物质:
R18=苄基、酰基、烷氧羰基、苄氧羰基、三烷基甲硅烷基或磺酰基(保护基的实例);
X=离去基团,如卤素、烷基或芳基磺酰氧基:
2.使用2-(1,2-二氯乙基)环氧乙烷经下述反应序列得到式(Ⅲm)的起
3.向N-苄基马来酰亚胺(任选由一或二个甲基或苯基取代)加合叠氮化物,得到式(Ⅲn)的起始物质:
R19=H、烷基或苄基。
4.用3,4-环氧吡咯烷(1),由亚硫酰二氯进行环化反应,得到式(Ⅲo)的起始化合物:
5.使用3,4-环氧吡咯烷(1),由乙醇胺进行分子内醚化作用,得到式(Ⅲp)
6.使用氨基乙醛二甲基乙缩醛,经过分子内1,3-偶极环加合反应,得到式(Ⅲq)的起始化合物:
7.从N-苄基-吡啶-2,3-二羧酰亚胺开始,通过下述反应步骤得到式(Ⅲr)或式(Ⅲl)起始化合物:
8.将N-苄基马来酰亚胺加合2-氯乙胺,得到3-(2-氯乙基氨基)琥珀酰亚胺,然后反应得到式(Ⅲt)的起始化合物:
9.将2-甲基-2-丙烯醛二甲基腙与N-苄基马来酰亚胺反应,得一种环状加合物,然后按下列反应序列得到式(Ⅲu)的起始化合物:
按照上述一般反应路线,可以制备以下起始化合物实例。可制成并使用它们的非对映体混合物、非对映体纯物质以及对映体纯物质:
4-氨基-3-羟基吡咯烷;
3-羟基-4-甲基氨基吡咯烷;
4-二甲基氨基-3-羟基吡咯烷;
4-乙基氨基-3-羟基吡咯烷;
3-氨基-4-甲氧基吡咯烷;
4-甲氧基-3-甲基氨基吡咯烷;
3-二甲基氨基-4-甲氧基吡咯烷;
3-乙基氨基-4-甲氧基吡咯烷;
3-氨基-4-乙氧基吡咯烷;
4-乙氧基-3-甲基氨基吡咯烷;
3-二甲基氨基-4-乙氧基吡咯烷;
4-乙氧基-3-乙基氨基吡咯烷;
3-羟基-4-羟氨基吡咯烷;
3-羟基-4-甲氧基氨基吡咯烷;
3-羟氨基-4-甲氧基吡咯烷;
4-甲氧基-3-甲氧基氨基吡咯烷;
4-苄氨基-4-甲氧基吡咯烷;
4-甲氧基-3-((5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基氨基)吡咯烷;
3-氨基-4-甲基巯基吡咯烷;
3-乙酰氧基-4-二甲基氨基吡咯烷;
3-乙酰氨基-4-甲氧基吡咯烷;
4-甲氧基-3-甲氧羰基氨基吡咯烷;
3-甲酰氨基-4-甲氧基吡咯烷;
3-氨基-4-甲氧基-2-甲基吡咯烷;
3-氨基-4-甲氧基-5-甲基吡咯烷;
4-甲氧基-2-甲基-3-甲基氨基吡咯烷;
4-甲氧基-5-甲基-3-甲基氨基吡咯烷;
3-氨基-4-甲氧基-2-苯基吡咯烷;
4-甲氧基-3-甲基氨基-5-苯基吡咯烷;
3-甲基-2,7-二氮杂二环〔3.3.0〕辛烷;
4-甲基-2,7-二氮杂二环〔3.3.0〕辛烷;
5-甲基-2,7-二氮杂二环〔3.3.0〕辛烷;
3,5-二甲基-2,7-二氮杂二环〔3.3.0〕辛烷;
1,5-二甲基-2,7-二氮杂二环〔3.3.0〕辛烷;
2-氧杂-4,7-二氮杂二环〔3.3.0〕辛烷;
3,3-二甲基-2-氧杂-4,7-二氮杂二环〔3.3.0〕辛烷;
3-氧杂-2,7-二氮杂二环〔3.3.0〕辛烷;
1,2-二甲基-3-氧杂-2,7-二氮杂二环〔3.3.0〕辛烷;
2,5-二甲基-3-氧杂-2,7-二氮杂二环〔3.3.0〕辛烷;
2,8-二甲基-3-氧杂-2,7-二氮杂二环〔3.3.0〕辛烷;
5-甲基-3-氧杂-2,7-二氮杂二环〔3.3.0〕辛烷;
2-氧杂-4,7-二氮杂二环〔3.3.0〕辛-3-烯;
3-甲基-2-氧杂-4,7-二氮杂二环〔3.3.0〕辛-3-烯;
3-苯基-2-氧杂-4,7-二氮杂二环〔3.3.0〕辛-3-烯;
6-甲基-2-氧杂-4,7-二氮杂二环〔3.3.0〕辛-3-烯;
8-甲基-2-氧杂-4,7-二氮杂二环〔3.3.0〕辛-3-烯;
3-甲基-2,8-二氮杂二环〔4.3.0〕壬烷;
4-甲基-2,8-二氮杂二环〔3.3.0〕壬烷;
5-甲基-2,8-二氮杂二环〔3.3.0〕壬烷;
6-甲基-2,8-二氮杂二环〔3.3.0〕壬烷;
3-甲基-2-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
4-甲基-2-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
1-甲基-2-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
3,5-二甲基-2-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
2-硫杂-5,8-二氮杂二环〔4.3.0〕壬烷;
5-甲基-2-硫杂-5,8-二氮杂二环〔4.3.0〕壬烷;
3,5-二甲基-2-硫杂-5,8-二氮杂二环〔4.3.0〕壬烷;
3-氧杂-2,8-二氮杂二环〔4.3.0〕壬烷;
2-甲基-9-氧杂-2,8-二氮杂二环〔4.3.0〕壬烷;
4-甲基-3-氧杂-2,8-二氮杂二环〔4.3.0〕壬烷;
2,5-二甲基-3-氧杂-2,8-二氮杂二环〔4.3.0〕壬烷;
3-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
5-甲基-3-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
1,5-二甲基-3-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷;
4,4-二甲基-3-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷。
在(Ⅱ)与(Ⅲ)反应时,化合物(Ⅲ)亦可以其盐酸盐形式使用,该反应最好在一种稀释剂中进行,反用稀释剂例如有二甲基亚砜、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、六甲基磷酰胺、环丁砜、乙腈、水、一种醇如甲醇、乙醇、正丙醇或异丙醇、乙二醇单甲醚或吡啶。也可使用这些稀释剂的混合物。
可以使用的酸脱除剂是一切常见的无机和有机酸结合剂。优选的有碱金属氢氧化物、碱金属碳酸盐、有机胺和脒。其中特别适用的有: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〕十一碳-7-烯(DBU)或过量胺(Ⅲ)。
反应温度可在广范围内变化。一般,采用约20-200℃反应温度,优选为80-180℃。
可在常压进行反应,但也可以加压反应。一般,反应是在约1-100巴压力进行,优选为1-10巴之间。
在进行本发明的反应时,每摩尔羧酸(Ⅱ)使用1-15摩尔,优选为1-6摩尔化合物(Ⅲ)。
在反应过程中,可用适当的羟基保护基将自由羟基保护起来,例如可用四氢吡喃基,反应完毕后,再将保护基除掉(见J.F.W.McOmie,Protective Groups in Organic Chemistry(1973)p.104)。
在反应过程中,可用适当的氨基保护基团来保护自由的氨基官能团,例如可用乙氧羰基或叔丁氧羰基,反应完毕后用适当的酸处理而将保护基除去,例如用盐酸或三氟乙酸(见HoubenWeyl,Methoden der organischen Chemie,volume E4,p.144(1983);J.F.W.McOmie,Protective Groups in Organic Chemistry(1973),p.43)。
按本发明制备该种酯时,优选是将其基础酸在过量醇中在强酸存在下反应,所用强酸如硫酸、无水氯化氢、甲磺酸、对甲苯磺酸、酸性离子交换树脂;反应温度约20-200℃,优选为约60-120℃。反应所产生的水亦可用共沸蒸馏法除掉,可用氯仿、四氯化碳、苯或甲苯。
制备该酯的另一方法是将其基础酸在溶剂如二甲基甲酰胺中与二甲基甲酰胺二烷基乙缩醛一起加热。
用作为药物前体的(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基的酯可由该基础酸的碱金属盐在一种溶剂中与4-溴甲基-或4-氯甲基-5-甲基-1,3-二氧杂环戊二烯-2-酮反应,所用溶剂如二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜或四甲基脲,温度为0至约100℃,优选为0-50℃。
按本发明的化合物的酸加合盐的制备是采用常规方法,例如将该甜菜碱溶解于过量的含水酸中,并使用与水混溶的有机溶剂如甲醇、乙醇、丙酮或乙腈使该盐沉淀。亦可将当量的甜菜碱和酸在水中或醇例如乙二醇单甲醚中加热,然后蒸发至干,或用抽滤法分出沉淀的盐。适用于药物的盐例如有盐酸、硫酸、乙酸、乙醇酸、乳酸、琥珀酸、柠檬酸、洒石酸、甲磺酸、4-甲苯磺酸、半乳糖醛酸、葡糖酸、embonic酸、谷氨酸、天冬氨酸的盐。
按本发明的羧酸的碱金属或碱土金属盐的制备例如可将该甜菜碱溶解于少于当量量的碱金属或碱土金属氢氧化物溶液,过滤分出未溶解的甜菜碱并将滤液蒸发至干。适用于药物的盐有钠、钾或钙盐。制备相应的银盐是将碱金属或碱土金属盐与适当的银盐如硝酸银反应而得。
除在各实例中提到的活性化合物之外,亦可制备表1中例举的各化合物,这些化合物的存在形式可以是非对映体混合物,也可以是非对映体纯化合物或对映体纯化合物。
本发明的化合物除显示低毒性外,还显示广谱抗菌性质,包括革兰
氏阳性和革兰氏阴性菌,特别是抗肠杆菌科细菌;还能抗那些对各种抗生素如青霉素、头孢子菌素、氨基葡萄糖苷、磺胺和四环素有抗药性的细菌。
这些有用性质使之适用于作为药物中的化学治疗活性化合物,也可用作无机和有机物料的防腐物质,特别是用于各类有机物料如聚合物、润滑剂、染料、纤维、皮革、纸、木材、食品、水。
按本发明的化合物对广谱的微生物有活性。在它们辅助下可以防治革兰氏阳性菌、革兰氏阴性菌和类菌微生物,并可预防、医治、减轻由这些病原引起的疾病。
按本发明的化合物对细菌和类菌微生物的活性特别强。因此特别适用于人类药物和兽药,用以预防和化学治疗由这些病原引致的局部和全身感染。
例如,可以治疗和/或预防由下列病原或病原混合体所引致的局部和/或全身疾病:革兰氏阳性球菌,例如葡萄球菌(Staph.aureus,Staph.epidermidis)和链球菌(Strept.agalactiae,Strept.faecalis,Strept.pneumoniae,Strept.pyogenes);革兰氏阴性球菌(Neisseria gonorrhoeae)以及革兰氏阴性杆菌,如肠杆菌科,如埃希氏大肠杆菌、流感嗜血杆菌、Citrobacter(Citrob.freundii,Citrob.divernis)、沙门氏菌属以及志贺氏菌属;还包括克雷白氏杆菌属(Klebs.pneumoniae,Klebs.oxytoca)、肠杆菌(Ent.aerogenes,Ent.agglomerans)、Hafnia、沙雷氏菌属(Serr.marcescens)、变形杆菌属(Pr.mirabilis,Pr.rettgeri,Pr.vulgaris)、Providencia、Yersinia;还包括Acinetobacter类。此外,其抗菌谱还包括假单孢菌属(Ps.aeruginosa,Ps.maltophilia)以及厌氧菌类,例如脆弱拟杆菌、Peptococcus类、Peptostreptococcus以及梭状芽孢杆菌类;还有支原菌属(M.pneumoniae,M.hominis,M.urealyticum)以及分支杆菌属,例如结核
分支杆菌。
上述各种病原仅作为举例,并非限定其范围。由上述病原或由其混合感染所引致并可由本发明的化合物进行预防、治疗或减轻的疾病,例如有:人类传染病,例如耳炎、咽炎、肺炎、腹膜炎、肾盂肾炎、膀胱炎、心内膜炎、全身性感染、支气管炎(急性、慢性)、脓毒性感染、上呼吸道疾病、扩散性全毛细支气管炎、肺气肿、痢疾、肠炎、肝脓肿、尿道炎、***炎、***、胃肠道感染、骨及关节感染、胆囊纤维变性、皮肤感染、手术后伤口感染、脓肿、蜂窝织炎、伤口感染、烧伤部位感染、烫伤、口腔部位感染、牙科手术后感染、骨髓炎、脓毒性关节炎、胆囊炎、腹膜及阑尾炎、胆管炎、腹内脓肿、胰腺炎、窦炎、乳突炎、乳腺炎、扁桃体炎、斑疹伤寒、脑膜炎及神经***感染、输卵管炎、子***、生殖器感染、***炎、眼部感染。
除可治疗人类疾病外,还可医治其他种属的细菌感染,例如:猪:大肠下痢、肠毒血症、脓毒病、痢疾、沙门氏杆菌病、***炎-子官炎-无乳症症状、***炎;
反 动物(牛、羊、山羊):下痢、脓毒病、支气管肺炎、沙门氏杆菌病、巴氏杆菌病、枝原体病、生殖器感染;
马:支气管肺炎、关节病、产期及产后感染、沙门氏杆菌病;
狗及猫:支气管肺炎、下痢、皮炎、耳炎、尿道感染、***炎;家禽(鸡、火鸡、鹌鹑、鸽、观赏鸟类等):枝原体病、埃希氏大肠杆菌感染、慢性呼吸道疾病、沙门氏杆菌病、巴氏杆菌病、鹦鹉热。
也可以治疗产业和观赏鱼类养育中遇到的细菌疾病,其抗菌谱超出前面提到的病原,例如还包括巴氏菌属、布鲁氏菌属、Campylobacter、李斯忒氏菌属、丹毒丝菌属、棒状杆菌属、包柔氏螺旋体属、密螺旋体属、诺卡氏菌属、立克次氏体属、耶尔赞氏体属。
本发明还包括药物配制剂,其中含有按本发明的一种或多种化合物,
或是含有一种或多种本发明的活性化合物以及无毒性、惰性的适于药用的赋形剂,还包括生产这些配制剂的方法。
本发明还包括制成单位剂量的药物配制剂。即该配制剂制成单个份量的形式,例如片剂、糖衣片剂、胶囊、药丸、栓剂及安瓿,其中的活性化合物含量相当于单次剂量的分数或倍数。在单位剂量中例如可含有1、2、3或4个单次剂量,或是1/2、1/3或1/4的单次剂量。一个单次剂量最好是含有每日给药剂量的全部、其半量、其三分之一量或四分之一量。
适用的无毒、惰性药用赋形剂包括任何类型的固态、半固态或液态稀释剂、填充剂或制剂辅助剂。
优选的药物配制剂包括片剂、糖衣片剂、胶囊、药丸、颗粒剂、栓剂、溶液、悬浮液、乳状液、糊剂、油膏、凝胶、软膏、洗剂、粉剂、喷剂。
片剂、糖衣片剂、胶囊、药丸和颗粒剂中除含有活性化合物外,可含有惯用的赋形剂,例如(a)填充剂和增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇、二氧化硅;(b)粘合剂,如羧甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮;(c)保湿剂,如甘油;(d)崩解剂,如琼脂、碳酸钙、碳酸钠;(e)阻溶解剂,如石蜡;(f)吸收促进剂,如季铵化合物;(g)润湿剂,如十六醇、甘油单硬脂酸酯;(h)吸附剂,如高岭土、膨润土;(i)润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、固态聚乙二醇,或是从(a)到(i)各类物质的混合物。
这些片剂、糖衣片剂、胶囊、药丸和颗粒剂可以带有惯用的含遮光剂的包衣和外壳,并且可以使之延迟释放活性化合物,使之只在肠道中或部分在肠道中释放,例如可以使用聚合物和蜡类作为嵌入物料。
还可以应用上述一种或多种赋形剂将活性化合物制成微粒包封的形式。
栓剂中除含有活性化合物外,可含有惯用的水溶性或不溶性赋形剂,例如用聚乙二醇、脂肪、例如可可脂和高级酯类(例如C16脂肪酸与C14醇所成的酯),或这些物质的混合物。
油膏、糊剂、膏剂和凝胶中除含有活性化合物外,可含有惯用的赋形剂,如动植物脂肪、蜡类、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧烷、膨润土、二氧化硅、滑石粉、氧化锌,或这些物质的混合物。
粉剂和喷剂中除含有活性化合物外,可含有惯用的赋形剂,例如乳糖、滑石粉、二氧化硅、氢氧化铝、硅酸钙、聚酰胺粉末,或使用这些物质的混合物。喷剂中还可含有惯用的推进剂,如氯氟代烃类。
溶液剂如乳状液剂中除含有活性化合物外,可含有惯用的赋形剂,如溶剂、加溶剂、乳化剂,例如水、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、油料特别是棉子油、花生油、玉米芽油、橄榄油、蓖麻油、芝麻油、甘油、甘油缩甲醛、四氢呋喃醇、聚乙二醇、失水山梨醇脂肪酸酯,或这些物质的混合物。
在非肠道给药时,亦可将溶液和乳状液剂制成无菌和血液等渗形式的。
悬浮液剂中除含有活性化合物外,可含有惯用的赋形剂,例如液体稀释剂,如水、乙醇、丙二醇、悬浮剂如乙氧基化的异硬脂醇、聚氧亚乙基山梨糖醇和失水山梨醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、黄蓍胶,以及这些物质的混合物。
上述各种形式的配制剂中还可含有着色料、防腐剂以及气味及味道改进添加剂,例如薄荷油、桉叶油,以及甜味剂例如糖精。
在前述的药物制剂中,治疗用活性化合物的优选含量范围为占全体混合物的约0.1-99.5%(重量),最好约0.5-95%(重量)。
上述的药物制剂中,除含有本发明的化合物之外还可含有其他药物活性化合物。
可采用惯用方法制备上述的药物制剂,例如将活性化合物与赋形剂混合到一起。
上述的制剂可用于人类和动物,约药方式可以是口服、直肠给药、非肠道(静脉、肌内、皮下)、脑池内、***内、腹膜内、局部(粉剂、油膏、滴剂)给药,用于治疗中空空间和体腔内的感染。适用的制剂有注射液、口服治疗的溶液和悬浮液、凝胶、倾注用制剂、乳液剂、油膏或滴剂。在局部治疗方面,可用眼科及皮肤科制剂、银盐及其他盐、耳滴剂、眼用油膏、粉剂或溶液。在兽医方面,可通过饲料或饮水将适当制剂给药。此外,凝胶、粉剂、片剂、延迟释放片剂、预混合剂、浓缩剂、颗粒剂、丸粒、boli、胶囊、气溶胶、喷剂、吸入剂均可用于人类和动物。此外,按本发明的化合物可以加入到其他赋形物质例如塑料(用于局部治疗的塑料链)、胶原或骨粘合剂中。
一般,业已证明在人类药物及兽药中,本发明活性化合物的适宜给药量是每24小时每千克体重约0.5-500毫克,优选为5-100毫克,并可分为数次给药,从而可达到期望的结果。在单次剂量中,本发明活性化合物优选含量为每千克体重约1-80毫克,最好3-30毫克。但是,也可能不按上述剂量,这取决于所治疗患者的类别和体重,疾病特点及严重程度,制剂的类型,药物的给药量以及给药的时间间隔。
因此在某些情况下使用低于上述的剂量已足够,而另一些情况下必须超过上述的剂量。每种病况下最适宜剂量和给药类型很容易由本领域技术人员根据其专业知识作出决定。
可以将本发明的新化合物以惯用浓度和制剂形式加入到饲料或配成饲料中,或加入到饮用水中。这样就可以预防、治疗和/或减轻革兰氏阴性或革兰氏阳性菌的感染,并可促进生长和改进饲料利用效率。
通过对等敏感试验(iso-sensitest)琼脂(Oxoid)用系列稀释法测定最低抑制浓度(MIC)。对于每种受试物质准备一系列琼脂板,其中含活性化合物的浓度按双倍稀释序列。使用多点接种器(Denley)将各琼脂板接种。在接种时,采用病原过夜培养,该病原事先以如下方式稀释,使每一接种点含有约10菌落形成颗粒。将接种后的琼脂板于37℃培育,约20小时后,检定细菌生长结果。MIC值(微克/毫升)是指用肉眼观察不到细菌生长的活性化合物最低浓度。
实例A
7-氯-1-环丙基-6,8-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸
将8.0克1-环丙基-5,6,7,8-四氟-1,4-二氢-4-氧代-3-喹啉羧酸和7.9毫升亚硫酰二氯一起煮沸,至无气体逸出为止。将混合物于真空中浓缩,向剩余物中加入50毫升乙醇,将混合物煮沸2小时。冷却至室温,分离出沉淀的固体物。
收得:8.6克 7-氯-1-环丙基-5,6,8-三氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯,
熔点:166-168℃。
将1.6毫升(0.015摩尔)氰基乙酸乙酯加入到50毫升无水二噁烷中,并于20℃加入0.58克氢化钠(按80%浓度物料计)。30分钟后,加入3.45克(0.01摩尔)实例A(a)的物质。将混合物煮沸回流6小时。冷却至20℃,用水稀释,用盐酸酸化。分离出固体物,干燥,从异丙醇中重结晶。
收得:2.3克7-氯-5-(氰基乙氧基羰基甲基)-1-环丙基-6,8-二氟-1,4-二氢-4-氧代-3-喹啉羧酸乙酯,
熔点:156-157℃。
将2.3克实例A(b)物质与6毫升乙酸、5毫升水和0.5毫升硫酸于140℃一起加热4小时。混合物冷却至20℃并用水稀释。分出固体物,用水洗涤,干燥。
收得:1.6克5-羧甲基-7-氯-1-环丙基-6,8-二氟-1,4-二氢-4-氧代-3-喹啉羧酸,
熔点:236-238℃(分解)。
元素分析:
计算值:C 50.3 H 3.0 N 3.9 Cl 9.9
实测值:50.5 3.2 3.7 10.0
50.6 3.2 3.8 9.9
将1.0克(2.8毫摩尔)实例A(c)物质和0.9克(8.4毫摩尔)1,4-二氮杂二环〔2.2.2〕辛烷于20毫升二甲基亚砜中于140℃加热3小时。然后高真空除去溶剂,剩余物用硅胶色谱分离(洗脱:二氯甲烷/甲醇=99/1)。
收得:0.2克7-氯-1-环丙基-6,8-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸,
熔点:195-197℃。
实例1
将0.56克(2毫摩尔)1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸与0.384克(3毫摩尔)2,8-二氮杂二环〔4.3.0〕壬烷和0.672克(6毫摩尔)1,4-二氮杂二环〔2.2.2〕辛烷在3.5毫升二甲基亚砜中加热至140℃历时2小时。冷却后,用高真空除去DMSO。用乙腈溶取剩余物。分离出固体物,用乙腈洗涤,于60-80℃干燥。
收得:0.7克 1-环丙基-7-(2,8-二氮杂二环〔4.3.0〕壬-8-基)-6-氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸,
熔点:174-176℃,分解。
实例2
将0.28克(1毫摩尔)1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸与0.19克(1.5毫摩尔)2-氧杂-5,8-二氮杂二环〔4.3.0〕壬烷及0.34克(3毫摩尔)1,4-二氮杂二环〔2.2.2〕辛烷在3.5毫升二甲基亚砜中于140℃加热2小时。用高真空脱除二甲基亚砜。剩余物与乙腈一起搅拌,分离出固体物。
收得:0.27克 1-环丙基-6-氟-1,4-二氢-5-甲基-7-(2-氧杂-5,8-二氮杂二环〔4.3.0〕壬-8-基)-4-氧代-3-喹啉羧酸,
熔点:273-275℃。
实例3
将0.14克(0.5毫摩尔)1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸与0.084克(0.75毫摩尔)2,7-二氮杂二环〔3.3.0〕辛烷及0.17克(1.5毫摩尔)1,4-二氮杂二环〔2.2.2〕辛烷于3.5毫升二甲基亚砜中于140℃加热2小时。高真空脱除二甲基亚砜,向剩余物加入乙腈,形成固体物。
收得:0.15克 1-环丙基-7-(2,7-二氮杂二环〔3.3.0〕辛-7-基)-6-氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸,
熔点:232-234℃,分解。
实例4
将0.28克(1毫摩尔)1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸与0.213克(1.5毫摩尔)5-甲基-3-氧代-5,8-二氮杂二环〔4.3.0〕壬烷和0.34克(3毫摩尔)1,4-二氮杂二环〔2.2.2〕
辛烷于3.5毫升二甲基亚砜中于140℃加热2小时。用高真空脱除溶剂,剩余物与乙腈一同搅拌,得到0.22克 1-环丙基-6-氟-1,4-二氢-5-甲基-7-(5-甲基-3-氧代-5,8-二氮杂二环〔4.3.0〕壬-8-基)-4-氧代-3-喹啉羧酸。
熔点:208-210℃,分解。
实例5
将0.28克(1毫摩尔)1-环丙基-6,7-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸与0.17克(1.5毫摩尔)1,4-二氮杂二环〔3.2.1〕辛烷及0.34克(3毫摩尔)1,4-二氮杂二环〔2.2.2〕辛烷于3.5毫升二甲基亚砜中于140℃加热2小时。高真空脱除溶剂后,将剩余物与乙腈一同搅拌,分离出固体物。
收得:0.24克 1-环丙基-7-(1,4-二氮杂二环〔3.2.1〕辛-4-基)-6-氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸,
熔点:274-276℃,分解。
实例B
6,7-二氟-1-(2,4-二氟苯基)-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸
将21克 3-乙氧基-2-(2,4,5-三氟-6-甲基苯甲酰)丙烯酸乙酯加入到55毫升乙醇中,冷却条件下滴加入9.4克 2,4-二氟苯胺。混合物于25℃搅拌1小时,加入55毫升水,分离出沉淀的固体物。
收得:25克 3-(2,4-二氟苯基氨基)-2-(2,4,5-三氟-6-甲基苯甲酰)丙烯酸乙酯,
熔点:109-110℃。
将12.5克实例B(a)物质和5.1克碳酸钾在60毫升二甲基甲酰胺中于140℃加热4小时。混合物冷却至室温后,用水稀释。分离沉淀的固体物并干燥。
收得:11.3克 6,7-二氟-1-(2,4-二氟苯基)-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸乙酯,
熔点:157-159℃。
11.2克实例B(b)物质、70毫升乙酸、70毫升水及3.5毫升硫酸于140℃加热4小时。混合物冷却至室温后,用水稀释,分出固体物并干燥,得10.3克本标题化合物,熔点:277-278℃。
实例6
将0.6克实例B物质、0.57克1,4-二氮杂二环〔2.2.2〕辛烷和0.25克2,8-二氮杂二环〔4.3.0〕壬烷于6毫升二甲基亚砜中于室温搅拌,直至用薄层色谱法检测不到起始物质为止。将混合物真空浓缩,向剩余物中加入水,分离出固体物。
收得:0.6克7-(2,8-二氮杂二环〔4.3.0〕壬-8-基)-1-(2,4-二氟苯基)-6-氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸,
熔点:247-248℃。
Claims (8)
1、按下列式(I)的喹诺酮羧酸衍生物,以及它们的适于药用的水合物及酸加合盐,以及其基础酸的碱金属盐、碱土金属盐、银盐以及
盐:
其中:
R1是直链或支链C1-C4烷基,并可任选由羟基、卤素、C1-C3烷氧基或C1-C3烷硫基、C3-C9环烷基所取代,该C3-C9环烷基又可任选由卤素、C1-C3烷基、C1-C4链烯基所取代,还包括C1-C3烷氧基、氨基、C1-C3单烷基氨基、C2-C6二烷基氨基、苯基,该苯基还可任选由卤素取代;
R2是氢、C1-C4烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R3是C1-C4烷基;
R4是如下列的基团,并在环系中任选由羟基或甲基所取代:
其中:
E是R5-N、O或S;
G是
-(CH2)j-,-CH2-O-CH2-,
j是1、2或3;
R5是氢、C1-C4烷基、链烯基或链炔基并任选由羟基、苄基所取代,该苄基又可任选由硝基或氨基、C2-C4氧代烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基所取代;
R6是氢或甲基;
R4还可以是如下式所表示的基团:
其中:
l是0、1或2;
m是1或2,其中p+m可以是1、2或3;
n是1或2;
X2和X3可以相同或不同,并且是氧、硫、NH或N-CH3;
R7是氢、C1-C3烷基、烯丙基或炔丙基;
R8是氢、C1-C3烷基或C3-C6环烷基,其中R7+R8一起可以成为
-CH2CH2-O-CH2CH2-或-(CH2)k-,其中k可以是3、4或5;
R9是氢、C1-C3烷基或C1-C3酰基;
R10是氢或C1-C3烷基;
R4还可以是如下式的结构:
其中:
R11可以是H、C1-C3烷基或C1-C2酰基;
R12可以是H、C1-C3烷基、OH或OCH3,其中R11和R12一起也可以成为C1-C3亚烷基桥,并可任选由甲基单取代或二取代;
R13可以是H、C1-C3烷基、芳基、杂环芳基、苄基、C1-C4烷氧羰基、C1-C4酰基或(5-甲基-2-氧代1,3-二氧戊环-4-基)甲基;
R14可以是H或C1-C4烷基;
R15可以是H或CH3或苯基;
R16可以是H或CH3或苯基;
R17可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O,也可通过CH2;
Z可以是O或S;
A是氢、卤素、甲基、氰基、硝基,或与R1一起形成如下结构的桥:
可以是R-或S-构型。
2、按权利要求1的式(Ⅰ)化合物,
其中:
R1是乙基、异丙基、环丙基、乙烯基、叔丁基、2-羟乙基、2-氟乙基、氨基、甲基氨基、苯基、4-氟苯基或2,4-二氟苯基;
R2是氢、C1-C3烷基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R3是C1-C3烷基;
R4是如下式的取代的基团,并且在其环系中任选由甲基所取代:
其中:
E是R5-N、O或S;
G是
j是1、2或3;
R5是氢、C1-C3烷基、链烯基或链炔基,并且任选由羟基、苄基所取代,该苄基又任选由硝基、氨基或C2-C4氧代烷基所取代;
R6是氢或甲基;
R4还可以是如下式的基团:
其中:
l是0、1或2;
m是1或2,其中p+m一起可以是1、2或3;
n是1或2;
X2和X3可以相同或不同,并且是氧、硫或N-CH3;
R7是氢、C1-C2烷基或乙酰基;
R8是氢或C1-C2烷基;
其中R7+R8一起还可以是如下基团:-CH2CH2-O-、-CH2CH2-或-(CH2)k-,
其中k可以是3、4或5;
R9是氢、C1-C2烷基或乙酰基;
R10是氢或C1-C2烷基;
R4还可以是如下结构的基团:
其中:
R11可以是H、C1-C3烷基或C1-C2酰基;
R12可以是H、C1-C3烷基、OH或OCH3,其中R11和R12一起也可以成为C1-C2亚烷基桥,并可任选由甲基单取代或二取代;
R13可以是H、C1-C3烷基、羟烷基、苯基、苄基、C1-C4烷氧羰基、C1-C2酰基或(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基;
R14可以是H或C1-C2烷基;
R15可以是H或CH3;
R16可以是H或CH3;
R16可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O或者通过CH2;
Z是O;
A是H、氟、氯、甲基、氰基或硝基,或者可与R1形成如下结构的桥:
包括R-或S-构型。
3、按权利要求1的式(Ⅰ)化合物,
其中:
R1是乙基、乙烯基、叔丁基、环丙基、2-羟乙基、2-氟乙基、甲基氨基、4-氟苯基或2,4-二氟苯基;
R2是氢或C1-C2烷基;
R3是C1-C3烷基;
R4是如下式的基团,并且任选在环系中由甲基取代:
其中:
E是R5-N;
G是-(CH2)j-;
j是1或2;
R5是氢、C1-C3烷基、链烯基或链炔基,并任选由羟基、苄基所取代,该苄基又任选由硝基、氨基或C2-C4氧代烷基所取代;
R6是氢或甲基;
R4还可以是如下式的基团:
其中:
l是0、1或2;
m是1或2,其中p+m一起可以是1、2或3;
n是1;
X2和X3可以相同或不同,并且是氧或N-CH3;
R7是氢或甲基;
R8是氢或甲基,其中R7+R8一起可以成为-CH2CH2-O-CH2CH2-或-(CH2)k-,其中k可以是3、4或5;
R9是氢、C1-C3烷基或C1-C3酰基;
R10是氢或C1-C3烷基;
R4还可以是如下结构的基团:
其中:
R11可以是H、C1-C2烷基或乙酰基;
R12可以是H或C1-C2烷基,其中R11和R12还可以一起成为C1-C2亚烷基桥,并可任选由甲基所取代;
R13可以是H、C1-C2烷基、羟乙基、苄基、C1-C4烷氧羰基或C1-C2酰基;
R14可以是H或CH3;
R15可以是H或CH3;
R16可以是H或CH3;
R17可以是H或CH3;
Y可以是O、CH2、CH2CH2或CH2-O,其中CH2-O基团与氮的连接可以通过O或通过CH2;
Z可以是O,
A是H、氟或氯,或与R1一起而成为如下结构的桥
包括R-或S-构型。
4、权利要求1中式(Ⅰ)化合物的制备方法,其特征在于将下列式(Ⅱ)化合物:
其中:
R1、R2、R3和A与权利要求1所述定义相同,
X4是卤素,特别是氟或氯,
与下列式(Ⅲ)化合物进行反应:
其中:
R4按权利要求1所述定义,
该反应是在酸清除剂存在下进行,并除掉R4上所带的保护基。
5、将按权利要求1的式(Ⅰ)化合物应用于治疗人类或动物疾病的方法中。
6、含有按权利要求1的式(Ⅰ)化合物的药物制剂。
7、应用按权利要求1的式(Ⅰ)化合物生产药物制剂。
8、7-氯-1-环丙基-6,8-二氟-1,4-二氢-5-甲基-4-氧代-3-喹啉羧酸。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP3910663.2 | 1989-04-03 | ||
DE3910663A DE3910663A1 (de) | 1989-04-03 | 1989-04-03 | 5-alkylchinoloncarbonsaeuren |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1046162A true CN1046162A (zh) | 1990-10-17 |
CN1035945C CN1035945C (zh) | 1997-09-24 |
Family
ID=6377683
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN90101902A Expired - Fee Related CN1035945C (zh) | 1989-04-03 | 1990-04-02 | 5-烷基喹诺酮羧酸衍生物的制备方法 |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0391132A1 (zh) |
JP (1) | JP3046035B2 (zh) |
KR (1) | KR0156245B1 (zh) |
CN (1) | CN1035945C (zh) |
AU (1) | AU638005B2 (zh) |
CA (1) | CA2013449C (zh) |
DD (1) | DD298400A5 (zh) |
DE (1) | DE3910663A1 (zh) |
FI (1) | FI901615A0 (zh) |
HU (2) | HUT58056A (zh) |
IL (1) | IL93954A0 (zh) |
NO (1) | NO173547C (zh) |
NZ (1) | NZ233142A (zh) |
PH (1) | PH27364A (zh) |
PT (1) | PT93639A (zh) |
ZA (1) | ZA902510B (zh) |
Cited By (1)
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CN1073112C (zh) * | 1996-02-23 | 2001-10-17 | 拜尔公司 | 任选取代的8-氰基-1-环丙基-7-(2,8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸及其衍生物 |
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US4920120A (en) * | 1988-01-25 | 1990-04-24 | Warner-Lambert Company | Antibacterial agents |
MY105136A (en) * | 1988-04-27 | 1994-08-30 | Daiichi Seiyaku Co | Optically active pyridonecarboxylic acid derivatives. |
DD285601A5 (de) * | 1988-07-15 | 1990-12-19 | Bayer Ag,De | Verfahren zur herstellung von 7-(1-pyrrolidinyl)-3-chinolon- und naphthyridoncarbonsaeure-derivaten |
US5177210A (en) * | 1989-04-17 | 1993-01-05 | Bayer Aktiengesellschaft | Preparation of 2,7-diazabicyclo(3.3.0)octanes |
US5241076A (en) * | 1989-04-17 | 1993-08-31 | Bayer Aktiengesellschaft | 1,4-diazatricyclo [6.3.0.0]undecanes |
DE59009705D1 (de) * | 1989-04-17 | 1995-11-02 | Bayer Ag | Verfahren zur Herstellung von 2,7-Diazabicyclo(3.3.0)octanen. |
WO1992021659A1 (en) * | 1991-05-28 | 1992-12-10 | Daiichi Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivative |
DE4120646A1 (de) * | 1991-06-22 | 1992-12-24 | Bayer Ag | 7-isoindolinyl-chinolon- und naphthyridoncarbonsaeure-derivate |
TW209865B (zh) * | 1992-01-10 | 1993-07-21 | Bayer Ag | |
KR960003611B1 (ko) * | 1992-07-23 | 1996-03-20 | 재단법인 한국화학연구소 | 신규한 디아자비시클로 알켄 유도체 및 그의 제조방법 |
DE4234078A1 (de) * | 1992-10-09 | 1994-04-14 | Bayer Ag | Chinoloncarbonsäuren |
DE4234330A1 (de) * | 1992-10-12 | 1994-04-14 | Bayer Ag | Chinoloncarbonsäuren |
CA2112165C (en) * | 1992-12-25 | 2003-04-08 | Makoto Takemura | Bicyclic amine derivatives |
AU4272793A (en) * | 1993-04-24 | 1994-11-21 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and process for preparing the same |
DE4329600A1 (de) * | 1993-09-02 | 1995-03-09 | Bayer Ag | Pyrido [1,2,3-d,e] [1,3,4] benzoxadiazinderivate |
DE4339134A1 (de) * | 1993-11-16 | 1995-05-18 | Bayer Ag | 1-(2-Fluorcyclopropyl)-chinolon- und -naphthyridoncarbonsäure-Derivate |
DE4408212A1 (de) * | 1994-03-11 | 1995-09-14 | Bayer Ag | 5-Vinyl- und 5-Ethinyl-chinolon- und -naphthyridon-carbonsäuren |
DE19546249A1 (de) * | 1995-12-12 | 1997-06-19 | Bayer Ag | Neue Kristallmodifikation des 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluor-1,4-dihydro-8-methoxy-4-oxo-3-chinolincarbonsäure Hydrochlorid (CDCH), Verfahren zu dessen Herstellung und diese enthaltende pharmazeutische Zubereitungen |
DE19633805A1 (de) * | 1996-02-23 | 1997-08-28 | Bayer Ag | Gegenenenfalls substituierte 8-Cyan-l-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]-nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäuren und ihre Derivate |
DE19652239A1 (de) * | 1996-12-16 | 1998-06-18 | Bayer Ag | Verwendung von 7-(2-Oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-chinolon- und -naphthyridoncarbonsäure-Derivaten zur Therapie von Helicobacter-pylori-Infektionen und den damit assoziierten gastroduodenalen Erkrankungen |
DE19854356A1 (de) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation A von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-/4.3.0/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
DE19854357A1 (de) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Semi-Hydrochlorid von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo/4.3.0/ -nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
DE19854355A1 (de) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
CA2498291C (en) | 2002-09-10 | 2009-04-07 | Pfizer Products Inc. | Diazabicyclic compounds useful in the treatment of cns and other disorders |
EP1666477B1 (en) | 2003-09-10 | 2013-07-03 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-substituted 3- cyclopropylaminomethyl-1- pyrrolidinyl) q uinolonecarboxylic acid derivative |
WO2008143343A1 (ja) | 2007-05-24 | 2008-11-27 | Kyorin Pharmaceutical Co., Ltd. | 14位置換基に複素芳香環カルボン酸構造を有するムチリン誘導体 |
CN101718743B (zh) * | 2009-11-30 | 2013-03-20 | 宁波大学 | 一种混合导体致密扩散障型氧传感器的制备方法 |
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DE3522405A1 (de) * | 1985-06-22 | 1987-01-02 | Bayer Ag | 1,8-verbrueckte 4-chinolon-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende arzneimittel und ihre verwendung zur herstellung von arzneimitteln |
DE3543513A1 (de) * | 1985-12-10 | 1987-06-11 | Bayer Ag | Enantiomerenreine 1,8-verbrueckte 4-chinolon-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende arzneimittel und ihre verwendung zur herstellung von arzneimitteln |
DE3601567A1 (de) * | 1986-01-21 | 1987-07-23 | Bayer Ag | 7-(azabicycloalkyl)-chinoloncarbonsaeure- und -naphthyridon-carbonsaeure-derivate |
DE3702393A1 (de) * | 1987-01-28 | 1988-08-11 | Bayer Ag | 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo- 3-chinolincarbonsaeuren, verfahren zu ihrer herstellung und diese enthaltende antibakterielle mittel |
US5563138A (en) * | 1987-04-16 | 1996-10-08 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
US4920120A (en) * | 1988-01-25 | 1990-04-24 | Warner-Lambert Company | Antibacterial agents |
-
1989
- 1989-04-03 DE DE3910663A patent/DE3910663A1/de not_active Withdrawn
-
1990
- 1990-03-20 NO NO901274A patent/NO173547C/no not_active IP Right Cessation
- 1990-03-21 EP EP90105293A patent/EP0391132A1/de not_active Withdrawn
- 1990-03-28 JP JP2077135A patent/JP3046035B2/ja not_active Expired - Lifetime
- 1990-03-28 AU AU52317/90A patent/AU638005B2/en not_active Ceased
- 1990-03-30 FI FI901615A patent/FI901615A0/fi not_active Application Discontinuation
- 1990-03-30 CA CA002013449A patent/CA2013449C/en not_active Expired - Fee Related
- 1990-03-30 NZ NZ233142A patent/NZ233142A/en unknown
- 1990-03-30 IL IL93954A patent/IL93954A0/xx unknown
- 1990-04-02 DD DD90339323A patent/DD298400A5/de not_active IP Right Cessation
- 1990-04-02 ZA ZA902510A patent/ZA902510B/xx unknown
- 1990-04-02 PT PT93639A patent/PT93639A/pt not_active Application Discontinuation
- 1990-04-02 CN CN90101902A patent/CN1035945C/zh not_active Expired - Fee Related
- 1990-04-03 KR KR1019900004548A patent/KR0156245B1/ko not_active IP Right Cessation
- 1990-04-03 PH PH40321A patent/PH27364A/en unknown
- 1990-04-03 HU HU912263A patent/HUT58056A/hu unknown
- 1990-04-03 HU HU902055A patent/HU204811B/hu not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1073112C (zh) * | 1996-02-23 | 2001-10-17 | 拜尔公司 | 任选取代的8-氰基-1-环丙基-7-(2,8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1,4-二氢-4-氧代-3-喹啉羧酸及其衍生物 |
Also Published As
Publication number | Publication date |
---|---|
ZA902510B (en) | 1991-01-30 |
DE3910663A1 (de) | 1990-10-04 |
PH27364A (en) | 1993-06-21 |
NO173547B (no) | 1993-09-20 |
AU638005B2 (en) | 1993-06-17 |
IL93954A0 (en) | 1990-12-23 |
FI901615A0 (fi) | 1990-03-30 |
CA2013449A1 (en) | 1990-10-03 |
JP3046035B2 (ja) | 2000-05-29 |
NO901274D0 (no) | 1990-03-20 |
AU5231790A (en) | 1990-10-04 |
DD298400A5 (de) | 1992-02-20 |
CN1035945C (zh) | 1997-09-24 |
HU912263D0 (en) | 1991-12-30 |
NZ233142A (en) | 1992-09-25 |
JPH02289583A (ja) | 1990-11-29 |
KR0156245B1 (ko) | 1998-11-16 |
NO901274L (no) | 1990-10-04 |
KR900016186A (ko) | 1990-11-12 |
HU204811B (en) | 1992-02-28 |
HUT56563A (en) | 1991-09-30 |
CA2013449C (en) | 2001-01-02 |
EP0391132A1 (de) | 1990-10-10 |
PT93639A (pt) | 1990-11-20 |
HU902055D0 (en) | 1990-08-28 |
NO173547C (no) | 1993-12-29 |
HUT58056A (en) | 1992-01-28 |
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