• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a quinoline derivative of the formula wherein Z is an amino group or a halogen atom, R, is a hydrogen atom or a methyl or ethyl group, R2 is a hydrogen atom or a methyl or fluoromethyl group, R3 and R4 are the same or different and each represents a hydrogen atom or a methyl group, and n is 1 or 2; and esters thereof and salts thereof and processes for preparation thereof. These compounds show excellent antibacterial activity and are useful antibacterial agents.
    公开号:SU1635898A3
    申请号:SU874203544
    申请日:1987-10-27
    公开日:1991-03-15
    发明作者:Мацумото Юн-Ичи；Миямото Теруюки；Эгава Хироси；Накамура Синичи
    申请人:Дайниппон Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    Stage (2). The above compound (28 g) was dissolved in dry tetrahydrofuran and allowed to react with 60% sodium hydride (3.85 g) at room temperature to obtain 1-cyclopropyl-5,6,7,8-tetrafluoro-ethyl ester 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (18.4 g), m.p. 17 (L71 ° C.
    Stage (3). The above compound (10 g) was hydrolyzed by heating under reflux the compound in a mixture with glacial acetic acid (60 ml), water (500 ml) and concentrated sulfuric acid (7 ml) for 30 minutes to obtain 1-cyclopropyl- 5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (8.7 g), m.p. 181-182 ° C.
    PRI me R 2.
    Preparation of 5-benzyl-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. A mixture of the product (28.2 g) obtained in Example 1 (step (2)), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g) and acetonitrile (140 ml) is heated at 100-110 ° C in for 1 h, 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester is obtained (21.4 g), which is recrystallized ethanol, m.p. 134-135 ° C.
    Example 3: 5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    (1) 5-Beneyl-1-cyclopropyl-b, 7,8-trifluoro-1,4-dihydro-4-oxo-inolin-3-carboxylic acid ethyl ester (20 g) is dissolved in acetic acid (100 g ml) and ethanol (150 ml) and the mixture is subjected to hydrogenolysis in the presence of 5% palladium on carbon (0.5 g) to obtain 5-amino-1-cyclopropyl-6,7,8-trifluoro-1 ethyl ester, 4-dihydro-4-oxoquinoline-3-carboxylic acid (14.1 g), which is recrystallized from a mixture of chloroform and ethanol, m.p. 236-237 ° C.
    (2) A mixture of the above compound (12.6 g), acetic acid (80 ml), water (50 ml) and concentrated sulfuric acid (9 ml) is heated at 100-110 ° C for 40 minutes to obtain 5-amino -1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.1 g), which is recrystallized from a mixture of chloroform and ethanol, m.p. 294-295 ° C.
    Example 3: Preparation of 7- (4-acetyl-3-methyl-1-piperazinyl) -5-amino-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-5-carboxy new acid:
    A mixture of 5-amino-1-cyclopropyl-6, 7.8, trifluoro-1 .4-dihydro-4-oxoquinol and n-3 carboxylic acid (1.25 g). 1-acetyl-2-methylpiperazine (2.0 g) and pyridine (13 ml) are heated at 105-110 ° C for 1 h with stirring. The reaction mixture is evaporated to dryness under reduced pressure and to a residue
    water is added. The mixture is extracted with chloroform and the extract is dried. After evaporation of the chloroform, ethanol is added to the residue. The resulting crystals are filtered and recrystallized from a mixture of chloroform and ethanol,
    0 to obtain 7- {4-acetyl-3-methyl-1-piperazinyl) -5-amino-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 258-260 ° C.
    PRI me R 4.
    Preparation of 5-amino-1-cyclo5 propyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1.4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.
    A mixture of the compound obtained in Example 3 (1.26 g) and a 20% aqueous solution of sodium hydroxide with ethanol was heated under reflux for 12 hours. The reaction mixture was treated with activated carbon and adjusted to pH 1-2 with 10% hydrochloric acid. After cooling
    5, the resulting crystals are filtered and recrystallized from a mixture of water and ethanol to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-di-hydro-4 hydrochloride -oxoquinoline-3-carboxylic acid
    0 (1.12 g). M.p. more than 300 ° C. PRI me R 4.
    Preparation of 5-amino-1-cyclop role of l-6,8-difluoro-7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carbonic acid .
    By the same method as described in example 3, a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-ethoxy-carbonyl 0 3- methyl piperazine and dimethyl sulfoxide are stirred at 150 ° C for 2 hours to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethoxycarbonyl-2-methyl-1-piperazinyl) -1 , 4-dihydro-4-oxoquinoline-35 carboxylic acid, m.p. 220-225 ° C. PRI me R 5.
    Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (2-methyl-1-piperazinyl) -1,4-di-hydro-4-oxoquinoline-3-carboxylic acid.
    0Hydrolize according to the method described in
    example 2, and then the reaction mixture is neutralized. The resulting crystals are filtered and recrystallized from acetonitrile to obtain 5-amino-15 cyclopropyl-6,8-difluoro-7- (2-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-car - boom acid; M.p. 224-226 ° C. PRI me R 6.
    Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-6enzyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    According to the method described in Example 3, with the difference that instead of 1-acetyl-2-methyl-piperazine 1-benzyl-piperazine is used, 5-amino-1-cyclopropyl-b, 8-difluoro-7- (4- benzyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-8-carboxylic acid,
    Example.
    Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    Reduce catalytically in the presence of 5% palladium on carbon in a mixture of acetic acid and ethanol to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4 -oxoquinoline-3-carboxylic acid; M.p. 263-264 ° C.
    Example
    Preparation of 5-benzylamino-1-cyclopropyl-b, 8-difluoro-7- (4-methyl-1-piperaoinyl) -1.4-dihydro-4-oxoquinoline-3-carboxylic acid.
    A mixture of 1-cyclopropyl-5,6,8-trifluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxocoquinoline-3-carboxylic acid (1.0 g), benzylamine (420 mg) and pyridine (5 ml) are heated at 100-110 ° C for 3 hours. The reaction mixture is evaporated to dryness under reduced pressure. After water was added to the residue, the mixture was acidified with 10% aqueous acetic acid and extracted with chloroform. The extract is dried and evaporated. The resulting crystals are recrystallized from a mixture of ethanol and ether to obtain 5-benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -, 4-dihydro-4-oxoquinoline -3-carboxylic acid (730 mg), mp mp 133-133 ° C.
    PRI me R 9.
    Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-di-hydro-4-oxoquinoline-3-carbonic acid.
    A mixture of 5-benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-hydroxy-4-oxoquinoline-3-carboxylic acid (700 mg), 5% palladium on carbon (0.2 g), acetic acid (10 ml) and ethanol (15 ml) were stirred at room temperature for 30 minutes under a stream of hydrogen. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. After adding water to the residue, the mixture is adjusted to pH 8 with aqueous ammonia. The resulting crystals are filtered to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 510 mg), m.p. 254-255 ° C.
    I'll try it on.
    Preparation of 1-cyclopropyl-5-ethoxy-carbonyl-amino-6,8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-di-5-hydroxy-4-oxoquinoline ethyl ester 3-carboxylic acid,
    According to the method described in Example 3, 1-cyclopropyl-5-ethoxycarbonylamino-6,7,8-trifluoro-1,4-dihydro-4-10 oxoquinoline-8-carboxylic acid ethyl ester (T. 189- 190 ° C) is reacted with 2-methylpiperazine to obtain 1-cyclopropyl-5-ethoxycarbonyl-amino-6,8-difluoro-7- (3-methyl-1-pipera-5 zinyl) -1 ethyl ester, 4-dihydro-4-oxoquinoline-3-carboxylic acid. EXAMPLE
    Preparation of 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-methyl-1-pipera-0-zinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.
    A mixture of ethyl 1-cyclopropyl-5-ethoxycarbonylamino-b, 8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxo 5 quinoline-3-carboxylic acid, 20% the aqueous sodium hydroxide and ethanol is heated under reflux for 12 hours. The reaction mixture is treated with activated carbon and adjusted to pH 1-2 with 10% hydrochloric acid. After cooling, the resulting crystals are collected by filtration and recrystallized from a mixture of water and ethanol to obtain 5-amino-1-cyclo-5-propyl-6,8-difluoro-7- (3-methyl-1-piperazinyl-yl) hydrochloride 1.4-dihydro-4-oxoquinoline-3-carboxylic acid, T. square more than 300 ° C. PRI me R 12.
    Preparation of 5-acetylamino-1-cyclopro-0-Dil-6,8-difluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carbonic acid.
    According to the method described in example 3,
    5-acetylamino-1-cyclopropyl-6,7,8-trif5 tor-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (MP. 247-248 ° C) is subjected to
    interaction with 1-formyl piperazine,
    to obtain 5-acetylamino-1-cyclopropyl-6, 8-difluoro-7- (4-formyl-1-piperazylnyl) -1.4-dihydro-4-oxoquinoline-3-carboxylic acid.
    PRI me R 13.
    Preparation of 5-amino-1-cyclopropyl-6.8-difluoro-7- (1-piperazinyl) -1, 5 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.
    5 - Acetylamino-1-cyclopropyl-6,8-di, -fluoro-7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid
    treated according to the method described in
    Example 6 to obtain 5-amino-1-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. more than 300 ° C
    The chemotherapeutic activities of the compounds of the invention are presented in examples 8-11, described above. Tested compounds include:
    Compound 1: 5-amino-1-cyclopropyl-6.8-difluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    Compound 2: 5-amino-1-cyclopropyl-b, 8-difluoro-7- {3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    Compound 3: 5-amino-1-cyclopropyl-b, 8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    Compound 4: 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    Compound 5: 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid;
    compound 6; 5-amino-1-cyclopropyl-b, 8-difluoro-7- (3-fluoromethyl-1-piperaoinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    Compound 7: 1-cyclopropyl-5,6,8-trifluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (product of example 11);
    Compound 8: 1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydro-4-hydroxyquinoline-3-carboxylic acid (Example 12);
    compound 9; 1-cyclopropyl-5,6.8-trifluoro-7- (3,5-dimethyl-1-pyrazinyl} -1,4-dihydro-4-hydroxyquinoline-3-carboxylic acid (Example 13):
    Compound A: 5-amino-1-ethyl-6,8-difluoro-7- (1-piperazinyl) -114-dihydro-4-oxoquinoline-3-carboxylic acid.
    MH20 F. J A, COOH
    HNO F -,
    Example 14.C2H5
    5-amino-1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    1) 7- (4-Acetyl-cis-3,5-dimethyl-1-piperazinyl) -5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3- carboxylic
    the acid was treated in the same manner as in Example 2, and 5-amino-1-cyclopropyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl) hydrochloride was obtained; -1.4 -dihydro-oxoquinoline-3-carboxylic acid, mp, 300 ° C.
    2) This compound was dissolved in water and the solution was neutralized with 10% aqueous ammonia to give 5-amino-1-cyclo-propyl-6,8-difluoro-7- (cis-3,5-dimethyl-1-piperazinyl ) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 258-260 ° C. EXAMPLE 15 5-Amino-1-cyclopropyl-6,8-difluoro-75 (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    5-Benzylamino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was
    0 was treated in the same manner as described in Example 5, and 5-amino-1-cyclopropyl-6,8-difluoro-7- (4-ethyl--1-piperazinyl) -1,4-dihydro- was obtained. 4-oxoquinol-in-3-carboxylic acid. M.p. 236-237 ° C.
    5P rime 16.
    5-amino-1-cyclopropyl-b, 8-difluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    7- (4-Acetyl-3-fluoromethyl-1-piperazin0 yl) -5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was hydrolyzed by the same as described in example 2, and then the reaction mixture was neutralized. The obtained crystals were filtered and 5-amino-1-cyclopropyl-6,8-difluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained, mp . 237-238 ° C.
    0Example17.
    1-Cyclopropyl-5,6,8-trifluoro-7- (1-piperazinyl) -, 4-dihydro-4-oxoquinoline-3-carboxylic acid.
    1) A mixture of 1-cyclopropyl-5.6,8-trifluoro-5 7- (4-formyl-1-piperazinyl) -1,4-dihydro-4oxoquinoline-3-carboxylic acid (0.5 g) and 15% salt Acidic acid (15 ml) was stirred at 90-100 ° C for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure and the crystals formed were recrystallized from water to obtain 1-cyclopropyl-5,6,8-trifluoro-7- { 1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.25 g), m.p.
    5 270-280 ° C (directly).
    2) The above compound (150 mg) was dissolved in water (5 ml) and the pH was adjusted to 7-8 with 10% aqueous ammonia. The resulting crystals are filtered, washed with water and dried to obtain 1-cyclopropyl-5,6.8-trifluoro-7- (1-pylerasinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (140 mg), T .pl. 208-213 ° C.
    PRI me R 18.
    1 -Cyklop ropyl-5, b, 8-trifluoro-7- (3-met-yl-1 -piperazinyl) -, 4-dihydro-4-oxoquinoline-3-carboxylic acid.
    7- (4-Acetyl-3-methyl-1-piperazinyl) -1-cyclone ropil-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is treated in the same manner as described in Example 11 (1), (2), to obtain 1-cyclopropyl-5,6,8-trifluoro-7- (3-methyl-1-piperazinyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid , M.p. 235-237 ° C.
    PRI me R 19.
    1-Cyclopropyl-5,6,8-trifluoro-7- (cis-3, 5-dimethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    1-Cyclopropyl-5,6.8-trifluoro-7- (4-form l-cis-3,5-dimethyl-1-pip srazn yl) - 1,4-dihydro-4-oxoquinoline-3-carboxylic acid treated in the same manner as described in Example 11 (1), (2) to obtain 1-cyclopropyl-5, b, 8-trifluoro-7- (cis-3.5-dimethyl--1-piperazinyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 259 260 ° C.
    Example 20
    1-Cyclop ropyl-5.6,8-trifluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxocoquinoline-3-carboxylic acid.
    A mixture of 1-cyclop ropyl-5.6.8-trifluoro-7- (3-fluoromethyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, potassium carbonate and water is stirred at room temperature for 3 hours. The pH of the reaction mixture is adjusted to 7-8 using acetic acid and the resulting crystals are filtered off. Recrystallization from chloroform gives 1-cyclopropyl-5,6,8-trifluoro-7- (3-fluoromethyl-1-piperazinyl) -1, 4-dihydro-4-ocg, oquinoline-3-carboxylic acid, T mp. 219-220 ° C
    PRI me R 21.
    The in vitro antibacterial activity is presented in Table. 1. The numbers in the table. Figure 1 shows the minimum inhibition concentrations (MKIs) (and g / ml) calculated for the free base. The minimum inhibition concentration was determined using a twofold agar dilution method using Mueller-Hinton agar. One loop of the culture of the test microorganisms expressed overnight in a liquid Müller-Hinton medium was inoculated onto ten milliliter agar layers in petri dishes containing the drug. The bacterial inocula contains approximately 10 colony-forming units. Bacterial growth was observed after 20 h of growth at 37 ° C. MKI was defined as a lower 5 drug concentration that prevents visible bacterial growth. Observation:
    for 14 days in the case of Staphylococcus aureus 505774 and 10 Streptococcus pneumoniae: 1 Neuflld; within 7 days in case of other microorganisms. Example 22
    The anti-mycoplasmic activity of Compound I is presented in Table. 3. The numbers in the table show the minimum inhibition concentrations (MKIs) (p g / ml) calculated for the free base,
    0 The minimum inhibition concentration was determined using a twofold agar method using Chenoc agar. Three microliters (ql) of the culture of the tested microorganisms 5 in the liquid medium Chanok inoculated on 10 ml agar layers containing drugs in Petri dishes. The growth of mycoplasma is observed after growing at 37 ° C under the conditions presented below. MKI is defined as the lowest concentration of the drug, which prevents the growth of mycoplasma microscopically.
    Growing conditions for Mycoplasma 5 pneumoniae
    for 7 days under aerobic conditions Mycoplasma arginlni and Acholeplasma Laidlawil;
    e for 2 days under aerobic conditions Mycoplasma hyorhlns;
    for 3 days under aerobic conditions. Other microorganisms for 2 days under anaerobic conditions. PRI me R 23.
    5 Antibacterial activity of Compound 1 against Campylobacter Jejunl is presented in Table. 4. The numbers in the table show the minimum inhibition concentration. 0P rime 24.
    In vivo efficacy against systemic infections in mice is presented in Table. 2
    Each of the compounds is dissolved in de-5 ionized water. Each of the solutions was administered orally to mice infected with each of the test microorganisms under the conditions shown below, and the average effective dose (EDZO) was calculated using a probe assay. The numbers in the table. 2 shows the EDU values (mg / kg) calculated for the free base.
    Experimental conditions.
    Mice: male mice (ddY-S) weighing approximately 20 g.
    Infections:
    Staphylococcus aureus 50774 - intravenous infection with 5 x 108 cells per mouse suspended in saline;
    Streptococcus pneumonlae 1 Neufeld - intraperitoneal infection of 3 x 10 cells per mouse suspended in a liquid medium based on brain infusion core;
    Pseudomonas aeruglnosa12 is an intraperitoneal infection with approximately 5x10 cells per mouse suspended in a tryptosium liquid medium with 4% mucin.
    Treatment:
    four times immediately 6, 24 and 30 hours after infection in the case of Streptococcus pneumonlae 1;
    twice immediately and 6 hours after infection in the case of other microorganisms.
    The minimum inhibition concentration was determined using a twofold agar dilution method using blood-containing Mueller-Hinton agar. One whole loop of the culture of the tested microorganisms in Muller-Hinton liquid medium is inoculated onto a ten milliliter layer of agar containing the drug in petri dishes. Bacterial growth is observed after 48 hours of growth at 37 ° C under microaerobic conditions, MKI is defined as the lowest concentration of drug that prevents visible bacterial growth.
    PRI me R 25 (acute toxicity).
    A solution containing each of compounds 1, 2 and 3 according to the invention in various concentrations is orally administered to male mice (ddY) at a dose of 0.1 ml per 10 g of live weight. The number of dead mice was counted after 7 days, and the average lethal dose (1 dbo. Mg / kg) was calculated according to the Beckrens-Caber method.
    The results are presented in table. five.
    From the results presented in table. 5, it can be seen that the compounds 1, 2, 3, 7, 8 and 9 according to the invention have low oral toxicity and can be classified as low toxic;
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing quinoline derivatives of the formula;
     L o
    F X / COOH
    where Z is an amino group or halogen;
    A - halogen or a group of General formula
    R
    R Yach
    where Ri is a hydrogen, methyl or ethyl group;
    R2 is hydrogen, methyl or fluoromethyl group;
    Yaz and R4 are the same or different each hydrogen or methyl group, provided that Z and A are not simultaneously halogen atoms, or pharmaceutically acceptable esters, or their pharmaceutically acceptable salts of these derivatives or esters, characterized in that in the compound of the formula Z o
    F JOCCOOY
    where Z is an amino group, a halogen or a protected amino group;
    A - halogen or a group of General formula
    R4L R,
    NR:
    X
    ; 3
    where RI is a hydrogen, methyl or ethyl group, or an amino-SHT group, provided that at least either Z is a protected amino group or RI is an amino-protecting group; hydrogen or lower alkyl;
    R2, R3 and R4 are as defined, the protecting groups are removed to isolate the desired product, where Y is lower alkyl, or to hydrolyze and isolate the desired product as an acid or a pharmaceutically acceptable salt.
    Priority signs: 29.10.85 with A - a group of the general formula
    BUT
    R3 R /,
    m
    where Ra is a methyl group;
    Ri, R2, R4 is hydrogen;
    Z is an amino group, halogen;
    12.17.85 with A - halogen, Ri, R2, Pz and RA - hydrogen; R3 is a methyl group; RI, RZ and R4 are hydrogen, RI is a methyl group; Ra, R3 and R4 are hydrogen; Z is an amino group;
    17.02.86 at RI is an ethyl group, when R2, R3, R4 is hydrogen, R3 is a methyl group, when Ri, R, R4 is hydrogen; RS and R2 is a methyl group when RI is hydrogen, R4 is hydrogen; R ' and R2 are methyl groups when Ri and R3 are hydrogen; Z is an amino group.
    Anti-bacterial activity in vitro
    In vivo efficacy against systemic infections
    in mice
    Anti-mycoplasmic activity
    Table 1
    table 2
    Table 3
    Antibacterial activity against Campylobacter Jejunl
    Acute oral toxicity in mice
    Table 4
    Table 5
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    US4720495A|1988-01-19|Benzo[ij]quinolizine-2-carboxylic acids useful for treating bacterial infection
    US4001243A|1977-01-04|Substituted benzo|quinolizine-2-carboxylic acids and derivatives thereof
    SU1456015A3|1989-01-30|Versions of method of producing derivatives of 1,8-naphthyridine or acid-additive salts thereof
    SU1519529A3|1989-10-30|Method of producing quinoline derivatives, its pharmaceutically acceptable ester or their pharmaceutically acceptable salts
    US4380543A|1983-04-19|Antimicrobial 8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acids
    US3985753A|1976-10-12|7-Hydroxy-benzo[ij]quinolizine-2-carboxylic acids and derivatives thereof
    US4348521A|1982-09-07|Substituted pyridoquinoxaline-6-carboxylic acids and derivatives thereof
    US3506668A|1970-04-14|Method of preparing 8-hydroxy-quinolines
    US4499270A|1985-02-12|Substituted pyridoquinoxaline-6-carboxylic acids and derivatives thereof
    US4524148A|1985-06-18|Antimicrobial 8,9-dihalobenzo[ij]quinolizine carboxylic acids
    US4456606A|1984-06-26|Substituted naphtho[ij]quinolizines
    同族专利:
    公开号 | 公开日
    DK170593B1|1995-11-06|
    JPH0714918B2|1995-02-22|
    LU88596I2|1995-07-10|
    DK170774B1|1996-01-15|
    YU137291A|1994-01-20|
    FI87457C|1993-01-11|
    NO170726C|1992-11-25|
    JPS62277362A|1987-12-02|
    YU183586A|1988-04-30|
    DE10075028I1|2000-12-14|
    LU90621I2|2000-10-09|
    IL80404A|1990-06-10|
    GR3002475T3|1992-12-30|
    DE3650018D1|1994-09-08|
    ES2057197T3|1994-10-16|
    NL970020I2|1998-01-05|
    IL80404D0|1987-01-30|
    CA1340402C|1999-02-23|
    AR243520A1|1993-08-31|
    NL970020I1|1997-08-01|
    US4795751A|1989-01-03|
    AR243178A1|1993-07-30|
    AU594983B2|1990-03-22|
    DE10075028I2|2004-01-29|
    PT83643A|1986-11-01|
    DE3650018T2|1995-01-05|
    EP0375658A1|1990-06-27|
    EP0221463A2|1987-05-13|
    DK514586D0|1986-10-28|
    NL300014I2|2001-02-01|
    MY100574A|1990-12-15|
    AT109472T|1994-08-15|
    HU200452B|1990-06-28|
    CN86107491A|1987-04-29|
    JPH0541633B2|1993-06-24|
    FI864299A|1987-04-30|
    SU1598873A3|1990-10-07|
    YU137191A|1994-01-20|
    EP0221463B1|1991-08-14|
    HUT43839A|1987-12-28|
    DE3680859D1|1991-09-19|
    FI87457B|1992-09-30|
    PH22862A|1989-01-19|
    YU46414B|1993-10-20|
    NZ218089A|1989-03-29|
    DK514586A|1987-04-30|
    NL300014I1|2000-10-02|
    NO864247D0|1986-10-23|
    NO864247L|1987-04-30|
    NO170726B|1992-08-17|
    DK25992A|1992-02-28|
    EP0375658B1|1994-08-03|
    CN1009930B|1990-10-10|
    EP0221463A3|1987-12-02|
    PT83643B|1988-10-14|
    AT66210T|1991-08-15|
    AU6427786A|1987-04-30|
    KR910006806B1|1991-09-02|
    DK25992D0|1992-02-28|
    AR242031A1|1993-02-26|
    ES2029786T3|1992-10-01|
    JPH0543551A|1993-02-23|
    KR870004019A|1987-05-06|
    FI864299A0|1986-10-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3753993A|1971-05-17|1973-08-21|Sterling Drug Inc|1,4-dihydro-4-oxo-7-pyridyl-3-quinoline-carboxylic acid derivatives|
    DE3033157A1|1980-09-03|1982-04-01|Bayer Ag, 5090 Leverkusen|7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM|
    JPS58174367A|1982-04-07|1983-10-13|Tanabe Seiyaku Co Ltd|Quinoline derivative and its preparation|
    DE3248507A1|1982-12-29|1984-07-05|Bayer Ag, 5090 Leverkusen|MICROBICIDE AGENTS BASED ON CHINOLONIC CARBONIC ACID|
    DE3248506A1|1982-12-29|1984-07-05|Bayer Ag, 5090 Leverkusen|1-CYCLOPROPYL-6-FLUOR-1,4-DIHYDRO-4-OXO-7 -3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS|
    DE3306771A1|1983-02-25|1984-08-30|Bayer Ag, 5090 Leverkusen|CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM|
    DE3318145A1|1983-05-18|1984-11-22|Bayer Ag, 5090 Leverkusen|7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS|
    CS274601B2|1983-07-27|1991-09-15|Dainippon Pharmaceutical Co|Method of 1,8-naphthyridine derivative production|
    JPS60169475A|1984-02-14|1985-09-02|Dai Ichi Seiyaku Co Ltd|Quinoline derivative|
    EP0160578B1|1984-02-17|1989-11-23|Daiichi Seiyaku Co., Ltd.|1,8-naphthyridine derivatives|
    US4571396A|1984-04-16|1986-02-18|Warner-Lambert Company|Antibacterial agents|
    ZA852369B|1984-04-26|1985-12-24|Abbott Lab|Quinoline antibacterial compounds|
    DE3420743A1|1984-06-04|1985-12-05|Bayer Ag, 5090 Leverkusen|7-AMINO-1-CYCLOPROPYL-6,8-DIHALOGEN-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS|
    DE3420798A1|1984-06-04|1985-12-05|Bayer Ag, 5090 Leverkusen|7- - AND 7- -3-CHINOLONIC CARBONIC ACIDS|
    JPS6110574A|1984-06-25|1986-01-18|Hokuriku Seiyaku Co Ltd|6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative|
    IE58742B1|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|
    JPS6191183A|1984-10-11|1986-05-09|Kyorin Pharmaceut Co Ltd|Quinolonecarboxylic acid derivative|
    EP0181521A1|1984-10-19|1986-05-21|Otsuka Pharmaceutical Co., Ltd.|Antimicrobial 1-substituted Phenyl-4-oxoquinoline-3-carboxylic acid compounds|
    US4636506A|1984-12-06|1987-01-13|Pfizer, Inc.|7-heterocyclic-1,4-dihydroquinolones|
    EP0191185B1|1984-12-14|1990-03-07|Daiichi Seiyaku Co., Ltd.|Quinoline-carboxylic acid derivatives|
    US4657913A|1985-04-18|1987-04-14|Warner-Lambert Company|Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents|
    JPS6259263A|1985-09-10|1987-03-14|Kyorin Pharmaceut Co Ltd|Quinolonecarboxylic acid derivative|
    US4668680A|1985-12-12|1987-05-26|Warner-Lambert Company|5-amino-6,8-difluoroquinolones as antibacterial agents|
    US4977154A|1985-12-12|1990-12-11|Warner-Lambert Company|5-amino and 5-hydroxy-6-fluoroquinolones as antibacterial agents|
    EP0230053A3|1986-01-17|1988-03-30|American Cyanamid Company|7-piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids|
    EP0242789A3|1986-04-25|1990-09-05|Dainippon Pharmaceutical Co., Ltd.|Novel quinoline derivates and processes for preparation thereof|
    GB8612137D0|1986-05-19|1986-06-25|Fujisawa Pharmaceutical Co|Quinolone compounds|US4977154A|1985-12-12|1990-12-11|Warner-Lambert Company|5-amino and 5-hydroxy-6-fluoroquinolones as antibacterial agents|
    EP0242789A3|1986-04-25|1990-09-05|Dainippon Pharmaceutical Co., Ltd.|Novel quinoline derivates and processes for preparation thereof|
    DE3711193A1|1987-04-02|1988-10-13|Bayer Ag|5-SUBSTITUTED CHINOLON AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES|
    US5591744A|1987-04-16|1997-01-07|Otsuka Pharmaceutical Company, Limited|Benzoheterocyclic compounds|
    US4780468A|1987-08-07|1988-10-25|Warner-Lambert Company|8-trifluoromethyl quinolones as antibacterial agents|
    US5164392A|1987-10-16|1992-11-17|Dainippon Pharmaceutical Co., Ltd.|Quinoline derivatives and antibacterial agent containing them|
    IL88003A|1987-10-16|1992-11-15|Dainippon Pharmaceutical Co|Quinoline derivatives,their preparation and pharmaceutical compositions containing them|
    AU609974B2|1988-05-18|1991-05-09|Warner-Lambert Company|Improved process for the preparation of 5-amino-7- -quinoline-3-carboxylic acids|
    JPH0674261B2|1988-06-21|1994-09-21|塩野義製薬株式会社|Quinolonecarboxylic acid derivative|
    JP2709604B2|1988-06-29|1998-02-04|大日本製薬株式会社|Prevention or removal of mycoplasma contamination|
    US5262417A|1988-12-06|1993-11-16|The Upjohn Company|Antibacterial quinolone compounds|
    FR2655545B1|1989-12-11|1994-06-10|Rhone Poulenc Sante|NEW THERAPEUTIC APPLICATION OF FLUOROQUINOLONE DERIVATIVES.|
    DE4019023A1|1990-06-14|1991-12-19|Bayer Ag|METHOD FOR PRODUCING CHINOLINE CARBONIC ACIDS|
    JP2613139B2|1990-07-19|1997-05-21|エスエス製薬株式会社|Quinolonecarboxylic acid derivatives|
    US5342846A|1990-12-05|1994-08-30|Synphar Laboratories, Inc.|7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid compounds and 7- 4-oxoquinoline-3-carboxylic acid derivatives useful as antibacterial agents|
    FR2681863B1|1991-09-27|1995-02-03|Rhone Dpc Europ|SOLUTION OF SPARFLOXACIN, ITS PREPARATION AND SALT CONSTITUTING IT.|
    EP0601197A4|1992-05-26|1994-10-26|Ss Pharmaceutical Co|5-aminoquinolonecarboxylic acid derivative and antibacterial containing the same as active ingredient.|
    WO1993025545A1|1992-06-09|1993-12-23|Korea Research Institute Of Chemical Technology|Novel quinoline derivatives and processes for preparing the same|
    US5290794A|1992-10-27|1994-03-01|Warner Lambert Co.|Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms|
    US5646163A|1992-10-30|1997-07-08|The Procter & Gamble Company|Quinolone 5- antimicrobials|
    CN1038326C|1993-07-20|1998-05-13|爱斯制药株式会社|5-aminoquinolone carboxylic acid derivative and antibacterial agent containing the same as active ingredient|
    US5532239A|1993-08-02|1996-07-02|Assistance Publique - Hopitaux De Paris|Therapeutic application of fluoroquinolone derivatives|
    IL143535D0|1998-12-04|2002-04-21|Influx Inc|Inhibitors of multidrug transporters|
    CA2367373C|1999-03-17|2011-09-20|Daiichi Pharmaceutical Co., Ltd.|Medicinal compositions|
    CN1091103C|1999-04-02|2002-09-18|中国科学院上海药物研究所|Compounds of carbostyrils and their preparation and use|
    US6957105B2|2002-03-26|2005-10-18|Cardiac Pacemakers, Inc.|Method and apparatus for detecting oscillations in cardiac rhythm with electrogram signals|
    KR100519158B1|2002-12-21|2005-10-06|주식회사유한양행|A process for preparation of quinolone carboxylate derivatives|
    US20070196398A1|2006-02-17|2007-08-23|Murthy Yerramilli V S|Fluoroquinolone fatty acid salt compositions|
    US7973022B2|2006-02-17|2011-07-05|Idexx Laboratories, Inc.|Fluoroquinolone carboxylic acid salt compositions|
    US20070197548A1|2006-02-17|2007-08-23|Murthy Yerramilli V S|Fluoroquinolone compositions|
    US20080139574A1|2006-11-30|2008-06-12|Cadila Healthcare Limited|Novel quinoline derivatives|
    US20200215074A1|2017-06-22|2020-07-09|Cipla Limited|Method of Treatment of Cancer|
    CN112870196B|2019-11-11|2022-02-18|山东畜牧兽医职业学院|Composition for treating drug-resistant microbial bacteria|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP24225785|1985-10-29|
    JP28532385|1985-12-17|
    JP3262786|1986-02-17|LV930260A| LV5478A3|1985-10-29|1993-04-23|Method of Acquiring Islands of Quinoline Derivatives or Pharmaceutically Acceptable Esters or Pharmaceutically Acceptable Derivatives or Esters thereof|
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