CN1091103C - Compounds of carbostyrils and their preparation and use - Google Patents
Compounds of carbostyrils and their preparation and use Download PDFInfo
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- CN1091103C CN1091103C CN99113598A CN99113598A CN1091103C CN 1091103 C CN1091103 C CN 1091103C CN 99113598 A CN99113598 A CN 99113598A CN 99113598 A CN99113598 A CN 99113598A CN 1091103 C CN1091103 C CN 1091103C
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Abstract
The present invention relates to a carbostyril compound with anti-mycoplasma activity, which can be used for resisting mycoplasmal infection.
Description
The present invention relates to the synthetic and biological activity of a class carbostyril compound, the preparation method of a class carbostyril compound and specifically as the purposes of anti-mycoplasma medicine,
Mycoplasma is the same with bacterium and virus, is a kind of common pathogenic microorganism.Mycoplasma contamination often give HUMAN HEALTH, animals and plants and RESEARCH ON CELL-BIOLOGY cause significant damage [the rear people progress of anti-mycoplasma antibiotic of Tang. external medicine-microbiotic fascicle, 1985,6:351].Human body is common eight mycoplasma species, and wherein mycoplasma pneumoniae can cause primary atypical pneumonia, and this obstinate respiratory tract disease is very big to human health damage.Mycoplasma infection also can cause non gonococcal urethritis, diseases such as rheumatoid arthritis and some Infertility, miscarriage and newborn infant's under-weight.Mycoplasma can also cause livestock, poultry and laboratory animal multiple diseases.Mycoplasma contamination in the cell cultures is an extremely general worldwide problem, and particularly passage cell cultivation [Guo Yongjun. mycoplasma contamination removes in the cell cultures.External medicine-microbiology fascicle, 1989,4:166].It is reported that the Europe positive rate that is detected of each laboratory clone in 1992 is 55%.Shoudu Inst. of Pediatrics in 1993 uses culture method and has detected domestic 77 passage cell samples, and the mycoplasma contamination rate is 49%.This pollution not only influences the growth and the metabolism of cell, can also influence the function of cell sometimes, has a strong impact on the research work of cytobiology.After entering the nineties, separate at mycoplasma, cultivate, context of detection has obtained develop rapidly, this makes people to the seriousness of mycoplasma harm darker understanding arranged, mycoplasma contamination has the trend [Kobayashi H et al.J Vet Med Sci 1996,11:1107] of rising in recent years in addition, so all attach great importance to the study on prevention of mycoplasma infection both at home and abroad.The control mycoplasma infection uses macrolide antibiotics such as erythromycin (EM), josamycin (JM), leucomycin (LM) etc. usually, and tsiklomitsin (TC) and doxycycline are also commonly used, and wherein erythromycin is the choice drug of controlling various mycoplasma contaminations.Yet bacteria-like infects the same, and mycoplasma has produced serious resistance to microbiotic such as erythromycin, and the thorny problem that this has become that the mycoplasma treatment faces is so the development of new anti-mycoplasma drug is very necessary and significant.Quinolones is a bacterium topoisomerase II specific inhibitor, discovers some quinolone medicine of new generation such as Sparfloxacin (Sparfloxacin), and the husky star of super prestige (trovafloxacin) etc. has good mycoplasma activity.
So an object of the present invention is to seek a series of active quinolone compounds of mycoplasma that have.Another purpose is their mycoplasma activity of research, to find the anti-mycoplasma drug of better effects if.A class quinolone compounds of the present invention can be used following general formula:
Wherein
R
1=CH
2CH
3, C such as cyclopropyl
1-C
5Alkyl or cycloalkyl
R
5=H, NH
2R
8=H, F
R
3=CH
3, CH
2CH
3, CH
2CHMe
2, CH
2CCl
3Deng C
1-C
5Side chain or straight-chain paraffin R
4=H, CH
3Deng C
1-C
5Side chain or straight-chain paraffin n=1,2 carbostyril compounds of the present invention mainly make through the following steps: 1 presses currently known methods, and (Domagala JM et al.J.Med.Chem.1991 is 34:1142) through some steps reaction synthetic intermediates 1～5; 2 compounds 1～5 are at pyridine, and dimethyl formamide is that the piperazine condensation of heterocyclic substituted gets the above-claimed cpd 6～16 that piperazine ring contains heterocyclic substituted with 1-position nitrogen-atoms respectively in the aprotic polar solvents such as dimethyl sulfoxide (DMSO); 3 compounds 1～5 are pressed currently known methods (Domagala JM et al.J.Med.Chem.1991,34,1142), at pyridine, dimethyl formamide, in the aprotic polar solvents such as dimethyl sulfoxide (DMSO) respectively and piperazine, the 2-methylpiperazine, bridged piperazine derivatives condensations such as high piperazine get the 7-position by quinolone compounds 17 that bridged piperazine derivatives replaced; The quinolone compounds of 4 step 3 gained and alkyl chloride manthanoate react to such an extent that the above-claimed cpd 18～35 that carbamate replaces is contained in the 7-position in alkaline aqueous solution or tetrahydrofuran (THF), chloroform, acetone equal solvent.Advantages such as carbostyril compound of the present invention has very strong mycoplasma activity, can be used as anti-mycoplasma drug, and its preparation method has the reaction conditions gentleness, and abundant raw material is easy to get, and operation and aftertreatment are easy.The present invention implements by following more detailed reactions steps: respectively with fluorochlorobenzene amine, trifluoromethyl aniline and tetrafluorobenzoic aid are that starting raw material is by currently known methods synthetic intermediate compound 1～5
Compound 1 is that the bridged piperazine derivatives of heterocyclic substituted is at pyridine with the 1-position nitrogen-atoms of 1～8 times of molar weight respectively, dimethyl formamide, in dimethyl sulfoxide (DMSO) or any suitable aprotic polar solvent in room temperature to 180 ℃ temperature range internal reaction 4～12 hours, top condition is that the mol ratio of compound 1 and bridged piperazine derivatives is 1: 2～4, refluxes 6 hours in the pyridine.The pressure reducing and steaming solvent, with chloroform, methyl alcohol, ethanol, dimethyl formamide etc. or between them the mixture of arbitrary proportion be solvent recrystallization, piperazine ring contains the above-claimed cpd 6～11 of heterocyclic substituted.
Identical with preparation compound 6～11 reaction conditionss, compound 2 and 1-position nitrogen-atoms be the bridged piperazine derivatives of heterocyclic substituted react 12～16.
Compound 1～5 is at pyridine, dimethyl formamide, in the aprotic polar solvents such as dimethyl sulfoxide (DMSO) respectively and piperazine, the 2-methylpiperazine, bridged piperazine derivatives condensations such as high piperazine get the 7-position by quinolone compounds 17 that bridged piperazine derivatives replaced;
Compound 17 is at alkaline aqueous solution such as sodium bicarbonate, yellow soda ash, potassium hydroxide, other any inorganic base aqueous solution or tetrahydrofuran (THF) such as sodium hydroxide, chloroform, methylene dichloride, ethyl acetate, in the ether isopolarity aprotic organic solvent (contain organic bases such as triethylamine etc. and make acid scavenger), reacted 1～24 hour at subzero 10 ℃ to 80 ℃ with straight or branched alkyl chloride manthanoate, acidifying, filtering-depositing or pressure reducing and steaming organic solvent, precipitation or residue ethyl acetate, ethanol, methyl alcohol, the water and the mixed solvent recrystallization of arbitrary proportion between them can get the above-claimed cpd 18～35 that 7-position amido-containing acid ester replaces.
Wherein
R
1=CH
2CH
3, C such as cyclopropyl
1C
5Alkyl or cycloalkyl
R
5＝H，NH
2
R
8＝H，F
R
3=CH
3, CH
2CH
3, CH
2CHMe
2, CH
2CCl
3Deng C
1C
5Side chain or straight-chain paraffin
R
4=H, CH
3Deng C
1C
5Side chain or straight-chain paraffin
N=1,2 structural formula of compound that the present invention relates to see Table 1.Wherein
Table 1 compound 6～16 and 18～36 structural formula numbering structural formula numbering structural formula 6
22
7
23
8
24
9
25
10
26
11
27
12
28
13
29
14
30
15
31
16
32
18
33
19
34
20
35
21
Biological activity determination:
Ordinary method is adopted in the mycoplasma determination of activity.Substratum is composed as follows: 1: 1 OX-heart Digestive system, and 0.5% sodium-chlor, 0.15% potassium primary phosphate, 10% self-control fresh yeast leach liquor, 0.002 is phenol red, 10% calf serum.U
U4Add 0.1% urea, pH=6.0 ± 0.5.Mh, Mo, Ms add 0.1% arginine, pH=6.8～7.0.The glucose serum of Mg, Mp interpolation 1% increases to 15% pH=7.6～7.8.The spiral shell substance adds 10% sucrose, pH=7.2～7.4.Minimum inhibition mycoplasma drug substrate concentration MIC (μ g/ml) adopts continuous multiple dilution method to measure.The MIC measured value sees Table 2.The mycoplasma activity of table 2 compound 6～16,18～36 and other control drug (MIC: μ g/ml)
Mycoplasma
*Sample number Uu
4Uu
8Mh Ms Mg Mgal CH-1 CR-16 0.25 0.25 0.125 0.125 1 0.031 0.5 0.57 2 0.5 2 2 ＞8 0.5 4 48 0.25 0.062 0.062 0.062 0.25 0.031 0.125 0.1259 8 4 2 2 8 1 4 810 0.25 0.125 0.062 0.062 0.5 ＜0.004 0.125 0.2511 2 0.5 1 0.5 4 0.125 1 212 0.25 0125 ＜0.004 0.031 2 0.031 1 0.513 8 8 1 1 8 0.125 4 814 0.5 0.5 4 0.062 4 0.031 0.5 0.2515 0.25 0.125 0.062 0.031 1 0.062 0.5 0.516 0.5 0.125 0.008 0.002 4 0.008 1 118 0.5 0.5 0.25 0.125 0.5 0.016 0.25 0.12519 2 0.5 1 1 8 0.25 2 220 0.5 0.25 0.125 0.25 0.5 0.031 0.125 0.12521 0.5 0.25 0.062 0.125 1 0.031 0.25 0.2522 0.5 0.5 0.25 0.25 1 0.061 0.25 0.2523 0.5 0.125 0.125 0.125 0.25 0.031 0.125 0.12524 2 1 1 1 2 0.25 1 125 0.25 0.25 0.016 0.016 1 ＜0.004 0.25 0.2526 4 1 0.125 0.125 4 0.008 2 127 0.25 0.062 0.016 0.031 2 0.031 0.25 0.528 0.5 0.25 0.008 0.25 2 ＜0.004 0.05 0.2529 2 0.5 4 2 4 0.125 1 130 4 1 ＞8 2 4 0.25 1 131 0.5 0.5 2 1 2 0.125 0.5 0.532 1 1 0.5 0.25 2 0.002 0.5 0.533 2 2 1 0.25 4 0.125 1 134 1 1 0.25 0.25 2 0.031 0.5 0.535 4 4 4 2 8 0.25 2 2CPLX 8 4 2 1 2 0.032 0.125 0.25LEVO 0.5 0.5 0.5 0.25 0.5 0.016 0.125 0.125SPLX 0.25 0.25 0.031 0.031 0.062 ＜0.004 0.062 0.125JM 0.125 0.125 0.125 0.25 0.004 ＜0.004 0.125 0.062LM 0.25 0.125 0.25 0.25 0.04 0.04 0.125 0.125Uu
4, Uu
8-ureaplasma urealyticum; Mh-mycoplasma hominis: Ms-mycoplasma salivarium; Mg-mycoplasma genitalium: Mgal-chicken virus mycoplasma; CH-1-honeybee spiral shell substance; CR-1-rape flower spiral shell substance.The CPLX-Ciprofloxacin; The LEVO-Levofloxacin; The SPLX-Sparfloxacin; The JM-josamycin; The LM-leucomycin.As known from Table 2, the related quinolone compounds of this patent has very strong mycoplasma activity, compound 8,10,18,20,23,25 etc. particularly, its specific activity Ciprofloxacin and that Levofloxacin is strong is suitable with Sparfloxacin, josamycin and cylindrulite mycin.Show the mycoplasma activity stronger for Uu and Mh chemical compound lot than Sparfloxacin, josamycin and cylindrulite mycin.The related quinolone compounds of this patent can be used for the treatment and the removing of mycoplasma infection in human body, animal, plant and the cell cultures or pollution.
Further with embodiment the present invention is described below, it does not limit the present invention.
Nuclear magnetic resonance spectrum is measured on Bruker AM-400, and mass spectrum carries out on MAT-95 type mass spectrograph.Ultimate analysis is finished by Shanghai organic chemistry institute of Chinese Academy of Sciences analyzer room.Fusing point instrument model is BUeHI 510 types, and thermometer is not calibrated.Column chromatography silica gel does not add explanation and is the 200-300 order, and Haiyang Chemical Plant, Qingdao produces.
Most preferred embodiment is tested 1 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-(2-pyridyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (6) 4 (140mg, 0.495mmol) and 1-(2-pyridyl) piperazine (170mg, 1.04mmol) be dissolved in the pyridine (10ml), 80～100 ℃ of reactions 4 hours.The pressure reducing and steaming solvent, residue adds chloroform (10ml) generation and precipitates with aqueous sodium hydroxide solution (10ml) dissolving of 1 volumetric molar concentration, filters, and dry back ethanol-dimethyl formamide recrystallization gets faint yellow solid 140mg (66%).mp243～244℃。MS(EI，m/z)[426
+]。
1HNMR (CF
3COOD) δ: 1.45 (2H, m, cyclopropyl CH
2), 1.65 (2H, m, cyclopropyl CH
2), 4.00 (4H, m, 2 * NCH
2), 4.15 (4H, m, 2 * CH
2N), 4.55 (1H, m, cyclopropyl CH), 7.15 (1H, m, pyridine ring C
3-H), 7.35 (1H, m, pyridine ring C
5-H), 8.05 (1H, m, C
5-H), 8.25 (2H, m, pyridine ring C
4-H, C
6-H), 9.35 (1H, s, C
2-H). and test 2 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-(2-pyrimidyl)-1-piperazine)-4-Oxoquinoline-3-carboxylic acid (7) experimental implementation is with experiment 1.Productive rate 67%.mp273～274℃。MS(EI，m/z)[427
+]。
1HNMR (CF
3COOD) δ: 1.75 (2H, m, cyclopropyl CH
2), 1.90 (2H, m, cyclopropyl CH
2), 4.25 (4H, m, 2 * NCH
2), 4.55 (4H, m, 2 * CH
2N), 4.85 (1H, m, cyclopropyl CH), 7.45 (1H, m, C
5-H), 8.50 (1H, m, pyrimidine ring C
5-H), 9.00 (2H, m, pyrimidine ring C
4-H, C
6-H), 9.65 (1H, s, C
2-H). test 3 1-cyclopropyl-6,8-two fluoro-1, and 4-dihydro-7-(4-(2-pyrazinyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (8) 4 (100mg, 0.353mmol) and 1-(2-pyrazinyl) piperazine (121mg, 0.737mmol) be dissolved in the pyridine (10ml), 80 ℃ of reactions 4 hours.The pressure reducing and steaming solvent, residue dissolves with the aqueous sodium hydroxide solution (10ml) of 1 volumetric molar concentration, water washs (2 * 10ml) with chloroform, the hcl acidifying that adds 2 moles is to PH=3～4, filter the precipitation of producing, precipitate water, washing with alcohol successively, drying, dimethyl formamide-ethyl alcohol recrystallization gets safran solid 100mg (47%).mp236～238℃。MS(EI，m/z)[427
+]。
1HNMR (CF
3COOD) δ: 1.35 (2H, m, cyclopropyl CH
2), 1.55 (2H, m, cyclopropyl CH
2), 3.80 (4H, m, 2 * NCH
2), 4.05 (4H, m, 2 * CH
2N), 4.45 (1H, m, cyclopropyl CH), 7.85 (1H, s, pyrazine ring C
3-H), 8.10 (1H, m, C
5-H), 8.45 (1H, m, pyrazine ring C
5-H), 8.65 (1H, m, pyrazine ring C
6-H), 9.30 (1H, s, C
2-H). and test 4 1-cyclopropyl-6,8-two fluoro-1, (4-(2-(5-5-flumethiazine base)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (9) operation is with experiment 1 for 4-dihydro-7-.Productive rate 67%.mp?247～249℃。MS(EI，m/z)[494
+]。
1HNMR (CF
3COOD) δ: 1.90 (2H, m, cyclopropyl CH
2), 2.05 (2H, m, cyclopropyl CH
2), 4.45 (4H, m, 2 * NCH
2), 4.60 (4H, m, 2 * CH
2N), 5.00 (1H, m, cyclopropyl CH), 7.95 (1H, m, C
5-H), 8.60 (2H, m, pyridine ring C
3-H, C
4-H), 8.70 (1H, s, pyridine ring C
6-H), 9.80 (1H, s, C
2-H). and test 5 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-(2-thiazolyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (10) experimental implementation is with experiment 1.Productive rate 33%.mp261～262℃。MS(EI，m/z)[432
+]。
1HNMR (CF
3COOD) δ: 1.40 (2H, m, cyclopropyl CH
2), 1.55 (2H, m, cyclopropyl CH
2), 3.85 (4H, m, 2 * NCH
2), 3.95 (4H, m, 2 * CH
2N), 4.45 (1H, m, cyclopropyl CH), 6.90 (1H, m, thiazole ring C
4-H), 7.25 (1H, m, thiazole ring C
5-H), 8.15 (1H, m, C
5-H), 9.30 (1H, s, C
2-H). test 6 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-(4-(7-chloro quinoline give repeated exhortations base))-1-piperazine)-4-Oxoquinoline-3-carboxylic acid (11) experimental implementation is with experiment 3.Productive rate 56%.mp＞275℃。MS(EI，m/z)[510
+]。
1HNMR (CF
3COOD) δ: 1.45 (2H, m, cyclopropyl CH
2), 1.55 (2H, m, cyclopropyl CH
2), 4.00 (4H, m, 2 * NCH
2), 4.25 (4H, m, 2 * CH
2N), 4.50 (1H, m, cyclopropyl CH), 7.15 (1H, m, quinoline give repeated exhortations the ring C
3-H), 7.60 (1H, m, quinoline give repeated exhortations the ring C
5-H), 7.95 (1H, s, quinoline give repeated exhortations the ring C
8-H), 8.15 (2H, m, quinoline give repeated exhortations the ring C
5-H, C
6-H), 8.40 (1H, m, quinoline give repeated exhortations the ring C
2-H), 9.30 (1H, s, C
2-H). test 7 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-(2-pyridyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (12) 5 (100mg, 0.336mmol) and 1-(2-pyridyl) piperazine (215mg, 1.32mmol) be dissolved in the pyridine (10ml), 100 ℃ of reactions 5 hours.The pressure reducing and steaming solvent, residue filters with aqueous sodium hydroxide solution (10ml) dissolving of 1 volumetric molar concentration, filtrate to pH=3, is filtered the precipitation of producing with hcl acidifying, precipitates water, washing with alcohol successively, drying, dimethyl formamide-ethyl alcohol recrystallization get faint yellow solid 100mg (67%).mp250～251℃。MS(EI，m/z)[441
+]。
1HNMR (CF
3COOD) δ: 1.25 (2H, m, cyclopropyl CH
2), 1.45 (2H, m, cyclopropyl CH
2), 3.75 (4H, m, 2 * NCH
2), 3.95 (4H, m, 2 * CH
2N), 4.25 (1H, m, cyclopropyl CH), 7.00 (1H, m, pyridine ring C
5-H), 7.30 (1H, m, pyridine ring C
3-H), 7.85 (1H, m, pyridine ring C
4-H), 8.05 (1H, m, pyridine ring C
2-H), 9.10 (1H, s, C
2-H). test 8 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro 7-(4-(2-(5-5-flumethiazine base))-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (13) 5 (78mg, 0.261mmol) and 1-(2-5-flumethiazine base) piperazine (230mg, 1.00mmol) be dissolved in the pyridine (10ml), 100 ℃ of reactions 5 hours.The pressure reducing and steaming solvent, residue dissolves with the aqueous sodium hydroxide solution (10ml) of 1 volumetric molar concentration, oily matter is separated out in placement, tell oily matter, add water (10ml), arrive pH=3 with hcl acidifying, filter the precipitation of producing, precipitate water, washing with alcohol successively, drying gets faint yellow solid 40mg (30%).mp263～264℃。MS(EI，m/z)[509
+]。
1HNMR (CF
3COOD) δ: 1.30 (2H, m, cyclopropyl CH
2), 1.50 (2H, m, cyclopropyl CH
2), 3.85 (4H, m, 2 * NCH
2), 4.10 (4H, m, 2 * CH
2N), 4.30 (1H, m, cyclopropyl CH), 7.45 (1H, m, pyridine ring C
3-H), 8.15 (1H, m, pyridine ring C
4-H), 8.25 (1H, s, pyridine ring C
2-H), 9.10 (1H, s, C
2-H). and test 9 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-(2-pyrimidyl)-1-piperazine)-4-Oxoquinoline-3-carboxylic acid (14) operation is with experiment 8.Productive rate 54%.mp274～275℃。MS(EI，m/z)[442
+]。
1HNMR (CF
3COOD) δ: 1.20 (2H, m, cyclopropyl CH
2), 1.40 (2H, m, cyclopropyl CH
2), 3.75 (4H, m, 2 * NCH
2), 4.15 (4H, m, 2 * CH
2N), 4.30 (1H, m, cyclopropyl CH), 7.00 (1H, m, pyrimidine ring C
5-H), 8.60 (2H, m, pyrimidine ring C
4-H, C
6-H), 9.10 (1H, s, C
2-H). and test 10 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-(2-pyrazinyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (15) operation is with experiment 7.Yield 47%.mp293～294℃。MS(EI，m/z)[442
+]。
1HNMR (CF
3COOD) δ: 1.25 (2H, m, cyclopropyl CH
2), 1.45 (2H, m, cyclopropyl CH
2), 3.70 (4H, m, 2 * NCH
2), 4.00 (4H, m, 2 * CH
2N), 4.25 (1H, m, cyclopropyl CH), 7.85 (1H, s, pyrazine ring C
3-H), 8.40 (1H, m, pyrazine ring C
5-H), 8.60 (1H, m, pyrazine ring C
6-H), 9.10 (1H, s, C
2-H). and test 11 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-(2-thiazolyl)-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (16) operation is with experiment 7.Productive rate 56%.mp267～268℃。MS(EI，m/z)[448
+]。
1HNMR (CF
3COOD) δ: 1.25 (2H, m, cyclopropyl CH
2), 1.40 (2H, m, cyclopropyl CH
2), 4.80 (4H, m, 2 * NCH
2), 3.90 (4H, m, 2 * CH
2N), 4.25 (1H, m, cyclopropyl CH), 6.90 (1H, m, thiazole ring C
4-H), 7.20 (1H, m, thiazole ring C
5-H), 9.10 (1H, s, C
2-H). test 12 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (18) 17a (R
1=cyclopropyl, R
4=R
5=H, R
8=F, n=1) (40mg, 0,115mmol) be dissolved in 0.1 mole the aqueous sodium hydroxide solution (4ml), be cooled to 0 ℃, add Vinyl chloroformate (24mg, 0.221mmol).0 ℃ was reacted room temperature reaction 1 hour 30 minutes.The hcl acidifying of 2 volumetric molar concentrations is to pH=3～4, and (3 * 10ml) extract chloroform.Combined chloroform solution, water, saturated common salt are washed once drying successively.The pressure reducing and steaming chloroform, residue methylene chloride-methanol recrystallization gets 30mg white solid (63%).mp228～229℃。MS(EI，m/z)[421
+]。
1HNMR (CDCl
3) δ: 1.30 (3H, t, J=7Hz, CH
3), 1.65 (4H, m, cyclopropyl CH
2CH
2), 3.35 (4H, m, 2 * NCH
2), 3.65 (4H, m, 2 * CH
2N), 4.00 (1H, m, cyclopropyl CH), 4.20 (2H, m, J=7Hz, OCH
2), 7.95 (1H, m, C
5-H), 8.80 (1H, s, C
2-H). test 13 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(2-methyl-4-ethoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (19) 17b (R
1=cyclopropyl, R
5=H, R
4=CH
3, R
8=F, and n=1) (50mg, 0.138mmol), Vinyl chloroformate (30mg, 0.271mmol).Operation is with experiment 12.Productive rate 83%.mp225～227℃。MS(EI，m/z)[435
+]。
1HNMR (CDCl
3) δ: 1.25 (3H, t, J=7Hz, ethyl CH
3), 1.35 (3H, t, J=7Hz, piperazine ring CH
3), 1.65 (4H, m, cyclopropyl CH
2CH
2), 3.35 (7H, m, 2 * CH
2N, NCH
2, NCH), 3.95 (1H, m, cyclopropyl CH), 4.15 (2H, m, J=6Hz, OCH
2), 7.95 (1H, m, C
5-H), 8.80 (1H, s, C
2-H). test 14 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(the high piperazinyl of 4-ethoxycarbonyl-1-)-4-Oxoquinoline-3-carboxylic acid (20) 17c (R
1=cyclopropyl,, R
4=R
5=H, R
8=F, and n=2) (50mg, 0.138mmol), Vinyl chloroformate (30mg, 0.271mmol).Operation is with experiment 12.Productive rate 75%.mp176～177℃。MS(EI，m/z)[435
+]。
1HNMR (CDCl
3) δ: 1.25 (3H, t, J=7Hz, ethyl CH
3), 1.65 (4H, m, cyclopropyl CH
2CH
2), 2.05 (2H, m, high piperazine ring CH
2), 3.60 (8H, m, 2 * CH
2N, 2 * NCH
2), 4.00 (1H, m, cyclopropyl CH), 4.15 (2H, m, J=7Hz, OCH
2), 7.95 (1H, m, C
5-H), 8.80 (1H, s, C
2-H). and test 15 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-isobutyl boc-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (21) 17a (40mg, 0,115mmol), isobutyl chlorocarbonate (30mg, 0.220mmol).Operation is with experiment 12.Productive rate 90%.mp215～217℃。MS(EI，m/z)[449
+]。
1HNMR (CDCl
3) δ: 0.95 (6H, d, J=7Hz, 2 * CH
3), 1.25 (2H, m, cyclopropyl CH
2), 1.30 (2H, m, cyclopropyl CH
2), 2.00 (1H, m, isobutyl-CH), 3.35 (4H, m, 2 * NCH
2), 3.65 (4H, m, 2 * CH
2N), 3.90 (2H, d, J=6Hz, OCH
2), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C
5-H), 8.80 (1H, s, C
2-H). and test 16 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(2-methyl-4-methoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (22) 17b (50mg, 0.138mmol), Vinyl chloroformate (26mg, 0.276mmol).Operation is with experiment 12.Productive rate 78%.mp229～230℃。MS(EI，m/z)[421
+]。
1HNMR (CDCl
3) δ: 1.15 (2H, m, cyclopropyl CH
2), 1.30 (2H, m, cyclopropyl CH
2), 1.38 (3H, t, J=7Hz, piperazine ring CH
3), 3.35 (7H, m, 2 * CH
2N, NCH
2, NCH), 3.75 (3H, s, OCH
3), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C
5-H), 8.80 (1H, s, C
2-H). and test 17 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7-(4-methoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (23) 17a (40mg, 0,115mmol), Vinyl chloroformate (26mg, 0.276mmol).Operation is with experiment 12.Productive rate 75%.mp204～205℃。MS(EI，m/z)[407
+]。
1HNMR (CDCl
3) δ: 1.15 (2H, m, cyclopropyl CH
2), 1.30 (2H, m, cyclopropyl CH
2), 3.35 (4H, m, 2 * NCH
2), 3.65 (4H, m, 2 * CH
2N), 3.75 (3H, s, OCH
3), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C
5-H), 8.75 (1H, s, C
2-H).Test 18 1-cyclopropyl-6,8-two fluoro-1,4-dihydro-7 (the high piperazinyl of 4-4-isobutyl boc-1-)-4-Oxoquinoline-3-carboxylic acid (24) 17c (50mg, 0.138mmol), isobutyl chlorocarbonate (37mg, 0.270mmol).Operation is with experiment 12.Productive rate 63%.mp176～177℃。MS(EI，m/z)[463
+]。
1HNMR (CDCl
3) δ: 0.95 (6H, d, J=7Hz, 2 * CH
3), 1.15 (2H, m, cyclopropyl CH
2), 1.30 (2H, m, cyclopropyl CH
2), 2.00 (3H, m, isobutyl-CH, high piperazine ring CH
2), 3.60 (8H, m, 2 * NCH
2, 2 * CH
2N), 3.85 (2H, d, J=7Hz, OCH
2), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C
5-H), 8.75 (1H, s, C
2-H). test 19 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (25) 17d (R
1=cyclopropyl, R
4=H, R
5=NH
2, R
8=F, and n=1) (50mg, 0,137mmol), Vinyl chloroformate (30mg, 0.270mmol).Operation is with experiment 12.Productive rate 75%.mp283～284℃。MS(EI，m/z)[436
+]。
1HNMR (CDCl
3) δ: 1.05 (2H, m, cyclopropyl CH
2), 1.20 (2H, m, cyclopropyl CH
2), 1.30 (3H, t, J=7Hz, CH
3), 3.30 (4H, m, 2 * NCH
2), 3.60 (4H, m, 2 * CH
2N), 3.90 (1H, m, cyclopropyl CH), 4.20 (2H, m, J=7Hz, OCH
2), 8.65 (1H, s, C
2-H).Test 20 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-isobutyl boc-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (26) 17d (40mg, 0,115mmol), isobutyl chlorocarbonate (37mg, 0.270mmol).Operation is with experiment 12.Productive rate 70%.mp257～258℃。MS(EI，m/z)[464
+]。
1HNMR (CDCl
3) δ: 0.95 (6H, d, J=7Hz, 2 * CH
3), 1.05 (2H, m, cyclopropyl CH
2), 1.25 (2H, m, cyclopropyl CH
2), 2.00 (1H, m, isobutyl-CH), 3.35 (4H, m, 2 * NCH
2), 3.65 (4H, m, 2 * CH
2N), 3.95 (2H, d, J=6Hz, OCH
2), 4.10 (1H, m, cyclopropyl CH), 8.65 (1H, s, C
2-H). and test 21 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(4-methoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (27) 17d (40mg, 0,115mmol), methyl-chloroformate (26mg, 0.276mmol).Operation is with experiment 12.Productive rate 69%.mp277～278℃。MS(EI，m/z)[422
+]。
1HNMR (CDCl
3) 1.05 (2H, m, cyclopropyl CH
2), 1.25 (2H, m, cyclopropyl CH
2), 3.35 (4H, m, 2 * NCH
2), 3.55 (4H, m, 2 * CH
2N), 3.75 (3H, s, OCH
3), 3.95 (1H, m, cyclopropyl CH), 8.75 (1H, s, C
2-H). test 22 1-cyclopropyl-5-amino-6,8-two fluoro-1,4-dihydro-7-(the high piperazinyl of 4-ethoxycarbonyl-1-)-4-Oxoquinoline-3-carboxylic acid (28) 17e (R
1=cyclopropyl,, R
4=H, R
5=NH
2, R
8=F, and n=2) (50mg, 0.137mmol), Vinyl chloroformate (30mg, 0.271mmol).Operation is with experiment 12.Productive rate 60%.mp216～217℃。MS(EI，m/z)[450
+]。
1HNMR (CDCl
3) δ: 1.05 (2H, m, cyclopropyl CH
2), 1.20 (2H, m, cyclopropyl CH
2), 1.28 (3H, t, J=7Hz, ethyl CH
3), 2.00 (2H, m, high piperazine ring CH
2), 3.45 (4H, m, 2 * CH
2N), 3.65 (4H, m, 2 * CH
2N), 3.90 (1H, m, cyclopropyl CH), 4.15 (2H, m, J=7Hz, OCH
2), 8.50 (1H, s, C
2-H). test 23 1-ethyls-6,8-two fluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (29) 17f (R
1=ethyl,, R
4=R
5=H, R
8=F, and n=1) (70mg, 0.208mmol), Vinyl chloroformate (40mg, 0.380mmol).Operation is with experiment 12.Productive rate 53%.mp248～249℃。MS(EI，m/z)[410
+]。
1HNMR (CDCl
3) δ: 1.30 (3H, t, J=7Hz, oxygen ethyl CH
3), 1.30 (3H, t, J=6Hz, nitrogen ethyl CH
3), 3.40 (4H, m, 2 * NCH
2), 3.70 (4H, m, 2 * CH
2N), 4.20 (2H, m, J=7Hz, OCH
2), 4.50 (2H, m, J=7Hz, NCH
2), 8.00 (1H, m, C
5-H), 8.60 (1H, s, C
2-H). and test 24 1-ethyls-6,8-two fluoro-1,4-dihydro-7-(4-isobutyl boc-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (30) 17f (70mg, 0.208mmol), isobutyl chlorocarbonate (52mg, 0.380mmol).Operation is with experiment 12.Productive rate 55%.mp261～262℃。MS(EI，m/z)[438
+]。
1HNMR (CDCl
3) δ: 0.95 (6H, d, J=7Hz, 2 * CH
3), 1.55 (3H, t, J=7Hz, nitrogen ethyl CH
3), 1.95 (1H, m, isobutyl-CH), 3.35 (4H, m, 2 * NCH
2), 3.75 (4H, m, 2 * CH
2N), 3.90 (2H, d, J=6Hz, OCH
2), 4.45 (2H, m, J=7Hz, NCH
2), 4.65 (4H, m, 2 * CH
2N), 8.00 (1H, m, C
5-H), 8.60 (1H, s, C
2-H).Test 25 1-ethyls-6,8-two fluoro-1,4-dihydro-7-(4-methoxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid (31) 17f (70mg, 0.208mmol), methyl-chloroformate (40mg, 0.417mmol).Operation is with experiment 12.Productive rate 49%.mp242～243℃。MS(EI，m/z)[396
+]。
1HNMR (CDCl
3) δ: 1.65 (3H, t, J=6Hz, nitrogen ethyl CH
3), 3.35 (4H, m, 2 * NCH
2), 3.50 (4H, m, 2 * CH
2N), 3.55 (3H, s, OCH
3), 4.45 (2H, m, J=4Hz, NCH
2), 8.00 (1H, m, C
5-H), 8.60 (1H, s, C
2-H). test 25 1-cyclopropyl-6-fluoro-7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (32) 17g (R
1=cyclopropyl,, R
4=R
5=R
8=H, and n=1) (70mg, 0.211mmol), Vinyl chloroformate (40mg, 0.368mmol).Operation is with experiment 12.Productive rate 59%.mp＞295℃。MS(EI，m/z)[403
+]。
1HNMR (CDCl
3) δ: 1.20 (2H, m, cyclopropyl CH
2), 1.30 (3H, t, J=7Hz, CH
3), 1.40 (2H, m, cyclopropyl CH
2), 3.30 (4H, m, 2 * NCH
2), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2 * CH
2N), 4.20 (2H, d, J=7Hz, OCH
2), 7.35 (H, d, J=7H, C
8-H), 8.05 (1H, d, J=7Hz, C
5-H), 8.75 (1H, s, C
2-H).Test 27 1-cyclopropyl-6-fluoro-7-(4-isobutyl boc-1-piperazinyl)-1, and 4-dihydro-4-Oxoquinoline-3-carboxylic acid (33) 17g (70mg, 0.211mmol), isobutyl chlorocarbonate (50mg, 0.367mmol).Operation is with experiment 12.Productive rate 55%.mp?286～287℃。MS(EI，m/z)[431
+]。
1HNMR (CDCl
3) δ: 0.95 (6H, d, J=7Hz, 2 * CH
3), 1.20 (2H, m, cyclopropyl CH
2), 1.40 (2H, m, cyclopropyl CH
2), 1.95 (1H, m, isobutyl-CH), 3.30 (4H, m, 2 * NCH
2), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2 * CH
2N), 4.90 (2H, d, J=6Hz, OCH
2), 7.35 (H, d, J=7Hz, C
8-H), 8.05 (1H, d, J=7Hz, C
5-H), 8.75 (1H, s, C
2-H).Test 28 1-cyclopropyl-6-fluoro-7-(4-methoxycarbonyl-1-piperazinyl)-1, and 4-dihydro-4-Oxoquinoline-3-carboxylic acid (34) 17g (70mg, 0.211mmol), methyl-chloroformate (40mg, 0.432mmol).Operation is with experiment 12.Productive rate 61%.mp?282～283℃。MS(EI，m/z)[389
+]。
1HNMR (CDCl
3) δ: 1.20 (2H, m, cyclopropyl CH
2), 1.40 (2H, m, cyclopropyl CH
2), 3.30 (4H, m, 2 * NCH
2), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2 * CH
2N), 3.75 (3H, s, OCH
3), 7.40 (H, d, J=7Hz, C
8-H), 8.05 (1H, d, J=7H, C
5-H), 8.75 (1H, s, C
2-H).Test 31 1-ethyl-6-fluoro-7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (35) 17h (R
1=ethyl,, R
4=R
5=R
8=H, and n=1) (70mg, 0.219mmol), Vinyl chloroformate (40mg, 0.368mmol).Operation is with experiment 12.Productive rate 59%.mp＞295℃。MS(EI，m/z)[391
+]。
1HNMR (CDCl
3) δ: 1.30 (3H, t, J=6Hz, oxygen ethyl CH
3), 1.65 (3H, t, J=6Hz, nitrogen ethyl CH
3), 3.25 (4H, m, 2 * NCH
2), 3.50 (4H, m, 2 * CH
2N), 4.15 (2H, m, J=4Hz, NCH
2), 3.70 (4H, m, 2 * CH
2N), 4.90 (2H, d, J=7Hz, OCH
2), 6.85 (H, d, J=7Hz, C
8-H), 8.10 (1H, d, J=7Hz, C
5-H), 8.65 (1H, s, C
2-H).
Claims (9)
1. the quinolone compounds of a class formation shown in general formula
Wherein: R
1=C
1-C
5Branched-chain or straight-chain alkyl or cyclopropyl; R
5=H, NH
2R
8=H, F;
Wherein: R
2For
R
3Be C
1-C
5Side chain or straight-chain paraffin;
R
4Be H or C
1-C
5Side chain or straight-chain paraffin;
N is 1,2.
2. quinolone compounds according to claim 1 is characterized in that R
3Be CH
3, CH
2CH
3, CH
2CHMe
2Or CH
2CCl
3
3. quinolone compounds according to claim 1 is characterized in that R
4Be CH
3
4. the preparation method of quinolone compounds according to claim 1 is characterized in that
A. be starting raw material synthetic intermediate compound 1-5 with fluorochlorobenzene amine, trifluoromethyl aniline and tetrafluorobenzoic aid respectively;
B. compound 1-5 is at pyridine, and dimethyl formamide is that the piperazine condensation of heterocyclic substituted gets the compound 6-16 that piperazine ring contains heterocyclic substituted with 1-position nitrogen-atoms respectively in the aprotic polar solvents such as dimethyl sulfoxide (DMSO);
C. compound 1-5 is at pyridine, dimethyl formamide, in the aprotic polar solvents such as dimethyl sulfoxide (DMSO) respectively and piperazine, the 2-methylpiperazine, bridged piperazine derivatives condensations such as high piperazine get the 7-position by quinolone compounds 17 that bridged piperazine derivatives replaced;
D. quinolone compounds 17 and alkyl chloride manthanoate react to such an extent that 7-contains the compound 18-35 that carbamate replaces in alkaline aqueous solution or tetrahydrofuran (THF), chloroform, acetone equal solvent.
5. the preparation method of quinolone compounds according to claim 4, it is characterized in that compound 1-5 is that the mol ratio of the bridged piperazine derivatives condensation of heterocyclic substituted is 1 with 1-position nitrogen-atoms respectively: 1-8, top condition is 1: 2-4.
6. the preparation method of quinolone compounds according to claim 4, it is characterized in that compound 1-5 is that the solvent of the bridged piperazine derivatives condensation of heterocyclic substituted is a particularly pyridine of suitable aprotic polar solvent with 1-position nitrogen-atoms respectively, dimethyl formamide, dimethyl sulfoxide (DMSO).
7. the preparation method of quinolone compounds according to claim 4, it is characterized in that compound 17 and the reaction of straight or branched alkyl chloride manthanoate, solvent is the inorganic alkaline aqueous solution such as sodium bicarbonate, yellow soda ash, potassium hydroxide, sodium hydroxide etc. or polar non-proton organic solvent such as tetrahydrofuran (THF), chloroform, methylene dichloride, ethyl acetate, ether.
8. the application of quinolone compounds according to claim 1 in the preparation anti-mycoplasma drug.
9. quinolone compounds according to claim 1 is the application in the mycoplasma pollution in scavenger cell is cultivated.
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| RU2005102004A (en) * | 2002-06-27 | 2005-10-20 | Шеринг Акциенгезельшафт (De) | SUBSTITUTED QUINOLINS AS CCR5 RECEPTOR ANTAGONISTS |
| CN106047797A (en) * | 2016-08-19 | 2016-10-26 | 上海逍鹏生物科技有限公司 | Reagent, kit and treatment for treating mycoplasma contamination |
| CN109912504B (en) * | 2019-04-04 | 2020-11-10 | 山东省联合农药工业有限公司 | Quinoline carboxylic acid compound and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101832A (en) * | 1984-06-04 | 1987-01-31 | 拜尔股份公司 | The method for preparing 7-(3-aryl-1-piperazinyl)-3-quinolone carboxylic acid and 7-(3-encircles ethyl-1-piperazinyl)-3-quinolone carboxylic acid |
| CN87101731A (en) * | 1986-03-04 | 1987-09-16 | 杏林制药株式会社 | Carbostyril carboxylic acid derivatives that replaces on No. 8 positions and preparation method thereof |
| CN86108942A (en) * | 1985-12-12 | 1987-11-04 | 沃纳-兰伯特公司 | Amino and the 5-hydroxyl-6 as the 5-of antimicrobial drug, 8-two fluoroquinolones |
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
-
1999
- 1999-04-02 CN CN99113598A patent/CN1091103C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101832A (en) * | 1984-06-04 | 1987-01-31 | 拜尔股份公司 | The method for preparing 7-(3-aryl-1-piperazinyl)-3-quinolone carboxylic acid and 7-(3-encircles ethyl-1-piperazinyl)-3-quinolone carboxylic acid |
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
| CN86108942A (en) * | 1985-12-12 | 1987-11-04 | 沃纳-兰伯特公司 | Amino and the 5-hydroxyl-6 as the 5-of antimicrobial drug, 8-two fluoroquinolones |
| CN87101731A (en) * | 1986-03-04 | 1987-09-16 | 杏林制药株式会社 | Carbostyril carboxylic acid derivatives that replaces on No. 8 positions and preparation method thereof |
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