CN102643230B - 7-site substituted quinolone compound and application thereof in preparation of anti-tumor medicaments - Google Patents
7-site substituted quinolone compound and application thereof in preparation of anti-tumor medicaments Download PDFInfo
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- CN102643230B CN102643230B CN201210093123.5A CN201210093123A CN102643230B CN 102643230 B CN102643230 B CN 102643230B CN 201210093123 A CN201210093123 A CN 201210093123A CN 102643230 B CN102643230 B CN 102643230B
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- -1 quinolone compound Chemical class 0.000 title claims abstract description 38
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 201000005202 lung cancer Diseases 0.000 claims abstract description 8
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 8
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 5
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
- 150000007660 quinolones Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 230000000719 anti-leukaemic effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 208000032839 leukemia Diseases 0.000 abstract description 6
- 230000001472 cytotoxic effect Effects 0.000 abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 56
- 238000010792 warming Methods 0.000 description 42
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- JJWDELPVPRCLQN-UHFFFAOYSA-N 1-ethyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 JJWDELPVPRCLQN-UHFFFAOYSA-N 0.000 description 8
- 229960003405 ciprofloxacin Drugs 0.000 description 8
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 6
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical class ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
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- 230000002401 inhibitory effect Effects 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- ZIZGWNOAHUCACM-UHFFFAOYSA-N 2-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=CC=C1S(Cl)(=O)=O ZIZGWNOAHUCACM-UHFFFAOYSA-N 0.000 description 2
- KMVZDSQHLDGKGV-UHFFFAOYSA-N 2-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC=C1S(Cl)(=O)=O KMVZDSQHLDGKGV-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- OINWZUJVEXUHCC-UHFFFAOYSA-N 3-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=CC(S(Cl)(=O)=O)=C1 OINWZUJVEXUHCC-UHFFFAOYSA-N 0.000 description 2
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 2
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
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Abstract
The invention discloses a 7-site substituted quinolone compound shown as a formula (I). The compound shows cytotoxic activity for a human lung cancer cell line A549, a human leukemia cell line HL-60 and a human cervical cancer cell line Hela, and can be used for preparing lung cancer, leukemia and cervical cancer resistant medicaments.
Description
(1) technical field
The present invention relates to a kind of 7-position substituted quinolone compounds, and in the application of preparing in anti-tumor drug.
(2) background technology
The common pharmacologically active of carbostyril compound is antibacterial, You Qidong etc. have reported compound [CN 1473827A] and the benzo five-membered heterocycle-4-of the fluoro-3-of 7-piperazinyl-6-carbostyril compound [the J Med Chem that quinolone 3-position is replaced by benzoglyoxaline, benzoxazole and benzothiazole, 2009,52 (18): 5649-5661] there is anti-tumor activity.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide the new substituted compound in quinolone 7-position with anti-tumor activity, provides it in the application of preparing in medicine for treating tumor thing simultaneously.
The present invention is starting raw material with various substituted phenylsulfonyl chlorides, react with cyanamide and generate N-cyano-aryl sulfonamide compounds, the carbostyril compound replacing with 7-piperazinyl again reacts has prepared the compound that a series of new quinolone 7-positions replace, and these compounds have anti-tumor activity.
For solving the problems of the technologies described above, the invention provides following technical scheme:
A kind of suc as formula the 7-position substituted quinolone compounds shown in (I)
In formula (I), R is C
1～10straight chained alkyl or branched-chain alkyl, C
3～10cycloalkyl;
Ar is phenyl or substituted-phenyl, the alkyl that the substituting group on described substituted-phenyl is C1～C5, the haloalkyl of C1～C5 or halogen, and described halogen is F, Cl, Br or I.
Described R is preferably ethyl or cyclopropyl, most preferably is cyclopropyl.
Described Ar is preferably phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 2-chloro-phenyl-, 2-trifluoromethyl or 3-chloro-phenyl-, most preferably is 2-chloro-phenyl-.
Further, the present invention also provides suc as formula the 7-position substituted quinolone compounds shown in (I) in the application of preparing in antitumor drug.
Concrete, described 7-position substituted quinolone compounds can be applicable to prepare anti-lung-cancer medicament, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
Concrete, described 7-position substituted quinolone compounds can be applicable to prepare anti-leukemia medicine, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
Concrete, described 7-position substituted quinolone compounds can be applicable to prepare medicament for resisting cervical cancer, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
The preparation method of the 7-position substituted quinolone compounds shown in formula of the present invention (I) is shown below:
In formula (IV), R is C
1～10straight chained alkyl or branched-chain alkyl, C
3～10cycloalkyl;
In formula (II) or formula (III), Ar is phenyl or substituted-phenyl, the alkyl that the substituting group on described substituted-phenyl is C1～C5, the haloalkyl of C1～C5 or halogen, and described halogen is F, Cl, Br or I.
Concrete, described preparation method is:
In the reaction system that is solvent at butanone by the aryl sulfonyl chloride shown in formula (II) and cyanamide, at 40～60 DEG C of temperature, react 2～5h, N-cyano-aryl sulfonamide compounds shown in production (III), add again the compound shown in formula (IV), at 75～90 DEG C of temperature, react 2～5h, reaction finishes rear reaction mixture and pours in cold water after cooling, separate out solid, filter, filter cake washing, dry, water recrystallization make the 7-position substituted quinolone compounds shown in formula (I).
The ratio of the amount of substance of the compound shown in the aryl sulfonyl chloride shown in described formula (II), cyanamide, formula (IV) is 1: 1～1.5: 0.8～1.
The invention provides a kind of 7-position substituted quinolone compounds with anti-tumor activity, experimental data shows: the compounds of this invention (compound 1j) is to human lung cancer cell line A549, human leukemia cell line HL-60 and human cervical carcinoma cell are that Hela shows cytotoxic activity, can be used for preparing anti-lung cancer, leukemia, medicament for resisting cervical cancer.
(4) embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
In following embodiment, agents useful for same is commercially available.Norfloxacin hydrochloride involved in the present invention and ciprofloxacin HCl market are on sale.
Embodiment 1
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-(4-benzene sulfonyl guanidine radicals-1-piperazinyl)-3-quinoline carboxylic acid (1a)
Benzene sulfonyl chloride 1.76g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains white crystal 2.25g, 221～225 DEG C of fusing points, yield 55%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.35 (m, 2H, C
6h
5), 7.58 (m, 3H ,-C
6h
5), 7.86 (d, 1H, J=9.0Hz, 5-H), 8.82 (s, 1H, 2-H), 8.91 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MS m/z501 (100%, M
+).
Embodiment 2
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-(4-benzene sulfonyl guanidine radicals-1-piperazinyl)-3-quinoline carboxylic acid (1b)
Benzene sulfonyl chloride 1.76g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50% cyanamide aqueous solution (wherein containing cyanamide 0.015mol) of 1.26g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains white crystal 2.87g, 295～298 DEG C of fusing points, yield 70%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropyl CH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.33-7.42 (m, 2H, C
6h
5), 7.48-7.65 (m, 3H ,-C
6h
5), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MS m/z 513 (100%, M
+).
Embodiment 3
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-Methyl benzenesulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1c)
4-toluene sulfonyl chloride 1.90g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains white crystal 3.20g, 257～260 DEG C of fusing points, yield 76%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 2.45 (s, 3H, Ar-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.35 (m, 2H, C
6h
5), 7.58 (m, 3H ,-C
6h
5), 7.86 (d, 1H, J=9.0Hz, 5-H), 8.82 (s, 1H, 2-H), 8.91 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MSm/z 515 (100%, M
+).
Embodiment 4
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-Methyl benzenesulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1d)
4-toluene sulfonyl chloride 1.90g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains white crystal 2.22g, 262～265 DEG C of fusing points, yield 85%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 2.45 (s, 3H ,-CH
3), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.22 (d, 1H, J=3.0Hz, 8-H), 7.38 (m, 2H, C
6h
4), 7.58 (m, 2H ,-C
6h
4), 7.86 (d, 1H, J=9.0Hz, 5-H), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MSm/z 527 (100%, M
+).
Embodiment 5
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1e)
4-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains pale yellow crystals 3.29g, 297～299 DEG C of fusing points, yield 75%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.46 (m, 2H, C
6h
4), 7.66 (m, 2H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.95 (s, 1H, 2-H), 9.11 (bs, 2H, NH), 15.10 (bs, 1H, COOH); MS m/z 535 (100%, M
+).
Embodiment 6
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1f)
4-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains pale yellow crystals 3.68g, 288～291 DEG C of fusing points, yield 84%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.36 (m, 2H, C
6h
4), 7.60 (m, 2H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MS m/z 547 (100%, M
+).
Embodiment 7
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-trifluoromethyl benzene sulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1g)
4-trifluoromethyl benzene sulfonyl chloride 2.44g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains off-white color crystal 3.53g, 217～220 DEG C of fusing points, yield 76%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.56 (m, 2H, C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.22 (m, 2H ,-C
6h
4), 8.86 (s, 1H, 2-H), 9.15 (bs, 2H, NH), 15.08 (bs, 1H, COOH); MS m/z 569 (100%, M
+).
Embodiment 8
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(4-trifluoromethyl benzene sulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1h)
4-trifluoromethyl benzene sulfonyl chloride 2.44g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains off-white color crystal 3.86g, 248～251 DEG C of fusing points, yield 83%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.47 (m, 2H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.06 (m, 2H, C
6h
4), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MSm/z 581 (100%, M
+).
Embodiment 9
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(2-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1i)
2-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains light yellow crystal 3.54g, 255～258 DEG C of fusing points, yield 74%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.46 (m, 3H, C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.46 (m, 1H ,-C
6h
4), 8.95 (s, 1H, 2-H), 9.11 (bs, 2H, NH), 15.10 (bs, 1H, COOH); MSm/z 535 (100%, M
+).
Embodiment 10
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(2-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1j)
2-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains light yellow crystal 2.78g, 286～289 DEG C of fusing points, yield 58%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.46 (m, 3H, C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.46 (m, 1H ,-C
6h
4), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MS m/z 547 (100%, M
+).
Embodiment 11
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(2-trifluoromethyl benzene sulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1k)
2-trifluoromethyl benzene sulfonyl chloride 2.44g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains off-white color crystal 3.30g, 218～221 DEG C of fusing points, yield 71%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.64-7.85 (m, 3H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.50 (m, 1H ,-C
6h
4), 8.95 (s, 1H, 2-H), 9.11 (bs, 2H, NH), 15.10 (bs, 1H, COOH); MSm/z 569 (100%, M
+).
Embodiment 12
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(2-trifluoromethyl benzene sulfonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (11)
2-trifluoromethyl benzene sulfonyl chloride 2.44g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains light yellow crystal 3.53g, 237～240 DEG C of fusing points, yield 76%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.64-7.85 (m, 3H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.50 (m, 1H ,-C
6h
4), 8.73 (s, 1H, 2-H), 9.18 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MSm/z 581 (100%, M
+).
Embodiment 13
1-ethyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(3-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1m)
3-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds norfloxacin hydrochloride 2.84g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains off-white color crystal 2.53g, 222～225 DEG C of fusing points, yield 58%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.41 (t, 3H, J=4.5Hz ,-CH
3), 3.19 (m, 4H ,-CH
2, piperazine), 3.43 (m, 4H ,-CH
2, piperazine), 4.58 (q, 2H, J=4.5Hz ,-CH
2me), 7.17 (d, 1H, J=3.0Hz, 8-H), 7.35-7.60 (m, 3H, C
6h
4), 7.86 (s, 1H ,-C
6h
4), 7.95 (d, 1H, J=9.0Hz, 5-H), 8.86 (s, 1H, 2-H), 9.16 (bs, 2H, NH), 15.00 (bs, 1H, COOH); MS m/z 535 (100%, M
+).
Embodiment 14
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-7-[4-(3-chlorobenzene sulphonyl guanidine radicals)-1-piperazinyl]-3-quinoline carboxylic acid (1n)
3-chlorobenzene sulfonyl chloride 2.11g (0.01mol), butanone 30mL adds reaction flask, be warming up to 40 DEG C, slowly splash into the 50wt% cyanamide aqueous solution (wherein containing cyanamide 0.01mol) of 0.84g, drip finish after be warming up to 60 DEG C, stirring reaction 3h, adds ciprofloxacin HCl 2.94g (0.008mol), be warming up to 80 DEG C and continue reaction 3h, be cooled to 40 DEG C, reaction mixture is poured in cold water and separated out solid, filter, washing filter cake, dry, water recrystallization obtains off-white color crystal 2.01g, 228～232 DEG C of fusing points, yield 42%
1h NMR (DMSO-d
6, 300MHz) and δ (ppm) 1.18 (m, 2H, cyclopropyl CH
2cH
2), 1.33 (m, 2H, cyclopropylCH
2cH
2), 3.33 (m, 4H ,-CH
2, piperazine), 3.53 (m, 4H ,-CH
2, piperazine), 3.83 (m, 1H, cyclopropyl CH), 7.28 (d, 1H, J=3.0Hz, 8-H), 7.35-7.60 (m, 3H, C
6h
4), 7.86 (s, 1H ,-C
6h
4), 7.90 (d, 1H, J=9.0Hz, 5-H), 8.63 (s, 1H, 2-H), 9.23 (bs, 2H, NH), 15.05 (bs, 1H, COOH); MS m/z 547 (100%, M
+).
Embodiment 15
Antitumour activity test
Principle: cell is decomposed into Thiazolyl blue (MTT) water-fast bluish voilet crystallization and is deposited in cell by plastosome lytic enzyme, crystallisate can be by dmso solution, measure its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, indirectly reflect propagation situation and the number change of cell.
1. material
1.1. cell: A549: lung cancer cell line
HL-60: human leukemia cell line
Hela: human cervical carcinoma cell strain
Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences cell bank.
1.2. reagent:
1.2.1DMEM substratum: Gibco company product.
1.2.3MTT:Sigma company's product, Shanghai Cellular Biotech Co., Ltd.'s packing of growing directly from seeds.
1.2.4 foetal calf serum: Gibco company product.
1.2.5 penicillin-Streptomycin sulphate: Gibco company product.
1.2.6EDTA-trysinization liquid: Gibco company product.
1.2.7 positive control: cis-platinum: Qilu Pharmaceutical Co., Ltd..
Irinotecan: Quzhou, Zhejiang the earth Pharmaceutical Technology Co., Ltd
1.3. instrument
1.3.1CO
2incubator: NAPCO company of U.S. product.
1.3.2 inverted microscope: Japanese OLYMPUS company product.
1.3.3 Biohazard Safety Equipment: LABCONCO company of U.S. product.
1.3.4 microplate reader: upper Hisoon reaches Medical Devices Co., Ltd.'s product.
1.3.5LDZX-40BI the vertical automatic electric heating pressure steam sterilizer of type: Shenan Medical Appliances Factory, Shanghai's product.
1.3.6Thermo IEC high-speed refrigerated centrifuge, power & light company of U.S. product.
2. experimental procedure
The preparation of 2.1 samples: get the prepared compound of embodiment 1～14 and positive control sample, every 1mg dissolves with 40 μ L DMSO, get 1000 μ L nutrient solutions for 2uL (nutrient solution of step 2.2.1 preparation) dilution, making concentration is 50 μ g/mL, then uses nutrient solution serial dilution to working concentration.
2.2 the cultivation of cell
2.2.1 the preparation of substratum: contain 800,000 unit penicillin, 1.0g Streptomycin sulphate, 10% inactivated fetal bovine serum in every 1000mL substratum.
2.2.2 the cultivation of cell: tumor cell inoculation, in substratum, is put to 37 DEG C, 5%CO
2in incubator, cultivate, 3～5d goes down to posterity.
The restraining effect of 2.3 working samples to growth of tumour cell
By EDTA-trysinization liquid digestion for cell, and be diluted to 1 × 10 with substratum
6/ mL, is added in 96 porocyte culture plates, and every hole 100uL, puts 37 DEG C, 5%CO
2in incubator, cultivate.After inoculation 24h, add the sample with substratum dilution, every hole 100 μ L, each concentration adds 3 holes, puts 37 DEG C, 5%CO
2in incubator, cultivate, add the MTT of 5mg/mL after 72h in cell cultures hole, every hole 10 μ L, put 37 DEG C and hatch 3h, add DMSO, every hole 150 μ L, and with vibrator vibration, Shi Jia Za dissolves completely, by microplate reader colorimetric under 490nm wavelength.Use not containing sample with similarity condition, containing the cell of the culture medium culturing of same concentration DMSO in contrast, according to the inhibiting rate of formula (1) calculation sample to growth of tumour cell, and the inhibiting rate of compound cell growth under each concentration, calculate the half-inhibition concentration (IC of each sample with SPSS software (purchased from SPSS Inc. of the U.S.)
50)
Inhibiting rate (%)=(OD
blank-OD
sample)/OD
blank× 100% formula (1)
Result shows, compound 1j prepared by embodiment 10 is to human lung cancer cell line A549, and human leukemia cell line HL-60 and human cervical carcinoma cell are that Hela shows cytotoxic activity, IC
50value is respectively 39.61,23.35 and 21.47 μ gmL
-1.
Claims (6)
1. one kind suc as formula the 7-position substituted quinolone compounds shown in (I)
In formula (I), R is C
1～10straight chained alkyl or branched-chain alkyl, C
3～10cycloalkyl;
Ar is phenyl or substituted-phenyl, the alkyl that the substituting group on described substituted-phenyl is C1～C5, the haloalkyl of C1～C5 or halogen, and described halogen is F, Cl, Br or I.
2. 7-as claimed in claim 1 position substituted quinolone compounds, is characterized in that described R is that cyclopropyl, Ar are 2-chloro-phenyl-.
3. 7-as claimed in claim 1 or 2 position substituted quinolone compounds is in the application of preparing in antitumor drug.
4. application as claimed in claim 3, is characterized in that described 7-position substituted quinolone compounds is in the application of preparing in anti-lung-cancer medicament, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
5. application as claimed in claim 3, is characterized in that described 7-position substituted quinolone compounds is in the application of preparing in anti-leukemia medicine, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
6. application as claimed in claim 3, is characterized in that described 7-position substituted quinolone compounds is in the application of preparing in medicament for resisting cervical cancer, and the R of described 7-position substituted quinolone compounds is that cyclopropyl, Ar are 2-chloro-phenyl-.
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