CN100441580C - Quinolyl dione derivative and its application in preparing antibiotic medicine - Google Patents
Quinolyl dione derivative and its application in preparing antibiotic medicine Download PDFInfo
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- CN100441580C CN100441580C CNB2006100364840A CN200610036484A CN100441580C CN 100441580 C CN100441580 C CN 100441580C CN B2006100364840 A CNB2006100364840 A CN B2006100364840A CN 200610036484 A CN200610036484 A CN 200610036484A CN 100441580 C CN100441580 C CN 100441580C
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- dione derivative
- quinolyl dione
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- 125000005493 quinolyl group Chemical group 0.000 title claims abstract description 34
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 230000003115 biocidal effect Effects 0.000 title abstract 3
- 229960003085 meticillin Drugs 0.000 claims abstract description 11
- 241000192125 Firmicutes Species 0.000 claims abstract description 4
- 241000191940 Staphylococcus Species 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000000844 anti-bacterial effect Effects 0.000 claims description 6
- 229940088710 antibiotic agent Drugs 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 6
- 239000010931 gold Substances 0.000 claims description 6
- 229910052737 gold Inorganic materials 0.000 claims description 6
- 230000000845 anti-microbial effect Effects 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 abstract description 7
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108010059993 Vancomycin Proteins 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 229960003165 vancomycin Drugs 0.000 description 3
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102100025142 Beta-microseminoprotein Human genes 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 101100185029 Homo sapiens MSMB gene Proteins 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 108010034396 Streptogramins Proteins 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- -1 oxazolidine ketones Chemical class 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to one kind of quinolyl dione derivative and its application in preparing antibiotic medicine, especially medicine for resisting meticillin resistant Staphylococcus aureus (MRSA). Experiment shows that the quinolyl dione derivative has powerful inhibition on Gram-positive bacteria, especially MRSA and may be used in preparing effective antibiotic medicine. The structural expression of the quinolyl dione derivative is shown.
Description
Technical field
The present invention relates to a class quinolyl dione derivative and the purposes in the preparation antibacterials thereof.This medicine particularly has very strong restraining effect to methicillin-resistant gold staphylococcus (MRSA) to gram-positive microorganism.
Background technology
The anti-microbial type medicine is the medicine that an at present the most frequently used class is treated bacterial infection.For many years along with microbiotic in the popularizing and using of the whole world, and have serious unreasonable abuse condition, no matter be that multiple Resistant strain has all appearred in gram positive bacterium or negative bacteria.Wherein the resistance problem of gram-positive microorganism is particularly serious, methicillin resistant staphylococcus aureus (the methicillin-resistant Staphylococcus aureus that occurs in the world wide, MRSA) and staphylococcus epidermidis (methicillin-resistant Staphylococcus epidermdis, MRSE), penicillin-fast streptococcus pneumoniae (penicillin-resistant Streptococcus pneunoniae, PRSP) and the faecalis of vancomycin resistance (vancomycin-resistant Enterococci, VRE) etc., be the current clinical middle serious problems that exist.The infection that these drug-resistant bacterias are caused also lacks effective medicine at present.Press for no cross resistance of development and more effective new texture antimicrobial drug.At present, can resist the newtype drug of Resistant strain, among developing and developing as a series of medicines such as streptogramin, daptomycin and oxazolidine ketones.
Summary of the invention
The purpose of this invention is to provide the new quinolyl dione derivative of a class, and this compounds is in preparation medicament for resisting gram-positive bacteria, the application in the medicine of particularly anti-methicillin-resistant gold staphylococcus (MRSA).
Quinolyl dione derivative of the present invention is as shown in the formula shown in the I:
Formula I
R among the formula I
1The group of representative is :-H or C
1-C
4Alkyl etc.;
R among the formula I
2The group of representative is :-OH or-NH
2Deng;
R among the formula I
3The group of representative is :-H or-CH
3Deng.
Quinolyl dione derivative of the present invention can obtain by chemical synthesis process.Common quinolyl dione derivative of the present invention can prepare by following reaction (formula II):
Formula II
Show that by extracorporeal bacteria inhibitor test quinolyl dione derivative of the present invention is to gram-positive microorganism, particularly anti-methicillin-resistant gold staphylococcus (MRSA) has very strong restraining effect, and to non-pathogenic bacteria, very little as the intestinal bacteria restraining effect.Animal acute toxicity test shows that this compounds toxicity is very low, IC
50Greater than 2.2g/kg mouse body weight.Therefore quinolyl dione derivative of the present invention can be used for preparation treatment gram positive bacteria infection, the medicine that particularly anti-methicillin-resistant gold staphylococcus (MRSA) infects.
The present invention also provides a kind of medicine that bacterium (gram-positive microorganism) infects that is used for the treatment of, and particularly treats the medicine that methicillin-resistant gold staphylococcus (MRSA) waits infection; This medicine contains above-mentioned quinolyl dione derivative and pharmaceutically acceptable auxiliary.This medicine can be made the form of injection, tablet, pill, capsule, suspension agent or emulsion and use.Its route of administration can be oral, through skin, and vein or intramuscular injection.
Embodiment
The invention will be further described by the following examples.
Embodiment one: compound K LT-2's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.02mol methyl aceto acetate join in the dehydrated alcohol of 20-80mL, under agitation add the pyridine of 0.01-0.08mol, back flow reaction 2-15 hour.After the cooling, promptly there is solid to separate out, filters.The gained solid matter obtains orange-yellow quinolyl dione derivative KLT-2 through column chromatography for separation.m.p.221-223℃。m.p.221-223℃。
1H?NMR?δ9.74(d，1H)，8.98(d，1H)，8.43(d，1H)，8.21(d，1H)，7.80(d，1H)，7.65(t，1H)，7.43(t，1H)，4.38(q，2H)，1.39(t，3H)。MS(m/z)：321(M
++1)。
The structural formula of quinolyl dione derivative KLT-2 is as follows:
Embodiment two: quinolyl dione derivative KLT-N1's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.02mol methyl acetoacetate join in the dehydrated alcohol of 20-80mL, under agitation add the 3-aminopyridine of 0.01-0.08mol, back flow reaction 5-25 hour.After the cooling, promptly there is solid to separate out, filters.The gained solid matter obtains the quinolyl dione derivative KLT-N1 of purple through column chromatography for separation.m.p.＞350℃。
1H?NMR?δ9.20(d，1H)，8.95(d，1H)，8.40(d，1H)，7.76(d，1H)，7.21(d，1H)，6.90(t，1H)，6.72(d，1H)，3.39(s，3H)，3.14(s，2H)。MS(m/z)：321(M
+)。
The structural formula of quinolyl dione derivative KLT-N1 is as follows:
Embodiment three: quinolyl dione derivative KLT-N2's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.02mol methyl aceto acetate join in the dehydrated alcohol of 20-80mL, under agitation add the 3-aminopyridine of 0.01-0.08mol, back flow reaction 5-20 hour.After the cooling, promptly there is solid to separate out, filters.The gained solid matter obtains the quinolyl dione derivative KLT-N2 of purple through column chromatography for separation.m.p.＞350℃。
1H?NMR?δ9.20(d，1H)，8.96(d，1H)，8.40(d，1H)，7.76(d，1H)，7.20(d，1H)，6.72(t，1H)，4.42(q，1H)，3.14(s，2H)，1.34(t，3H)。MS(m/z)：335(M
+)。
The structural formula of quinolyl dione derivative KLT-N2 is as follows:
Embodiment four: quinolyl dione derivative KLT-01's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.02mol methyl acetoacetate join in the dehydrated alcohol of 20-80mL, under agitation add the 3-pyridone of 0.01-0.08mol, back flow reaction 5-20 hour.After the cooling, promptly there is solid to separate out, filters.The gained solid matter obtains orange-yellow quinolyl dione derivative KLT-01 through column chromatography for separation.m.p.＞350℃。
1H?NMR?δ9.36(d，1H)，8.93(d，1H)，8.53(d，1H)，7.79(d，1H)，7.21(d，1H)，6.82(d，1H)，4.00(s，3H)。MS(m/z)：322(M
+)。
The structural formula of quinolyl dione derivative KLT-01 is as follows:
Embodiment five: quinolyl dione derivative KLT-02's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.02mol methyl aceto acetate join in the dehydrated alcohol of 20-80mL, under agitation add the 3-pyridone of 0.01-0.08mol, back flow reaction 5-20 hour.After the cooling, promptly there is solid to separate out, filters.The gained solid matter obtains orange-yellow quinolyl dione derivative KLT-02 through column chromatography for separation.m.p.＞350℃。
1H?NMR?δ9.39(d，1H)，8.92(d，1H)，8.54(d，1H)，7.78(d，1H)，7.21(d，1H)，6.82(d，1H)，4.49(q，2H)，1.46(t，3H)。MS(m/z)：336(M
+)。
The structural formula of quinolyl dione derivative KLT-02 is as follows:
Embodiment six: the quinolyl dione derivative anti-microbial activity is measured
Use MIC (μ g/ml) value of agar dilution determination test compound.
1. the preparation of antibacterials stoste: original liquid concentration is for measuring more than 10 times of maximum concentration, and with the degerming of filtration method, packing is standby in a small amount after preparing.
2. the preparation of pastille agar: stoste is diluted to 10 gradient concentrations with half dilution method.Get 1ml respectively and add a series of marks of having carried out, internal diameter is in the flat board of 90mm.Get the MH agar 19ml of 50 degree of having sterilized again, add in the flat board mixing postcooling.
3. inoculation: with inoculator inoculation one by one on the pastille flat board of drawing good mark, each inoculum size is 1～2 a μ L (bacteria containing amount about 10
6CFU/mL).Inoculation does not at last contain the growth control plate of medicine, to check the existing state of test bacterium in the whole experiment.
4. hatch: after treating that inoculation point bacterium liquid is done, flat board is put 37 ℃ and is hatched 18-24h.
5. the result judges: bacterium colony grow fully the lowest concentration of drug that suppressed fully for this medicine to detecting the MIC of bacterium.Single colony growth can be ignored.
The quinolyl dione compound of finding test demonstrates significant inhibition activity to several gram-positive microorganisms.Wherein, quinolyl dione derivative KLT-2 has very strong inhibition activity to the golden staphylococci (MRSA) of methicillin-resistant, and is active higher 4 times than the vancomycin of positive control.
Quinolyl dione derivative anti-microbial activity measurement result
Claims (6)
1. suc as formula the quinolyl dione derivative shown in the I:
Formula I
R among the formula I
1The group of representative is :-H or C
1-C
4Alkyl; R
2The group of representative is :-OH or-NH
2R
3The group of representative is :-H or-CH
3
2. the described quinolyl dione derivative of claim 1 is as the application of preparation antibacterials.
3. according to the described application of claim 2, it is characterized in that described antibacterials are medicines of resisting gram-positive bacteria.
4. according to the described application of claim 2, it is characterized in that described antibacterials are medicines of anti-methicillin-resistant gold staphylococcus.
5. one kind is used for the antimicrobial medicine, it is characterized in that this medicine contains described quinolyl dione derivative of claim 1 and pharmaceutically acceptable auxiliary.
6. according to the described medicine of claim 5, it is characterized in that this medicine is injection, tablet, pill, capsule, suspension agent or emulsion.
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|---|---|---|---|
| CNB2006100364840A CN100441580C (en) | 2006-07-14 | 2006-07-14 | Quinolyl dione derivative and its application in preparing antibiotic medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100364840A CN100441580C (en) | 2006-07-14 | 2006-07-14 | Quinolyl dione derivative and its application in preparing antibiotic medicine |
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| Publication Number | Publication Date |
|---|---|
| CN1887884A CN1887884A (en) | 2007-01-03 |
| CN100441580C true CN100441580C (en) | 2008-12-10 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093358B (en) * | 2011-02-21 | 2012-09-05 | 中山大学 | Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament |
| AU2016205137B2 (en) * | 2015-01-08 | 2020-01-30 | Linkun AN | Furoquinolinediones as inhibitors of TDP2 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998028304A1 (en) * | 1996-12-20 | 1998-07-02 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Pro-drugs and counterparts of camptothecin, their application as medicines |
| CN1354746A (en) * | 1999-05-04 | 2002-06-19 | 日进素材产业株式会社 | 6.7-disubstituted-5,8-quinolinedione derivatives as antifungal agent |
| US20040063754A1 (en) * | 2000-11-20 | 2004-04-01 | Hisashi Takahashi | Dehalogeno compounds |
| CN1491944A (en) * | 2003-09-19 | 2004-04-28 | 中国医学科学院医药生物技术研究所 | 5-amino-8-methoxy quinolone carboxylic acid derivatives and its preparation |
| US6762181B1 (en) * | 1999-03-10 | 2004-07-13 | Daiichi Pharmaceutical Co., Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
-
2006
- 2006-07-14 CN CNB2006100364840A patent/CN100441580C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998028304A1 (en) * | 1996-12-20 | 1998-07-02 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Pro-drugs and counterparts of camptothecin, their application as medicines |
| US6762181B1 (en) * | 1999-03-10 | 2004-07-13 | Daiichi Pharmaceutical Co., Ltd. | Aminomethylpyrrolidine derivatives having aromatic substituents |
| CN1354746A (en) * | 1999-05-04 | 2002-06-19 | 日进素材产业株式会社 | 6.7-disubstituted-5,8-quinolinedione derivatives as antifungal agent |
| US20040063754A1 (en) * | 2000-11-20 | 2004-04-01 | Hisashi Takahashi | Dehalogeno compounds |
| CN1491944A (en) * | 2003-09-19 | 2004-04-28 | 中国医学科学院医药生物技术研究所 | 5-amino-8-methoxy quinolone carboxylic acid derivatives and its preparation |
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