CN102283845B - Application of ectoine and derivatives thereof in preparing tuberculosis treatment medicine - Google Patents
Application of ectoine and derivatives thereof in preparing tuberculosis treatment medicine Download PDFInfo
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- tetrahydropyrimidine
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- 239000003814 drug Substances 0.000 title claims abstract description 28
- 201000008827 tuberculosis Diseases 0.000 title claims abstract description 12
- WQXNXVUDBPYKBA-YFKPBYRVSA-N ectoine Chemical compound CC1=[NH+][C@H](C([O-])=O)CCN1 WQXNXVUDBPYKBA-YFKPBYRVSA-N 0.000 title abstract description 9
- WQXNXVUDBPYKBA-UHFFFAOYSA-N Ectoine Natural products CC1=NCCC(C(O)=O)N1 WQXNXVUDBPYKBA-UHFFFAOYSA-N 0.000 title abstract description 6
- 230000002685 pulmonary effect Effects 0.000 claims description 6
- 229960003350 isoniazid Drugs 0.000 abstract description 9
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 abstract description 9
- 210000004072 lung Anatomy 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 238000001647 drug administration Methods 0.000 abstract 2
- NGFIWZGOPMUCQD-UHFFFAOYSA-N CC1=NC=C(C(=N1)C(=O)O)O.C1(C2C(C(=O)O1)=CCCC2)=O Chemical compound CC1=NC=C(C(=N1)C(=O)O)O.C1(C2C(C(=O)O1)=CCCC2)=O NGFIWZGOPMUCQD-UHFFFAOYSA-N 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 32
- 241000193830 Bacillus <bacterium> Species 0.000 description 15
- BVWAOXGNDVRQSO-UHFFFAOYSA-N 3-hydroxy-2,6-dihydro-1h-pyrimidine Chemical compound ON1CNCC=C1 BVWAOXGNDVRQSO-UHFFFAOYSA-N 0.000 description 13
- 241001597008 Nomeidae Species 0.000 description 11
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 11
- JQXXHWHPUNPDRT-YOPQJBRCSA-N chembl1332716 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CCN(C)CC1 JQXXHWHPUNPDRT-YOPQJBRCSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229960001225 rifampicin Drugs 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 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 6
- 239000002609 medium Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- GTPQXTSQORFWTG-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine-4-carboxylic acid Chemical compound OC(=O)C1NCNC=C1 GTPQXTSQORFWTG-UHFFFAOYSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 4
- 210000002421 cell wall Anatomy 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960003405 ciprofloxacin Drugs 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000581650 Ivesia Species 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- KGTSLTYUUFWZNW-PPJQWWMSSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate pyridine-4-carbohydrazide Chemical compound NNC(=O)c1ccncc1.CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c(O)c(\C=N\N4CCN(C)CC4)c(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C KGTSLTYUUFWZNW-PPJQWWMSSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
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- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 230000000249 desinfective effect Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
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- 238000012827 research and development Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000005326 tetrahydropyrimidines Chemical class 0.000 description 2
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- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- -1 amine butanols Chemical class 0.000 description 1
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- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001355 anti-mycobacterial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 239000003926 antimycobacterial agent Substances 0.000 description 1
- 229940058307 antinematodal tetrahydropyrimidine derivative Drugs 0.000 description 1
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- 208000030208 low-grade fever Diseases 0.000 description 1
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- 230000017074 necrotic cell death Effects 0.000 description 1
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- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel application of ectoine and derivatives thereof, i.e. the application of ectoine and derivatives thereof in preparing tuberculosis treatment medicine, wherein the ectoine derivatives contain 1, 4, 5, 6-tetrahydrophthalic anhydride-2-methyl-5-hydroxy-4-pyrimidine carboxylic acid. The lung drug administration effect is better, the dose of 1-100mg/kg has good safety and effectiveness, the drug administration dose of 1-10mg/kg can play good curative effects, and the application of ectoine and derivatives thereof in preparing tuberculosis treatment medicine has the synergistic effect with isoniazide.
Description
Technical field
The present invention relates to the application in preparation tuberculosis treatment medicine of tetrahydropyrimidine and derivant thereof.
Background technology
Pulmonary tuberculosis is the chronic infectious disease that is caused by tubercule bacillus, can involve a plurality of organs of whole body, but the most common with pulmonary tuberculosis.Its pathological characteristic is tubercle and caseous necrosis, is prone to form the cavity.Mostly clinically is chronic process, and minority can suddenly play morbidity.Respiratory systems performances such as low grade fever, General Symptoms such as weak and cough, spitting of blood are often arranged.
Phthisical chemotherapy is the application of SCC particularly, make human with phthisical struggle in obtained the achievement that attracts people's attention.But along with increasing of anti-multiple medicines pulmonary tuberculosis and HIV sufferers, the rise of incidence of tuberculosis has for the third time appearred in the whole world, and control has brought great difficulty to tuberculosis.World Health Organization (WHO) thinks that at present, fashion trend has appearred in pulmonary tuberculosis etc., and various countries should pay attention to the research and development of phthisical control and tuberculosis treatment medicine.
Tubercule bacillus has begun to occur drug resistance to isoniazid and the rifampicin that in the pulmonary tuberculosis control, once played a significant role; Though QNS, aminoglycosides medicine and rifamycin drug etc. all have certain therapeutical effect to pulmonary tuberculosis; But it treats lack of specific; Curative effect is limited, often needs multiple medication combined administration just certain therapeutic effect can be arranged.
The research and development of new antituberculotics have begun to cause paid certain attention at present, but still lack special certain, many target spots, medicine more efficiently.
Tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry by name 1; 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4; 5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5; 6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid; Be the amino acid derivativges of finding in 1985, in recent years, tetrahydropyrimidine has been used to cosmetics, as preserving moisture or the sun-proof articles use.
Summary of the invention
To above-mentioned prior art, the purpose of this invention is to provide a kind of new purposes of tetrahydropyrimidine and derivant thereof, tetrahydropyrimidine and derivant thereof the application in preparation tuberculosis treatment medicine specifically.
For realizing above-mentioned purpose, the technical scheme that the present invention adopts is:
The application in preparation tuberculosis treatment medicine of tetrahydropyrimidine and derivant thereof.
Said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
The administering mode of said tetrahydropyrimidine and derivant thereof is a pulmonary administration.
The dosage of said tetrahydropyrimidine and derivant thereof is (0.5～100) mg/kg.
The dosage of said tetrahydropyrimidine and derivant thereof is (1～10) mg/kg.
The discovery that the inventor is surprised under study for action when tetrahydropyrimidine and derivant pulmonary administration thereof, has unexpected therapeutical effect to pulmonary tuberculosis, and during with the isoniazid administering drug combinations, more remarkable treatment effect.
The inventor finds in studying in vivo and in vitro that tetrahydropyrimidine has multiple therapeutical effect to pulmonary tuberculosis, and has antiinflammatory, inhibition pulmonary fibrosis, increases the pharmacological actions such as permeability of bacillus tubercle cell wall.Therefore, tetrahydropyrimidine produce chemical sproof probability can be littler.
Tetrahydropyrimidine described in the technical scheme of the present invention, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name; 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1; 4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1; 4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid.1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is that those skilled in the art are known.
Term used herein " pulmonary administration " is promptly through the lung administration, and this is that those skilled in the art are known.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explanation.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.
Embodiment 1 tetrahydropyrimidine and derivant thereof are to phthisical external pharmacodynamics test
Bacillus tuberculosis's reference culture H37Rv is inoculated in the Luo Shi slant medium, cultivates for 4 weeks for 37 ℃.Get centrifugal back of an amount of culture and normal saline mixing, precipitate and get upper strata bacterium liquid after 20 minutes, put in the Luo Shi slant medium that contains the variable concentrations medicine, inoculum density is 10
6CFU/point, 37 ℃ when being cultured to the growth control pipe and having bacterium colony to form, the observed and recorded result.
Wherein the Luo Shi slant medium method for preparing of drug is identical with common Luo Shi slant medium method for preparing, and medicine adds culture medium before culture medium adds test tube.
Experimental group institute medicament is respectively: tetrahydropyrimidine, hydroxy tetrahydro pyrimidine, isoniazid and rifampicin, and every kind of medicine is all set a plurality of concentration; The matched group microbionation is in the Luo Shi slant medium of drug not, and inoculum density is 1 * 10
6CFU/point.
Test index comprises the minimum inhibitory concentration (MIC) of various medicines and the morphological feature of each group H37Rv cell.
Result of the test is seen table 1.
Table 1 respectively organize medicine minimum inhibitory concentration (MIC, mg/L)
| Tetrahydropyrimidine | The hydroxy tetrahydro pyrimidine | Isoniazid | Rifampicin | |
| MIC | 0.15 | 0.12 | 0.28 | 2 |
Visible by table 1, the fungistatic effect to Bacillus tuberculosis's reference culture H37Rv of tetrahydropyrimidine and hydroxy tetrahydro pyrimidine is significantly higher than present widely used antimycobacterial drug isoniazid and rifampicin.
Morphological observation is given, and the cell wall space of tetrahydropyrimidine and hydroxy tetrahydro pyrimidine group Bacillus tuberculosis reference culture H37Rv is significantly greater than matched group, isoniazid group and rifampicin group.Prompting tetrahydropyrimidine and hydroxy tetrahydro pyrimidine have certain effect to bacteria cell wall, and can improve the permeability of bacillus tubercle cell wall, help medicine and get into antibacterial, the performance antibacterial action.
Embodiment 2 tetrahydropyrimidines and derivant thereof are to the external pharmacodynamics test of anti-multiple medicines tubercule bacillus
MDR-TB bacterial strain (anti-isoniazid, rifampicin, different amine butanols, streptomycin bacterial strain) is from Henan Province's tuberculosis prevention and treatment institute.Inoculation in the Luo Shi slant medium, was cultivated for 5 weeks for 37 ℃, and inspection colony growth situation selects the vigorous culture medium of colony growth to be divided into 3 groups, adds tetrahydropyrimidine, hydroxy tetrahydro pyrimidine or the ciprofloxacin of 0.2mg/ml respectively.37 ℃ are continued to cultivate observation colony growth situation after 3 days, and calculate bacteriostasis rate.
Each is organized the bacteriostasis rate of medicine and sees table 2.
Table 2 is respectively organized the bacteriostasis rate (%) of medicine
| Tetrahydropyrimidine | The hydroxy tetrahydro pyrimidine | Ciprofloxacin | |
| Bacteriostasis rate | 87.6 | 92.3 | 51.9 |
Visible by table 2, tetrahydropyrimidine and hydroxy tetrahydro pyrimidine are significantly higher than ciprofloxacin to the bacteriostasis of anti-multiple medicines tubercule bacillus.
Embodiment 3 tetrahydropyrimidines and derivant thereof are to pharmacodynamics test in the phthisical body
Experiment uses bacterium to be Bacillus tuberculosis's reference culture H37Ra.
Kunming mouse, female, body weight 18-25g, afterbody with 75% alcohol disinfecting after, the tubercule bacillus suspension 0.2ml of every mouse tail vein injection 1mg/ml.Observed 2 days after the modeling; Select satisfactory 40 mices for use; Be divided into 4 groups by randomization; Every group 10, pulmonary administration gives tetrahydropyrimidine 6mg/kg (EA group), tetrahydropyrimidine 15 mg/kg (EB group), tetrahydropyrimidine 45 mg/kg (EC group), normal saline (S group) and rifampicin 8mg/kg (L group) respectively.Each treated animal administration every day 1 time, administration is 7 days altogether.
Administration finishes back 2 days, observes the mortality rate of each treated animal, and the SABC method is surveyed the T cell subsets, measures the tubercule bacillus number of each treated animal lungs survival then.
The result sees table 3 and table 4.
Respectively organize the mouse T cell subgroup after table 3 tetrahydropyrimidine and the rifampicin administration and change (CFU, 10
4)
| CD4 | CD8 | CD4/CD8 | |
| The EA group | 52.61 | 12.47 | 4.22 |
| The EB group | 57.24 | 12.09 | 4.73 |
| The EC group | 56.40 | 12.42 | 4.54 |
| The S group | 32.16 | 11.02 | 2.92 |
| The L group | 42.97 | 12.10 | 3.55 |
Visible by table 3, CD4 of each dose groups animal of tetrahydropyrimidine and D4/CD8 all are significantly higher than normal saline group and rifampicin group, and the prompting tetrahydropyrimidine can significantly improve the pulmonary tuberculosis immune function of mice.
Tubercule bacillus number (CFU, 10 of lungs survival after table 4 tetrahydropyrimidine and the rifampicin administration
4)
| The EA group | The EB group | The EC group | The L group | |
| The tubercule bacillus number of lungs survival | 1.17 | 1.19 | 2.04 | 10.21 |
Visible by table 4, tetrahydropyrimidine is disliked therapeutical effect significantly owing to rifampicin to mouse lung tuberculosis model, and tetrahydropyrimidine all can be brought into play therapeutical effect preferably at bigger dosage range.
Each treated animal mortality rate is zero.
Above result shows that tetrahydropyrimidine has therapeutical effect to pulmonary tuberculosis in more heavy dose of scope, and safety is higher.
Embodiment 4 hydroxy tetrahydro pyrimidines and isoniazid administering drug combinations are to pharmacodynamics test in the phthisical body
Kunming mouse, female, body weight 18-25g, afterbody with 75% alcohol disinfecting after, the tubercule bacillus suspension 0.2ml of every mouse tail vein injection 1mg/ml.Observed 2 days after the modeling; Select satisfactory 20 mices for use, be divided into 2 groups, 10 every group by randomization; Pulmonary administration gives hydroxy tetrahydro pyrimidine 8 mg/kg (E group), isoniazid 8mg/kg (I group) and compositions (hydroxy tetrahydro pyrimidine 4 mg/kg add isoniazid 4mg/kg, the C group) respectively.Each treated animal administration every day 1 time, administration is 4 days altogether.
Administration finishes back 2 days, measures the tubercule bacillus number of each treated animal lungs survival.
The result sees table 5.
Tubercule bacillus number (CFU, 10 of each treated animal lungs survival after table 5 administration
4)
| The E group | The I group | The C group | |
| The tubercule bacillus number of lungs survival | 1.29 | 8.35 | 0.42 |
Visible by table 5, there are synergism in hydroxy tetrahydro pyrimidine and isoniazid, and the two administering drug combinations can significantly improve the inhibitory action to tubercule bacillus.
Claims (4)
1.1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5, the application of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic in preparation tuberculosis treatment medicine.
2. application according to claim 1 is characterized in that: said 1,4,5, and 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5, the administering mode of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is a pulmonary administration.
3. application according to claim 1 is characterized in that: said 1,4,5, and 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5, the dosage of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is (0.5～100) mg/kg.
4. application according to claim 1 is characterized in that: said 1,4,5, and 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5, the dosage of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is (1～10) mg/kg.
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| CN102961380A (en) * | 2012-11-16 | 2013-03-13 | 济南环肽医药科技有限公司 | Pharmaceutical composition for treating acute lung injury |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201035070A (en) * | 2009-03-30 | 2010-10-01 | Astellas Pharma Inc | Pyrimidine compound |
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| TW201035070A (en) * | 2009-03-30 | 2010-10-01 | Astellas Pharma Inc | Pyrimidine compound |
Non-Patent Citations (1)
| Title |
|---|
| Ulrich Sydlik et.al..The Compatible Solute Ectoine Protects against Nanoparticle-induced Neutrophilic Lung Inflammation.《AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE》.2009,第180卷第29-35页. * |
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|---|---|---|---|---|
| CN102961380A (en) * | 2012-11-16 | 2013-03-13 | 济南环肽医药科技有限公司 | Pharmaceutical composition for treating acute lung injury |
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