CN1075946C - Process for preparing synergetic antimalarial-compound naphthoquine phosphate - Google Patents
Process for preparing synergetic antimalarial-compound naphthoquine phosphate Download PDFInfo
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- CN1075946C CN1075946C CN97111840A CN97111840A CN1075946C CN 1075946 C CN1075946 C CN 1075946C CN 97111840 A CN97111840 A CN 97111840A CN 97111840 A CN97111840 A CN 97111840A CN 1075946 C CN1075946 C CN 1075946C
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- plasmodium
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- 230000002195 synergetic effect Effects 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 title 1
- 201000004792 malaria Diseases 0.000 claims abstract description 34
- 229960004191 artemisinin Drugs 0.000 claims abstract description 25
- 229960000981 artemether Drugs 0.000 claims abstract description 7
- 229960002970 artemotil Drugs 0.000 claims abstract description 7
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 claims abstract description 7
- 229960002521 artenimol Drugs 0.000 claims abstract description 7
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims abstract description 7
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 30
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- QTYPWHKJEDCDNH-UHFFFAOYSA-N 2-[(tert-butylamino)methyl]-4-[(7-chloroquinolin-4-yl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol;phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(O)=O.C1CCCC2=C(O)C(CNC(C)(C)C)=CC(NC=3C4=CC=C(Cl)C=C4N=CC=3)=C21 QTYPWHKJEDCDNH-UHFFFAOYSA-N 0.000 claims description 4
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- 150000001875 compounds Chemical class 0.000 abstract description 30
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to a preparing method of synergetic antimalarial-compound naphthoquine phosphate, which mixes a naphthoquine phosphate compound with synergetic value, an artemisinin compound with synergetic value, the derivant of the artemisinin compound (or artesunate, artemether, arteether, dihydroartemisinin) and an additive in accordance with the specification of pharmacology to make a compound prescription. Thus, the effect of the compound prescription on treating the malaria is increased.
Description
The present invention relates to a kind of preparation method of synergetic antimalarial-compound naphthoquine phosphate.
Compound naphthoquine phosphate is (I) to be combined in the doses ratio with the artemisine antimalarial compound (II) with same potentiation malaria effect value by the antimalarial NAPHTHOQUINE PHOSPHATE with potentiation malaria effect value (being called for short the naphthols quinoline).
NAPHTHOQUINE PHOSPHATE is a naphthane phenols antimalarial compound that is not widely used as yet in the antimalarial field, is a kind of agent for killing of plasmodium blood schizont (phorozoon) of new construction type.This medical instrument has following characteristics: 1. subtertian malaria that strain causes to multiple Drug resistance plasmodium and tertian malaria all have obvious curative effects; 2. clinical application amount less (adult treatment total amount 0.8-1.0 gram, preventive dose are the 0.4-0.5 gram); 3. hold and imitate malaria effect, patient's cure rate height (under above-mentioned dosage, cure rate reaches 98-100%); 4. there is the effect of potentiation malaria to be worth (with other antimalarial, especially the effect of tangible potentiation malaria is arranged) with artemisinin-based antimalarial drug 5 usefulness; Its weak point is that to kill plasmodium speed slow than artemisine, if give with heavy dose of or can produce one when surpassing therapeutic dose (more than 1 gram) and cross liver damage.
Artemisine compounds (II) comprises that (R is-O-(C=O) (CH for the arteannuin (R=O) that comes out from Herba Artemisiae annuae (Artemisia amua L) separation and Extraction and semi-synthetic derivant artesunate
2)
2COONa), Artemether (R is O) (CH
3) (R is O-CH to arteether
2CH
3) and dihydroartemisinine (R is OH), be the new construction that same class contains peroxy-radical sesquiterpene ester, be the agent for killing of schizont (phorozoon) in the plasmodium blood.The malaria characteristics of this compounds are: it is effective 1. to resist the chloroquine pernicious malaria; 2. it is fast plasmodium erythrocytic stage phorozoon to be killed speed, and it is fast therefore to control the malaria symptom; 3. there is the effect of potentiation malaria to be worth (effect of tangible potentiation malaria being arranged) with naphthols quinoline 5 usefulness, its shortcoming is that parasite killing is not thorough when the general treatment dosage and the short course of treatment (3 days), protozoon recrudescence rate height (reaching more than 50%), need escalated dose and extend the period of treatment (5-7 days) could thoroughly kill plasmodium and improve cure rate, but therefore the often increase that causes drug toxicity owing to the increase and the prolongation of the course of treatment of dosage is greatly limited in clinical practice.
In addition, developed immunity to drugs worm strain and bamboo telegraph spreads the current pernicious malaria that accounts for world's malaria morbidity sum 80% to antimalarial commonly used, though each state all prevents and treats the new antimalarial agent of Drug resistance worm strain in development, but plasmodium is fast more than the speed of development new drug to the speed that new drug develops immunity to drugs, so that shortens greatly the service life of new drug.In view of this, must adopt two or more medicine that is worth by potentiation to form the research channel of Synergistic compound for the research of new antimalarial agent.
The compound recipe that the present invention proposes is compatible through experimental results demonstrate the naphthols quinoline and the arteannuin in the artemisine compounds, or derivatives thereof artesunate, Artemether, arteether or the dihydroartemisinine that have the effect of potentiation malaria to be worth mutually, form compound recipe in the doses ratio, make tablet, be used for the treatment of and prevent various malaria (comprising drug-fast subtertian malaria and tertian malaria).
In view of having, the naphthols quinoline have characteristics and the artemisine compounds of holding the effect killing action (to comprise artemisic succinate to plasmodium erythrocytic stage phorozoon, Artemether, arteether, arteannuin and dihydroartemisinine) pair advantage that plasmodium erythrocytic stage phorozoon is killed fast all arranged, its purpose is to bring into play the different advantage of two each tool of class antimalarial, the weakness that respectively has sublated is (slower as naphthols quinoline parasite killing speed, though the artemisine parasite killing is thorough soon and not, protozoacide recrudescence rate height), therefrom find out two medicine proper dosage ratios, form the compound recipe that potentiation is arranged, to bring into play the mutual supplement with each other's advantages effect of two medicines in the malaria treatment, can delay speed and time that plasmodium develops immunity to drugs, can reach higher cure rate again, and can utilize the characteristics of its lasting effect, as long-acting preventive drug.
Show that to the curative effect of Mus malaria, monkey malaria and people's subtertian malaria with to the acute and long term toxicity test of Mus, Canis familiaris L. naphthols quinoline and arteannuin (or artesunate or Artemether or arteether or dihydroartemisinine) are 1 to the potentiation dosage ratio of Mus malaria: 1-50 by compound naphthoquine phosphate; Potentiation dosage ratio to monkey malaria and subtertian malaria is 1: the compound recipe that 1-50 prepares with this ratio carries out toxicity test proof nothing and increases malicious phenomenon.
Naphthols quinoline and arteannuin are with optimum dose proportion, do not influence under drug effect or the toxigenous solid adjuvant material situation in interpolation, are mixed with compound tablet.
The technical scheme and the embodiment of compound naphthoquine phosphate of the present invention are as follows:
Embodiment one: the drug dose proportioning of compound naphthoquine phosphate
(1) determines that by animal experiment the dosage ratio of this compound recipe naphthols quinoline and artemisine compounds (arteannuin or artesunate or Artemether or arteether or dihydroartemisinine) concerns and two medicine potentiations
The white mice that infects with Bai Shi plasmodium (Plasmodium berghei) is a test model, with Orthogonal Experiment and Design and inhibition test method on the 4th, measure each addition dosage group plasmodium suppression ratio, and obtain the ED50 and the ED90 of each serial addition dosage with the linear regression equation computing method respectively.
(2) use addition line graphic record to analyze the type of action of compound recipe
On vertical coordinate and abscissa line, mark the ED90 of two single medicines respectively, and it is linked to be line as the phase ledger line.The person was for being summation action between medicine near the point of all two medicine addition dosage group ED90 was positioned at the phase ledger line; Be positioned at below the phase ledger line and and potentiation arranged between medicine away from this line person; Be positioned at phase ledger line top, and be antagonism between medicine away from this line person.
(3) the determining of two best proportionings of single medicine in exponential calculating of potentiation and the compound recipe
Carrying out the medicine contrast test below the phase ledger line or near the point of phase ledger line, and with prescription list medicine ED50-ED90. respectively with compound recipe in the ratio of corresponding single medicine ED50, ED90 dosage be the potentiation index.Select the potentiation index of single medicine in the compound recipe all to be the optimal dose ratio greater than compound recipe two single pharmaceutical quantities ratios of 2 above the higher person.
Obtain anti-Mus malaria two medicine optimum dose proportions of this compound recipe and potentiation index by this formula.
Embodiment two: the evaluating drug effect of compound naphthoquine phosphate
(1) Mus malaria evaluating drug effect
" inhibition test on the 4th " method of employing, in infecting the plasmodial white mice of Bai Shi, measure compound naphthoquine phosphate and single medicine oral administration (filling stomach) thereof, once a day, continuous four days, measure ED50, the ED90 (mg/kg/day.MKD) of Bai Shi normal strain of Mus malaria and anti-chloroquine strain, and obtain resistance index (or claiming the resistant multiple) I50, I90. divided by normal strain ED50 or ED90 with anti-chloroquine strain ED50 or ED90
(2) monkey malaria evaluating drug effect
Use the DavidsonShi method, set different three the dose ratio compatibility groups of naphthols quinoline and two single pharmaceutical quantities groups, every group of 3 monkeys with arteannuin.Infect Rhesus Macacus with Nuo Shi plasmodium cynomolgi erythrocytic stage phorozoon, when plasmodium erythrocyte parasitic rate rises to when higher oral (filling stomach) single administration.Observe each monkey protozoon 24 hours rates of descent, clearance times and no return (or claim resume combustion) situation was arranged in 105 days,, also promptly obtain the optimum dose proportion of compound recipe two medicines to judge every naphthols quinoline and the arteannuin compatibility person that obtains the optimum curative effect.
(3) to the evaluating drug effect of Plasmodium falciparum
Adopt chloroquine sensitivity in vivo test (observing 28 days) method, set different four dosage than 5 usefulness with naphthols quinoline, arteannuin tablet, and two single medicines, an oral administration is treated no complication malaria patient.With 24 hours rates of descent of fever time, plasmodium, clearance time and in 28 days the plasmodium phorozoon have no return (or resume combustion) to judge drug effect.Every person that obtains the optimum curative effect also is naphthols quinoline and the obtained optimum dose proportion of arteannuin 5 usefulness.
Embodiment three: the test of compound naphthoquine phosphate parasite killing speed
After adopting a gastric infusion treatment of white mice of the normal plant height density of infected mice malaria parasitemia, observe the protozoon number change, measure that plasmodium descends 90%, clearance time and negative conversion rate or resume combustion time, and the insecticidal effect of compound recipe and single medicine relatively.
Embodiment four, compound naphthoquine phosphate are tested the curative effect of malaria
Adopt single administration, observe 30 days method continuously, behind the gastric infusion of mice that infects the normal strain of plasmodium, checked plasmodium mass formed by blood stasis situation at interval in 3-4 days, do not occur the protozoon person in the blood until 30 days for curing fully.
Embodiment five: the compound naphthoquine phosphate Drug resistance is observed
(1) cross-resistance
With PetersShi " inhibition test on the 4th " method, the single medicine naphthols quinoline of compound recipe and component thereof and arteannuin are resisted the Mus malaria of chloroquine (RCQ), anti-naphthols quinoline (RNQ) and (RQ) strain of anti-arteannuin and sensitive strain respectively and carry out the medicaments insensitive property testing.For the ratio of drug resistance strain protozoon with sensitive strain protozoacide ED90, obtain resistance index (being the resistant multiple) I90 with each medicine, thereby judge the Drug resistance degree of plasmodium to compound medicine, its standard is:
I90=1 is responsive
I90=2-10 is slight resistance
I90=11-100 is the moderate resistance
I90＞100 are the severe resistance
(2) delaying drug resistance
With oral (filling stomach) administration, the drug dose incremental method is cultivated the Bai Shi Mus plasmodium of medicaments insensitive, makes it to produce the drug resistance strain, measures time and resistance intensity that its resistance occurs then.
Embodiment six: the compound naphthoquine phosphate pharmacological toxicology is learned and is estimated
(1) general pharmacology is learned test
With white mice, rat and cat is experimental animal model, and drug dose is with compound recipe 1,10 times to Mus malaria sensitive strain drug effect ED90 (MKD); Other establishes not administration matched group.After animal once oral (filling stomach) administration, carry out every pharmacology index observing and mensuration, i.e. white mice voluntary activity number of times and the situation of change that hot plate causes blood pressure, heart rate, electrocardio and the respiratory frequency of pain action-reaction and rat temperature and cat judged the influence of medicine to neural, cardiovascular and respiratory system.
(2) toxicology test
Carry out the compound recipe acute toxicity and long term toxicity test has or not potentiation to understand this compound recipe according to country's " provisions for new drugs approval " regulations:
1. acute toxicity test
(1) acute toxicity test in mice
White mice is divided into 10 groups at random by body weight, every group 10, male and female half and half, design once oral respectively or each 5 dosage group of two kinds of route of administration of abdomen control injection in naphthols quinoline and arteannuin suitable dose ratio, observe continuously and calculated LD50, LD5 with the Bliss method in 14 days, and with LD50 and ED50, LD5 and ED95 calculate chemotherapeutic index and safety coefficient respectively.
Other establishes naphthols quinoline, each 5 dosage group of arteannuin list medicine, and an oral administration is measured LD50, presses the mixing virulence that the Finney formula calculates compound recipe.Mix virulence value＞2.7 and be potentiation,＜0.4 is the virulence antagonism, and 0.5-2.6 is the virulence summation action.
(2) rat acute toxicity test
Use the Wistar rat, press naphthols quinoline and arteannuin preset proportion and set 5 dosage groups, 10 every group, male and female half and half, once oral (filling stomach) administration was observed 14 days, and record reaction of animals and death toll are calculated LD50, LD95.
(3) Canis familiaris L. acute toxicity test
Select 6 health male, press the compound tablet of preset proportion, establish 6 dosage by Diechman50% metering incremental method with naphthols quinoline and arteannuin than lattice Canis familiaris L., 1 Canis familiaris L. of each dosage, an oral administration was observed 14 days.The record poisoning manifestations continues or extinction time, characteristics and death time.The maximum dose level that poisoning manifestations do not occur is maximum tolerated dose (MTD), causes that dead minimum dose is approximate lethal dose (ALD).Test dead Canis familiaris L. and need do postmortem.
2. long term toxicity test
(1) rat long term toxicity test
Establish 3 dosage groups with naphthols quinoline and arteannuin by preset proportion, with Wistar rat random packet, each 24 of each dosage group and normal control (not administration) groups, male and female half and half, every day oral administration once, continuous 14 days.Observe animal performance every day, after the drug withdrawal 24 hours, live at random for every group and kill 2/3 (each 8 of male and female), residue 1/3 (each 4 of male and female) continue to observe to works in 28 days extremely.
Observation item: situations of change such as animal mental act, activity, fur, every Mus body weight of survey in per 7 days and food ration are once behind the first medicine; Do hematology, blood biochemical and histopathology and bone marrow smear, cut sections for microscopic examination, every inspection data are carried out statistical procedures and significance test, the every check result of analysis-by-synthesis is for compound recipe provides the analysis foundation to the reversibility situation of poisoning fatal dose, toxic dose and the basic security dosage of rat and poisoning target organ, pathological changes.
(2) long term toxicity test of Canis familiaris L.
With health than lattice Canis familiaris L., with the normal control group that naphthols quinoline and arteannuin divide 3 dosage groups to establish not administration in addition by the compound tablet of setting proportioning, every group of 6 Canis familiaris L.s, male and female half and half, every day oral administration once, continuous 14 days.2/3 (each 2 of male and female) are killed in work in 24 hours after the drug withdrawal, remaining 1/3 (each 1 of male and female) continue to observe to works in 28 days extremely.
Observation item: physical signs and clinical manifestation comprise: appetite, feel sick, vomiting, defecation, action gait, the mental status, activity, tic, dead state etc., write down once every day item by item.Body weight, heart rate, appetite, breathing, body temperature etc. are surveyed once weekly.
Blood test, blood biochemical analysis, urinalysis, electrocardiogram, optical fundus, bone marrow smear and section and histopathologic examination etc., all check all processing and significance tests by statistics of data.
Comprehensive every inspection and observed result are determined poisoning fatal dose, toxic dose and basic security dosage and the poisoning target organ of compound recipe to Canis familiaris L., the reversibility situation of pathological changes etc.
Claims (6)
1. a pharmaceutical composition for the treatment of malaria comprises NAPHTHOQUINE PHOSPHATE (I), artemisinin derivative (II) and pharmaceutically acceptable dressing, it is characterized in that the NAPHTHOQUINE PHOSPHATE and the dosage ratio of artemisinin derivative are 1: 1～50,
Wherein, R is oxygen, hydroxyl, O-(C=O) (CH
2)
2COONa, O-CH
3Or O-CH
2CH
3
2. according to the pharmaceutical composition of claim 1, it is characterized in that artemisinin derivative is an arteannuin.
3. according to the pharmaceutical composition of claim 1, it is characterized in that artemisinin derivative is a dihydroartemisinine.
4. according to the pharmaceutical composition of claim 1, it is characterized in that artemisinin derivative is a sodium artesunate.
5. according to the pharmaceutical composition of claim 1, it is characterized in that artemisinin derivative is an Artemether.
6. according to the pharmaceutical composition of claim 1, it is characterized in that artemisinin derivative is an arteether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97111840A CN1075946C (en) | 1997-06-24 | 1997-06-24 | Process for preparing synergetic antimalarial-compound naphthoquine phosphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97111840A CN1075946C (en) | 1997-06-24 | 1997-06-24 | Process for preparing synergetic antimalarial-compound naphthoquine phosphate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1203078A CN1203078A (en) | 1998-12-30 |
| CN1075946C true CN1075946C (en) | 2001-12-12 |
Family
ID=5171910
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97111840A Expired - Lifetime CN1075946C (en) | 1997-06-24 | 1997-06-24 | Process for preparing synergetic antimalarial-compound naphthoquine phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1075946C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327841C (en) * | 2003-02-10 | 2007-07-25 | 沈恒 | Novel compound antimalarial preparation method |
| CN111249275A (en) * | 2020-03-03 | 2020-06-09 | 云南省寄生虫病防治所 | Compatibility scheme of medicine for treating vivax malaria and using method thereof |
| CN113440527B (en) * | 2020-03-24 | 2024-05-28 | 中国科学院上海药物研究所 | Application of naphthoquine or naphthoquine-containing combined preparation in resisting coronavirus |
-
1997
- 1997-06-24 CN CN97111840A patent/CN1075946C/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| 《中国医药工业杂志》，20(8) 1989.8.31 邓蓉仙，"我国近几年抗疟药研究新进展" * |
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| Publication number | Publication date |
|---|---|
| CN1203078A (en) | 1998-12-30 |
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