CN101346381A - New anti-malaria derivatives of 4-aminoquinoline - Google Patents
New anti-malaria derivatives of 4-aminoquinoline Download PDFInfo
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- CN101346381A CN101346381A CNA2006800486047A CN200680048604A CN101346381A CN 101346381 A CN101346381 A CN 101346381A CN A2006800486047 A CNA2006800486047 A CN A2006800486047A CN 200680048604 A CN200680048604 A CN 200680048604A CN 101346381 A CN101346381 A CN 101346381A
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Abstract
New derivatives of 4-aminoquinoline which have a general formula A-X-Y-T where A is a 4-aminoquinolinic nucleus, X and Y are spacers and T represents a nitrogenous ring or an aminic group, substituted if necessary. These are powerful antimalarial compounds active on both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.
Description
Technical field
The present invention relates to novel antimalarial compound, particularly have the derivative of the 4-quinolylamine of western pyridine ring in quinolixiding and the pyrroles.
Background of invention
In developing country, malaria remains the most serious wherein a kind of disease, and 1 to 3 million people's death is arranged every year, 3 to 500,000,000 cases.The most serious malaria form is caused by plasmodium falciparum.
Antimalarial two kinds of the most frequently used medicines are chloroquine and sulfadoxine-pyrimethamine, but have become the area of endemic in most of malaria, and their effect becomes worse and worse, and the result is that the M ﹠ M relevant with malaria is more and more higher.The major cause of this shortage effect has generally had tangible resistance and structure unrelated drugs to exist crossed resistance relevant with parasite to common anti-malaria medicaments.
Resist malaria, very need new medicine, particularly for the effective new drug of drug resistant falciparum malaria protozoon bacterial strain.Ideal situation is, it is effective that new malaria medicine should resist medicated strain, reasonably playing a role in the time (ideal is 3 days or following), obtain good therapeutic action, child, pregnant woman are good to its resistance, but also cheap (D.A.Fidock etc., Antimalarial drug discovery:efficacy models forcompound screening, Nature Reviews 3,509-520 (2004)).
Summary of the invention
The 4-aminoquinoline derivatives anti-malarial of novelty of the present invention is effectively, and also is activated for the plasmodium falciparum strain of anti-chloroquine.
Compound of the present invention such as following general formula are represented:
In the formula,
R is Cl, Br, trifluoromethyl;
M be 0 or part in Au, Rh, Ru; Described part is selected from PR '
3, wherein: when M was gold, R ' was phenyl or C2-C4 alkyl; When M is rhodium, R ’ Shi Ring octadiene; When M was ruthenium, R ' was second same quinoline acidic group; When M is gold, can there be PF
6 -Or NO
3 -Group; When M is rhodium or ruthenium, can there be Cl
-
X is the group shown in the following formula,
Wherein R2 and R3 can be identical or different, can be H or straight or branched alkyl, are preferably (CH
2) n-CH
3, wherein n=0-10 better is 1-3, or with-CH
3,-OCH
3,-CF
3, F, Cl, Br are single replaces or disubstituted phenyl ring;
Y is CH
2-(NH)
n-(CH
2)
m, n=0,1 wherein, m=0-10 is preferably 1-3;
T is the group shown in the following formula:
T also can be the group shown in the following formula,
T can also be the group shown in the following formula,
Wherein, R4 and R5 can be identical or different, can be H or straight or branched alkyl, are preferably (CH
2) n-CH
3, n=0-5 wherein, perhaps R4 and R5 form ring together, for example 5 of pyrrolidines yuan of rings.
Preferred compounds of the invention are following compounds:
(7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(four Hydrogen-pyrrolizine-7a-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine;
(7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(eight Hydrogen-quinolizine-1-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine;
(7-chloro-quinolyl-4)-[2,5-dimethyl-3-(tetramethyleneimine-1-ylmethyl)-pyrroles-1-yl]-amine;
(7-chloro-quinolyl-4)-(3-diethylamino methyl-2,5-dimethyl-pyrroles-1-yl)-amine;
[3-(tributyl amino-methyl)-2,5-dimethyl-pyrroles-1-yl]-(7-chloro-quinolyl-4)-amine;
(7-chloro-quinolyl-4)-(3-diethylamino methyl-2-methyl-5-phenyl-pyrroles-1-yl)-amine;
(7-chloro-quinolyl-4)-(3-diethylamino methyl-2-phenyl-5-methyl-pyrroles-1-yl)-amine.
According to the present invention, above-mentioned two kinds of compounds (7-chloro-quinolyl-4)-(3-diethylamino methyl-2-methyl-5-phenyl-pyrroles-1-yl)-amine and (7-chloro-quinolyl-4)-(3-diethylamino methyl-2-phenyl-5-methyl-pyrroles-1-yl)-amine can obtain with form of mixtures, and their ratios in mixture can be different from confirmable.Advantageously, above-claimed cpd can be to use individually, also can form the mixture of variable ratio and uses.
7-chloro-N-(2-methyl-5-phenyl-3-(tetramethyleneimine-1-ylmethyl)-1H-pyrroles-1-yl) quinoline-4-amine
Vitro test the effect of compound of the present invention for the plasmodium falciparum strain of and anti-chloroquine responsive to chloroquine, their IC
50Value is between 10 to 200ng/ml.
The abdominal cavity give with oral compound of the present invention after, the body build-in test their effect, find they effect and chloroquine quite or better.In addition, the toxicity of these compounds in mammalian cell (WEHI clones 13 mouse cells) is very low, its IC
50>10000nM.
Pharmacy acceptable salt, for example mineral acid and organic acid, amino acid whose salt also constitute a part of the present invention.Preferable salt is hydrochloride, phosphoric acid salt, vitriol, Citrate trianion and fumarate.
The particular case of Zhi Liao disease or state as required, the amount that patient accepts compound of the present invention is that treatment is gone up effectively and well-tolerated, this can be determined by those skilled in the art.For example, compound per daily dose of the present invention is approximately 1 to 60mg/kg, is preferably 3 to 30mg/kg.
Compound of the present invention also can use with the form of capacity formulation, and the character of use depends on selected medication.
According to conventional methods, adopt compatible pharmaceutically acceptable vehicle or carrier to can be made into pharmaceutical compositions.
For example, pharmaceutical compositions comprises capsule, tablet, syrup, pulvis and granula, make instant solution, injectable, rectum gives and nose in the preparation that gives.Preferred medication is oral.
Following examples are unrestricted, only further describe the present invention, for those skilled in the art preparation with use compound of the present invention.
Embodiment
Synthesizing of embodiment 1. (7-chloro-quinolyl-4)-(2,5-dimethyl-pyrroles-1-yl)-amine
767mg (6.72mmoles) acetonyl-acetone is added in the suspension of being made up of 5.6ml Glacial acetic acid and 1.084g (5.6mmoles) 7-chloro-4-diazanyl quinolylamine (Aldrich).This suspension is heated to 65 ℃, kept 3 hours.Evaporate acetic acid, roughage reclaims with the water of ammoniacal liquor alkalization.Filter to isolate throw out, wash with water, silica gel flash chromatography method purifying, the eluent mixture that this chromatography adopts is the methylene dichloride that contains 1% methyl alcohol.Use the diethyl ether washed product, its fusing point is 225.8-227.5 ℃.
Embodiment 2. (7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(eight Hydrogen-quinolizine-1-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine synthetic
Putting into the amino lupinane dihydrochloride of 530mg (2.2mmoles) in the 10ml round-bottomed flask (makes in the method that Farmaco Ed.Sci. describes according to people such as F.Sparatore, 1969,24, p.587-621), 0.19ml (2.2mmoles) 37% formaldehyde and 0.67ml Glacial acetic acid.Mixture reacts under agitation condition, transfers to then in the 50ml two neck round-bottomed flasks that contain 544mg (2mmoles) (7-chloro-quinolyl-4)-(2,5-dimethyl pyrrole-1-yl)-amine (method of pressing embodiment 1 is made).Under nitrogen atmosphere, reaction mixture stirred 2 hours.The roughage water that obtains reclaims, and the chloroform extraction suspension is used in the alkalization of 20% sodium hydroxide in separatory funnel.After the sodium sulfate dehydration, organic phase is evaporated to drying.Silica gel purification solid, elutriant are CH
2Cl
2, CH
3OH and NH
3(96: 3.6: 0.4) mixture.Component after the evaporation is washed with diethyl ether, obtains product, 188-191 ℃ of its fusing point.
Synthesizing of embodiment 3. (7-chloro-quinolyl-4)-(3-diethylamino methyl-2,5-dimethyl-pyrroles-1-yl)-amine
In the 5ml flask, put into 0.16ml (1.5mmoles) diethylamine, 0.13ml (1.5mmoles) 37% formaldehyde and 0.5ml Glacial acetic acid.The solution that obtains reacts under 0 ℃ and agitation condition, is transferred to then in the 50ml flask that contains 408mg (1.5mmoles) (7-chloro-quinolyl-4)-(2,5-dimethyl-pyrroles-1-yl)-amine (press the method making of embodiment 1).Nitrogen atmosphere and 25 ℃ of following stirrings 2 hours.Mixture is suspended from water and the 2N sodium hydroxide, arrives the alkaline pH value until it, uses dichloromethane extraction then.After the evaporation organic phase, residue silicon-dioxide column purification, elutriant are CH
2Cl
2, CH
3OH and NH
3(97: 2,7: 0,3) mixture.Component after the evaporation obtains product with the mixture washing in 70: 30 of diethyl ether/sherwood oil, and its fusing point is 248-251 ℃, can decompose.
Embodiment 4.[3-(tributyl amino-methyl)-2,5-dimethyl-pyrroles-1-yl]-(7-chloro-quinolyl-4)-amine synthetic
In the 5ml round-bottomed flask, put into 0.17ml (1.65mmoles) TERTIARY BUTYL AMINE, 0.14ml (1.65mmoles) 37% formaldehyde and 0.5ml Glacial acetic acid.The solution that obtains is reacted, be transferred to then in the 50ml round-bottomed flask that contains 408mg (1.5mmoles) (7-chloro-quinolyl-4)-(2,5-dimethyl-pyrroles-1-yl)-amine.Reaction is 2 hours under nitrogen atmosphere and agitation condition.The roughage water that obtains reclaims, the alkalization of 20% sodium hydroxide.The suspension that obtains is transferred to separatory funnel, uses dichloromethane extraction.After the sodium sulfate dehydration, organic phase is evaporated to drying, the solid that obtains silica gel flash chromatography method purifying, elutriant is CH
2Cl
2, CH
3OH and NH
3(96: 3.6: 0.4) mixture.The product that obtains reclaims with hexanaphthene/diethyl ether at 50: 50, filters, and evaporating solns obtains product, 101.2-103.5 ℃ of its fusing point.
Embodiment 5. (7-chloro-quinolyl-4)-[2,5-dimethyl-3-(tetramethyleneimine-1-ylmethyl)-pyrroles-1-yl]-amine
In the 5ml flask, put into 0.13ml (1.5mmoles) tetramethyleneimine, 0.13ml (1.5mmoles) 37% formaldehyde and 0.5ml Glacial acetic acid.The solution that obtains reacts under 0 ℃ and agitation condition, is transferred to then in the 50ml flask that contains 408mg (1.5mmoles) (7-chloro-quinolyl-4)-(2,5-dimethyl-Bi Ka And-1-yls)-amine (press the method making of embodiment 1).Reaction is 2 hours under nitrogen atmosphere and agitation condition.Add 20% sodium hydroxide to mixture, until arriving alkaline pH value, product dichloromethane extraction then.After the evaporation organic phase, thick residue column purification, elutriant is the mixture of methylene dichloride in methyl alcohol, the highest gradient is that concentration is 20%.The fusing point of product is 164-166 ℃.
The preparation of embodiment 6.7-chloro-N-(3-((diethylamino) methyl)-2-methyl-5-phenyl-1H-pyrroles-1-yl) quinoline-4-amine
6.1.2-ethanoyl-4-oxo-4-phenylbutyrate
Put into 20ml anhydrous diethyl ether and 230mg (10mmoles) fine metal sodium in three neck round-bottomed flasks, described flask is furnished with the reflux exchanger by the calcium chloride valve protection.
Splash into 1.52ml (12mmoles) methyl aceto acetate in the 2ml anhydrous diethyl ether to described solution.
Mixture is reflux under nitrogen gas stream and agitation condition, until the sodium Metal 99.5 completely dissolve.Simultaneously, form the sodium salt of white solid methyl aceto acetate.
In the suspension that obtains, splash into by 2g (10mmoles) bromoacetophenone and be dissolved in solution in the 26ml anhydrous diethyl ether, be cooled to room temperature then.After above-mentioned solution added, about 2 hours of mixture reflux leached Sodium Bromide then, and organic phase is through reduction vaporization.
By the silica gel tlc monitoring reaction course, elutriant adopts CH
2Cl
2/ ethyl acetate (10: 1).
Roughage is with silica gel flash chromatography method purifying, and elutriant is a gradient from 60: 40 to 30: 70 hexanaphthene and dichloromethane mixture.Obtain the 2.2g water white oil, its yield is 88%.
(6.2.1-7-chloroquinoline-4-base is amino)-2-methyl-5-phenyl-1H-pyrroles-3-carboxylic acid, ethyl ester
1.2g (6.2mmoles) 2-ethanoyl-4-oxo-4-phenylbutyrate is dropwise splashed in the solution of being made up of 7ml Glacial acetic acid and 1.2g (6.2mmoles) 7-chloro-4-diazanyl quinoline, and described solution is contained in 25ml to be furnished with in the backflow two neck flasks of calcium chloride valve.
In case after above-mentioned adding was finished, the backflow heated solution was 2 hours under nitrogen atmosphere and agitation condition.
By the silica gel tlc monitoring reaction course, elutriant adopts ethyl acetate/hexanaphthene (7: 3).
In reaction process, it is xanchromatic that solution begins, and transfers brown afterwards to.
After 2 hours, solution reclaims with methylene dichloride, and the organic phase that obtains is washed up hill and dale with freezing 1N sodium hydroxide solution, becomes alkalescence until the water that washs usefulness.
Water is reconsolidated, and alkalization once more is with a large amount of dichloromethane extractions.
Reconsolidate organic phase, anhydrous sodium sulfate dehydration steams to dry.
The roughage that obtains silica gel flash chromatography method purifying, elutriant is cyclohexane/ethyl acetate mixture (60: 40).
Behind the recrystallization, obtain the 1.98g solid in diethyl ether/sherwood oil, be white paste, fusing point is 165-168 ℃.The reaction yield is 79%.
(6.3.1-7-chloroquinoline-4-base is amino)-N, N-diethyl-2-methyl-5-phenyl-1H-pyrroles-3-carboxylic acid amides
The three neck round-bottomed flasks that to be furnished with by calcium chloride valve protection reflux exchanger are placed in the ice bath.In flask, put into 6ml dry toluene and 0.081ml (0.78mmoles) diethylamine.Under induction stirring, splash into the trimethyl aluminium of 0.4ml 2M (0.8mmoles) in toluene to frozen soln.
In case above-mentioned adding is finished, allow about 1 hour of solution room temperature reaction under nitrogen atmosphere and agitation condition.
Then, add 250mg (0.62mmoles) 1-(7-chloroquinoline-4-base is amino)-2-methyl-5-phenyl-1H-pyrroles-3-carboxylic acid, ethyl ester, about 24 hours of the suspension that obtains reflux under nitrogen atmosphere and agitation condition forms yellow solution therebetween, transfers brown again to.
By the silica gel tlc monitoring reaction course, elutriant adopts methylene chloride (10: 0.5).
After having spent 24 hours, reclaim solution with a large amount of ethyl acetate, add the freezing sodium hydroxide solution of 1N to organic phase, formation aluminium hydroxide also leaches.
After aqueous phase separation, the organic phase dehydration, and dry.
Roughage silica gel flash chromatography method purifying, elutriant is the mixture that contains the methylene dichloride of 0.5-2% methyl alcohol.
After the washing of ethanol/diethyl ether (7: 3) mixture, obtain 135mg crystalline solid, yield is 51%.
6.4.7-chloro-N-(3-((diethylamino) methyl)-2-methyl-5-phenyl-1H-pyrroles-1-yl) quinoline-4-amine (CM7/I)
With 120mg (0.28mmoles) 1-(7-chloroquinoline-4-base amino)-N, N-diethyl-2-methyl-5-phenyl-1H-pyrroles-3-carboxylic acid amides is divided into small portion and joins 120mg (3.16mmoles) LiAlH in the 10ml anhydrous diethyl ether
4Suspension in, this suspension is placed in the two neck round-bottomed flasks of being furnished with reflux exchanger.After in case above-mentioned adding is finished, about 4 hours of suspension reflux under nitrogen and agitation condition.
By the silica gel tlc monitoring reaction course, elutriant adopts CH
2Cl
2/ methyl alcohol/NH
3(10/1/0.1).
After having spent 4 hours, the reaction suspension is handled with the 1N sodium hydroxide solution, and formation aluminium hydroxide also leaches.
After aqueous phase separation, the organic phase dehydration, and dry.Roughage silica gel flash chromatography method purifying, elutriant is the mixture that contains the methylene dichloride of 1-7% methyl alcohol.
Behind methylene dichloride/petroleum ether mixture, obtain the 76mg solid, but fusing point and decomposition point are between 156.5 to 160 ℃.
The reaction yield is 65.5%.
Similarly, adopt suitable reagent and parent material, synthetic (7-chloro-quinolyl-4)-(3-diethylamino methyl-2-phenyl-5-methyl-pyrroles-1-yl)-amine (CM7/II).
The preparation of embodiment 7.7-chloro-N-(2-methyl-5-phenyl-3-(tetramethyleneimine-1-ylmethyl)-1H-pyrroles-1-yl) quinoline-4-amine
(7.1. 1-(7-chloroquinoline-4-base is amino)-2-methyl-5-phenyl-1H-pyrroles-3-yl) (tetramethyleneimine-1-yl) Mei Shedong (methadone)
The three neck round-bottomed flasks that to be furnished with by calcium chloride valve protection reflux exchanger are placed in the ice bath.In flask, put into 6ml dry toluene and 0.07ml (0.78mmoles) tetramethyleneimine.Under induction stirring, splash into the trimethyl aluminium of 0.4ml2M (0.8mmoles) in toluene to frozen soln.
In case above-mentioned adding is finished, allow about 1 hour of solution room temperature reaction under nitrogen atmosphere and agitation condition.
Then, add 250mg (0.62mmoles) 1-(7-chloroquinoline-4-base is amino)-2-methyl-5-phenyl-1H-pyrroles-3-carboxylic acid, ethyl ester, the suspension that obtains about 24 hours of reflux under nitrogen atmosphere and induction stirring condition forms yellow solution therebetween, transfers the brown precipitation again to.
By the silica gel tlc monitoring reaction course, elutriant adopts methylene chloride (10: 1).
After having spent 24 hours, leach solid also with a large amount of toluene and diethyl ether washing; The control of TLC confirms to obtain needed product.
Obtain the 220mg acid amides at last, yield is 86%.
7.2.7-chloro-N-(2-methyl-5-phenyl-3-(tetramethyleneimine-1-ylmethyl)-1H-pyrroles-1-yl) quinoline-4-amine
200mg (0.28mmoles) (1-(7-chloroquinoline-4-base amino)-2-methyl-5-phenyl-1H-pyrroles-3-yl) (tetramethyleneimine-1-yl) Mei Shedong is divided into small portion joins 230mg (6.06mmoles) LiAlH in the 20ml anhydrous diethyl ether
4Suspension in, this suspension is placed in the two neck round-bottomed flasks of being furnished with reflux exchanger.
After in case above-mentioned adding is finished, about 4 hours of suspension reflux under nitrogen and agitation condition.
By the silica gel tlc monitoring reaction course, elutriant adopts CH
2Cl
2/ methyl alcohol/NH
3(10/1/0.1).
After having spent 4 hours, the reaction suspension is handled with the 1N sodium hydroxide solution, and formation aluminium hydroxide also leaches.
After aqueous phase separation, the organic phase dehydration, and dry.Roughage silica gel flash chromatography method purifying, elutriant is the mixture that contains the methylene dichloride of 1-6% methyl alcohol.
After the diethyl ether washing, obtain the 95mg solid, fusing point is between 172.5 to 176 ℃.
The reaction yield is 51%.
The Au composite of embodiment 8. embodiment 2 compounds
Reflux down, 200mg (0.4mmoles) triphenylphosphine gold trichloride is dissolved in the 20ml acetonitrile, the solution that obtains joins 148.8mg (0.8mmoles) Potassium Hexafluorophosphate (KPF
6) in, heated 30 minutes.Add 371mg (0.82mmoles) (7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(eight Hydrogen-quinolizine-1-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine, mixture keeps refluxing 48 hours, after the cooling, leaches the throw out that obtains.
Concentrated filtrate adds several ethers, is placed in the refrigerator.The solid of separating is filtered off, with the washing of anhydrous ether/acetonitrile (1/3) mixture.Concentrated solution is handled with ether once more, is placed in the refrigerator.Repeat this program repeatedly, all filter out throw out at every turn.At last, solution steams to dry, with ether wash residual thing, and dry.
Embodiment 9. biological datas
Vitro test compound of the present invention finds that they all are effective for plasmodium falciparum strain (CQ-S) D10 of chloroquine sensitivity and plasmodium falciparum strain (CQ-R) W2 of anti-chloroquine.Test result is listed in the table below.
Compound | D10(CQ-S) (IC 50ng/ml) | W2(CQ-R) (IC 50ng/ml) |
Embodiment 2 | 32.0±2.4 | 24.2±7.4 |
Embodiment 3 | 24.6±9.0 | 68.8±1.4 |
Embodiment 4 | 17.4±3.7 | 91.1±19.2 |
Embodiment 5 | 28.6±9.6 | 119.3±22.8 |
Chloroquine | 16.1±2.6 | 170.1±41.3 |
n=4±SD
According to the present invention, provide below and the compound of embodiment 6 and 7 data relevant and that represent with CM7/I and CM8 respectively.
Method (Trager, W. according to Trager and Jensen; Jensen, J.B.; Science 1976,193, and 673), but done some modification, keep the plasmodium falciparum substratum.With the bacterial strain W2 of the bacterial strain D10 of chloroquine sensitivity and anti-chloroquine remain on the RPMI 1640 that contains 5% hematocrit (A group positive human red blood cell) (EuroClone, Celbio) and NaHCO
3Among the 24mM, add 10% heat inactivation human plasma A group, 20mM Hepes, 2Mm glutamine.Culture remains on and contains 1%O
2, 5%CO
2, 94%N
237 ℃ of atmosphere in.Product is dissolved among water (chloroquine) or the DMSO, is diluted to substratum subsequently and obtains needed concentration (final concentration of DMSO<1%, nontoxic) parasite.Compound is distributed on 96 orifice plates (COSTAR) of flat bottom aperture.The asynchronous distribution of culture medium that contains 1-1.5% parasitemia and 1% final concentration hematocrit is configured on the aperture, cultivates 72 hours for 37 ℃.Amending method (Makler, M. according to Makler; Hinrichs, D.; Am.J.Trop.Med.Hyg.1993,48 (2), 205; D.Monti, N.Basilico, S.Parapini, E.Pasini, P.Olliaro ﹠amp; D.Taramelli.FEBS Letters 2002,522,3), by spectrophotometry (OD
650) activity of measuring parasite serum lactic dehydrogenase (pLDH) determines parasitic growing state.The anti-malarial activity is to suppress the concentration (IC of half substratum
50) represent; Each IC
50Value all is the mean value of at least three different experiments repeating.
D10
Experiment 1 experiment 2 experiments 3 experiments 4 mean value SD
CM7/I 18.8 14.3 15.8 16.30 2.29
CM8 12.8 17.9 26.6 19.10 6.98
CQ 20.4 14.6 8.6 8.3 12.98 5.74
W2
Vari237 Vari239 Vari245 mean value SD
CM7/I 18.3 16.7 32.94 22.65 1.13
CM8 15.3 36 73.12 41.47 14.64
CQ 30 72.8 145 82.60 30.26
Claims (12)
1. with the compound shown in the following formula:
In the formula,
R is Cl, Br, trifluoromethyl;
M be 0 or part on one of them Au, Rh, Ru atom; Described part is selected from PR '
3, wherein: when M was gold, R ' was phenyl or C2-C4 alkyl; When M is rhodium, R ’ Shi Ring octadiene; When M was ruthenium, R ' was second same quinoline acidic group; When M is gold, randomly also there is the PF that is connected with M
6 -Or NO
3 -Group; When M is rhodium or ruthenium, randomly also there is the Cl that is connected with M
-
X is the group shown in the following formula,
Wherein R2 and R3 are identical or different, are H or straight or branched alkyl, are preferably (CH
2) n-CH
3, wherein n=0-10 better is 1-3; Or with-CH
3,-OCH
3,-CF
3, F, Cl, Br are single replaces or disubstituted phenyl ring;
Y is CH
2-(NH)
n-(CH
2)
m, n=0,1 wherein, m=0-10 is preferably 1-3;
T is the group shown in the following formula:
Or
Or,
Wherein, R4 and R5 are identical or different, are H or straight or branched alkyl, are preferably (CH
2) n-CH
3, n=0-5 wherein, perhaps R4 and R5 form ring together.
2. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(four Hydrogen-pyrrolizine-7a-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine.
3. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-(2,5-dimethyl-3-{[(eight Hydrogen-quinolizine-1-ylmethyl)-amino]-methyl }-pyrroles-1-yl)-amine.
4. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-[2,5-dimethyl-3-(tetramethyleneimine-1-ylmethyl)-pyrroles-1-yl]-amine.
5. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-(3-diethylamino methyl-2,5-dimethyl-pyrroles-1-yl)-amine.
6. compound as claimed in claim 1, wherein, described compound is [3-(tertiary butyl amino-methyl)-2,5-dimethyl-pyrroles-1-yl]-(7-chloro-quinolyl-4)-amine.
7. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-(3-diethylamino methyl-2-methyl-5-phenyl-pyrroles-1-yl)-amine.
8. compound as claimed in claim 1, wherein, described compound is (7-chloro-quinolyl-4)-(3-diethylamino methyl-2-phenyl-5-methyl-pyrroles-1-yl)-amine.
9. compound as claimed in claim 1, wherein, described compound is 7-chloro-N-(2-methyl-5-phenyl-3-(tetramethyleneimine-1-ylmethyl)-1H-pyrroles-1-yl) quinoline-4-amine.
10. pharmaceutical composition, wherein said pharmaceutical composition contains just like the described compound of claim 1 to 9 as activeconstituents and pharmaceutically acceptable vehicle or carrier.
11. as the purposes of the described compound of claim 1 to 9 in the medicine of preparation treatment malaria.
12. treat because the purposes in the medicine of the malaria that the plasmodium falciparum strain of anti-chloroquine causes in preparation as the described compound of claim 1 to 9.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT002008A ITMI20052008A1 (en) | 2005-10-21 | 2005-10-21 | NEW ANTIMALARIC DERIVATIVES OF 4-AMINOCHINOLINA |
ITMI2005A002008 | 2005-10-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101346381A true CN101346381A (en) | 2009-01-14 |
Family
ID=37735214
Family Applications (1)
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CNA2006800486047A Pending CN101346381A (en) | 2005-10-21 | 2006-10-20 | New anti-malaria derivatives of 4-aminoquinoline |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1937686A1 (en) |
CN (1) | CN101346381A (en) |
AP (1) | AP2008004444A0 (en) |
IT (1) | ITMI20052008A1 (en) |
WO (1) | WO2007045987A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102898369A (en) * | 2012-11-05 | 2013-01-30 | 上海书亚医药科技有限公司 | 3-amino-7-bromoquinoline-2-ethyl formate and preparation method thereof |
CN106146466A (en) * | 2016-06-30 | 2016-11-23 | 珠海赛隆药业股份有限公司(长沙)医药研发中心 | Vonoprazan fumarate intermediate, its preparation method and the method for preparation Vonoprazan fumarate |
CN107915720A (en) * | 2016-10-08 | 2018-04-17 | 常州市第四制药厂有限公司 | The new preparation process of Wo Nuolazan |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2743903A1 (en) | 2008-11-18 | 2010-05-27 | The Government Of The United States Of America D.B.A.The Department Of V Eterans Affairs | Compounds for treating parasitic disease |
JP6026441B2 (en) | 2011-03-04 | 2016-11-16 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | Aminoquinolines as kinase inhibitors |
TWI547494B (en) | 2011-08-18 | 2016-09-01 | 葛蘭素史克智慧財產發展有限公司 | Amino quinazolines as kinase inhibitors |
AR092530A1 (en) | 2012-09-13 | 2015-04-22 | Glaxosmithkline Llc | AMINO-QUINOLINE COMPOSITE, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOUND FOR THE PREPARATION OF A MEDICINAL PRODUCT |
TWI592417B (en) | 2012-09-13 | 2017-07-21 | 葛蘭素史克智慧財產發展有限公司 | Prodrugs of amino quinazoline kinase inhibitor |
AR094707A1 (en) | 2013-02-21 | 2015-08-19 | Glaxosmithkline Ip Dev Ltd | COMPOUND OF QUINAZOLIN-4-AMINA, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE FOR THE TREATMENT OF A DISEASE MEDIATED BY THE RIP2 KINASE |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7132431B2 (en) * | 2001-03-14 | 2006-11-07 | The University Of Liverpool | Anti-malarial compounds |
ITMI20032044A1 (en) * | 2003-10-21 | 2005-04-22 | Univ Degli Studi Milano | CHINOLIZIDINIL AND CHINOLIZIDINILALCHIL-DERIVATIVES OF 4-AMINO-CHINOLINE WITH ANTIMALARIC ACTIVITY |
-
2005
- 2005-10-21 IT IT002008A patent/ITMI20052008A1/en unknown
-
2006
- 2006-10-20 CN CNA2006800486047A patent/CN101346381A/en active Pending
- 2006-10-20 EP EP06809083A patent/EP1937686A1/en not_active Withdrawn
- 2006-10-20 WO PCT/IB2006/002946 patent/WO2007045987A1/en active Application Filing
-
2008
- 2008-04-26 AP AP2008004444A patent/AP2008004444A0/en unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102898369A (en) * | 2012-11-05 | 2013-01-30 | 上海书亚医药科技有限公司 | 3-amino-7-bromoquinoline-2-ethyl formate and preparation method thereof |
CN106146466A (en) * | 2016-06-30 | 2016-11-23 | 珠海赛隆药业股份有限公司(长沙)医药研发中心 | Vonoprazan fumarate intermediate, its preparation method and the method for preparation Vonoprazan fumarate |
CN107915720A (en) * | 2016-10-08 | 2018-04-17 | 常州市第四制药厂有限公司 | The new preparation process of Wo Nuolazan |
CN107915720B (en) * | 2016-10-08 | 2020-09-11 | 常州市第四制药厂有限公司 | Novel preparation method of Vonoprazan |
Also Published As
Publication number | Publication date |
---|---|
ITMI20052008A1 (en) | 2007-04-22 |
EP1937686A1 (en) | 2008-07-02 |
WO2007045987A1 (en) | 2007-04-26 |
AP2008004444A0 (en) | 2008-04-30 |
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