CN102743387A - New use of 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpurine - Google Patents

New use of 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpurine Download PDF

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CN102743387A
CN102743387A CN2012100699905A CN201210069990A CN102743387A CN 102743387 A CN102743387 A CN 102743387A CN 2012100699905 A CN2012100699905 A CN 2012100699905A CN 201210069990 A CN201210069990 A CN 201210069990A CN 102743387 A CN102743387 A CN 102743387A
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amino
benzylamino
methylol
propyl group
purine
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王升启
杨静
刘娟
李康
韩明明
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Institute of Radiation Medicine of CAMMS
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Abstract

The present invention relates to a new use of a small molecule inhibitor, and specifically to a use of a CDK small molecule selective inhibitor 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpurine or a pharmaceutically-acceptable salt thereof in preparation of drugs for treatment of hand-foot-mouth disease virus infection-related diseases caused by EV71 and the like.

Description

The new purposes of 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine
Technical field:
The present invention relates to the new purposes of chemicals 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine; Specifically a kind of cell cycle protein dependent kinase (Cyclin-dependent kinases, CDKs) the new purposes of selective depressant 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine in the medicine of preparation treatment and prevention EV71 (enterovirns type 71) virus (Human enterovirus 71) infection.
Background technology
Enterovirns type 71 (EV71) belongs to the member of Picornaviridae (Picomaradae) enterovirus genus (Enterovirus), belongs to human intestine's virus of A.EV71 can cause large-scale outbreak of epidemic, can be with serious CNS complication or lethal pulmonary edema, and it is very serious that it infects harm.The medicine of present anti-EV71 virus is broad-spectrum antiviral medicament such as ribavirin only, but the antiviral curative effect is general.Therefore, research and development effectively prevent and control the viral method of EV71 to have become the task of top priority.
6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine; Be cyclin dependent kinase (cyclin-depend kinases, CDKs) selective depressant of CDC2/cyclin B, CDK2/cyclinA, CDK2/cyclin E, CDK5/p35 in the family.Recent study finds that 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine has the growth inhibited effect to kinds of tumor cells in the cell in vitro test.2009, Cyclacel company accomplished 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine antineoplastic second phase randomized clinical trial.Aspect antiviral research, there is report to show that roscovitine has the effect of DNA viruses such as anti-herpes zoster virus, cytomegalovirus, human polyoma virus and retrovirus HIV.But so far; Also do not have the active report of RNA virus resisting about 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine; Do not suppress the report that RNA viruses duplicates yet, do not cause the report of hand-foot-mouth disease viral infection about 6-(benzylamino)-2 (R)-[[1-(methylol) propyl group] amino]-anti-EV71 of 9-isopropyl purine etc. about suppressing cell cycle dependent kinase endonuclease capable.This laboratory combines the strategy of experimentation to find to suppress cell cycle dependent kinase endonuclease capable first through the applying biological informatics and suppresses duplicating of EV71 virus, and (benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine all has the viral activity of significant anti-EV71 in vivo and in vitro to find 6-first.
Summary of the invention
The objective of the invention is to study 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-morbific activity of the anti-EV71 viral infection of 9-isopropyl purine, for the prevention and the treatment of EV71 viral infection relevant disease provides medicine.
6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine also is described to 2-(1-methylol propyl group is amino)-6-benzylamine-9-isopropyl-purine, and adopted name is roscovitine.As used at this, term " 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine " comprises the R and the S enantiomer that have split, its mixture and raceme thereof.The structure of the corresponding isomer of R and S shows below:
Figure BSA00000685525900021
S enantiomer
Figure BSA00000685525900022
R enantiomer
This research is through utilizing micromolecule selective depressant 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine to suppress in the host cell and the closely-related CDK protein function of virus replication, thereby reaches the morbific purpose of anti-EV71 viral infection.In RD cell (human rhabdomyosarcoma's cell) is, estimate 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine and suppressed EV71 virus replication and cytopathogenic characteristic; The result shows that 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can suppress duplicating and cytopathic effect of EV71 virus in dose dependent ground; Further at EV71 6-(benzylamino)-2-[[1-(methylol) propyl group] the amino]-9-isopropyl purine anti-EV71 viral infection pathogenic activity in vivo that infected the newborn rat model evaluation; The result is presented at mouse model; 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can protect EV71 to infect the dead mouse that causes; Improving EV71, to infect the weight of mice cause slow; And suppressing viral the duplicating of EV71 in the EV71 infecting mouse tissue, prompting 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can develop into the medicine of prevention and treatment EV71 viral infection relevant disease.
According to the present invention; CDKs micromolecule selective depressant 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can effectively suppress the infection duplication of EV71 virus, might become the medicine of treatment and prevention EV71 viral infection relevant disease.
According to the present invention, 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine drug acceptable salt comprises the acid-addition salts that they are suitable.Salt is the salt that forms with following acid: strong inorganic acid, like mineral acid, phosphoric acid or halogen acids; Strong organic carboxyl acid is not as replacing or replace 1 to 4 carbon atom alkane carboxylic acid of (as by halo), for example; Saturated or undersaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or neighbours' phthalic acid, hydroxy carboxylic acid, for example ascorbic acid, hydroxyacetic acid, lactic acid, malic acid, tartaric acid or citric acid; Aminoacid, for example aspartic acid or glutamic acid; Benzoic acid; Or and organic sulfonic acid, as not replacing or replace (C1-C4) alkyl sulfonic acid or the aryl sulfonic acid of (as by halo), like methanesulfonic acid or p-methyl benzenesulfonic acid.
According to the present invention, 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can be made into pharmaceutical preparation by means known in the art.
According to the present invention; Treatment of the present invention is formed; Comprise pharmacokinetics, pharmacokinetics, mode of administration, route of administration, the receptor's of specific medication age, body weight, hepatic and renal function state, character, degree and the treatment time limit etc. of disease according to different situations, with the appropriate dosage administration.
Enforcement of the present invention has important social benefit and economic benefit to the treatment of the EV71 viral infection of serious harm human health.
Description of drawings:
Figure 16-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine suppresses the effect of EV71 pathological changes caused by virus on RD cell dosage dependency ground.
Figure 26-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine is to the toxic action of RD cell.
Figure 36-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine has improved the survival rate of EV71 virus infected mice.
Figure 46-(benzylamino)-2-weight of mice that [[1-(methylol) propyl group] amino]-9-isopropyl purine has improved due to the EV71 viral infection is slow.
Figure 56-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine has suppressed the rna level of EV71 virus in the EV71 virus infected mice tissue.
The specific embodiment
Embodiment one:
Present embodiment explains that mainly 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine is in the morbific activity of the anti-EV71 viral infection of RD cell (human rhabdomyosarcoma's cell).
Materials and methods
1.RD cell, virus and medicine configuration
The EV71 Strain is international standard strain BrCr strain, through infecting the breeding of increasing of RD cell, then mixing, packing and be stored in-70 ℃ subsequent use.The RD cell culture fluid is DMEM (GIBCO) culture fluid that contains 10% hyclone.When measuring, viral infection and cytopathy use the liquid of keeping that contains 2% hyclone.6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine is dissolved as 20mM with DMSO, be stored in after the packing-20 ℃ subsequent use.
2.6-suppressing the dosage dependence effect of EV71 pathological changes caused by virus, (benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine detects
The RD cell is cultivated in 37 ℃, 5%CO2 incubator in containing the DMEM culture medium (GIBCO) of 10% hyclone.The observation of cell growth conditions is good, is cultured to the logarithmic growth after date, and with in cell inoculation to the 96 porocyte culture plate, cover with next day 75～80% with 8000～10000 cells/well.Dilute 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine to 20 μ M with DMEM.With 96 orifice plates of the DMEM culture medium (GIBCO) that contains 10% hyclone that covers with 75～80%RD cell change into contain 2% hyclone to keep liquid subsequent use.Set up 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine five Concentraton gradient of 0.125,0.25,0.5,1.0,2.0 μ M to add in 96 orifice plates respectively; Each sequence is established three multiple holes, and sets up viral infection matched group and normal cell matched group.Behind the effect 60min, every hole adds EV71 viral dilution liquid, and final concentration is 100TCID50/0.1ml, cultivates 2d for 37 ℃.Utilize Cell Counting Kit-8 (DoJinDo product) method at ELIASA (BIO-RAD product; Model: Model 680) goes up the cytopathy degree (representing) of measuring, and calculate the viral suppression ratio of medicine: [(OD test-OD virus)/(OD cell-OD virus)] * 100 with following formula with OD450.The repeated trials secondary, calculating mean value.
3.6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine detects the toxic action of RD cell
The RD cell is spread 96 porocyte culture plates, and cover with next day 75～80%.With the RD cell that covers with 75～80% change into contain 2% hyclone to keep liquid subsequent use.Set up five Concentraton gradient of 5,10,20,40,80 μ M to 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine respectively; Each concentration is set up three multiple holes; And set up RD cell negative control group; Cultivate 2d for 37 ℃, mirror is observed the influence of 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine pair cell form down.Utilize Cell Counting Kit-8 (DoJinDo product) method to go up and measure the cytopathy degree (with OD at ELIASA (BIO-RAD product, model: Model 680) 450Represent), and calculate median toxic dose CC 50
The result:
1.6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine suppresses the dosage dependence effect of EV71 pathological changes caused by virus
As shown in Figure 1,6-(benzylamino)-2-[[1-(methylol) propyl group] amino] but-cytopathic effect of the inhibition EV71 of 9-isopropyl purine dose dependent in 0-2.0 μ M scope virus, it suppresses the IC that the EV71 viral infection causes CPE 50Be 0.213uM.
2.6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine is to the toxic action of RD cell
Set up 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine five Concentraton gradient of 5,10,20,40,80 μ M to carry out toxicity trial respectively; The CCK8 testing result shows 6-(benzylamino)-2-, and [[1-(methylol) propyl group] amino]-on cell proliferation did not make significant difference when 9-isopropyl purine concentration reached 10 μ M, its median toxic dose CC 50Be 27.77 μ M.
Conclusion
6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine bodies has the morbific effect of significant anti-EV71 viral infection outward.
Embodiment two
Present embodiment is mainly explained at EV71 infecting mouse model; 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine dose dependent improves the survival rate of EV71 virus infected mice; The newborn rat weight increase that improves due to the EV71 viral infection is slow, and has significantly suppressed the rna level of EV71 virus in mouse lung, brain, intestinal and the muscle.
Materials and methods
1.ICR neonatal rat, virus and control drug
Animal model is SPF level 7 age in days ICR neonatal rats, and the EV71 Strain is international standard strain BrCr strain.The positive control medicine is IFN α-2a.
2.6-anti-EV71 virus activity detects in (benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine bodies
Order SPF level 7 age in days ICR neonatal rats 6 nests, before the experiment beginning it is weighed and divide into groups.Mice set up respectively 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine 2mg/kg/d,, 4mg/kg/d,, 6mg/kg/d group, set up normal physiological saline control group, EV71 viral infection matched group, IFN α-2a positive drug matched group simultaneously.Mice to having divided into groups experimentizes, and carries out disinfection with povidone iodine at mice one side flank place earlier, carries out disinfection with 75% ethanol then, then injects normal saline, virus or the medicine of corresponding dosage according to body weight.Normal physiological saline control group is ined succession and is injected five days physiology saline; First day injecting virus of virus group, back injection in four days same dose is a normal saline; IFN α-2a positive drug matched group and 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-each dosed administration group of 9-isopropyl purine was injected a certain amount of EV71 virus according to body weight earlier in first day; Injectable drug after 1 hour; Give four days medicines later on continuously; Administration finishes the back and continues to observe for 2 weeks, and weighing every day record body weight is also calculated survival rate.
After infection the 14th day, put to death mice, get lung, brain, intestinal and leg muscle tissue; Use Trizol RNA extraction test kit (Invitigen) extraction and respectively organize RNA; Quantitatively, respectively get 0.1 μ g, use the RNA copy number that the EV71 fluorescent quantificationally PCR detecting kit detects EV71 virus in the tissue.
The result
EV71 viral infection matched group begins to occur dead at viral infection in the time of 10 days; To infecting the back the 14th day, survival rate is reduced to 20%, and 2mg/kg/d administration group does not demonstrate significant curative effect; And 4mg/kg/d and 6mg/kg/d administration group all demonstrate significant protective effect; After infection the 14th day, survival rate was respectively 88.9% and 100%, all is significantly higher than positive drug IFN α-2a matched group (Fig. 3).Aspect weight increase, the mice weight increase of 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine 4mg/kg/d administration group is significantly higher than viral infection matched group (Fig. 4).In suppressing EV71 infecting mouse tissue the EV71 viral RNA horizontal aspect; As shown in Figure 5; The EV71 viral RNA is reduced to 7.84% of viral RNA in the virus infected mice lung tissue in 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine 4mg/kg/d processed group mouse lung tissue; Reduce to 89.72% in the cerebral tissue, reduce to 73.50% in the intestinal tissue, and reduce to 55.66% in the muscular tissue; Prompting 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can significantly suppress the viral level in viral level, the especially lung tissue in the EV71 virus infected mice tissue.
Conclusion
6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can improve the survival rate of EV71 virus infected mice; It is slow to alleviate the newborn rat weight increase that the EV71 viral infection causes, and can reduce the viral level in virus infected mice lung, brain, intestinal and the muscular tissue.

Claims (5)

  1. (1.6-benzylamino)-2-[[1-(methylol) propyl group] amino] but-9-isopropyl purine or its medication salt is used for treating the purposes of the medicine of EV71 viral infection relevant disease in preparation.
  2. 2. according to claim 1, wherein said 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine also is named as 2-(1-methylol propyl group is amino)-6-benzylamine-9-isopropyl-purine, its general roscovitine by name.
  3. 3. according to claim 1; Wherein said 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine can be the S enantiomer of 6-(benzylamino)-2-[[1-(methylol) propyl group] amino]-9-isopropyl purine, R enantiomer or raceme.
  4. 4. according to claim 1, wherein said medicine contains one or more pharmacy acceptable carriers.
  5. 5. purposes according to claim 1, wherein said medicine can be processed injection, freeze-dried powder, microsphere, powder, powder spray, aerosol, enteric coating, millimicro ball, microemulsion or emulsion.
CN2012100699905A 2012-03-16 2012-03-16 New use of 6-(benzylamino)-2-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpurine Pending CN102743387A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016520101A (en) * 2013-05-31 2016-07-11 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 2,3-butanediamide epoxide compounds and methods for their preparation and use

Citations (1)

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WO2010085924A2 (en) * 2009-01-28 2010-08-05 Univerzita Palackeho V Olomouci Substituted 6-(2-aminobenzylamino)purine derivatives, their use as medicaments and preparations containing these compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010085924A2 (en) * 2009-01-28 2010-08-05 Univerzita Palackeho V Olomouci Substituted 6-(2-aminobenzylamino)purine derivatives, their use as medicaments and preparations containing these compounds

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Title
TSAN-CHI CHEN等: "Enterovirus 71 triggering of neuronal apoptosis through activation of Abl-Cdk5 signalling", 《CELLULAR MICROBIOLOGY》, vol. 9, no. 11, 30 November 2007 (2007-11-30), pages 2676 - 2688 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016520101A (en) * 2013-05-31 2016-07-11 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 2,3-butanediamide epoxide compounds and methods for their preparation and use
EP3006432A4 (en) * 2013-05-31 2016-10-26 Inst Pharm & Toxicology Amms 2,3-butanediamide epoxide compound and preparation method and use thereof
US9630957B2 (en) 2013-05-31 2017-04-25 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China 2,3-butanediamide epoxide compound and preparation method and use thereof

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Application publication date: 20121024