CN1330922A - Medicinal composition for treating or preventing diseases associated with immunodeficiency virus and reverse transcription virus - Google Patents
Medicinal composition for treating or preventing diseases associated with immunodeficiency virus and reverse transcription virus Download PDFInfo
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- CN1330922A CN1330922A CN 00109701 CN00109701A CN1330922A CN 1330922 A CN1330922 A CN 1330922A CN 00109701 CN00109701 CN 00109701 CN 00109701 A CN00109701 A CN 00109701A CN 1330922 A CN1330922 A CN 1330922A
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Abstract
The present invention relates to a medicinal composition for preventing and treating the diseases associated with HIV virus and reverse transcription virus and suppressing the replication of said viruses. It contains a compound, and the pharmacologically receptable salt and carrier. The combination of said compound with other anti-virus agents is also related.
Description
The present invention relates to comprise the new pharmaceutical composition of the chemical compound of formula I.Described compositions can be used for treatment and HIV and retrovirus diseases associated, and suppresses HIV and retroviral duplicating.In addition, described compositions can randomly make up with other antiviral agent.
As everyone knows, the disease of people's acquired immune deficiency syndrome (AIDS) (AIDS) is caused by human immunodeficiency virus (HIV).
The same with other viruses, if HIV does not occupy the host's of its infection biosynthesis device, just can not carry out self-replication.Described synthesizer is forced to produce the structural protein that virus provides.These albumen are to be encoded by the hereditary material in the virion that has infected.But as a kind of retrovirus, the hereditary material of HIV is RNA, and is DNA not resembling in the genome of host cell.Therefore, viral RNA should be converted into DNA, is integrated into then in the genome of host cell, so that host cell can produce desirable virus protein.RNA finishes by using reverse transcriptase (RT) to the conversion of DNA, and this enzyme is included in infected and has together in the virion of RNA.Reverse transcriptase has three kinds of known enzymatic functions, promptly, the dependent archaeal dna polymerase of RNA, ribonuclease and the dependent archaeal dna polymerase of DNA.RT at first plays the part of the effect of the dependent archaeal dna polymerase of RNA, to produce the single stranded DNA duplicate of viral RNA.Then, as ribonuclease, RT discharges the DNA that is produced by protovirus RNA, and destroys original RNA.At last, as the dependent archaeal dna polymerase of DNA, RT uses first DNA chain as template, to produce second compensatory DNA chain.Then other enzymes by being called intergrase are integrated into two chains of double-stranded DNA in the genome of host cell.
Known most compounds can suppress the enzymatic functions of hiv reverse transcriptase.Known a category of HIV-1 RT inhibitor is a nucleoside analog.This compounds comprise zidovudine (ZDV), 2 ', 3 '-didanosine (ddI) and 2 ', 3 '-zalcitabine (ddC).Other classifications are non-nucleoside analogs.This compounds comprises nevirapine (nevirapine), and this medicine is a 11-cyclopropyl-5,11-dihydro-4-methyl-6H-bipyridyl [3,2-b:2 ', 3 '-e] [1,4] diazepine-6-ketone.The nevirapine of non-nucleoside and other specially suitable chemical compounds are described in the 5th, 336, in No. 972 United States Patent (USP)s.
But, because HIV is easy to produce toleration to known antiviral agent (as protease inhibitor and reverse transcriptase inhibitors), so the therapeutic effect of these medicaments is lower than what expect usually.In addition, the necessary dosage of these medicaments all can have side effects for most patient.Modal defective is to Normocellular toxicity.Therefore, those skilled in the art are still continuing the novel antiviral agent of development, and its effective dose can produce more effective therapeutical effect to the disease that HIV causes.
Recently, existing people finds that the necessary intergrase of virus replication can be used as the target of the antiviral agent of developing other classifications.This has special potentiality for using in the anti-hiv inhibitor of development.In HIV and other retrovirus, it is necessary will being integrated into by the dna replication dna thing that the rna gene group obtains in the host cell chromosome for effective virus replication and virus multiplication.More specifically, enzyme is sequentially following is acted on: by 3 of viral DNA '-end removes dinucleotide unit (being called " 3 '-handle ").Through 3 '-chain handled is transferred in the nucleus by kytoplasm.Through 3 '-the compensation fracture by the 5-base pair of the chain handled is incorporated in the corresponding host DNA in the nucleus (being called " strand displacement ").In addition, intergrase is not still found and the similar function of people's cell.Therefore, infection is useful to integrase inhibitor for the treatment reverse transcription.
Although intergrase is being played the part of important effect in retroviral life cycle, the relevant information that hiv integrase is had the chemical compound of selective inhibitory also seldom has report.At present, the primary categories of integrase inhibitor comprises DNA bonding agent, topoisomerase enzyme inhibitor, aurin tricarboxyli acid (ATA), CAPE (CAPE) and two catechol, or the like.
Have and report in biochemical test, have chemical compound lot can suppress hiv integrase.But most these chemical compounds almost do not have activity or do not have activity at all in tissue culture, and are not having selectivity aspect its mechanism of action.These results show that described chemical compound does not have selectivity aspect the activation of eliminating hiv integrase, and the chemical compound of perhaps described inhibition hiv integrase can not enter in the cell.Particularly, though most compounds shows the activity that suppresses intergrase in the vitro enzyme experiment, but still can not prove that this chemical compound has HIV (human immunodeficiency virus)-resistant activity in the body.For example, actinomycin D and CAPE have the activity of vitro inhibition intergrase.But, do not report that also they have HIV (human immunodeficiency virus)-resistant activity.
CAPE is the product of propolis.Known CAPE has resisting mitosis, anticancer, antiinflammatory and immunoregulation effect.In addition, CAPE optionally suppresses rodent zooblast and human tumor cells that virus transforms and that oncogene transforms, comprise clone's adenocarcinoma (HT-29), melanoma (HU-1, SK-MEL-28 and SK-MEL-MO), human breast carcinoma (MCF-7) and Fischer mouse embryo desmocyte (CREF), or the like.CAPE also can make human leukemia HL-60 cell's stasi, and suppresses DNA, RNA and proteic the synthesizing of HL-60 cell.But CAPE dosage and time dependence ground blocking-up tumor necrosis factor are to the activation of NF-Kappa B.CAPE also can be used as the fat oxidation enzyme inhibitor, the performance antioxidant activity.
The purpose of this invention is to provide a kind of being used for the treatment of or the pharmaceutical composition of prevention and HIV and retrovirus diseases associated.
Another object of the present invention provides a kind of pharmaceutical composition that HIV and retrovirus duplicate that is used to suppress.
A further object of the present invention provides the combination of compositions of the present invention and known antiviral agent.
Below with reference to embodiment and accompanying drawing the present invention is described in more detail.In the accompanying drawings:
Fig. 1 is the cytoactive of cultivating in the tetrazole experiment at trace 24 hours.
Fig. 2 is the cytoactive of cultivating in the tetrazole experiment at trace 48 hours.
Fig. 3 is that these cells are respectively by following viral infection: (A) virus (JRCSF) of macrophage tropism's virus (NL-43), (B) T cytotropism and (C) amphitropic virus (89.6) with the result of blood monocyte around the CAPE treatment of variable concentrations.
Fig. 4 is that these cells are respectively by following viral infection: (A) virus (JRCSF) of macrophage tropism's virus (NL-43), (B) T cytotropism and (C) amphitropic virus (89.6) with the result of blood monocyte around caffeic methyl ester's treatment of variable concentrations.
Fig. 5 is that these cells are respectively by following viral infection: (A) virus (JRCSF) of macrophage tropism's virus (NL-43), (B) T cytotropism and (C) amphitropic virus (89.6) with the result of blood monocyte around the PEDMC treatment of variable concentrations.
Meeting among the figure has following connotation:
Among Fig. 3-5, (+) representative when infect finishing, keep after the washing add the original concentration of chemical compound.
Among Fig. 3-5, chemical compound is removed in (-) representative after washing.
Among Fig. 1-5, transverse axis is represented the concentration (μ M) of test compounds.
Among Fig. 3-5, the longitudinal axis is represented the antigenic concentration of viral P24 (unit).
Among Fig. 1-2, the longitudinal axis is represented relative percent.
The present invention relates to can be used for to treat or the formula I compound of the disease that prevention is relevant with HIV and retrovirus and materia medica thereof on acceptable salt. More specifically, the compound of formula I can be used for treatment or prevention such as aids (AIDS), the syndrome (ARC) relevant with AIDS and adult T-cell leukemia's etc. disease. Therefore, the invention provides a kind of being used for the treatment of or the pharmaceutical composition of the disease that prevention is relevant with HIV and retrovirus, it comprises on the formula I compound of effective dose and the materia medica thereof acceptable carrier on acceptable salt and the materia medica,Wherein: Ar represents aryl, and it is unsubstituted or by halogen, hydroxyl or C1-6Alkoxyl replaces, and A represents C1-6Alkylidene, C2-6Alkenylene or C2-6Alkynylene, m are the integers of 0-6, and B represents hydrogen, C1-6Alkyl or aryl, described aryl can be unsubstituted or by halogen, hydroxyl, C1-6Alkyl, C2-6Thiazolinyl or C2-6Alkynyl substituted.
Preferred formula I compound is acceptable salt on following compound or its materia medica, and wherein, Ar represents phenyl or naphthyl, and it is unsubstituted or by halogen, hydroxyl or C1-6Alkoxyl replaces, and A represents C1-4Alkylidene or C2-4Alkenylene, m represent the integer of 0-3, and B represents C1-3Alkyl or phenyl, described phenyl are unsubstituted or by halogen, hydroxyl or C1-6Alkyl replaces.
Preferred formula I compound is acceptable salt on following compound or its materia medica, and wherein, Ar represents phenyl, and it is by halogen, hydroxyl or methoxy substitution, and A represents C2-3Alkylidene, m represent the integer of 0-2, and B represent methylidene or phenyl.
Most preferred formula I compound is selected from following group: CAPE (CAPE), PEDMC (PEDMC), caffeic acid methyl ester (MC) and 4-bromo-cinnamic acid phenethyl ester, or acceptable salt on their materia medica.
Have now found that acceptable salt pair HIV duplicates and has strong inhibition activity on the chemical compound of formula I and the materia medica thereof.In addition, the intergrase of retrovirus and HIV is a high homology.Therefore, the present invention also provides a kind of pharmaceutical composition that HIV and retrovirus duplicate that is used to suppress, and it comprises acceptable carrier on aforesaid formula I chemical compound and the materia medica.
The chemical compound of formula I can have one or more chiral centre.Therefore, it has various stereoisomer forms.That is to say that the chemical compound of formula I comprises all these isomers.
The chemical compound of formula I and the starting material that is used for its preparation can prepare according to known method, for example below with reference to the method for describing in the document (people such as He Zhao, J.Med.Chem.1997,40,1186-1194; People such as Chinthalapally B.Rao, Chem.Biol.Interactions, 84 (1992) 277-290; Or the like).That is to say that the chemical compound of formula I can prepare according to the reaction in the above-mentioned document according to known and suitable reaction sequence.This preparation also can be finished by known method is carried out little improvement.But, be not described in detail this preparation method at this.
Now, AIDS patient be with chicken not the wine therapy treat.But the HIV among some patient has produced toleration to known antiviral agent, therefore can not realize effectively treatment or prevention.For realizing treatment effectively or prevention AIDS or relevant disease and suppress virus replication, must with the compound use of other antiviral agent.Therefore, the invention provides the combination of formula I chemical compound and one or more antiviral agent.Described antiviral agent is selected from following group: protease inhibitor, as indinavir, ritonavir or nelfinavir; Nucleoside reverse transcriptase inhibitor, as zidovudine (ZDV), lamivudine (3TC), stavudine (d4T), 2 ', 3 '-didanosine (ddI) or 2 ', 3 '-zalcitabine (ddC); Non-nucleoside reverse transcriptase inhibitor is as nevirapine; And integrase inhibitor.
Be understandable that the pharmaceutical preparation administration simultaneously or sequentially that the chemical compound in this combination can be identical or different.If the order administration, should not lose the synergistic therapeutic effect of combination medicine-feeding active component when postponing other active component of administration.It will also be appreciated that various active component or its any physiology that the present invention uses in making up go up functionalized derivant, no matter simultaneously still order administration all can be independent or a plurality of or with the form administration of any combination.The preferred administration simultaneously of active component in the described combination or with the form order administration of independent pharmaceutical preparation, most preferably administration simultaneously.
Though the active component in the combination can be used the raw material administration, preferred form administration with pharmaceutical preparation.Pharmaceutical preparation according to the present invention comprises according to acceptable carrier or excipient on combination of the present invention and one or more materia medicas and optional other treatment agent.Described carrier is being accepted must making us aspect the compatibility with other compositions of preparation, and its receptor is not had detrimental effect.If the separate constituent in the individually dosed combination, they use with the form of pharmaceutical preparation usually.
It should be understood that another feature that the present invention makes us wishing is by one patient's drug packages administration drug regimen of the present invention, perhaps the patient of each preparation packing comprises the explanation that the indication patient correctly uses the present invention to make up in the packing.
Be used for that acceptable salt can form suitable dosage form with at least a solid, liquid and/or semiliquid excipient or adjuvant on the present invention's formula I chemical compound and/or its materia medica.
Useful excipient is to be applicable to through intestinal (oral), non-ly not have interactional inorganic or Organic substance through intestinal or topical and with above-claimed cpd, and Ru Shui, oil, benzylalcohol, ethylene glycol, Polyethylene Glycol, gelatin, sugar are as lactose or starch, magnesium stearate, Pulvis Talci and petroleum jelly.Particularly, tablet, pill, coated tablet, capsule, powder, granule, syrup or drop can be used for oral administration; Suppository is used for rectally; Solution and suspensoid, Emulsion and injection are used for non-through enteral administration; And cream, frost and powder agent are used for topical.But also lyophilizing of chemical compound of the present invention is used for preparation example such as injection then.These preparations can be sterilized, and/or comprise adjuvant, as lubricant, antiseptic, stabilizing agent and/or wetting agent, emulsifying agent, buffer agent, coloring agent, flavoring agent and/or sweeting agent.
Because the antiviral agent to patient's administration high dose can cause toxicity easily, pharmaceutical composition provided by the invention or combination comprise the formula I chemical compound of safe and effective amount, and wherein this safe and efficient amount is 0.1-1000 μ M, are preferably 100-400 μ M.
Concrete dosage level to the single patient administration should be determined by all possible factor, the order of severity of the mode of the activity of used particular compound, age, body weight, health status, sex, diet, administration and time, discharge rate, drug regimen and disease to be treated for example, or the like.Oral administration is preferred route of administration.
Embodiment 1Synthetic 4-bromo-cinnamic acid phenethyl ester
Thoroughly mix 500mg (1eq.) 4-bromobenzaldehyde and the solution of 562mg (2eq.) malonic acid in the 4ml pyridine, add the piperidines of 266ml then.With mixture heated to 80 ℃ totally 2 hours, and reheat to 115 ℃ totally 8 hours.After the cooling, reactant mixture is poured onto in the 250ml cold water.Slowly add the hydrochloric acid of 10ml, make the solution acidify thus.The isolated by filtration crystal is used cold water washing 4 times then.Thick acid is dissolved in the sodium hydrate aqueous solution (1: 20).Filtering solution with the dilution of 10ml cold water, is used 1: 1 hcl acidifying then.Filtering mixt, with 20ml cold water washing crystal, and with chloroform extraction (productive rate 77%).
With 4-bromo-cinnamic acid (1eq.) and 8ml chloroform and SO
2Cl
2(3eq.) place together.With mixture heated to 70 ℃ totally 7 hours, concentrate then and form acyl chlorides.Acyl chlorides is dissolved in the chloroform (10ml), in 5 minutes time, this drips of solution is added in phenethanol (2eq.) and the solution of pyridine (2eq.) in the 10ml chloroform then.Stirred the mixture 30 minutes, and used the pure system of column chromatography then, obtain 4-bromo-cinnamic acid phenethyl ester (productive rate 88.6%).
Embodiment 2Caffeic acid phenethyl base ester (CAPE), caffeic methyl ester (MC) and PEDMC (PEDMC) are to the cytotoxicity of blood monocyte (PBMC) on every side
In 24 orifice plates, make CAPE, the MC of PBMC cell and various concentration (0.1,0.5,1,5,10,25,50,100,200 with 400 μ M) contact 48 hours with PEDMC.With the blue dye excretion analysis of cells of trypanosomicide viability.More specifically, for measuring the growth inhibited effect of MC, CAPE and PEDMC, cell was put into 6 orifice plates totally 48 hours, wherein above-mentioned medicament is several subcellular fraction toxic concentrations.With the concentration adjustment of DMSO for being lower than 0.5%.The cell that will obtain from the plate of 4 repeated experiments with Hank balanced salt solution (HBSS) washing once.According to this method, by isolating buoyant dead cell in the cell monolayer of living.Pair cell dyes and counting with trypanosomicide is blue then.Survivaling cell sum in the matched group is decided to be 100% survival rate, and uses cell and matched group to compare, to determine the % survival rate through chemicals treatment.Calculate % survival rate by the sum of the survivaling cell in matched group and the chemicals treatment group through the cell of chemicals treatment.
The results are shown in shown in the following table 1.Even when the dosage of height to 400 μ M, the survival rate of the PBMC that handles through high dose CAPE, MC or PEDMC does not have significant difference during with low dosage processing (as 0.1-10 μ M).This result shows that test compounds pair cell under these high doses does not have cytotoxicity.
CAPE, MC and PEDMC are to the cytotoxicity of PBMC
(the dead cell quantity in 400 cell countings is as follows, and the quantity of dead cell in the matched group
Be 9 cells)
Embodiment 3Trace is cultivated the cytoactive in the tetrazole experiment
| Concentration (μ M) | ???????????CAPE | ????????????MC | ???????????PEDMC | |||
| The quantity of dead cell in 400 cell countings | The % survival rate | The quantity of dead cell in 400 cell countings | The % survival rate | The quantity of dead cell in 400 cell countings | The % survival rate | |
| ????400 | ????8 | ??392/391 ??(100.3％) | ????7 | ??393/391 ??(100.5％) | ????6 | ??394/391 ??(100.8％) |
| ????200 | ????7 | ??393/391 ??(100.5％) | ????8 | ??392/391 ??(100.3％) | ????7 | ??393/391 ??(100.5％) |
| ????100 | ????11 | ??389/391 ??(99.5％) | ????7 | ??393/391 ??(100.5％) | ????10 | ??390/391 ??(99.7％) |
| ????50 | ????12 | ??388/391 ??(99.2％) | ????11 | ??389/391 ??(99.5％) | ????10 | ??390/391 ??(99.7％) |
| ????25 | ????5 | ??395/391 ??(101％) | ????11 | ??389/391 ??(99.5％) | ????8 | ??392/391 ??(100.3％) |
| ????10 | ????10 | ??390/391 ??(99.7％) | ????7 | ??393/391 ??(100.5％) | ????9 | ??391/391 ??(100％) |
| ????5 | ????10 | ??390/391 ??(99.7％) | ????9 | ??391/391 ??(100％) | ????11 | ??389/391 ??(99.5％) |
| ????1 | ????7 | ??393/391 ??(100.5％) | ????12 | ??388/391 ??(99.2％) | ????7 | ??393/391 ??(100.5％) |
| ????0.5 | ????9 | ??391/391 ??(100％) | ????7 | ??393/391 ??(100.5％) | ????10 | ??390/391 ??(99.7％) |
| ????0.1 | ????11 | ??389/391 ??(99.5％) | ????9 | ??391/391 ??(100％) | ????11 | ??389/391 ??(99.5％) |
According to people (Cancer Res.1988 such as Alley M.C.; 48 (3): method test cell activity 589-601).The principle of this method is, living cells is by the reduction of the dehydrogenase metabolism in mitochondrion MTT, promptly, 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyl tetrazole bromine (tetrazolium) makes it become the formazan crystal.This dissolution of crystals in propanol, is measured the OD value then at the 570nm place.This OD value can be indicated the quantity of living cells.The developmental condition of observation of cell at first.With cell dilution to 2 * 10
4Individual cell/ml.Get the sample of 100 μ l with micropipette, and put into 96 orifice plates.This plate was cultivated 24 hours down at 37 ℃, added the chemical compound to be tested that 100 μ l prepare in culture medium then in each hole.Cultivate after 48 hours, absorb supernatant, add the culture medium in 90 μ l/ holes and the MTT solution in 10 μ l/ holes then.Cultivate after 4 hours, absorb supernatant, add the DMSO in 100 μ l/ holes and the MTT solution in 10 μ l/ holes then.Each hole is stirred.Measure absorption value at the 570nm place.
As illustrated in fig. 1 and 2, not significant effect between PEDMC, CAPE and EC.These results show that cell is actually alive.
Embodiment 4The P24 of HIV and retrovirus-1 identifies
CAPE, MC and PEDMC with the various concentration that make among the embodiment 2 handle PBMC, and use macrophage tropism's (NL-43), (JRCSF) and the macrophage and the infection of T cell amphitropic (89.6) HIV-1 separator of T cytotropism simultaneously.Second day, remove the chemical compound that is added or remain under the identical concentration by washing.Sample is divided into two groups, and in the time of metainfective the 3rd and 7 day, collects the supernatant of culture medium respectively.The P24EIA test kit comparison of using Abbott Laboratory is being with or without the viral P24 antigen concentration of test compounds when existing.
Shown in Fig. 3-5, CAPE, MC and PEDMC significantly suppress virus replication.Particularly CAPE under 100 μ M or lower concentration and MC can 100% ground suppress the virus replication of various HIV separators.When the concentration of test compounds reduced gradually, the inhibitory action of virus replication also reduced gradually.In addition, for various HIV separators (NL-43, JRCSF or 89.6), activity does not have difference.Inhibiting looking be not to realize at access phase, and only be realization after virus is subsequently invaded.If the way it goes, this result shows that CAPE, MC and PEDMC can suppress various tropisms' the duplicating of HIV separator.
Detailed data among Fig. 1-5 is as follows:
MTT 24h CAPE EC PEDMC
0.1 97.49 98.38 92.38
0.5 104.67 105.82 98.72
1 109.25 110.22 98.25
5 102.41 101.18 94.33
10 93.07 102.41 98.72
25 98.65 109.46 107.27
50 95.49 92.15 102.03
100 96.15 98.07 106.06
200 106.8 99.69 97.93
400 108.62 89.69 94.8 Fig. 1
MTT?48h????CAPE??????EC?????????PEDMC
0.1????87.49?????103.81?????97.31
0.5????97.54?????98.92??????98.72
1??????104.18????103.37?????105.28
5??????99.74?????94.44??????104.07
10?????94.76?????98.35??????98.08
25?????96.92?????97.94??????98.78
50?????96.42?????98.19??????97.15
100????94.02?????98.77??????97.74
200????98.6??????98.83??????96.32
400 98.9 102.07 93.762CAPE NL43 ( + ) NL43 (-) CAPE JRCSF ( + ) JRCSF (-) CAPE 89.6 ( + ) 89.6 (-) 400 0 0 400 0 0 400 0 0200 0 0 200 0 0 200 0 0100 0 62.26 100 0 0 100 0 113.250 166.12 865.44 50 0 0 50 0 243.5325 975.64 988.28 25 0 0 25 0 182.4410 990.64 1000 10 642.72 34.42 10 230.32 255.215 1000 1000 5 965.62 1000 5 243.87 280.511 1000 1000 1 1000 1000 1 643.71 10000.5 1000 1000 0.5 1000 1000 0.5 899.22 949.750.1 1000 1000 0.1 1000 1000 0.1 1000 10003MC NL43 ( + ) NL43 (-) MC JRCSF ( + ) JRCSF (-) MC 89.6 ( + ) 89.6 (-) 400 0 2.53 400 0 0 400 0 0200 0 518.45 200 0 0 200 0 124.97100 0 687.24 100 0 0 100 8.91 278.4350 273.07 922.63 50 0 42.64 50 18.4 286.4625 220.63 1000 25 2.33 786.67 25 5.2 504.4210 1000 1000 10 2.53 828.46 10 14.36 624.395 1000 1000 5 58.13 1000 5 66.78 10001 1000 1000 1 1000 1000 1 149.67 966.670.5 1000 1000 0.5 1000 1000 0.5 954.88 10000.1 1000 1000 0.1 1000 1000 0.1 1000 10004PEDMC NL43 ( + ) NL43 (-) PEDMC JRCSF ( + ) JRCSF (-) PEDMC 89.6 ( + ) 89.6 (-) 400 640.7 898.4 400 348.96 869.4 400 84.85 494.91200 890.43 981.43 200 452.46 1000 200 187.69 539.82100 1000 1000 100 892.45 1000 100 238.49 64750 1000 1000 50 1000 1000 50 747.3 681.4225 1000 1000 25 1000 1000 25 886.42 927.410 1000 1000 10 1000 1000 10 965.48 932.675 1000 1000 5 1000 1000 5 1000 10001 1000 1000 1 1000 1000 1 1000 10000.5 1000 1000 0.5 1000 1000 0.5 1000 10000.1 1000 1000 0.1 1000 1000 0.1 1000 10005
Claims (19)
1, a kind of being used for the treatment of or the pharmaceutical composition of prevention and HIV and retrovirus diseases associated, it comprises on the formula I chemical compound of effective dose and the materia medica thereof acceptable carrier on acceptable salt and the materia medica,
Wherein: Ar represents aryl, and it is unsubstituted or by halogen, hydroxyl or C
1-6Alkoxyl replaces, and A represents C
1-6Alkylidene, C
2-6Alkenylene or C
2-6Alkynylene, m are the integers of 0-6, and B represents hydrogen, C
1-6Alkyl or aryl, described aryl can be unsubstituted or by halogen, hydroxyl, C
1-6Alkyl, C
2-6Thiazolinyl or C
2-6Alkynyl substituted.
2, pharmaceutical composition as claimed in claim 1, wherein, Ar represents phenyl or naphthyl, and it is unsubstituted or by halogen, hydroxyl or C
1-6Alkoxyl replaces, and A represents C
1-4Alkylidene or C
2-4Alkenylene, m are represented the integer of 0-3, and B represents C
1-3Alkyl or phenyl, described phenyl are unsubstituted or by halogen, hydroxyl or C
1-6Alkyl replaces.
3, pharmaceutical composition as claimed in claim 2, wherein, Ar represents phenyl, and it is replaced by halogen, hydroxyl or methoxyl group, and A represents C
2-3Alkylidene, m are represented the integer of 0-2, and B represent methylidene or phenyl.
4, pharmaceutical composition as claimed in claim 1, wherein, formula I chemical compound is selected from following group: CAPE (CAPE), PEDMC (PEDMC), caffeic acid methyl ester (MC) and 4-bromo-cinnamic acid phenethyl ester.
5, pharmaceutical composition as claimed in claim 1, wherein, described disease is acquired immune deficiency syndrome (AIDS) (AIDS), syndrome (ARC) and the adult T cell leukemia relevant with AIDS.
6, pharmaceutical composition as claimed in claim 1, wherein, the effective dose of formula I chemical compound is 0.1-1000 μ M.
7, pharmaceutical composition as claimed in claim 1, wherein, the effective dose of formula I chemical compound is 100-400 μ M.
8, a kind of combination, it comprises acceptable salt on the formula I chemical compound of one or more antiviral agent and effective dose and the materia medica thereof,
Wherein: Ar represents aryl, and it is unsubstituted or by halogen, hydroxyl or C
1-6Alkoxyl replaces, and A represents C
1-6Alkylidene, C
2-6Alkenylene or C
2-6Alkynylene, m are the integers of 0-6, and B represents hydrogen, C
1-6Alkyl or aryl, described aryl can be unsubstituted or by halogen, hydroxyl, C
1-6Alkyl, C
2-6Thiazolinyl or C
2-6Alkynyl substituted.
9, combination as claimed in claim 8, wherein, Ar represents phenyl or naphthyl, and it is unsubstituted or by halogen, hydroxyl or C
1-6Alkoxyl replaces, and A represents C
1-4Alkylidene or C
2-4Alkenylene, m are represented the integer of 0-3, and B represents C
1-3Alkyl or phenyl, described phenyl are unsubstituted or by halogen, hydroxyl or C
1-6Alkyl replaces.
10, combination as claimed in claim 9, wherein, Ar represents phenyl, and it is replaced by halogen, hydroxyl or methoxyl group, and A represents C
2-3Alkylidene, m are represented the integer of 0-2, and B represent methylidene or phenyl.
11, combination as claimed in claim 8, wherein, formula I chemical compound is selected from following group: CAPE (CAPE), PEDMC (PEDMC), caffeic acid methyl ester (MC) and 4-bromo-cinnamic acid phenethyl ester.
12, combination as claimed in claim 8, wherein, described antiviral agent is selected from following group: protease inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and integrase inhibitor
13, combination as claimed in claim 8, wherein, described protease inhibitor is selected from following group: indinavir, ritonavir and nelfinavir.
14, combination as claimed in claim 8, wherein, described nucleoside reverse transcriptase inhibitor is selected from following group: zidovudine (ZDV), lamivudine (3TC), stavudine (d4T), 2 ', 3 '-didanosine (ddI) and 2 ', 3 '-zalcitabine (ddC).
15, combination as claimed in claim 8, wherein, described non-nucleoside reverse transcriptase inhibitor is a nevirapine.
16, combination as claimed in claim 8, wherein, the effective dose of formula I chemical compound is 0.1-1000 μ M.
17, combination as claimed in claim 8, wherein, the effective dose of formula I chemical compound is 100-400 μ M.
18, combination as claimed in claim 8, wherein, active component administration simultaneously.
19, combination as claimed in claim 8, wherein, the administration of active component order.
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| CN 00109701 CN1330922A (en) | 2000-06-29 | 2000-06-29 | Medicinal composition for treating or preventing diseases associated with immunodeficiency virus and reverse transcription virus |
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| CN 00109701 CN1330922A (en) | 2000-06-29 | 2000-06-29 | Medicinal composition for treating or preventing diseases associated with immunodeficiency virus and reverse transcription virus |
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| Publication Number | Publication Date |
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| CN1330922A true CN1330922A (en) | 2002-01-16 |
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| CN 00109701 Pending CN1330922A (en) | 2000-06-29 | 2000-06-29 | Medicinal composition for treating or preventing diseases associated with immunodeficiency virus and reverse transcription virus |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107157978A (en) * | 2017-05-24 | 2017-09-15 | 中国药科大学 | Treat EBV+DLBCL and DLBCL medicine and composition |
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2000
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107157978A (en) * | 2017-05-24 | 2017-09-15 | 中国药科大学 | Treat EBV+DLBCL and DLBCL medicine and composition |
| CN107157978B (en) * | 2017-05-24 | 2021-06-18 | 中国药科大学 | Medicine and composition for treating EBV + DLBCL and DLBCL |
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