CN103288719A - Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead - Google Patents
Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead Download PDFInfo
- Publication number
- CN103288719A CN103288719A CN2012100546098A CN201210054609A CN103288719A CN 103288719 A CN103288719 A CN 103288719A CN 2012100546098 A CN2012100546098 A CN 2012100546098A CN 201210054609 A CN201210054609 A CN 201210054609A CN 103288719 A CN103288719 A CN 103288719A
- Authority
- CN
- China
- Prior art keywords
- hiv
- pyridone
- compounds
- lead
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to synthesis of a non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead. An NNRTI (non-nucleoside reverse-transcriptase inhibitor) aromatic methyl and aromatic carbonyl pyridone derivative is adopted as a lead compound, and a kind of HIV-1 reverse-transcriptase inhibitors with better bioactivity are obtained by a way of giving priority to the lead compound in reasonable design of medicines. According to the synthesis provided by the invention, the replication of HIV in MT-4 cells can be effectively inhibited; better pharmacokinetics properties and synergistic effect on AZF are realized; several HIV variants capable of generating drug resistance to the compounds are separated; since the mutation quantity caused by the compounds is reduced, the time of generating complete drug resistance is obviously delayed in comparison with nevirapine; and compared with other NNRTIs, the advantage of the compounds is that the synergistic effect on the phosphate of AZT is stronger, and the compounds can be applied to the combined therapy of AIDS (acquired immune deficiency syndrome).
Description
Technical field
The present invention relates to the HIV treatment of biomedicine field, particularly the sweet virus of AIDS inhibition of a kind of non-nuclear-pyridinone elder generation conductor is synthetic.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) be by the human immunodeficiency virus (humanimmunodeficiency virus, HIV) due to, one of chronic disease that is difficult to cure for current medical circle.HIV is a kind of chronic retrovirus, by to CDF+ lymphocyte and huge destruction of biting born of the same parents, causes the defective of human body defensive enginery, and causes opportunistic infection, psychosis, knurl disease behind the intrusion human body, in addition dead.In a single day HIV enters target cell, and viral single stranded RNA just is transcribed into double-stranded proviral DNA under the reversed transcriptive enzyme effect; Effect through endonuclease and intergrase enters among the host cell chromosome DNA, and the viral DNA that is integrated is transcribed small virus gene RNA and messenger RNA(mRNA); Synthetic virus protein produces ripe HIV particle and discharges from cell surface under the proteolytic enzyme effect, virus is bred in these steps of repetition.Block any step of above-mentioned life cycle and can effectively control copying of H1V virus.
Reverse transcriptase inhibitors be clinical application the earliest with one of inverase of most worthy.It can be divided into efabirenz (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) according to chemical structure.NRTI such as AZF, ddC, ddI, and 3TC, they activate into the triphosphate form and give birth in the DNA chain of growth, and immature chain is stopped growing; NNRTI does not need to be converted into earlier phos-phate forms and than NRTI low toxicity, because do not influence the activity of cell aggregation enzyme.
So far developed 30 multiclass NNRTI, structure has nothing in common with each other, and but all suppresses reverse transcriptase activity with noncompetitive mechanism.They are incorporated into the last allosteric lipophilic position of HIV-1RT, and this position approaches the combining site that but is different from NRTI.Therefore, uniting this two classes medicine of use might be perfect mutually, and strengthens the function that suppresses virus replication.External and in vivo test research has all proved this point, and therefore, NNRTI is the very promising anti-HIV-1 medicine of a class, especially with NRTI or PI coupling the time.The s-generation NNRTI of now big quantity research develops from first-generation NNRTI antiviral agent, chemical sproof first-generation NNRTI compares with quick generation, s-generation medicine has stronger antiviral activity and to the various variants of HIV-1 action spectrum widely, and has pharmacokinetics character preferably.
Since confirming for the first time on June 5th, 1981, AIDS has seized the life that surpasses 2,500 ten thousand people, and almost the invasion and attack of this serious illness are all failed to break away from each countries and regions in the world.The 2-10 in latent period of AIDS.It is 100%, 90% dead in back 2 years of diagnosis that general mortality rate is almost.Acquired immune deficiency syndrome (AIDS) becomes one of prevailing disease of tool destructive force on the history, it also is one of important indicator of whole world disease surveillance (survaillance), national governments see through to make laws to be attempted to control the scale of infection and by various educational propaganda means, increases the universe to the understanding of this disease.
By in by the end of September, 2011, China accumulative total is reported patients infected hiv and patient's 42.9 ten thousand examples, patient's 16.4 ten thousand examples wherein, dead 8.6 ten thousand examples.According to the numeral that ministry of Health of China is announced, central and local governments' financial AIDS preventing and controlling specific project expenditures at different levels were by 14.6 hundred million yuan of 30.6 hundred million yuan of being increased to 2010 in 2006.
Summary of the invention
In order to overcome the technical problem that exists in the prior art, the invention provides following technical scheme:
Synthesizing of the sweet virus of AIDS inhibition of a kind of non-nuclear-pyridinone elder generation conductor, be lead compound with the sweet class reverse transcriptase inhibitors of non-nuclear-fragrant methyl and fragrant carbonyl pyridone derivative, according to the preferential method of lead compound in the medicine appropriate design, thereby obtain the better HIV-1 reverse transcriptase inhibitors of a class biological activity.
As the preferred technical solution of the present invention, described fragrant methyl and fragrant carbonyl pyridine ketone adopt pyridone 5-ethyl and 6-methyl substituted, and increase substituent volume in 3 replacements of aromatic nucleus (aldehyde, fat, fine base), more favourable its resistance position effect.Change electronegativity simultaneously, thereby interact with HIV-1 better.
The beneficial effect that the present invention brings is: can efficiently suppress HIV and copy (HIV-IIIB EC50=4nmol.L in MT one 4 cells
-1HIV-1IIIB
(YI81C)EC50=13400nmol.L
-1HIV-
1NL4-3EC50=1nmol.L
-1HIV-I
NL4-3K103NEC50=1260nmol.L
-1) and have and pharmacokinetics character is preferably arranged and to the synergism of AZF.It is several that to produce chemical sproof HIV variant to this compounds separated.Because the sudden change quantity that causes of this compounds reduces, and compares with nevirapine, produce the complete chemical sproof time obviously to postpone.Compare with other NNRTI, the advantage of this compounds is the synergism stronger to the phosphoric acid salt of AZT, can be used for the combination therapy of AIDS.
Description of drawings
Fig. 1 prepares route 1 synoptic diagram for the present invention
Fig. 2 prepares route 2 synoptic diagram for the present invention
Fig. 3 is general formula synoptic diagram of the present invention
Embodiment
Below to by reference to the accompanying drawings preferred embodiment of the present invention being elaborated, thereby so that advantages and features of the invention can be easier to be it will be appreciated by those skilled in the art that protection scope of the present invention is made more explicit defining.
A kind of pair roller extruding power drive mechanism as shown in Figure 1, be used for mass transport, described transmission rig comprises top roll 1 and lower roll 2, one end of described top roll is fixedlyed connected with an end of three transmitting gears 3 and upper arm 4, one end of described lower roll 2 is fixedlyed connected with underarm 5 and three gears 3, the other end of described upper arm 4 is fixedly connected on the other end of underarm 5, and 3 two of described six transmitting gears are meshing.
The above; it only is one of the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; any those of ordinary skill in the art are in the disclosed technical scope of the present invention; variation or the replacement that can expect without creative work all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claims were limited.
Claims (2)
1. the sweet virus of AIDS inhibition of non-nuclear-pyridinone elder generation conductor is synthetic, it is characterized in that, be lead compound with the sweet class reverse transcriptase inhibitors of non-nuclear-fragrant methyl and fragrant carbonyl pyridone derivative, according to the preferential method of lead compound in the medicine appropriate design, thereby obtain the better HIV-1 reverse transcriptase inhibitors of a class biological activity.
2. the sweet virus of AIDS inhibition of a kind of non-nuclear according to claim 1-pyridinone elder generation conductor is synthetic, it is characterized in that, described fragrant methyl and fragrant carbonyl pyridine ketone adopt pyridone 5-ethyl and 6-methyl substituted, and replace (aldehyde 3 of aromatic nucleus, fat, fine base) increases substituent volume, more favourable its resistance position effect.Change electronegativity simultaneously, thereby interact with HIV-1 better.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100546098A CN103288719A (en) | 2012-03-05 | 2012-03-05 | Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100546098A CN103288719A (en) | 2012-03-05 | 2012-03-05 | Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103288719A true CN103288719A (en) | 2013-09-11 |
Family
ID=49090313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100546098A Pending CN103288719A (en) | 2012-03-05 | 2012-03-05 | Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103288719A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301254A (en) * | 1998-03-17 | 2001-06-27 | 帕克·休斯研究所 | Nonnucleoside inhibitors of reverse transcriptase for the treatment of hiv-infection |
| CN1303378A (en) * | 1998-04-27 | 2001-07-11 | 国家科研中心 | 3-(Amino-or aminoalkyl) pyridinone derivatives and their use for treatment of HIV related diseases |
| WO2002024650A2 (en) * | 2000-09-19 | 2002-03-28 | Centre National De La Recherche Scientifique (Cnrs) | Pyridinone and pyridinethione derivatives having hiv inhibiting properties |
| CN1646125A (en) * | 2002-02-14 | 2005-07-27 | 法玛西雅公司 | Substituted pyridinones as modulators of P38MAP kinase |
| CN1688548A (en) * | 2002-08-10 | 2005-10-26 | 田边制药株式会社 | Process for preparing quinolin antibiotic intermediates |
| WO2010009047A1 (en) * | 2008-07-14 | 2010-01-21 | Korea Research Institute Of Chemical Technology | Pyridone derivatives as non-nucleoside reverse transcriptase inhibitors |
-
2012
- 2012-03-05 CN CN2012100546098A patent/CN103288719A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301254A (en) * | 1998-03-17 | 2001-06-27 | 帕克·休斯研究所 | Nonnucleoside inhibitors of reverse transcriptase for the treatment of hiv-infection |
| CN1303378A (en) * | 1998-04-27 | 2001-07-11 | 国家科研中心 | 3-(Amino-or aminoalkyl) pyridinone derivatives and their use for treatment of HIV related diseases |
| WO2002024650A2 (en) * | 2000-09-19 | 2002-03-28 | Centre National De La Recherche Scientifique (Cnrs) | Pyridinone and pyridinethione derivatives having hiv inhibiting properties |
| CN1646125A (en) * | 2002-02-14 | 2005-07-27 | 法玛西雅公司 | Substituted pyridinones as modulators of P38MAP kinase |
| CN1688548A (en) * | 2002-08-10 | 2005-10-26 | 田边制药株式会社 | Process for preparing quinolin antibiotic intermediates |
| WO2010009047A1 (en) * | 2008-07-14 | 2010-01-21 | Korea Research Institute Of Chemical Technology | Pyridone derivatives as non-nucleoside reverse transcriptase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| ABDELLAH BENJAHAD等: ""4-benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: optimization and in bitro evaluation against clinically important HIV mutant strains"", 《J.MED.CHEM》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tan et al. | Left bundle branch block: current and future perspectives | |
| Al-Ali et al. | Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial | |
| Sweeney et al. | Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction | |
| Stewart | Optimal management of cytomegalovirus retinitis in patients with AIDS | |
| Fernandez-Fernandez et al. | Exploring sodium glucose co-transporter-2 (SGLT2) inhibitors for organ protection in COVID-19 | |
| Demșa et al. | Persistent left superior vena cava with absent right superior vena cava and discrete subaortic stenosis diagnosed in a patient with sick sinus syndrome: a case report and brief review of the literature | |
| d’Andrea et al. | Cancer screening in HIV-infected patients: Early diagnosis in a high-risk population | |
| Kim et al. | Beyond inhibition: a novel strategy of targeting HIV-1 protease to eliminate viral reservoirs | |
| Punekar et al. | A transcriptomics-based bioinformatics approach for identification and in vitro screening of FDA-approved drugs for repurposing against dengue virus-2 | |
| Jin et al. | Feasibility of left bundle branch area pacing combined with atrioventricular node ablation in atrial fibrillation patients with heart failure | |
| CN103288719A (en) | Synthesis of non-nucleoside HIV (human immunodeficiency virus) inhibitor pyridone lead | |
| Golamari et al. | Tricuspid stenosis | |
| Ceynowa-Sielawko et al. | Pharmacological cardioversion in patients with recent-onset atrial fibrillation and chronic kidney disease subanalysis of the CANT II study | |
| CN102791273A (en) | Small pyrimidine derivatives and methods of use thereof | |
| Alpers | Chikungunya and epidemic disease in the Indian Ocean World | |
| Darki et al. | Hypereosinophilic syndrome with cardiac involvement in a pregnant patient with multiple sclerosis | |
| Chuchuen et al. | Transport and transport properties of tenofovir from microbicide gels into vaginal tissue: analysis using raman spectroscopy | |
| Hurwitz et al. | HIV-1 spectrum disease, psychological distress, and cardiometabolic risk | |
| Vazi et al. | Inflammatory properties of tenofovir in human liver cells | |
| Lowndes et al. | Epidemiology of STIs: UK | |
| CN102295683A (en) | Anti-herpes simplex virus polypeptide and its application | |
| Narayanan | Zika virus therapeutic lead compounds discovery using chemoinformatics approaches | |
| Phan | Non-compaction cardiomyopathy misdiagnosed as dilated cardiomyopathy | |
| Singh et al. | Laryngeal myxoma: emergency management | |
| Swami et al. | Response to modified antitubercular drug regime and antiretroviral therapy in a case of HIV Infection with disseminated tuberculosis with isoniazid induced toxic epidermal necrolysis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130911 |