CN103910761B - Aminopurine phosphinyl vitamin e derivative and uses thereof - Google Patents
Aminopurine phosphinyl vitamin e derivative and uses thereof Download PDFInfo
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- 0 CC(CC*)=*NC(C(C)=NC=N)=[N+][I-]=C Chemical compound CC(CC*)=*NC(C(C)=NC=N)=[N+][I-]=C 0.000 description 6
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Abstract
The invention discloses aminopurine phosphinyl vitamin e derivative, there is the structure of general formula (I).Aminopurine phosphinyl vitamin e derivative of the present invention and salt thereof absorb well all in vivo, bioavailability is high, not only there is AntiHIV1 RT activity and the effect for the treatment of hepatitis B, but also there is anti-liver fibre-effects, therefore there is very high clinical value and huge industrialization prospect.The application in hepatic fibrosis medicines can be prevented and treated in preparation antiviral and preparation.General structure of the present invention is:
Description
Technical field
The invention belongs to medical compounds field, relate to a kind of aminopurine phosphinyl vitamin e derivative and uses thereof.
Background technology
Adefovir ester is the prodrug of Adefovir, and contestable suppresses HBV polymerase, and stops the prolongation of HBVDNA chain.This medicine is ratified to go on the market in the U.S. in September, 2002 by FDA, and China is existing many listings at present.
Tynofovir (WO99/05150) is a kind of new nucleotide antiviral agent of the U.S. lucky moral (Gilead) company exploitation listing.Calendar year 2001 is used for the treatment of the infection of human immunodeficiency virus (HIV) through U.S. FDA approval.Because result for the treatment of is definite, suitability is good, and dosage is suitable, is a line inverase of multiple treatment guidelines recommendation.Tenofovir disoproxil and compound preparation thereof have become the maximum anti-AIDS drug of current sales volume.The Main Function of tynofovir is the activity by suppressing reversed transcriptive enzyme, inserts DNA sequence dna and stops copying of virus.
Tenofovir disoproxil (tenofovirdisoproxil, 1) chemistry (R)-[[2-(6-amino-9H-purine-9-base)-1-methyl ethoxy] methyl] phosphonic acids diisopropyl oxygen carbonyl oxygen base methyl esters (commodity are called Viread) by name, in April, 2008 and August, European Union and U.S. FDA are according to a large amount of clinical test results, ratify again it respectively and be used for the treatment of hepatitis B (hepatitis B), and be described as one of best anti-hbv drug by expert.
Patent CN100396689C discloses Tenofovir compound, also has the activity suppressing HIV-1 virus and HBV virus replication.
Hepatitis B is disease caused after one infects body by hepatitis B virus (HBV).Hepatitis B virus is a kind of Hepadna Virus, and being mainly present in liver cell and damaging liver cell, cause liver cell inflammation, not timely and effective treatment, progression of disease can develop into hepatic fibrosis, liver cirrhosis even HCC(primary hepatocarcinoma).
Summary of the invention
The object of this invention is to provide a kind of aminopurine phosphinyl vitamin e derivative, this aminopurine phosphinyl vitamin e derivative has following general structure:
Wherein, R
1for-H ,-CH
3in one;
R
2for-VE ,-O (CH
2)
n-VE ,-O (CH
2)
ncO-VE ,-O (CH
2)
none in OCO-VE;
R
3for-OH or and R
2identical;
One wherein in n=1,2,3,4,5,6,7,8, described-VE is the one in natural VE or synthesising complex E alcohol residue;
Aminopurine phosphinyl vitamin e derivative (I) of the present invention, with the pharmaceutically conventional salify such as sour example hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartrate, fumaric acid; As R wherein
3during for-OH, again can with sodium hydroxide, potassium hydroxide, amino acid salify, described amino acid is a kind of salify in Methionin, arginine, Histidine, ornithine etc.
Another object of the present invention is to provide the application of described aminopurine phosphinyl vitamin e derivative (I) in preparation antiviral.Experiment confirms, aminopurine phosphinyl vitamin e derivative (I) provided by the invention is remarkable to the restraining effect of HePG2.2.15 cell expressing HBsAG, HbeAG, can effectively suppress hepatitis B virus DNA to copy.
Another object of the present invention is to provide the application of described aminopurine phosphinyl vitamin e derivative (I) in preparation control hepatic fibrosis medicines.Experiment confirms, aminopurine phosphinyl vitamin e derivative (I) provided by the invention effectively can improve the impact of N-nitrosodimethylamine on rat liver fibrosis, adds control fibrosis effect.
Aminopurine phosphinyl vitamin e derivative (I) of the present invention, can make tablet, capsule, granule or oral liquid according to the formulation of pharmaceutical field routine.
Aminopurine phosphinyl vitamin e derivative of the present invention and salt thereof are all new compounds, absorb good in vivo, bioavailability is high, not only there is AntiHIV1 RT activity and the effect for the treatment of hepatitis B, but also there is anti-liver fibre-effects, the novelty teabag that this is adefovir ester, tenofovir disoproxil does not all possess.
Embodiment
The present invention is further elaborated by following examples, but is not limit the invention in its any mode.
embodiment 1tynofovir-unit molecule synthesising complex E is connected product F-1 directly
0.01mol tynofovir is dissolved in 30mL anhydrous methylene chloride, adds 0.15molHOBt, stirring at room temperature 2 hours, then add 0.015molEDC, 0.01mol synthesising complex E and 0.04mol diisopropyl ethyl amine, room temperature reaction spends the night, recycling design, column chromatography for separation obtains product F-1.
1HNMR(CDCl
3)δ8.10-8.30(m,2H),3.91-4.24(m,5H),2.36-2.39(m,2H),1.92-2.09(m,9H),1.49-1.54(m,3H),1.35-1.37(m,4H),1.23-1.27(m,10H),1.05-1.12(m,12H),0.86(d,6H,
J=6.5Hz,),0.84(d,6H,
J=6.5Hz)。
embodiment 2tynofovir-bimolecular synthesising complex E is connected product F-2 directly:
Working method, with embodiment 1, changes the feed ratio of tynofovir and synthesising complex E into 1:3, obtains tynofovir-bimolecular synthesising complex E directly connected product F-2.
1HNMR(CDCl
3)δ8.12-8.31(m,2H),3.92-4.25(m,5H),2.37-2.39(m,4H),1.92-2.08(m,18H),1.49-1.55(m,6H),1.35-1.38(m,8H),1.23-1.28(m,17H),1.05-1.13(m,24H),0.87(m,12H),0.85(m,12H)。
embodiment 3adefovir-unit molecule synthesising complex E is connected product (F-3) directly
Adefovir, with embodiment 1, is substituted tynofovir by working method, is classified as 1:1 with the ratio of vitamin-E, obtains Adefovir-unit molecule synthesising complex E directly connected product (F-3).
1HNMR(CDCl
3)δ8.09-8.29(m,2H),3.91-4.24(m,6H),2.34-2.40(m,2H),1.92-2.12(m,9H),1.50-1.55(m,3H),1.33-1.38(m,4H),1.22-1.28(m,7H),1.06-1.14(m,12H),0.86(d,6H,
J=6.5Hz,),0.84(d,6H,
J=6.5Hz)。
embodiment 4adefovir-bimolecular synthesising complex E is connected product (F-4) directly
The ratio of Adefovir and vitamin-E, with embodiment 3, is classified as 1:3 by working method.
1HNMR(CDCl
3)δ8.10-8.29(m,2H),3.90-4.25(m,6H),2.32-2.41(m,4H),1.95-2.16(m,18H),1.50-1.55(m,6H),1.34-1.39(m,8H),1.24-1.30(m,14H),1.08-1.16(m,24H),0.86(d,12H,
J=6.5Hz,),0.84(d,12H,
J=6.5Hz)。
embodiment 5tynofovir-Wei E derivative the F-5 that ethyl carbonate ester connects
Natural for 0.01mol dimension E is dissolved in 40mL anhydrous propanone, adds 0.015molK
2cO
3, stirring at room temperature 1 hour, then adds 0.015mol ethyl chloroformate, and continue stirring at room temperature 3 hours, then add 0.01mol tynofovir and 0.05mol diisopropyl ethyl amine, room temperature reaction spends the night, recycling design, and column chromatography for separation obtains product F5.
1HNMR(CDCl
3)δ8.10-8.30(m,2H),4.34-4.52(m,4H),3.91-4.24(m,5H),2.36-2.39(m,2H),1.92-2.09(m,9H),1.49-1.54(m,3H),1.35-1.37(m,4H),1.23-1.27(m,10H),1.05-1.12(m,12H),0.86(d,6H,
J=6.5Hz,),0.84(d,6H,
J=6.5Hz)。
embodiment 6tynofovir-Wei E derivative the F-6 that ethyl carbonate ester connects
Working method, with embodiment 5, changes the ratio of tynofovir and vitamin e derivative into 1:3, obtained F2B.
1HNMR(CDCl
3)δ8.10-8.30(m,2H),4.34-4.52(m,8H),3.91-4.24(m,5H),2.36-2.39(m,4H),1.92-2.09(m,18H),1.49-1.54(m,6H),1.35-1.37(m,8H),1.23-1.27(m,20H),1.05-1.12(m,24H),0.86(m,12H),0.84(m,12H)。
embodiment 7adefovir-Wei E derivative the F-7 that ethyl carbonate ester connects
Adefovir, with embodiment 5, is substituted tynofovir by working method, is classified as 1:1 with the ratio of vitamin-E.
1HNMR(CDCl
3)δ8.10-8.25(m,2H),4.32-4.50(m,4H),3.90-4.22(m,6H),2.36-2.42(m,2H),1.95-2.14(m,9H),1.51-1.56(m,3H),1.32-1.38(m,4H),1.21-1.27(m,7H),1.07-1.12(m,12H),0.87(d,6H,
J=6.5Hz,),0.85(d,6H,
J=6.5Hz)。
embodiment 8adefovir-Wei E derivative the F-8 that ethyl carbonate ester connects
Adefovir, with embodiment 5, is substituted tynofovir by working method, is classified as 1:3 with the ratio of vitamin-E.
1HNMR(CDCl
3)δ8.10-8.25(m,2H),4.32-4.50(m,8H),3.91-4.22(m,6H),2.37-2.43(m,4H),1.95-2.15(m,18H),1.51-1.56(m,6H),1.32-1.38(m,8H),1.21-1.27(m,14H),1.07-1.12(m,24H),0.87(m,12H),0.85(m,12H)。
implementation column 9with the tynofovir-Wei E derivative F-9 that ether chain connects
Natural for 0.01mol dimension E is dissolved in 30mL anhydrous methylene chloride, adds 0.02mol salt of wormwood and 0.03mol α, ω-dihalo for hydrocarbon, stirring at room temperature 8 hours, then add 0.01mol tynofovir and 0.05mol diisopropyl ethyl amine, be warming up to back flow reaction and spend the night, obtained product F-9.
1HNMR(CDCl
3)δ8.10-8.24(m,2H),4.12-4.24(m,4H),3.90-4.22(m,5H),2.36-2.42(m,2H),1.96-2.14(m,11H),1.51-1.56(m,3H),1.33-1.39(m,4H),1.21-1.28(m,10H),1.09-1.12(m,12H),0.88(d,6H,
J=6.5Hz,),0.86(d,6H,
J=6.5Hz)。
embodiment 10with the tynofovir-Wei E derivative F-10 that ether chain connects
Working method, with embodiment 9, changes the ratio of tynofovir and vitamin e derivative into 1:3, obtained F-10.
1HNMR(CDCl
3)δ8.07-8.25(m,2H),4.12-4.29(m,8H),3.87-4.12(m,5H),2.36-2.42(m,4H),1.99-2.10(m,22H),1.50-1.59(m,6H),1.31-1.42(m,8H),1.21-1.32(m,20H),1.04-1.12(m,24H),0.90-0.88(m,12H),0.86-0.83(m,12H)。
embodiment 11with the Adefovir-Wei E derivative F-11 that ether chain connects
Adefovir, with embodiment 9, is replaced tynofovir by working method, is 1:1 with the ratio of vitamin e derivative, obtained F-11.
1HNMR(CDCl
3)δ8.10-8.24(m,2H),4.12-4.24(m,4H),3.90-4.22(m,6H),2.36-2.42(m,2H),1.96-2.14(m,11H),1.51-1.56(m,3H),1.33-1.38(m,4H),1.21-1.27(m,7H),1.09-1.13(m,12H),0.87(d,6H,
J=6.5Hz,),0.85(d,6H,
J=6.5Hz)。
embodiment 12with the Adefovir-Wei E derivative F-12 that ether chain connects
Adefovir, with embodiment 9, is replaced tynofovir by working method, is 1:3 with the ratio of vitamin e derivative, obtained F-12.
1HNMR(CDCl
3)δ8.11-8.25(m,2H),4.11-4.26(m,8H),3.88-4.12(m,6H),2.36-2.42(m,4H),1.96-2.14(m,22H),1.51-1.56(m,6H),1.33-1.38(m,8H),1.21-1.29(m,14H),1.09-1.16(m,24H),0.88(m,12H),0.85(m,6H)。
embodiment 13with the tynofovir-Wei E derivative F-13 that ester chain connects
Natural for 0.01mol dimension E is dissolved in anhydrous propanone, adds 0.015mol salt of wormwood, 0.011mol chloroacetyl chloride, stirring at room temperature 8 hours, then add 0.01mol tynofovir and 0.03mol diisopropyl ethyl amine, be warming up to back flow reaction and spend the night, obtained product F-13.
1HNMR(CDCl
3)δ8.11-8.26(m,2H),4.28-4.42(m,2H),3.93-4.25(m,5H),2.36-2.39(m,4H),1.92-2.06(m,9H),1.49-1.60(m,3H),1.35-1.39(m,4H),1.23-1.27(m,10H),1.05-1.10(m,12H),0.87(d,6H,
J=6.5Hz,),0.85(d,6H,
J=6.5Hz)。
embodiment 14with the tynofovir-Wei E derivative F-14 that ester chain connects
Working method, with embodiment 13, changes the ratio of tynofovir and vitamin e derivative into 1:3, obtained F-14.
1HNMR(CDCl
3)δ8.11-8.32(m,2H),4.34-4.52(m,4H),3.91-4.24(m,5H),2.35-2.42(m,8H),1.92-2.12(m,18H),1.49-1.54(m,6H),1.35-1.37(m,8H),1.23-1.27(m,20H),1.05-1.15(m,24H),0.86(m,12H),0.84(m,12H)。
embodiment 15adefovir-Wei E derivative the F-15 that ethyl ester connects
Adefovir, with embodiment 13, is substituted tynofovir by working method, is classified as 1:1 with the ratio of vitamin-E.
1HNMR(CDCl
3)δ8.10-8.23(m,2H),4.31-4.52(m,2H),3.91-4.25(m,6H),2.36-2.46(m,4H),1.89-2.16(m,9H),1.47-1.52(m,3H),1.30-1.38(m,4H),1.21-1.29(m,7H),1.07-1.13(m,12H),0.87(d,6H,
J=6.5Hz,),0.85(d,6H,
J=6.5Hz)。
embodiment 16adefovir-Wei E derivative the F-16 that ethyl ester connects
Adefovir, with embodiment 13, is substituted tynofovir by working method, is classified as 1:3 with the ratio of vitamin-E.
1HNMR(CDCl
3)δ8.10-8.28(m,2H),4.32-4.50(m,4H),3.91-4.24(m,6H),2.37-2.46(m,8H),1.91-2.15(m,18H),1.45-1.56(m,6H),1.36-1.39(m,8H),1.17-1.24(m,14H),1.05-1.12(m,24H),0.86(m,12H),0.84(m,12H)。
embodiment 17
Utilize HePG2.2.15 cell model, external investigation compound of the present invention produces the impact of HBsAG, HBeAG, HBV-DNA to HePG2.2.15 cell cultures, evaluates the activity of chemical combination anti-hepatitis B virus (HBV) of the present invention.
Adopt DMEM nutrient chemical, containing G418 and calf serum in nutrient chemical, culture condition 37 DEG C, 5%CO
2, incubation time 12 days, if DMEM nutrient solution group is control group.Get the cultivation supernatant liquor of 12 days respectively, make the mensuration of HBsAG, HBeAG, HBV-DNA, operate and to illustrate by test kit and carry out.Inhibiting rate=(control wells P/N value-test holes P/N value)/control wells P/N value × 100%.The results are shown in Table 1, table 2.
Illustrate that the restraining effect of the compounds of this invention to HePG2.2.15 cell expressing HBsAG, HbeAG is remarkable.
The compounds of this invention declines significantly to HePG2.2.15 cellular replication HBV-DNA quantity compared with control group, and explanation can effectively suppress hepatitis B virus DNA to copy.
embodiment 18
Body weight 165 ~ 205g male SD rat, be divided into normal group, model group, tenofovir disoproxil control group and each test group at random, model group, tenofovir disoproxil control group and each rats in test groups abdominal injection N-nitrosodimethylamine 10mg/kg for three days on end weekly, normal group intraperitoneal injection of saline for three days on end weekly, totally 3 weeks; While control group and each test group modeling, every day pours into corresponding medicine through stomach respectively, control group gavage every day tenofovir disoproxil 100mg/kg, test group every day respectively gavage the compounds of this invention (F-01, F-02, F-03,, F-16) 100mg/kg, the physiological saline of normal group and model group gavage same volume, also totally 3 weeks.Test the 4th week carotid artery sacrificed by exsanguination animal, get blood separation of serum ,-20 DEG C of freezing survey indices, cut whole liver, get right lobe of liver with position hepatic tissue 3 pieces, with normal saline flushing, one piece-70 DEG C preservations, fix with 10% neutral formalin for one piece, another block takes 0.5g, after 4 DEG C of ice baths, after tissue homogenate, add physiological saline and make 10% tissue homogenate, centrifugal, get supernatant liquor and do hepatic tissue lipid peroxy thing mda (MDA) and liver superoxide dismutase (SOD) detection; The content of pre-collagen type Ⅲ (PC III), hyaluronic acid (HA) and hepatic tissue SOD activity adopt radioimmunology to detect, and MDA adopts sulfo-veronal color method.
Through the hepatic tissue that 10% neutral formalin is fixing, through specimens paraffin embedding slices, do conventional H E and Masson dyeing.Hepatic fibrosis is divided into 0 ~ IV grade for molten standard, 0 grade: without hepatic fibrosis with reference to Qu; I grade: fibrillar connective tissue is only confined to portal area or portal area and expands, the tendency of oriented leaflet development; II grade: fibrillar connective tissue hyperplasia enters liver lobule 2/3 and has I grade of same change; III grade: fibrosis reticular tissue enters around central veins of hepatic lobules; IV grade: it is many places diffusivity hyperplasia that fibrosis reticular tissue enters at leaflet, has pseudolobuli to be formed, and have III grade of same change.The results are shown in Table 3, table 4.
The effect of tenofovir disoproxil to rat liver fibrosis is the same with model group, and on rat liver fibrosis without impact, the compounds of this invention all effectively can improve the impact of N-nitrosodimethylamine on rat liver fibrosis, reaches IV grade of pathology without 1 routine hepatic fibrosis.
The improvement of the compounds of this invention to hyaluronic acid (HA) is almost consistent with normal group; Pre-collagen type Ⅲ (PC III), hepatic tissue lipid peroxy thing mda (MDA) and liver superoxide dismutase (SOD) are also had greatly improved, illustrates that the compounds of this invention effectively can improve hepatic fibrosis index.
Claims (5)
1. an aminopurine phosphinyl vitamin e derivative, is characterized in that, has following formula I general structure:
Wherein, R
1for-H ,-CH
3in one;
R
2for-VE ,-O (CH
2)
n-VE ,-O (CH
2)
ncO-VE ,-O (CH
2)
none in OCO-VE;
R
3for-OH or and R
2with;
One wherein in n=1,2,3,4,5,6,7,8, described-VE is the one in natural VE alcohol residue or synthesising complex E alcohol residue,
。
2. the salt that formed with pharmaceutically conventional acid of a kind of aminopurine phosphinyl vitamin e derivative according to claim 1, it is characterized in that, described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartrate or fumaric acid.
3. the application of a kind of aminopurine phosphinyl vitamin e derivative according to claim 1 in preparation antiviral, is characterized in that, preparing the application in resisting HBV virus medicine.
4. a kind of aminopurine phosphinyl vitamin e derivative according to claim 1 prevents the application in hepatic fibrosis medicines in preparation.
5. the application according to claim 3 or 4, is characterized in that, the dosage form of described medicine is tablet, capsule, granule or oral liquid.
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| CN1810816A (en) * | 2006-03-07 | 2006-08-02 | 中国医学科学院医药生物技术研究所 | Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity |
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| CN1810816A (en) * | 2006-03-07 | 2006-08-02 | 中国医学科学院医药生物技术研究所 | Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity |
Non-Patent Citations (1)
| Title |
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| 肝纤维化的临床研究进展;梁健 等;《河北中医》;20120229;第34卷(第2期);第294-296页 * |
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