CN107595843A - A kind of Pervone derivative and its purposes for treating diabetes B - Google Patents
A kind of Pervone derivative and its purposes for treating diabetes B Download PDFInfo
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- CN107595843A CN107595843A CN201710933516.5A CN201710933516A CN107595843A CN 107595843 A CN107595843 A CN 107595843A CN 201710933516 A CN201710933516 A CN 201710933516A CN 107595843 A CN107595843 A CN 107595843A
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Abstract
The present invention relates to medicinal chemistry art, and in particular to the analog derivative shown in logical formula (I) and the pharmaceutical composition containing the analog derivative are preparing the purposes in treating diabetes B medicine.The compound has the function that to protect islet beta-cell apoptosis, the treatment available for diabetes B.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to a kind of Pervone derivative and its medicine group
Purposes of the compound in diabetes B is treated.The Pervone derivative has the function that to protect islet beta-cell apoptosis, can used
In the treatment of diabetes B.
Technical background
Data shows that the incidence of disease of whole world diabetes is in obvious ascendant trend, it has also become seriously endangers human health
One of principal disease.China at least possesses 92,000,000 diabetics, and more than 20 years old maturity-onset diabetes illness rate is 9.7%, and
The ratio of prediabetes be up to 15.5% (JAMA, 2013,310:948-959.), wherein diabetes B accounts for diabetic population
More than 90%.Complications caused by diabetes, including diabetic nephropathy, cardiovascular and cerebrovascular disease, diabetic eye diseases with
And diabetes etc., the physical and mental health of patient is drastically influence, white elephant, diabetes are brought to personal, family and society
Preventing and treating have become global pharmaceuticals industry questions of common interest.
The pathological characters of diabetes B are insulin resistances and beta Cell of islet carries out sexual exhaustion, and latter of which is 2 types sugar
Urinate disease progression and the deciding factor deteriorated (J Clin Endocrinol Metab, 2011,96:2354-2366.), one
The perspective study of Pima Indians follow-ups 7 years finds that the predictive factor that diabetes B occurs is β cell function indexs AIRg
(acute insulin response after glucose stimulates) rather than fat and insulin resistance (Diabetologia, 2001,44:929-
945).Therefore, for the function and quantity of protection β cells, effectively and persistently to control blood glucose, and it is concurrent to reduce diabetes chronic
Disease, it is the new strategy for developing diabetes B medicine.
Changchun amine system extracts an obtained main indole alkaloid composition from periwinkle, clinically uses extensively
, can be long-term use of in treatment cerebrovascular disorder, cerebral embolism, cerebral thrombosis and bleeding sequelae etc., Small side effects.Pervone makes
Diseased region brain tissue maintains and recovered the oxidation decomposition metabolism of glucose, the generation of lactic acid and the release of carbon dioxide is recovered just
Often, so as to expansion of cerebral vascular, Brain circlulation is improved.CN101888776 report pervones have anti-inflammatory work by suppressing NF- κ B paths
Property.
The content of the invention
The invention discloses the Pervone derivative shown in a kind of logical formula (I).The pharmacological results show, change of the invention
Compound can improve blood glucose and HbAle egg, have certain protective effect to beta Cell of islet.Therefore, the logical formula (I) of the present invention
Compound or its pharmaceutically acceptable salt as single therapy agent, or with other Remedies for diabetes combination can be used for
The treatment of diabetes B.
The present invention passes through pharmacodynamics test, it was demonstrated that general formula (I) compound, which has, prevents or treat diabetes B work(
Effect.
Wherein：R1For hydrogen or and R2Double bond is formed together；
R2For hydroxyl, hydrogen or and R1Double bond is formed together；
R3Represent following any structure group；
Wherein：R5For hydrogen, C1-C6Alkyl or C1-C6Hydroxyalkyl；
R6For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl or C3-C7Cycloalkyl；
R7For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl or C3-C7Cycloalkyl；
R8For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl, C3-C7Cycloalkyl, C1-C6Straight chained alkyl acyl group or C3-C7Cycloalkanes
Base acyl group；
R4Represent following any structure group；
Logical formula (I) compound pharmaceutically acceptable salt has same drug activity.
Currently preferred part of compounds is as follows：
Preferred compound：
The invention also discloses some new compounds, structural formula are as follows：
The invention also discloses the preparation method of logical formula (I) compound, including：
(1) pervone is under the catalysis of acid, through the compound shown in dehydration generating structure formula A-1.
Specifically, pervone is dissolved in solvent (for example, tetrahydrofuran, acetonitrile, toluene, dimethylformamide, dimethyl
Sulfoxide etc.) in and add sour (for example, sulfuric acid, phosphoric acid, polyphosphoric acids, p-methyl benzenesulfonic acid etc.), heating stirring reaction.Reaction terminates
Afterwards, compound A-1 is obtained through basification.
(2) pervone is under the catalysis of acid, through being dehydrated and the compound shown in ester exchange reaction generating structure formula A-2.
Specifically, by pervone be dissolved in propyl alcohol and add acid (for example, sulfuric acid, phosphoric acid, polyphosphoric acids, to toluene sulphur
Acid etc.), heating stirring reaction.After reaction terminates, compound A-2 is obtained through basification.
(3) A-1 is under the catalysis of alkali, through the compound shown in hydrolysis generating structure formula A-3.
Specifically, by A-1 be dissolved in solvent (for example, methanol, ethanol, tetrahydrofuran, water, etc.) in and add alkali (for example,
Potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide etc.), heating stirring reaction.After reaction terminates, acidified processing obtains chemical combination
Thing A-3.
(4) A-3 is in the presence of alkali, and paratoluensulfonyl chloride (TsCl), and intermediate is obtained through esterification, then with aqueous amine
Or the compound shown in substitution reaction generating structure formula B-1~B-12 occurs for amine.
Specifically, by A-3 be dissolved in solvent (for example, dichloromethane, chloroform, tetrahydrofuran etc.) and add alkali (for example,
Potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide etc.), and paratoluensulfonyl chloride (TsCl), reaction is stirred at room temperature.Then add again
Enter ammoniacal liquor or amine, after reaction terminates, reaction solution through washing, dry after concentration and obtain compound B-1~B-12 after purification.
(5) A-1 is in Lithium Aluminium Hydride (AlLiH4) in the presence of, through the compound shown in reduction reaction generating structure formula C-1.
Specifically, A-1 is dissolved in solvent (for example, methanol, ethanol, tetrahydrofuran etc.) and adds Lithium Aluminium Hydride
(AlLiH4), low temperature stirring reaction.After reaction terminates, reaction solution through washing, dry after concentration and obtain compound C- after purification
1。
(6) C-1 is in the presence of alkali, with R8Substitution reaction generating structure formula C-2~C-5 institutes occur for X (X=I, Br, Cl)
The compound shown.
Specifically, C-1 is dissolved in solvent (for example, dichloromethane, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran etc.) and added
Alkali (for example, potassium carbonate, sodium carbonate, sodium hydride, triethylamine, pyridine etc.) and R8X (X=I, Br, Cl), stirring reaction.Reaction knot
Shu Hou, reaction solution through washing, dry after concentration and obtain compound C-2~C-5 after purification.
(7) C-1 is in the presence of alkali, and chloro-carbonic acid (4- nitrobenzophenones) ester, and intermediate is obtained through esterification, then with amine
Compound shown in substitution reaction generating structure formula D-1~D-7 occurs for water or amine.
Specifically, by C-1 be dissolved in solvent (for example, dichloromethane, chloroform, tetrahydrofuran etc.) and add alkali (for example,
Potassium carbonate, sodium carbonate, potassium hydroxide, pyridine, triethylamine, sodium hydroxide etc.), and chloro-carbonic acid (4- nitrobenzophenones) ester, room temperature stir
Mix reaction.Then add ammoniacal liquor or amine, after reaction terminates, reaction solution through washing, dry after concentration and obtain chemical combination after purification
Thing D-1~D-7.
The invention also discloses a kind of pharmaceutical composition for diabetes B treatment, it includes medicine effective dose
The Changchun amine derivant (I) or its salt and pharmaceutically acceptable carrier of the present invention.
Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation, such as piece is made
Agent, capsule, pulvis, syrup, liquor, suspending agent, freeze-dried powder, injection etc., spices, sweetener, liquid or solid can be added
The common medicinal supplementary material such as filler or diluent.
The administering mode of compound of the present invention clinically can use the modes such as oral, injection, local administration.
When pharmaceutical preparation is used to treat made of the compound of the present invention, people is 1mg~1000mg/ days with dosage range.
Also the scope can be exceeded according to the difference and disease severity of formulation, dosage.
It is the pharmacological testing and result of part of compounds of the present invention below.
1st, cellular level test Changchun amine derivant stimulates STZ the protective effect of lower beta Cell of islet
The present invention uses the cell model of STZ inducing islet β Apoptosis, and detection method is mtt assay.Specific experiment flow
It is as follows：INS-1 cells are inoculated in 48 orifice plates in 5%CO237 DEG C of cultures in incubator.After cell attachment, 500 μM are added
STZ and testing compound are total to incubated cell 24 hours.Then, the MTT solution (5mg/mL) for adding 20 μ L continues to be incubated 4 hours.
Finally, 200 μ L dimethyl sulfoxide (DMSO) (DMSO) is added per hole after during shaking table (450r/min) shakes 10 minutes, treats purple crystal
All dissolvings, in the light absorption value that every hole under 490nm or 570nm wavelength, is detected on enzyme-linked immunosorbent assay instrument.
Evaluation of the Changchun amine derivant of table 1 to beta Cell of islet protective effect
Table 1 test result indicates that, the compounds of this invention all has preferable protection activity to beta Cell of islet, wherein, B-
3rd, C-1, F-3 and I-1 EC50Value be respectively 0.22 μM, 0.22 μM, 0.26 μM and 0.05 μM, beta Cell of islet is shown compared with
High protection activity.
2nd, the improvement result for the diabetic mice glycometabolism that pervone is induced STZ/ high fat diets (HFD)
The present invention gives diabetes B model mice (mouse of STZ/HFD inductions) chemical combination by way of intraperitoneal injection
Thing pervone (form of medication is Changchun amine hydrochlorate), the fasting blood-glucose of STZ/HFD inducing mouses, HbAle after measure administration
The quantity of insulin positive cells in albumen, oral glucose tolerance and pancreatic tissue, to study treatment of the compound to diabetes B
And improvement result.Specific experiment flow is as follows：The mouse of STZ/HFD inductions is after intraperitoneal injection STZ tri- days, according to measure fasting
Mouse is divided into 3 groups, respectively two dosage groups of blank control group and tested material by fasting blood-glucose result and body weight after 6 hours, often
9 mouse of group.Each group mouse is daily morning 10:00-11:00 respectively intraperitoneal injection give solvent (physiological saline), 30mg/kg
With 15mg/kg Changchun amine hydrochlorate.Fasting blood-glucose is monitored weekly once during administration, and fasting blood-glucose is after water is can't help in mouse fasting
6h is (from the morning 9:30-10:30 to afternoon 3:30-4:30) blood glucose value after, and count the average blood sugar of each group；After experiment terminates
Unified measure glycosylated hemoglobin (HbA1c).Each group mouse carries out oral glucose tolerance experiment, mouse fasting after being administered 4 weeks
Gavage 1g/kg glucose (Sigma) after night, taken according to time point (0,15,30,45,60,90,120min) from mouse tail vein
Blood measures blood glucose.After mouse is put to death, take the pancreatic tissue of each group mouse to be fixed, insulin is detected using ImmunohistochemistryMethods Methods
The quantity of positive cell.Data processing and statistical analysis：Data are represented with means standard deviation (mean ± sem), using Dan Yin
Plain variance analysis method carries out statistical analysis to data.
Experimental result is as follows：
(1) influence for the mouse fasting blood-glucose (fasting blood glucose, FBG) that pervone is induced STZ/HFD
(see Fig. 1)：Fasting blood-glucose maintains of a relatively high level always during blank control group mouse experiment.30mg/kg and 15mg/
Kg pervone plays hypoglycemic effect since second week, and the blood sugar level of administration group is initially located in solvent group from second week
Lower section, this phenomenon is continued until that experiment terminates.
(2) influence for the mouse glycosylated hemoglobin (HbA1c) that pervone is induced STZ/HFD (see Fig. 2)：Administration terminates
Afterwards, the glycosylated hemoglobin of two dosage groups of pervone is substantially lower than solvent group, illustrates that pervone has good long-term drop
Sugared activity.
(3) influence for the Mouse oral sugar tolerance (OGTT) that pervone is induced STZ/HFD (see Fig. 3)：Each group mouse in
4th week carries out oral glucose tolerance experiment after administration.To the Mouse oral 1g/kg of STZ/HFD inductions glucose (Sigma), press
Blood is taken to measure blood glucose from mouse tail vein according to time point (0,15,30,45,60,90,120min).Compared with solvent group, pervone
Two dosage can significantly improve STZ/HFD induction mouse oral glucose tolerance.
(4) influence for the mice pancreatic tectology that pervone is induced STZ/HFD (see Fig. 4)：, will after administration terminates
Each group mouse, which is put to death by specification and takes out pancreatic tissue, is fixed on 4% paraformaldehyde, then carries out histotomy and SABC
Experiment.Compared with solvent group, two dosage of pervone can dramatically increase pancreas in the pancreatic tissue of the mouse of STZ/HFD inductions
The quantity of island element positive cell, illustrate that pervone can effectively improve islet cells and be damaged.
As a result show, compared with solvent control group, pervone can significantly reduce the fasting blood-glucose of STZ/HFD inducing mouses
And glycated hemoglobin levels, and the oral glucose tolerance of mouse and the quantity of increase insulin positive cells are significantly improved, say
The bright compound has the function that the glycometabolism for improving STZ/HFD inducing mouses and reduction islet cells are impaired, has good
Hypoglycemic activity, the treatment available for diabetes B.
Brief description of the drawings
Fig. 1 is the influence for the mouse fasting blood-glucose that pervone is induced STZ/HFD
Fig. 2 is influence (the * * expressions P for the mouse glycosylated hemoglobin that pervone is induced STZ/HFD<0.01)
Fig. 3 be the Mouse oral sugar tolerance that pervone is induced STZ/HFD influence (figure A be that pervone is lured STZ/HFD
The influence for the mouse blood sugar led；Figure B is the TG-AUC that the Mouse oral sugar tolerance that pervone is induced STZ/HFD influences
Figure.* represents P<0.01；* * represent P<0.001)
Fig. 4 is that (figure A is pervone to STZ/ for the influence of the mice pancreatic tectology that pervone is induced STZ/HFD
The influence of insulin positive cells quantity in the mice pancreatic tissue of HFD inductions；Figure B is figure A quantitative result.* represents P<
0.01；* * represent P<0.001)
Embodiment
Embodiment 1
Compound A-1 synthesis
Take pervone (1.77g, 5mmol) and p-methyl benzenesulfonic acid (1.72g, 10mmol) to be dissolved in toluene (20mL), flow back
React 2h, be cooled to room temperature, solvent evaporated obtains clear yellow viscous thing, adds water (20mL), with 5% sodium hydroxide solution adjust pH to
8, there are a large amount of white solids to separate out, filter, then filter cake is eluted with ethanol (3mL), after drying white solid A-1 (1.55g,
92%).1H NMR(400MHz,CDCl3)δ(ppm):7.49 (d, J=7.2Hz, 1H), 7.25 (d, J=7.2Hz, 1H), 7.13-
7.21(m,2H),6.17(s,1H),4.19(s,1H),3.97(s,3H),3.23–3.40(m,2H),3.00–3.09(m,1H),
2.60–2.65(m,2H),2.50–2.56(m,1H),1.87–1.99(m,2H),1.71–1.80(m,1H),1.52–1.55(m,
1H), 1.40-1.45 (m, 1H), 1.02-1.06 (t, J=7.2Hz, 3H), 0.99-1.01 (m, 1H) .ESI-MS ((m/z) 337,
[M+H]+).
Embodiment 2
Compound A-2 synthesis
Take pervone (354mg, 1mmol) to be dissolved in normal propyl alcohol (6mL), be slowly added to the concentrated sulfuric acid (1mL), back flow reaction
8h, is cooled to room temperature, adds water (6mL) after solvent evaporated, adjusts pH to 8 with 5% sodium hydroxide solution, there is a large amount of white solids
Separate out, filter, then filter cake is eluted with ethanol (1mL), white solid A-2 (295mg, 81%) is obtained after drying.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (dd, J=8.8,2.0Hz, 1H), 7.24 (dd, J=8.8,2.0Hz, 1H), 7.17-
7.10(m,2H),6.11(s,1H),4.36-4.28(m,2H),4.15(s,1H),3.37-3.32(m,1H),3.28-3.21(m,
1H),3.07-2.98(m,1H),2.63-2.61(m,2H),2.53-2.48(m,1H),1.96-1.86(m,2H),1.83-1.74
(m,2H),1.73-1.66(m,1H),1.53-1.49(m,1H),1.42-1.38(m,1H),1.07-0.95(m,7H).ESI-MS
((m/z)365,[M+H]+).
Embodiment 3
Compound A-3 synthesis
The preparation such as A-2 should be operated, raw material substitutes normal propyl alcohol with isopropanol (6ml), after reaction terminates, is cooled to room temperature,
Add water (6mL) after solvent evaporated, adjust pH to 8 with 5% sodium hydroxide solution, there are a large amount of white solids to separate out, filter, then use
Ethanol (1mL) elutes filter cake, and white solid A-3 (270mg, 74%) is obtained after drying.1H NMR(400MHz,CDCl3)δ(ppm):
7.46 (d, J=7.2Hz, 1H), 7.27 (d, J=7.2Hz, 1H), 7.17-7.10 (m, 2H), 6.08 (s, 1H), 5.34-5.25
(m,1H),4.14(s,1H),3.37-3.32(m,1H),3.28-3.21(m,1H),3.07-2.98(m,1H),2.63-2.61
(m,2H),2.53-2.47(m,1H),1.98-1.85(m,2H),1.74-1.68(m,1H),1.53-1.49(m,1H),1.39
(d, J=6Hz, 3H), 1.37 (d, J=6Hz, 3H), 1.31-1.26 (m, 1H), 1.01 (t, J=7.2Hz, 3H), 1.04-0.97
(m,4H).ESI-MS((m/z)365,[M+H]+).
Embodiment 4
Compound B-1 synthesis
A-1 (1.68g, 5mmol) and sodium hydroxide (0.24g, 6mmol) is taken to be dissolved in absolute ethyl alcohol (10mL), backflow is anti-
3h is answered, room temperature is cooled to, adds water (10mL) after solvent evaporated, with second acid for adjusting pH to 3~4 or so, there are a large amount of off-white powders
Separate out, filter, then with water (15mL) elute filter cake, dry after off-white powder VCA (1.54g, 96%) take VCA (322mg,
1mmol) it is dissolved in paratoluensulfonyl chloride (380mg, 2mmol) in dichloromethane (6mL), after 4h is stirred at room temperature, adds ammoniacal liquor
(0.5mL), then 3h is reacted at room temperature, TLC detections, after reaction terminates, reaction solution is washed with water once, saturated sodium carbonate is washed twice, is taken
Organic phase is evaporated to obtain crude product, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-1 (266mg, 83%), is obtained
。1H NMR(400MHz,DMSO-d6)δ(ppm):7.48 (d, J=7.6Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 7.13-
7.20(m,2H),6.40(s,1H),6.04(s,1H),5.84(s,1H),4.17(s,1H),3.34–3.39(m,1H),3.22–
3.30(m,1H),3.00–3.09(m,1H),2.62–2.65(m,2H),2.49–2.54(m,1H),1.85–1.98(m,2H),
1.67–1.78(m,1H),1.50–1.53(m,1H),1.39–1.43(m,1H),0.98–1.06(m,4H).ESI-MS((m/z)
322,[M+H]+).
Embodiment 5
Compound B-2 synthesis
Operation such as B-1 preparation, raw material are substituted with methylamine (240mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-2 (278mg, 83%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.48 (d, J=7.6Hz, 1H), 7.13-7.28 (m, 3H), 6.05-6.06 (m, 1H), 5.70
(s,1H),4.17(s,1H),3.35–3.40(m,1H),3.22–3.30(m,1H),3.03–3.05(m,3H),2.63–2.65
(m,2H),2.50–2.54(m,1H),2.07(s,1H),1.83–1.97(m,2H),1.69–1.75(m,1H),1.50–1.53
(m,1H),1.39–1.43(m,1H),0.98–1.03(m,4H).ESI-MS((m/z)336,[M+H]+).
Embodiment 6
Compound B-3 synthesis
Operation such as B-1 preparation, raw material are substituted with ethamine (135mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-3 (321mg, 92%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.48 (dd, J=7.2,2.0Hz, 1H), 7.28 (dd, J=7.2,2.0Hz, 1H), 7.12-
7.19(m,2H),5.97(s,1H),5.70(s,1H),4.17(s,1H),3.50–3.58(m,2H),3.35–3.40(m,1H),
3.22–3.30(m,1H),3.00–3.09(m,1H),2.63–2.65(m,2H),2.49–2.54(m,1H),1.84–1.97(m,
2H), 1.72-1.76 (m, 1H), 1.50-1.54 (m, 1H), 1.39-1.44 (m, 1H), 1.26-1.30 (t, J=7.2Hz, 3H),
0.98–1.06(m,4H).ESI-MS((m/z)350,[M+H]+).
Embodiment 7
Compound B-4 synthesis
Operation such as B-1 preparation, raw material are substituted with propylamine (177mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-4 (323mg, 89%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.48 (d, J=7.2Hz, 1H), 7.27-7.29 (m, 1H), 7.12-7.19 (m, 2H),
5.98-6.01 (t, J=5.6Hz, 1H), 5.69 (s, 1H), 4.18 (s, 1H), 3.35-3.52 (m, 3H), 3.23-3.30 (m,
1H),3.00–3.09(m,1H),2.63–2.66(m,2H),2.49–2.55(m,1H),1.84–1.96(m,2H),1.75–1.80
(m,1H),1.64–1.70(m,2H),1.51–1.54(m,1H),1.39–1.44(m,1H),0.99–1.07(m,7H).ESI-MS
((m/z)364,[M+H]+).
Embodiment 8
Compound B-5 synthesis
Operation such as B-1 preparation, raw material are replaced with isopropylamine (177mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-5 (309mg, 85%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (dd, J=7.2,2.0Hz, 1H), 7.28 (dd, J=7.2,2.0Hz, 1H), 7.17-
7.10(m,2H),5.66(s,1H),4.36-4.28(m,1H),4.15(s,1H),3.37-3.33(m,1H),3.27-3.20(m,
1H),3.07-2.98(m,1H),2.63-2.61(m,2H),2.52-2.47(m,1H),1.97-1.80(m,2H),1.76-1.65
(m, 1H), 1.52-1.48 (m, 1H), 1.41-1.36 (m, 1H), 1.27 (d, J=6.4Hz, 3H), 1.25 (d, J=6.4Hz,
3H), 1.00 (t, J=7.2Hz, 3H), 0.96-1.03 (m, 4H) .ESI-MS ((m/z) 364, [M+H]+).
Embodiment 9
Compound B-6 synthesis
Operation such as B-1 preparation, raw material are substituted with butylamine (219mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-6 (324mg, 86%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.47 (dd, J=7.2,2.0Hz, 1H), 7.24 (dd, J=7.2,2.0Hz, 1H), 6.17-
6.20 (t, J=5.6Hz, 1H), 5.65 (s, 1H), 4.14 (s, 1H), 3.41-3.50 (m, 2H), 3.32-3.37 (m, 1H),
3.19–3.27(m,1H),3.02–3.06(m,1H),2.90(s,2H),2.61–2.63(m,2H),2.46–2.52(m,1H),
1.81–1.95(m,2H),1.57–1.63(m,2H),1.49–1.52(m,1H),1.37–1.43(m,2H),0.91–1.02(m,
7H) .ESI-MS ((m/z) 378, [M+H]+).
Embodiment 10
Compound B-7 synthesis
Operation such as B-1 preparation, raw material are replaced with cyclopropylamine (171mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-7 (297mg, 82%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (d, J=7.2Hz, 1H), 7.22 (d, J=7.2Hz, 1H), 7.17-7.10 (m, 2H),
6.03(s,1H),4.14(s,1H),3.37-3.32(m,1H),3.27-3.19(m,1H),3.07-3.00(m,1H),2.99-
2.92(m,1H),2.63-2.59(m,2H),2.51-2.46(m,1H),1.96-1.80(m,2H),1.75-1.64(m,1H),
1.51-1.47 (m, 1H), 1.41-1.36 (m, 1H), 0.99 (t, J=7.2Hz, 3H), 0.95-0.91 (m, 1H), 0.90-0.88
(m,2H),0.66-0.63(m,2H).ESI-MS((m/z)362,[M+H]+).
Embodiment 11
Compound B-8 synthesis
Operation such as B-1 preparation, raw material are replaced with cyclopentamine (255mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-8 (323mg, 83%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (dd, J=7.2,2.0Hz, 1H), 7.27 (dd, J=7.2,2.0Hz, 1H), 7.17-
7.10(m,2H),5.68(s,1H),4.49-4.40(m,1H),4.15(s,1H),3.38-3.33(m,1H),3.28-3.20(m,
1H),3.07-2.98(m,1H),2.63-2.60(m,2H),2.52-2.47(m,1H),2.15-2.06(m,1H),1.97-1.81
(m, 4H), 1.72-1.65 (m, 4H), 1.52-1.46 (m, 2H), 1.44-1.37 (m, 2H), 1.00 (t, J=7.2Hz, 3H),
1.02-0.96(m,4H).ESI-MS((m/z)390,[M+H]+).
Embodiment 12
Compound B-9 synthesis
Operation such as B-1 preparation, raw material are replaced with monoethanolamine (183mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-9 (289mg, 79%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.45 (d, J=6.4Hz, 1H), 7.24 (d, J=6.4Hz, 1H), 7.16-7.08 (m, 2H),
6.54-6.52 (m, 1H), 5.69 (s, 1H), 4.11 (s, 1H), 3.77 (t, J=5.6Hz, 2H), 3.67-3.59 (m, 1H),
3.56-3.49(m,1H),3.43(s,1H),3.33-3.28(m,1H),3.20-3.13(m,1H),3.04-2.95(m,1H),
2.61-2.57(m,2H),2.50-2.44(m,1H),1.94-1.78(m,2H),1.74-1.62(m,1H),1.51-1.43(m,
1H),1.42-1.34(m,1H),1.02-0.94(m,4H).ESI-MS((m/z)366,[M+H]+).
Embodiment 13
Compound B-10 synthesis
Operation such as B-1 preparation, raw material are replaced with Propanolamine (225mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-10 (285mg, 75%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (d, J=6.4Hz, 1H), 7.24 (d, J=6.4Hz, 1H), 7.17-7.10 (m, 2H),
6.52-6.49 (m, 1H), 5.72 (s, 1H), 4.13 (s, 1H), 3.73 (t, J=5.6Hz, 2H), 3.69-3.54 (m, 2H),
3.36-3.31(m,1H),3.25-3.18(m,1H),3.06-2.97(m,1H),2.62-2.56(m,2H),2.53-2.46(m,
1H),1.96-1.85(m,2H),1.83-1.78(m,2H),1.75-1.64(m,1H),1.53-1.44(m,1H),1.42-1.34
(m,1H),1.03-0.95(m,4H).ESI-MS((m/z)380,[M+H]+).
Embodiment 14
Compound B-11 synthesis
Operation such as B-1 preparation, raw material are replaced with diethylamine (219mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-11 (339mg, 90%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.49 (d, J=7.2Hz, 1H), 7.18-7.28 (m, 3H), 5.24 (s, 1H), 4.80 (s,
1H),3.78–3.81(m,1H),3.66–3.67(m,2H),3.33–3.36(m,1H),3.07–3.20(m,3H),2.12–2.31
(m,4H),1.68–1.77(m,1H),1.09–1.39(m,11H),0.84–0.91(m,1H).ESI-MS((m/z)378,[M+H
]+).
Embodiment 15
Compound B-12 synthesis
Operation such as B-1 preparation, raw material are replaced with di-n-propylamine (303mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-12 (348mg, 86%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (d, J=8.0Hz, 1H), 7.08-7.28 (m, 3H), 5.19 (s, 1H), 4.23 (s,
1H),3.54–3.61(m,1H),3.27–3.40(m,3H),3.00–3.09(m,2H),2.50–2.68(m,3H),1.93–2.02
(m, 1H), 1.77-1.83 (m, 4H), 1.44-1.55 (m, 4H), 1.18-1.24 (m, 1H), 0.90-1.02 (t, J=7.6Hz,
6H),0.75–0.90(m,4H).ESI-MS((m/z)406,[M+H]+).
Embodiment 16
Compound B-13 synthesis
Operation such as B-1 preparation, raw material are replaced with pyrrolidines (213mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-13 (305mg, 81%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46-7.44(m,1H),7.12-7.09(m,3H),5.32(s,1H),4.20(s,1H),
3.75-3.62(m,2H),3.38-3.30(m,2H),3.29-3.22(m,1H),3.07-2.98(m,2H),2.71-2.67(m,
1H),2.65-2.64(m,1H),2.53-2.47(m,1H),2.00-1.89(m,2H),1.86-1.77(m,4H),1.74-1.66
(m, 1H), 1.56-1.53 (m, 1H), 1.44-1.39 (m, 1H), 1.19-1.11 (m, 1H), 0.99 (t, J=7.2Hz, 3H)
.ESI-MS((m/z)376,[M+H]+).
Embodiment 17
Compound B-14 synthesis
Operation such as B-1 preparation, raw material are substituted with piperidines (255mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-14 (331mg, 85%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46-7.44(m,1H),7.12-7.09(m,3H),5.32(s,1H),4.20(s,1H),
3.75-3.62 (m, 2H), 3.38-3.30 7.47 (d, J=6.4Hz, 1H), 7.25-7.10 (m, 3H), 5.30 (s, 1H), 5.09
(s,1H),4.30-4.22(m,1H),3.91-3.63(m,3H),3.41-3.34(m,1H),3.31-3.25(m,1H),3.09-
3.01(m,1H),2.80-2.68(m,2H),2.56-2.50(m,1H),2.02-1.94(m,2H),1.83-1.44(m,9H),
1.25-1.19, (m, 1H) 1.01 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 390, [M+H]+).
Embodiment 18
Compound B-15 synthesis
Operation such as B-1 preparation, raw material are replaced with morpholine (261mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (methylene chloride/methanol=50:1) faint yellow solid B-15 (306mg, 78%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.46 (d, J=6.4Hz, 1H), 7.19-7.10 (m, 3H), 5.37 (s, 1H), 5.10 (s,
1H),4.28-4.16(m,1H),3.86-3.68(m,7H),3.39-3.34(m,1H),3.29-3.23(m,1H),3.07-2.98
(m,1H),2.66-2.65(m,2H),2.53-2.48(m,1H),1.98-1.89(m,1H),1.85-1.69(m,2H),1.57-
1.53 (m, 1H), 1.45-1.42 (m, 1H), 1.21-1.13 (m, 1H), 0.99 (t, J=7.2Hz, 3H) .ESI-MS ((m/z)
392,[M+H]+).
Embodiment 19
Compound C-1 synthesis
Take A-1 (1.68g, 5mmol) to be dissolved in anhydrous tetrahydro furan (20mL), be cooled to -50 DEG C, be slowly added to lithium hydride
Aluminium (475mg, 12.5mmol), stirring reaction 0.5h, TLC detection, after reaction terminates, adds a small amount of methanol to be quenched, then adds water
(20mL), is extracted with dichloromethane, merges organic phase, anhydrous sodium sulfate drying, and solvent evaporated obtains faint yellow solid C-1
(1.47g, 96%).1H NMR(400MHz,CDCl3)δ(ppm):7.69 (d, J=8.0Hz, 1H), 7.49 (d, J=8.0Hz,
1H), 7.12-7.24 (m, 2H), 5.13 (s, 1H), 4.85 (d, J=13.2Hz, 1H), 4.62 (d, J=13.2Hz, 1H), 4.18
(s,1H),3.34–3.39(m,1H),3.21–3.29(m,1H),3.00–3.09(m,1H),2.65–2.77(m,2H),2.49–
2.55(m,1H),2.20–2.21(m,1H),1.88–1.96(m,1H),1.73–1.81(m,2H),1.40–1.48(m,2H),
1.09-1.17 (m, 1H), 0.98-1.02 (t, J=7.6,3H) .ESI-MS ((m/z) 309, [M+H]+).
Embodiment 20
Compound C-2 synthesis
Take C-1 (308mg, 1mmol) and triethylamine (202mg, 2mmol) to be dissolved in dichloromethane (10mL), be slowly added to
Chloroacetic chloride (118mg, 1.5mmol), reaction 2h, TLC detection is stirred at room temperature, after reaction terminates, is washed with water twice, saturated sodium carbonate
Wash three times, organic phase anhydrous sodium sulfate drying, solvent evaporated obtains brown thing C-2 (339mg, 97%).1H NMR(400MHz,
CDCl3)δ(ppm):7.49 (d, J=8.0Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.12-7.21 (m, 2H), 5.37 (d, J
=13.2Hz, 1H), 5.21 (s, 1H), 4.96 (d, J=13.2Hz, 1H), 4.23 (s, 1H), 3.35-3.40 (m, 1H), 3.23-
3.31(m,1H),3.01–3.10(m,1H),2.67–2.77(m,2H),2.50–2.55(m,1H),2.11(s,3H),1.93–
2.00 (m, 1H), 1.70-1.81 (m, 2H), 1.42-1.50 (m, 2H), 1.11-1.19 (m, 1H), 1.01-1.04 (t, J=
7.6,3H).ESI-MS((m/z)351,[M+H]+).
Embodiment 21
Compound C-3 synthesis
Operation such as C-2 preparation, raw material substitutes chloroacetic chloride with propionyl chloride (138mg, 1.5mmol), after reaction terminates,
It is washed with water twice, saturated sodium carbonate is washed three times, and organic phase anhydrous sodium sulfate drying, solvent evaporated obtains tan solid C-3
(345mg, 95%).1H NMR(400MHz,CDCl3)δ(ppm):7.47 (d, J=8.4Hz, 1H), 7.38 (d, J=8.4Hz,
1H), 7.20-7.11 (m, 2H), 5.34 (d, J=13.2Hz, 1H), 5.18 (s, 1H), 4.94 (d, J=13.2Hz, 1H), 4.44
(s,1H),3.44-3.41(m,1H),3.40-3.35(m,1H),3.07-2.98(m,1H),2.95-2.92(m,1H),2.82-
2.75(m,1H),2.71-2.66(m,1H),2.36-2.31(m,2H),2.03-1.94(m,1H),1.88-1.83(m,1H),
1.82-1.73 (m, 1H), 1.46-1.42 (m, 1H), 1.28-1.25 (m, 1H), 1.13 (t, J=7.2Hz, 3H), 1.05-1.03
(m, 1H), 0.99 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 364, [M+H]+).
Embodiment 22
Compound C-4 synthesis
Operation such as C-2 preparation, raw material substitute chloroacetic chloride with isopropyl acyl chlorides (138mg, 1.5mmol), and reaction terminates
Afterwards, it is washed with water twice, saturated sodium carbonate is washed three times, and organic phase anhydrous sodium sulfate drying, solvent evaporated obtains tan solid
C-4 (338mg, 93%).1H NMR(400MHz,CDCl3)δ(ppm):7.46 (d, J=7.2Hz, 1H), 7.27 (d, J=
7.2Hz,1H),7.17-7.10(m,2H),6.08(s,1H),5.34-5.25(m,1H),4.14(s,1H),3.37-3.32(m,
1H),3.28-3.21(m,1H),3.07-2.98(m,1H),2.63-2.61(m,2H),2.53-2.47(m,1H),1.98-1.85
(m, 2H), 1.74-1.68 (m, 1H), 1.53-1.49 (m, 1H), 1.39 (d, J=6Hz, 3H), 1.37 (d, J=6Hz, 3H),
1.31-1.26 (m, 1H), 1.01 (t, J=7.2Hz, 3H), 1.04-0.97 (m, 4H) .ESI-MS ((m/z) 365, [M+H]+).
Embodiment 23
Compound C-5 synthesis
Operation such as C-3 preparation, raw material substitutes chloroacetic chloride with butyl chloride (160mg, 1.5mmol), after reaction terminates,
It is washed with water twice, saturated sodium carbonate is washed three times, and organic phase anhydrous sodium sulfate drying, solvent evaporated obtains yellow oil C-5
(364mg, 96%).1H NMR(400MHz,CDCl3)δ(ppm):7.47 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz,
1H), 7.18-7.10 (m, 2H), 5.35 (d, J=14.4Hz, 1H), 5.18 (s, 1H), 4.94 (d, J=14.4Hz, 1H), 4.26
(s,1H),3.39-3.34(m,1H),3.31-3.24(m,1H),3.07-2.98(m,1H),2.73-2.71(m,2H),2.57-
2.52 (m, 1H), 2.31 (t, J=7.2Hz, 2H), 2.00-1.91 (m, 1H), 1.80-1.71 (m, 2H), 1.68-1.61 (m,
2H), 1.48-1.40 (m, 2H), 1.17-1.10 (m, 1H), 0.99 (t, J=7.2Hz, 3H), 0.92 (t, J=7.2Hz, 3H)
.ESI-MS((m/z)379,[M+H]+).
Embodiment 24
Compound D-1 synthesis
C-1 (308mg, 1mmol) and p-nitrophenyl chloroformate ester (503mg, 2.5mmol) is taken to be dissolved in dichloromethane (10mL)
In, add pyridine (237mg, 3mmol), be stirred at room temperature reaction 3h, TLC detection, reaction terminate after, reaction solution be washed with water twice,
Saturated sodium carbonate is washed four times, organic phase anhydrous sodium sulfate drying, and intermediate is obtained after solvent evaporated.Intermediate is re-dissolved in dichloro
In methane (10mL), ammoniacal liquor (0.5mL) is added, then reacts at room temperature 1h, TLC detections, after reaction terminates, reaction solution is washed with water two
Secondary, saturated sodium carbonate is washed twice, takes organic phase to be evaporated to obtain crude product, through column chromatography (petroleum ether/acetone=5:1), obtain faint yellow
Solid D-1 (165mg, 47%).1H NMR(400MHz,CDCl3)δ(ppm):7.40 (d, J=8.0Hz, 2H), 7.09-7.20
(m, 2H), 5.45 (d, J=12.8Hz, 1H), 5.15 (s, 1H), 4.77 (d, J=12.8Hz, 1H), 4.01 (s, 1H), 2.81-
2.86(m,1H),2.65–2.71(m,1H),2.54–2.57(m,1H),2.45–2.47(m,1H),2.19(s,1H),2.06(s,
1H),1.80–1.92(m,2H),1.69–1.78(m,1H),1.52–1.62(m,1H),1.26–1.43(m,3H),1.05–1.09
(m, 1H), 0.98-1.02 (t, J=7.6,3H) .ESI-MS ((m/z) 352, [M+H]+).
Embodiment 25
Compound D-2 synthesis
Operation such as D-1 preparation, raw material are substituted with methylamine water solution (0.5ml) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-2 (186mg, 51%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.43 (d, J=8.0Hz, 2H), 7.10-7.20 (m, 2H), 6.32 (s, 1H), 5.40 (d, J
=12.8Hz, 1H), 5.15 (s, 1H), 4.85 (d, J=12.8Hz, 1H), 4.08 (s, 1H), 3.02-3.05 (m, 1H), 2.81-
2.82(m,5H),2.56–2.67(m,2H),1.84–2.05(m,2H),1.62–1.78(m,2H),1.38–1.44(m,2H),
1.05-1.12 (m, 1H), 0.97-1.01 (t, J=7.6,3H) .ESI-MS ((m/z) 366, [M+H]+).
Embodiment 26
Compound D-3 synthesis
Operation such as D-1 preparation, raw material are substituted with ethamine (135mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-3 (242mg, 64%), is obtained.1H NMR
(400MHz,CDCl3) δ 7.40 (d, J=8.0Hz, 2H), 7.09-7.19 (m, 2H), 6.43 (s, 1H), 5.46 (d, J=
12.8Hz, 1H), 5.13 (s, 1H), 4.76 (d, J=12.8Hz, 1H), 4.02 (s, 1H), 3.21-3.28 (m, 2H), 2.82-
2.87(m,1H),2.66–2.70(m,1H),2.56–2.62(m,2H),2.47–2.50(m,1H),2.00–2.05(m,1H),
1.79-1.87 (m, 2H), 1.60-1.78 (m, 2H), 1.33-1.43 (m, 2H), 1.13-1.16 (t, J=7.6,3H), 0.97-
1.01 (t, J=7.6,3H).ESI-MS ((m/z) 380, [M+H]+).
Embodiment 27
Compound D-4 synthesis
Operation such as D-1 preparation, raw material are substituted with propylamine (177mg, 3mmol) and triethylamine (303mg, 3mmol)
Ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-4 (243mg, 62%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.38 (d, J=8.0Hz, 2H), 7.10-7.19 (m, 2H), 6.41 (s, 1H), 5.44 (d, J
=12.8Hz, 1H), 5.10 (s, 1H), 4.74 (d, J=12.8Hz, 1H), 4.01 (s, 1H), 3.20-3.29 (m, 2H), 2.82-
2.87(m,1H),2.66–2.70(m,1H),2.56–2.64(m,2H),2.47–2.50(m,1H),2.00–2.04(m,1H),
1.79-1.87 (m, 2H), 1.63-1.78 (m, 2H), 1.23-1.47 (m, 4H), 1.12-1.15 (t, J=7.6,3H), 0.97-
1.00 (t, J=7.6,3H) .ESI-MS ((m/z) 394, [M+H]+).
Embodiment 28
Compound D-5 synthesis
Operation such as D-1 preparation, raw material are replaced with isopropylamine (177mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-5 (230mg, 58%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.37 (d, J=7.6Hz, 1H), 7.35 (d, J=7.6Hz, 1H), 7.26-7.06 (m, 2H),
6.34 (s, 1H), 5.45 (d, J=12.8Hz, 1H), 5.10 (s, 1H), 4.68 (d, J=12.8Hz, 1H), 3.99 (s, 1H),
3.88-3.81(m,1H),2.80-2.77(m,1H),2.69-2.62(m,1H),2.58-2.51(m,2H),2.49-2.44(m,
1H),1.89-1.80(m,1H),1.75-1.66(m,2H),1.61-1.52(m,1H),1.40-1.32(m,2H),1.28-1.24
(m, 1H), 1.14 (d, J=6.4Hz, 6H), 1.07-1.03 (m, 1H), 0.96 (t, J=7.2Hz, 3H), 0.87-0.82 (m,
1H).ESI-MS((m/z)394,[M+H]+).
Embodiment 29
Compound D-6 synthesis
Operation such as D-1 preparation, raw material are replaced with monoethanolamine (183mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-6 (194mg, 49%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.37 (d, J=8.0Hz, 2H), 7.18-7.06 (m, 3H), 5.47 (d, J=12.8Hz,
1H), 5.11 (s, 1H), 4.72 (d, J=12.8Hz, 1H), 3.93 (s, 1H), 3.72-3.66 (m, 2H), 3.37-3.27 (m,
2H),2.78-2.70(m,1H),2.67-2.55(m,1H),2.54-2.48(m,1H),2.47-2.35(m,3H),1.86-1.77
(m, 1H), 1.66-1.51 (m, 2H), 1.42-1.29 (m, 2H), 1.06-0.99 (m, 1H), 0.96 (t, J=7.2Hz, 3H)
.ESI-MS((m/z)396,[M+H]+).
Embodiment 30
Compound D-7 synthesis
Operation such as D-1 preparation, raw material are replaced with Propanolamine (225mg, 3mmol) and triethylamine (303mg, 3mmol)
For ammoniacal liquor, through column chromatography (petrol ether/ethyl acetate=3:1) faint yellow solid D-7 (176mg, 43%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.39-7.32(m,2H),7.26-7.20(m,1H),7.18-7.12(m,1H),7.11-
7.05 (m, 1H), 5.50 (d, J=12.8Hz, 1H), 5.11 (s, 1H), 4.67 (d, J=12.8Hz, 1H), 3.92 (s, 1H),
3.67 (d, J=6.0Hz, 2H), 3.39-3.25 (m, 2H), 2.69-2.48 (m, 4H), 2.44-2.38 (m, 1H), 2.34-2.26
(m,1H),1.84-1.75(m,1H),1.73-1.48(m,5H),1.42-1.30(m,2H),1.06-1.00(m,1H),0.96
(t, J=7.2Hz, 3H) .ESI-MS ((m/z) 410, [M+H]+).
Embodiment 31
Compound E-1 synthesis
Take B-3 (349mg, 1mmol) to be dissolved in absolute methanol (10mL), add 10% palladium carbon, reaction 6h is stirred at room temperature,
TLC is detected, and after reaction terminates, suction filtered through kieselguhr removes palladium carbon, crude product is obtained after solvent evaporated, through column chromatography (methylene chloride/methanol
=30:1) faint yellow solid E-1 (284mg, 81%), is obtained.1H NMR(400MHz,CDCl3)δ(ppm):7.52 (d, J=
7.6Hz, 1H), 7.13-7.19 (m, 3H), 5.13-5.16 (t, J=5.6Hz, 1H), 4.83 (d, J=7.2Hz, 1H), 3.85
(s, 1H), 3.24-3.38 (m, 2H), 3.08-3.20 (m, 2H), 2.96-3.05 (m, 1H), 2.78 (d, J=14.8Hz, 1H),
2.69 (d, J=14.8Hz, 1H), 2.56-2.59 (m, 1H), 2.13-2.18 (m, 1H), 2.03-2.09 (m, 1H), 1.71-
1.78(m,1H),1.36–1.45(m,3H),1.21–1.26(m,1H),0.87–0.95(m,7H).ESI-MS((m/z)352,[M
+H]+).
Embodiment 32
Compound F-1 synthesis
Take C-1 (308mg, 1mmol), phthalimide (22mg, 1.5mmol) and triphenylphosphine (394mg,
1.5mmol) it is dissolved in tetrahydrofuran (4mL), after 15min is stirred at room temperature, addition diisopropyl azodiformate (303mg,
1.5mmol), 80 DEG C are heated to reflux 1.5h；After reaction terminates, hydrazine hydrate (2ml), N are added2Lower 80 DEG C are protected to be heated to reflux
1.0h, after reaction terminates, be evaporated removing tetrahydrofuran, add water and DCM to be layered, washing twice, saturated sodium-chloride wash once, taken
Machine is mutually evaporated to obtain crude product, through column chromatography (methylene chloride/methanol=10:1) brown-red oil F-1 (138mg, 45%), is obtained
。1H NMR(400MHz,CDCl3)δ(ppm):7.54 (d, J=8.0Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.25-7.13
(m, 2H), 5.07 (s, 1H), 4.50 (s, 1H), 4.18 (d, J=14.8Hz, 1H), 3.86 (d, J=14.8Hz, 1H), 3.59-
3.54(m,1H),3.50-3.43(m,1H),3.10-3.01(m,2H),2.89-2.77(m,2H),2.02-1.96(m,1H),
1.95-1.83 (m, 2H), 1.54-1.50 (m, 1H), 1.32-1.30 (m, 1H), 1.21-1.13 (m, 1H), 1.02 (t, J=
7.2Hz,3H).ESI-MS((m/z)308,[M+H]+).
Embodiment 33
Compound F-2 synthesis
C-1 (308mg, 1mmol) and paratoluensulfonyl chloride (953mg, 5mmol) is taken to be dissolved in dichloromethane (6mL), room temperature
After stirring 5h, methylamine (1.0mL) and triethylamine (303mg, 3mmol) are added, then reacts at room temperature 8h, TLC detections, reaction terminates
Afterwards, reaction solution be washed with water once, saturated sodium carbonate wash twice, saturated sodium-chloride wash once, take organic phase to be evaporated to obtain crude product, through post
Chromatograph (methylene chloride/methanol=10:1) yellow oil F-2 (135mg, 42%), is obtained.1H NMR(400MHz,CDCl3)δ
(ppm):7.48 (d, J=8.0Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.19-7.09 (m, 2H), 5.00 (s, 1H), 4.16
(s, 1H), 4.14 (d, J=14.4Hz, 1H), 3.68 (d, J=14.4Hz, 1H), 3.38-3.33 (m, 1H), 3.29-3.21 (m,
1H),3.08-2.99(m,1H),2.74-2.63(m,2H),2.53-2.48(m,4H),2.48(s,3H),1.97-1.90(m,
1H),1.77-1.67(m,2H),1.46-1.43(m,1H),1.31-1.25(m,1H),1.17-1.08(m,1H),1.00(t,J
=7.2Hz, 3H) .ESI-MS ((m/z) 322, [M+H]+).
Embodiment 34
Compound F-3 synthesis
Operation such as F-2 preparation, raw material substitutes methylamine with ethamine (225mg, 5mmol), through column chromatography (dichloromethane
Alkane/methanol=10:1) light butter thing F-3 (178mg, 53%), is obtained.1H NMR(400MHz,CDCl3)δ(ppm):7.50
(d, J=8.4Hz, 1H) 7.47 (d, J=8.4Hz, 1H), 7.19-7.09 (m, 2H), 5.00 (s, 1H), 4.16 (s, 1H), 4.14
(d, J=14.4Hz, 1H), 3.67 (d, J=14.4Hz, 1H), 3.38-3.33 (m, 1H), 3.28-3.21 (m, 1H), 3.08-
2.99(m,1H),2.79-2.70(m,2H),2.69-2.63(m,2H),2.53-2.47(m,1H),1.97-1.88(m,1H),
1.78-1.69 (m, 2H), 1.46-1.37 (m, 2H), 1.16-1.09 (m, 4H) 1.12 (t, J=7.2Hz, 3H), 0.99 (t, J=
7.2Hz,3H).ESI-MS((m/z)336,[M+H]+).
Embodiment 35
Compound G-1 synthesis
F-1 (308mg, 1mmol) and DIPEA (258mg, 2mmol) is taken to be dissolved in tetrahydrofuran (6mL),
Propyl isocyanate (170mg, 2.0mmol) is slowly added dropwise under nitrogen protection, reaction 1h, TLC detection is stirred at room temperature, reaction terminates
Afterwards, washed three times with saturated sodium carbonate, saturated sodium-chloride is washed once, takes organic phase to be evaporated to obtain crude product, through column chromatography (dichloromethane/
Methanol=20:1) faint yellow solid G-1 (306mg, 75%), is obtained.1H NMR(400MHz,CDCl3)δ(ppm):7.39(dd,J
=7.6,1.2Hz, 2H), 7.17-7.06 (m, 2H), 6.17-6.11 (m, 1H), 5.42 (d, J=12.8Hz, 1H), 5.12
(s, 1H), 4.75 (d, J=12.8Hz, 1H), 4.02 (s, 1H), 3.23-3.11 (m, 3H), 2.93-2.85 (m, 1H), 2.78-
2.54(m,3H),2.52-2.45(m,1H),1.89-1.81(m,2H),1.75-1.67(m,2H),1.65-1.57(m,1H),
1.51-1.41 (m, 2H), 1.39-1.31 (m, 2H), 1.10-1.00 (m, 1H), 0.97 (t, J=7.2Hz, 3H), 0.92 (t, J
=7.2Hz, 3H) .ESI-MS ((m/z) 408, [M+H]+).
Embodiment 36
Compound G-2 synthesis
Operation such as G-1 preparation, raw material substitute isocyanic acid third with isopropyl isocyanate (170mg, 2.0mmol)
Ester, through column chromatography (methylene chloride/methanol=10:1) faint yellow solid G-2 (318mg, 78%), is obtained.1H NMR(400MHz,
CDCl3)δ(ppm):7.47 (d, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.17-7.12 (m, 1H), 7.10-
7.06(m,1H),5.05(s,1H),4.72-4.69(m,2H),4.68-4.62(m,1H),4.26-4.19(m,1H),3.94(s,
1H),3.90-3.82(m,1H),3.11-3.05(m,1H),2.94-2.84(m,1H),2.76-2.68(m,1H),2.66-2.59
(m,1H),2.58-2.53(m,1H),2.27-2.20(m,1H),1.82-1.76(m,2H),1.69-1.57(m,1H),1.46-
1.39 (m, 1H), 1.39-1.33 (m, 1H), 1.09 (d, J=2.0Hz, 3H), 1.07 (d, J=2.0Hz, 3H), 1.04-0.99
(m, 1H), 0.96 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 393, [M+H]+).
Embodiment 37
Compound H-1 synthesis
Take F-1 (307mg, 1mmol) andN, N- diisopropylethylamine(193mg, 1.5mmol) is dissolved in dichloromethane (10mL)
In, propionyl chloride (111mg, 1.2mmol) is slowly added under ice-water bath, reaction 0.5h, TLC detection is stirred at room temperature, after reaction terminates,
Washed three times with saturated sodium carbonate, organic phase anhydrous sodium sulfate drying, through column chromatography (methylene chloride/methanol=10:1), obtain
Faint yellow solid H-1 (320mg, 88%).1H NMR(400MHz,CDCl3)δ(ppm):7.46 (d, J=8.4Hz, 1H), 7.39
(d, J=8.4Hz, 1H), 7.18-7.14 (m, 1H), 7.13-7.09 (m, 1H), 5.68-5.66 (m, 1H), 5.06 (s, 1H),
4.75 (dd, J=15.26,4.4Hz, 1H), 4.35 (dd, J=15.26,4.4Hz, 1H), 4.17 (s, 1H), 3.38-3.33 (m,
1H),3.27-3.19(m,1H),3.07-2.98(m,1H),2.73-2.67(m,2H),2.53-2.48(m,1H),2.20-2.14
(m,2H),1.95-1.74(m,2H),1.73-1.66(m,1H),1.47-1.38(m,2H),1.16-1.07(m,4H),0.98.
(t, J=7.2Hz, 3H) .ESI-MS ((m/z) 364, [M+H]+).
Embodiment 38
Compound H-2 synthesis
Operation such as H-1 preparation, raw material substitutes chloroacetic chloride with isobutyryl chloride (128mg, 1.2mmol), through column chromatography
(methylene chloride/methanol=10:1) faint yellow solid H-2 (302mg, 80%), is obtained.1H NMR(400MHz,CDCl3)δ
(ppm):7.45 (d, J=8.0Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.16-7.07 (m, 2H), 5.75-5.71 (m,
1H), 5.05 (s, 1H), 4.75 (dd, J=15.6,4.4Hz, 1H), 4.30 (dd, J=15.6,4.4Hz, 1H), 4.14 (s,
1H),3.36-3.31(m,1H),3.24-3.16(m,1H),3.06-2.97(m,1H),2.72-2.61(m,2H),2.51-2.45
(m,1H),2.34-2.24(m,1H),1.93-1.74(m,2H),1.73-1.64(m,1H),1.46-1.37(m,2H),1.12
(d, J=6.8Hz, 3H), 1.09-1.06 (m, 4H), 0.97 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 378, [M+H]+).
Embodiment 39
Compound H-3 synthesis
Operation such as H-1 preparation, raw material substitutes chloroacetic chloride with ring propionyl chloride (125mg, 1.2mmol), through column chromatography
(methylene chloride/methanol=10:1) faint yellow solid H-3 (320mg, 85%), is obtained.1H NMR(400MHz,CDCl3)δ
(ppm):7.47 (d, J=8.4Hz, 1H), 7.42 (d, J=8.4Hz, 1H), 7.20-7.10 (m, 2H), 5.84-5.80 (m, 1H)
5.08 (s, 1H), 4.76 (dd, J=17.2,2.0Hz, 1H), 4.39 (dd, J=17.2,2.0Hz, 1H), 4.16 (s, 1H),
3.39-3.34(m,1H),3.28-3.20(m,1H),3.08-2.99(m,1H),2.73-2.63(m,2H),2.54-2.48(m,
1H),1.83-1.74(m,2H),1.73-1.66(m,1H),1.47-1.39(m,2H),1.31-1.24(m,1H),1.14-1.06
(m,1H),1.02-0.95(m,5H),0.76-0.66(m,2H).ESI-MS((m/z)376,[M+H]+).
Embodiment 40
Compound H-4 synthesis
Operation such as H-1 preparation, raw material substitutes chloroacetic chloride with butyl chloride (128mg, 1.2mmol), through column chromatography (two
Chloromethanes/methanol=10:1) faint yellow solid H-4 (302mg, 80%), is obtained.1H NMR(400MHz,CDCl3)δ(ppm):
7.45 (d, J=8.4Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 7.16-7.08 (m, 2H), 5.84-5.82 (m, 1H), 5.05
(s, 1H), 4.73 (dd, J=15.2,4.8Hz, 1H), 4.33 (dd, J=15.2,4.8Hz, 1H), 4.12 (s, 1H), 3.33-
3.29(m,1H),3.20-3.12(m,1H),3.05-2.96(m,1H),2.71-2.60(m,2H),2.48-2.43(m,1H),
2.17-2.05(m,2H),1.92-1.73(m,2H),1.71-1.66(m,1H),1.65-1.57(m,2H),1.45-1.37(m,
2H), 1.13-1.04 (m, 1H), 0.97 (t, J=7.2Hz, 3H), 0.89 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 378,
[M+H]+).
Embodiment 41
Compound H-5 synthesis
Operation such as H-1 preparation, raw material with chloroacetic chloride (231mg, 2.5mmol) substitute chloroacetic chloride (111mg,
1.2mmol), through column chromatography (methylene chloride/methanol=30:1) faint yellow solid H-5 (235mg, 60%), is obtained.1H NMR
(400MHz,CDCl3)δ(ppm):7.68 (d, J=8.0Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.18-7.10 (m, 2H),
5.54 (dd, J=17.2,2.0Hz, 1H), 4.82 (dd, J=17.2,2.0Hz, 1H), 4.60 (s, 1H), 4.16 (s, 1H),
3.38-3.33(m,1H),3.28-3.20(m,1H),3.07-2.98(m,1H),2.72-2.65(m,2H),2.53-2.49(m,
1H),2.48(s,6H),2.01-1.94(m,1H),1.77-1.67(m,1H),1.63-1.54(m,1H),1.43-1.35(m,
2H), 1.17-1.09 (m, 1H), 0.89 (t, J=7.2Hz, 3H) .ESI-MS ((m/z) 392, [M+H]+).
Embodiment 42
Compound I-1 synthesis
Take A-1 (336mg, 1mmol) to be dissolved in trifluoroacetic acid (6mL), be stirred at room temperature, N- iodos succinyl Asia is added portionwise
Amine (236mg, 1.05mmol), 1h is reacted, TLC detections, after reaction terminates, is evaporated except trifluoroacetic acid, then adds water and dichloromethane
Alkane is layered, and takes organic phase anhydrous sodium sulfate drying, solvent evaporated obtains crude product, through column chromatography (petroleum ether/acetone=3:1), obtain
Faint yellow iodo thing (346mg, 75%).Iodine grain (330mg, 1.3mmol) and triphenylphosphine (342mg, 1.3mmol) is taken to be dissolved in again
In toluene (4mL), it is in glassy yellow suspension that 0.5h, which is stirred at room temperature, to mixture, adds iodo thing (462mg, 1mmol), palladium
(6.8mg, 3%mmol), triethylamine (606mg, 6mmol) and formic acid (184mg, 4mmol), 80 DEG C of tube sealing reaction 4h, reaction knot
Shu Hou, be evaporated except toluene, then plus water and dichloromethane layering, reaction solution is washed with water once, saturated sodium carbonate wash twice, saturation
Sodium chloride is washed once, takes organic phase to be evaporated to obtain crude product, through column chromatography (petrol ether/ethyl acetate=5:1) yellow oil, is obtained
I-1 (273mg, 75%).1H NMR(400MHz,CDCl3)δ(ppm):10.03 (s, 1H), 8.02 (s, 1H), 7.70 (dd, J=
8.8,1.2Hz, 1H), 7.32 (d, J=8.8Hz, 1H), 6.30 (s, 1H), 4.13 (s, 1H), 3.97 (s, 3H), 3.40-3.35
(m,1H),3.30-3.22(m,1H),3.11-3.01(m,1H),2.68-2.61(m,1H),2.61-2.52(m,2H),2.00-
1.85 (m, 2H), 1.79-1.67 (m, 1H), 1.56-1.53 (m, 1H), 1.46-1.38 (m, 1H), 1.02 (t, J=7.2Hz,
3H),0.99-0.92(m,1H).ESJ-MS((m/z)365,[M+H]+).
Embodiment 43
Compound I-2 synthesis
Take I-1 (364mg, 1mmol) to be dissolved in methanol (6mL), add ammoniacal liquor (2ml) and iodine grain (504mg, 2mmol), room
Temperature stirring 1.0h, after reaction terminates, adds water and dichloromethane to be layered, reaction solution through saturated sodium thiosulfate wash twice, saturation chlorine
Change sodium to wash once, take organic phase to be evaporated to obtain crude product, through column chromatography (petrol ether/ethyl acetate=1:1) faint yellow solid I-, is obtained
2 (306mg, 85%).1H NMR(400MHz,CDCl3)δ(ppm):7.79 (s, 1H), 7.42 (d, J=8.4Hz, 1H), 7.31
(d, J=8.4Hz, 1H), 6.31 (s, 1H), 4.38 (s, 1H), 3.96 (s, 3H), 3.51-3.44 (m, 1H), 3.42-3.35 (m,
1H),3.09-3.00(m,1H),2.95-2.92(m,1H),2.75-2.61(m,2H),2.02-1.91(m,2H),1.87-1.81
(m,1H),1.61-1.57(m,1H),1.52-1.48(m,1H),1.04-0.97(m,4H).ESI-MS((m/z)362,[M+H
]+).
Embodiment 44
Compound I-3 synthesis
Take I-1 (364mg, 1mmol) to be dissolved in methanol (6mL), ice bath stirring under be added portionwise sodium borohydride (57mg,
1.5mmol), be stirred at room temperature 1.0h, after reaction terminates, add water and dichloromethane to be layered, reaction solution through wash twice, saturation chlorine
Change sodium to wash once, take organic phase to be evaporated to obtain crude product, through column chromatography (petroleum ether/acetone=1:1) yellow oil I-3, is obtained
(312mg, 85%).1H NMR(400MHz,CDCl3)δ(ppm):7.47 (d, J=2.0Hz, 1H), 7.21-7.15 (m, 2H),
6.16(s,1H),4.75(s,2H),4.12(s,1H),3.94(s,3H),3.35-3.30(m,1H),3.25-3.17(m,1H),
3.04-2.96(m,1H),2.59-2.53(m,2H),2.51-2.45(m,1H),1.95-1.84(m,2H),1.75-1.64(m,
1H), 1.52-1.48 (m, 1H), 1.40-1.35 (m, 1H), 1.25 (s, 1H), 1.00 (t, J=7.2Hz, 3H), 0.97-0.93
(m,1H).ESJ-MS((m/z)367,[M+H]+).
Embodiment 45
Compound I-4 synthesis
Take I-2 (361mg, 1mmol) to be dissolved in dioxane (6mL), add 15% aqueous sulfuric acid (2ml), 100 DEG C
Be heated to reflux 3h, after reaction terminates, then plus water and dichloromethane layering, reaction solution saturated sodium carbonate wash twice, saturation chlorination
Sodium is washed once, takes organic phase to be evaporated to obtain crude product, through column chromatography (petroleum ether/acetone=1:1) faint yellow solid I-4, is obtained
(311mg, 82%).1H NMR(400MHz,CDCl3)δ(ppm):8.01 (d, J=1.6Hz, 1H) 7.58 (dd, J=8.8,
1.6Hz, 1H), 7.25 (d, J=8.8Hz, 1H), 6.25 (s, 1H), 4.14 (s, 1H), 3.95 (s, 3H), 3.38-3.33 (m,
1H),3.28-3.20(m,1H),3.07-2.97(m,1H),2.67-2.49(m,3H),1.97-1.86(m,2H),1.75-1.69
(m, 1H), 1.54-1.51 (m, 1H), 1.44-1.40 (m, 1H), 1.01 (t, J=7.2Hz, 3H), 0.97-0.93 (m, 1H)
.ESJ-MS((m/z)380,[M+H]+).
Embodiment 46
Compound I-5 synthesis
Take I-1 (364mg, 1mmol) and ethamine (135mg, 3mmol) to be dissolved in methanol (6mL), add in batches under ice bath stirring
Enter Sodium triacetoxyborohydride (318mg, 1.5mmol), 1.0h is stirred at room temperature, after 1 reaction terminates, adds water and dichloromethane point
Layer, reaction solution through wash twice, saturated sodium-chloride wash once, take organic phase to be evaporated to obtain crude product, through column chromatography (dichloromethane/first
Alcohol=10:1) yellow oil I-5 (216mg, 55%), is obtained.1H NMR(400MHz,CDCl3)δ(ppm):7.50(s,1H),
7.23-7.18(m,2H),6.14(s,1H),4.05(s,1H),3.94(s,3H),3.92(s,2H),3.33-3.28(m,1H),
3.21-3.14(m,1H),3.03-2.94(m,1H),2.82-2.75(m,2H),2.56-2.44(m,3H),1.93-1.82(m,
2H), 1.74-1.62 (m, 1H), 1.49-1.45 (m, 1H), 1.36-1.33 (m, 1H), 1.26 (t, J=7.2Hz, 3H), 0.99
(t, J=7.2Hz, 3H), 0.95-0.88 (m, 1H) .ESJ-MS ((m/z) 394, [M+H]+)。
Claims (6)
1. formula I Pervone derivative or its pharmaceutically acceptable salt are preparing the medicine of prevention or treatment diabetes B
In purposes：
Wherein：
R1For hydrogen or and R2Double bond is formed together；
R2For hydroxyl, hydrogen or and R1Double bond is formed together；
R3Represent following any structure group；
Wherein
R5For hydrogen, C1-C6Alkyl or C1-C6Hydroxyalkyl；
R6For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl or C3-C7Cycloalkyl；
R7For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl or C3-C7Cycloalkyl；
R8For hydrogen, C1-C6Straight chained alkyl, C1-C6Hydroxyalkyl, C3-C7Cycloalkyl, C1-C6Straight chained alkyl acyl group or C3-C7Cycloalkyl acyl
Base；
R4Represent following any structure group；
2. the purposes of claim 1, its formula of I Pervone derivative is following any structure：
3. the purposes of claim 2, its formula of I Pervone derivative is following any structure：
4. the compound or its pharmaceutically acceptable salt of following any structure formula：
5. a kind of pharmaceutical composition, wherein the compound comprising claim 4 or its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier of receiving.
6. the compound of claim 4 or its pharmaceutically acceptable salt are used for the medicine for preparing prevention or treatment diabetes B
Purposes.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85106416A (en) * | 1985-08-26 | 1987-03-18 | 格德昂·理查德化学工厂股份公司 | Preparation nitro A Piao vincamine acid derivative and the method that contains the medicinal compositions of this analog derivative |
| US4680397A (en) * | 1984-04-25 | 1987-07-14 | Richter Gedeon Vegyeszeti Gyar Rt. | Apovincaminol derivative |
| US4883876A (en) * | 1987-09-07 | 1989-11-28 | Taisho Pharmaceutical Co., Ltd. | Acylated vincaminic acid derivatives |
| JPH0559051A (en) * | 1991-03-01 | 1993-03-09 | Taisho Pharmaceut Co Ltd | Apovincaminic acid amide derivative |
| CN101888776A (en) * | 2007-09-20 | 2010-11-17 | 罗切斯特大学 | Method and compositions for treatment or prevention of inflammatory conditions |
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2017
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| US4680397A (en) * | 1984-04-25 | 1987-07-14 | Richter Gedeon Vegyeszeti Gyar Rt. | Apovincaminol derivative |
| CN85106416A (en) * | 1985-08-26 | 1987-03-18 | 格德昂·理查德化学工厂股份公司 | Preparation nitro A Piao vincamine acid derivative and the method that contains the medicinal compositions of this analog derivative |
| US4883876A (en) * | 1987-09-07 | 1989-11-28 | Taisho Pharmaceutical Co., Ltd. | Acylated vincaminic acid derivatives |
| JPH0559051A (en) * | 1991-03-01 | 1993-03-09 | Taisho Pharmaceut Co Ltd | Apovincaminic acid amide derivative |
| CN101888776A (en) * | 2007-09-20 | 2010-11-17 | 罗切斯特大学 | Method and compositions for treatment or prevention of inflammatory conditions |
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| THANH-HOANG NGUYEN-VO, ET AL.: "EXPLORING ANTI-HYPERGLYCEMIC POTENTIAL OF ALKALOID COMPOUNDS FROM CATHARANTHUS ROSEUS G. DON (L) AGAINST VARIOUS TYPE II DIABETES TARGETS BY IN SILICO VIRTUAL SCREENING", 《WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES》 * |
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Application publication date: 20180119 |