CN107936000A - A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented - Google Patents
A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented Download PDFInfo
- Publication number
- CN107936000A CN107936000A CN201810056731.6A CN201810056731A CN107936000A CN 107936000 A CN107936000 A CN 107936000A CN 201810056731 A CN201810056731 A CN 201810056731A CN 107936000 A CN107936000 A CN 107936000A
- Authority
- CN
- China
- Prior art keywords
- compound
- bone
- osteoporosis
- medicine
- osteoclast
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention discloses a kind of glyoxaline compound of 2 trifluoromethyl substitution, its structural formula is
Description
Technical field
The invention belongs to drug design and synthesis field, be related to a kind of substitution of 2- trifluoromethyls glyoxaline compound and its
Application in medicine for treating osteoporosis is prevented.
Technical background
Osteoporosis is a health problem that is worldwide, increasingly attracting people's attention.The whole world about 2 at present
Hundred million people suffer from osteoporosis, its incidence leapt to common disease, the 7th of frequently-occurring disease.Osteoporosis is that the elderly is most common
Disease.In the U.S. and western countries, at the age more than 55 years old in postclimacteric women, the people for having half suffers from the different bone of degree
Matter osteoporosis, and suffer from osteoporosis person in the elderly of over-65s and be up to more than 95%.With the reach of science and the mankind
Progressive, the average life span constantly extends, and elderly population increase sharply, and the incidence of osteoporosis is also with appearance rapidly increase.
It is expected that the elderly to the year two thousand fifty whole world over-65s will increase to 15.55 hundred million by current 3.23 hundred million, osteoporosis is led at that time
Cause hip fracture that number occurs also will increase to 6,260,000, wherein Asia, Latin America, the Middle East and African state by current 1,660,000
The patient of family will account for more than 70%.Osteoporosis causes huge society and financial burden, constitute one it is serious global
Problem, has caused the very big concern of countries in the world.The arrival of aging society makes the incidence of osteoporosis increase increasingly, sternly
The quality of life of people is threatened again.
The osteoporosis epidemiology survey in 3 city of China Beijing, Shanghai and Chengdu is the results show that 60-69 Sui age bracket bone
The loose incidence women of matter and male are respectively 60% and 30% or so.Population base of China is big, and sufferers of osteoporosis face has reached
60000000~80,000,000, this brings serious burden to family and society.According to another the people of statistics national over-65s in 2000
Have 1.3 hundred million, account for the 10.7% of national population, it has also become typical veteran form country.And the patient with osteoporosis is at these
90% is accounted in crowd, and the patient of hip fracture will have 12%~40% to die of various complication in 1 year.In survivor
There is 50% human action inconvenience.This not only causes serious body and mind to patient and wrecks, while also adds to family and society huge
Big manpower and financial resources burden.Therefore, it is anti-aging to prevent osteoporosis, extends the service life, ensures the one of the quality of life of the people
A very urgent research topic.
Osteoclast is a kind of terminal differentiation multinuclear macrophage originating from candidate stem cell, is uniquely joined in bone metabolism
With the cell of bone information, it is in bone tissue this microenvironment by the portion perimeter blood of derived from bone marrow（Spleen）Monocyte and monokaryon
The osteoclastic precursor fusion of macrophage forms.Key link in bone remodeling is the bone information of osteoclast, it is being stablized normally
It is very important in bone homeostasis process.Some medicines such as bisphosphonates, calcitonin surround in anti-bone information medicine
Osteoclast is unfolded, and prevents to reduce bone information by suppressing the activity of osteoclast or treats osteoporosis.
The content of the invention
It is an object of the present invention to providing a kind of glyoxaline compound of 2- trifluoromethyls substitution, its structural formula is such as
Under：
。
Another object of the present invention is to provide a kind of application of compound in osteoclast increment medicine is suppressed.
Another object of the present invention is to provide a kind of compound to prepare prevention and/or treatment medicine for treating osteoporosis
In application.
Another object of the present invention is to provide a kind of synthesis road of the glyoxaline compound of the 2- trifluoromethyls substitution
Line is：
。
Further, its specific synthesis step is：
1）3- phenyl-1-propanols（Compound 1）With sulfonylation generation methanesulfonic acid 3- benzene occurs under paratoluensulfonyl chloride low temperature
Base propyl ester（Compound 2）；
2）Compound 2 heats reaction generation 1- (3- (3- in the presence of an inorganic base with 1- (3- hy droxy furan -2- bases) second -1- ketone again
Phenyl-propoxy) furans -2- bases) second -1- ketone（Compound 3）；
3）Bromo-reaction generation 2- bromo- 1- (3- (the 3- phenyl third of carbonyl α-carbon occurs with pyrrolidones hydrobromate for compound 3
Epoxide) furans -2- bases) second -1- ketone（Compound 4）；
4）Substitution reaction generation 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- base ammonia of amine occurs for compound 4
Base) ethane -1- ketone（Compound 5）；
5）The acylation reaction that amine occurs with 2,2,2- trifluoro-acetyl chlorides for compound 5 generates three fluoro- N- (2- oxos -2- (3- (3-
Phenyl-propoxy) furans -2- bases) ethyl)-N- (pyridine -2- bases) acetamide（Compound 6）；
6）Compound 6 occur again cyclization generation 2- (4- (3- (3- phenyl-propoxies) furans -2- bases) -2- trifluoromethyls -
1H- imidazoles -1- bases) pyridine（Compound 7）.
Further, synthesis step 1）Middle low temperature range is 0 ~ 10 DEG C, preferably 0 DEG C.
Further, synthesis step 2）In the inorganic base used can be sodium carbonate, potassium carbonate, cesium carbonate, saleratus,
It is preferred that potassium carbonate.
Further, synthesis step 2）In heating-up temperature be 50 DEG C -100 DEG C, preferably 85 DEG C.
Obviously, the above according to the present invention, according to the ordinary technical knowledge and means of this area, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Embodiment
Embodiment：
The synthesis of 1-1 methanesulfonic acid 3- phenylpropyl acrylates：
By 3- phenyl-1-propanols（Compound 1）(2.72g, 20mmol) is dissolved in dichloromethane (DCM) (25mL), adds three second
Amine (TEA) (4.05g, 40mmol) obtains mixture, and mixture then is cooled to 0 DEG C.Under agitation, delay into the mixture
It is slow to add paratoluensulfonyl chloride (MsCl) (5.72g, 30mmol), and reaction mixture stirred at 0 DEG C 1 it is small when, Ran Hou
Be stirred at room temperature 1 it is small when (until by HPLC detect reaction complete).After removing solvent, it is molten to add saturated sodium bicarbonate water
Liquid.Product is extracted with EtOAc (3 × 30mL) and washed with sodium bicarbonate solution and water, then removes solvent in a vacuum
After obtain methanesulfonic acid 3- phenylpropyl acrylates（Compound 2）, 3.86g, yield 90.0%.1H-NMR (400 MHz, CDCl3) δ:
1.82(m, 2H), 2.77(t, 2H), 3.16(s, 3H), 4.02(t, 2H), 7.15-7.26(m, 5H). 13C-NMR
(125 MHz, CDCl3) δ: 29.65, 34.34, 37.81, 67.65, 126.17, 128.33, 129.22,
142.31.LC-MS(ESI, pos, ion) m/z: 215[M+1]。
The synthesis of 1-2 1- (3- (3- phenyl-propoxies) furans -2- bases) second -1- ketone：
The compound 2 (3.86g, 18.01mmol) that above-mentioned synthesis step 1-1 is obtained is dissolved in anhydrous n,N-Dimethylformamide
(DMF) in (25mL), 1- (3- hy droxy furan -2- bases) second -1- ketone (2.27g, 18.01mmol) and potassium carbonate are then added
(7.47g, 54.03mmol).Mixture is heated at 85 DEG C 18 it is small when (completed until detecting reaction by HPLC), then will
It is cooled to room temperature.Saturated sodium bicarbonate aqueous solution is added in mixture, is extracted with ethyl acetate and uses sodium bicarbonate solution
Washed with water, after removing solvent in a vacuum, residue is obtained into off-white powder 1- (3- by purification by flash chromatography
(3- phenyl-propoxies) furans -2- bases) second -1- ketone（Compound 3）3.91g, yield 88.9%.1H-NMR (400 MHz,
CDCl3) δ: 2.05(m, 2H), 2.66(s, 3H), 2.77(t, 2H), 4.16(t, 2H), 6.28(d, 1H),
6.88(d, 1H), 7.15-7.26(m, 5H). 13C-NMR (125 MHz, CDCl3) δ: 24.66, 29.95,
34.34, 70.26, 111.03, 126.17, 128.33, 129.22, 137.15, 142.31, 146.41, 152.18,
193.54. LC-MS(ESI, pos, ion) m/z: 245[M+1]。
The synthesis of the bromo- 1- of 1-3 2- (3- (3- phenyl-propoxies) furans -2- bases) second -1- ketone：
At 0 DEG C, the compound 3 (3.91g, 16.00mmol) that synthesis step 1-2 is obtained is dissolved in anhydrous MeOH (30mL),
Then pyrrolidones hydrobromate (6.26g, 19.2mmol) is added into this solution.Then by reaction mixture in nitrogen atmosphere
Under when stirring 4 is small at 0 DEG C, and be allowed to warm to room temperature and continue stirring until reaction is completed (to detect by TLC or HPLC aobvious
Show).Then solvent is removed in a vacuum, the flash column chromatography isolated bromo- 1- of 4.48g yellow 2- (3- (the third oxygen of 3- phenyl
Base) furans -2- bases) second -1- ketone（Compound 4）Powder, yield 86.7%.1H-NMR (400 MHz, CDCl3) δ: 2.05(m,
2H), 2.77(t, 2H), 4.16(t, 2H), 4.58(s, 2H), 6.25(d, 1H), 6.88(d, 1H), 7.15-
7.26(m, 5H). 13C-NMR (125 MHz, CDCl3) δ: 29.95, 32.52, 34.34, 70.26, 111.03,
126.17, 128.33, 129.22, 134.87, 142.31, 146.41, 150.86, 191.83. LC-MS(ESI,
pos, ion) m/z: 323[M+1]。
The synthesis of 1-4 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- bases amino) ethane -1- ketone：
2-aminopyridine (0.94g, 10mmol) is dissolved in anhydrous DMF (20mL), then into solution add DIEA (3.88g,
30mmol), stirring one adds compound 4 (3.23g, 10mmol) after the meeting, by reaction mixture in a nitrogen atmosphere at room temperature
Stirring is until reaction is completed（Completed by TLC or HPLC detection reactions）.Then reaction mixture is diluted with cold water, uses acetic acid
Ethyl ester extracts dilution, by the organic layer of merging salt water washing and dried over sodium sulfate.Obtained after solvent is evaporated in vacuo
Required product 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- bases amino) ethane -1- ketone（Compound
5）, then crude product is purified by silica gel chromatography (2-4%MeOH/DCM), obtains purer compound 5,2.64g, production
Rate 78.5%.1H-NMR (400 MHz, CDCl3) δ: 2.05(m, 2H), 2.77(t, 2H), 3.00(s, 1H),4.16
(t, 2H), 5.00(s, 2H), 6.22(d, 1H), 6.81(t, 1H),6.88(d, 1H), 7.13(d, 1H),7.15-
7.26(m, 5H). 13C-NMR (125 MHz, CDCl3) δ: 29.95, 34.34, 46.62, 70.26, 108.84,
110.44, 111.03, 126.17, 128.33, 129.22, 136.64, 138.85, 142.31, 146.41,
149.77, 156.49, 158.35, 182.94.LC-MS(ESI, pos, ion) m/z: 337[M+1]。
Tri- fluoro- N- of 1-5 (2- oxos -2- (3- (3- phenyl-propoxies) furans -2- bases) ethyl)-N- (pyridine -2- bases) second
The synthesis of acid amides：
Compound 5 (1.68g, 5mmol) is dissolved in anhydrous DCM (20mL) at 0 DEG C, TEA is then added into solution
(1.52g, 15mmol), is slow added into 2,2,2- trifluoro-acetyl chlorides (1.99g, 15mmol).By reaction mixture in nitrogen gas
When stirring 3 is small at 0 DEG C under atmosphere, room temperature is then allowed to warm to, continues stirring until reaction is completed（Examined by TLC or HPLC
Reaction is surveyed to complete）.Then remove solvent under reduced pressure, obtain three fluoro- N- of crude product (2- oxos -2- (3- (3- phenyl-propoxies) furans -
2- yls) ethyl)-N- (pyridine -2- bases) acetamide（Compound 6）, with acetone and ethyl alcohol recrystallization, obtain after 1.83g refines
Compound 6, yield 84.5%.1H-NMR (400 MHz, CDCl3) δ: 2.05(m, 2H), 2.77(t, 2H), 4.16(t,
2H), 6.19(s, 2H), 6.32(d, 1H), 6.88(d, 1H), 7.15-7.26(m, 5H), 7.31(t, 1H),
8.02(t, 1H), 8.42(d, 1H), 8.85(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 29.95,
34.34, 48.47, 70.26, 111.03, 112.42, 117.32, 118.09, 126.17, 128.33, 129.22,
137.21, 138.68, 142.31, 146.41, 150.27, 150.62, 156.96, 157.15, 179.97. LC-MS
(ESI, pos, ion) m/z: 433[M+1]。
The synthesis of 1-6 2- (4- (3- (3- phenyl-propoxies) furans -2- bases) -2- Trifluoromethyl-1 H- imidazoles -1- bases) pyridine：
Compound 6 (1.83g, 4.23mmol) obtained above is dissolved in acetic acid (17.68mL), then under agitation to the above
Ammonium acetate (6.52g, 84.6mmol) is added in solution, reaction mixture is stirred overnight at 90 DEG C.Then reaction is mixed
Thing is cooled to room temperature, and is neutralized with saturated sodium bicarbonate solution.Then after being extracted with EtOAc, then silica gel column chromatography is passed through
（4-6%MeOH/DCM is eluted）Purifying, obtain product 2- (4- (3- (3- phenyl-propoxies) furans -2- bases) -2- trifluoromethyls -
1H- imidazoles -1- bases) pyridine（Compound 7）Off-white powder 1.47g, yield 84%.1H-NMR (400 MHz, CDCl3) δ:
2.05(m, 2H), 2.77(t, 2H), 3.89(q, 2H), 5.99(d, 1H), 7.06(d, 1H), 7.13-7.25(m,
5H), 7.39(t, 1H), 7.89(d, 1H), 8.00(t, 1H), 8.50(d, 1H), 8.86(s, 1H). 13C-NMR
(125 MHz, CDCl3) δ: 29.95, 34.34, 34.90, 70.26, 110.25, 123.60, 125.34,
126.17, 127.39, 128.33, 129.22, 130.90, 133.51, 136.19, 139.48, 142.30,
142.31, 149.00, 149.03, 151.97, 152.25. LC-MS(ESI, pos, ion) m/z: 414[M+1]。
Test example 1：Increment inhibitory action to osteoclast
First, experimental method
1st, osteoclast is separately cultured
Neck is drawn to put to death the Wistar rats in 24 h of birth, after distilled water cleans 1 min, 75% ethanol immersion 2min, separates stock
Bone, shin bone and humerus, carefully remove the soft tissue of bone surface, wipe out epiphysis, diaphyseal portion is washed 2 times with α-MEM nutrient solutions, is put into
In cold α-MEM nutrient solutions, backbone stringer is cut off with microsurgical scissors, marrow inner cavity surface sclerotin is gently scraped with scalpel
Enter in nutrient solution, then sclerotin fragment 2min is gently blown and beaten with round end suction pipe, the osteoclast that will attach on bone cips pours training
In nutrient solution, 15s is stood, draws upper cell suspension, it is about 10 that cell density, which is made,6The cell suspension of a/ml, is inoculated in preset
In 24 porocyte culture plates of coverslip, CO is put2Incubator（5% CO2, 37 DEG C）After cultivating 2h, the nutrient solution in culture hole is suctioned out
Not adherent heteroproteose cell is removed, is gently rinsed 2 times with the α-MEM of pre-temperature, is grouped and continues to cultivate after being administered according to packet,
Liquid 50% is changed per 48h.Above-mentioned α-MEM nutrient solutions are purchased from Hyclone companies.
2nd, packet and administration
Experiment is divided into medicine group to be measured and control group, is used in medicine group to be measured and contains 1 μm of ol/L testing compound（Corresponding embodiment
Middle difference compound）α-MEM nutrient solutions, with the α-MEM nutrient solutions for not containing 1 μm of ol/L testing compound in control group.
3rd, osteoclast morphologic observation
Carry out somatoscopy after 48h to cell under inverted microscope, while each glass creep plate takes 5 different 200 at random
Times visual field, counts apocyte（3 or more than 3）Sum it is osteoclastic as the time point on each slide（Sample）Cell is total
Number.
4th, statistical disposition
As a result represented with mean ± S.D., all data are handled using SPSS16.0 softwares, multiple-group analysis one way
ANOVA variance analyses, comparison among groups are examined with q；Two groups are compared and are examined with t.P <0.05 is statistically significant for difference.
5th, experimental result
1 osteoclast of table counts（A/piece,）
| Packet | Number |
| Control group | 28.1±3.6 |
| Compound 6 | 15.8±4.5* |
| Compound 7 | 6.5±3.3* |
Note：Compared with the control group, * P ＜ 0.05
Compared with control group, amount of osteoclast has prepared each compound in embodiment it can be seen from upper table result
Different degrees of reduction, and somatoscopy is carried out to cell under inverted microscope and finds the visible cell space of control group osteoclast
It is very big, it is clear-cut, in pan-fried oily egg shape, dumbbell shape, funnel type, chopper type etc., there are a large amount of pseudopodium to stretch around, nucleus is very
It is more, generally 8~15.And cell space diminution occurs in the osteoclast of compound 6 and compound 7 in experimental group, pseudopodium disappears
Lose, the apoptosis phenomenon such as karyopycnosis.Illustrate that increment of each compound of experimental group to osteoclast is inhibited.
Embodiment 2：To the preventive and therapeutic effect of vitamin A acid modeling osteoporosis rat
First, medicine is prepared
1st, vitamin A acid solution, accurately weighs vitamin A acid 3.0g, adds 0.5% CMC-Na solution to obtain 15mg/ml solution to 200ml, standby
With；
2nd, Ipriflavone solution, takes Ipriflavone 6.0g, adds DMSO 12ml, adds 0.5% CMC-Na solution to 300ml, obtains
20mg/ml solution, it is spare；
3rd, testing compound solution, is prepared by the compound in corresponding embodiment, accurately weighs 0.3g, adds DMSO 4ml, then add
Enter 0.5% CMC-Na solution to 100ml, obtain 3mg/ml solution, it is spare.
2nd, experimental method
Healthy female SD rats, 4 groups are randomly divided into by weight, are respectively control group（N=5）, model group（N=10）, it is positive right
According to group（Ipriflavone 100mg/kg, n=10）, some medicine groups to be measured（15mg/kg, n=10）.After experiment starts, per in the sky
Noon other each group gavages in addition to control group give vitamin A acid 75mg/kg（5ml/kg）, control group gives isometric 0.5% CMC-
Na, afternoon positive controls and medicine group to be measured give relative medicine solution respectively, control group and model group are given in equal volume
0.5% CMC-Na, continuous 2 weeks.
The left femur of animal is taken to use toy bone strength analyzer（YLS-16A toy bone strength analyzers,
Huaibei Zhenghua Biological Instrument Co., Ltd.）Measure the bone breaking force of femur, each sample be placed on position on instrument and
Direction is consistent；Residual bone is collected after measure, the wet gauze soaked with physiological saline wraps up, and seals after -20 DEG C of preservations
For measure bone calcium and bone phosphorus.
The grey method assay of bone calcium, bone phosphorus：Room temperature naturally to thaw, 120 DEG C of baking 12h, claim backbone weight in baking oven（W1）,
Bone is placed in 600 DEG C of muffle furnace ashing 3h again, makes the white bulk of bone, and claim bone ash weight（W2）.The bone ash that will be fully ground again
（0.1g）It is dissolved in excess（4ml）3% HNO3In, fully extraction（Place 2 days and shake up）, grey method measure calcium, phosphorus content.
3rd, experimental result
As a result represented with mean ± S.D., all data are handled using SPSS16.0 softwares, multiple-group analysis one way
ANOVA variance analyses, comparison among groups are examined with q；Two groups are compared and are examined with t.P <0.05 is statistically significant for difference.
2 the compounds of this invention of table is to bone breaking force and bone calcium, the influence of bone phosphorus
Note：Compared with model group, * P ＜ 0.05
From upper table result, to the rat of vitamin A acid modeling, the compounds of this invention 6 and compound 7 can increase bone breaking force
Size, and raise the content of bone calcium and bone phosphorus, illustrate that the compounds of this invention can have osteoporosis prevention and/or control
Treatment acts on, and osteoporosis new construction medicine can be used as to carry out more in-depth study and exploitation.
Claims (4)
1. a kind of glyoxaline compound of 2- trifluoromethyls substitution, its structural formula are as follows：
。
2. application of the compound as claimed in claim 1 in osteoclast increment medicine is suppressed.
3. application of the compound as claimed in claim 1 in prevention and/or treatment medicine for treating osteoporosis is prepared.
4. the synthetic route of compound as claimed in claim 1 is：
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810056731.6A CN107936000A (en) | 2018-01-21 | 2018-01-21 | A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810056731.6A CN107936000A (en) | 2018-01-21 | 2018-01-21 | A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107936000A true CN107936000A (en) | 2018-04-20 |
Family
ID=61937711
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810056731.6A Withdrawn CN107936000A (en) | 2018-01-21 | 2018-01-21 | A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107936000A (en) |
-
2018
- 2018-01-21 CN CN201810056731.6A patent/CN107936000A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105579433A (en) | Cryopyrin inhibitors for preventing and treating inflammation | |
| CN102250203A (en) | Beta-carboline aminoacid benzyl ester, preparation method and application thereof | |
| EP1896460B1 (en) | Benzofuranyl derivatives as 5-ht6-receptor inhibitors | |
| CN107964009A (en) | A kind of glyoxaline compound of 2- pyridine derivates substitution and its application in medicine for treating osteoporosis is prevented | |
| CN107936000A (en) | A kind of glyoxaline compound of 2 trifluoromethyl substitution and its application in medicine for treating osteoporosis is prevented | |
| CN107892687A (en) | A kind of 2 acetic acid esters glyoxaline compound and its application in medicine for treating osteoporosis is prevented and treated | |
| CN112679535A (en) | Small molecule PAD4 inhibitor and preparation method and application thereof | |
| CN108129465A (en) | A kind of glyoxaline compound of 2- pyrazines derivatives substitution and its application in medicine for treating osteoporosis is prevented | |
| CN108129466A (en) | A kind of 2- butyl imidazoles class compound and its application in medicine for treating osteoporosis is prevented | |
| CN104546835B (en) | Application of 3- (benzoyloxy phenyl) propanoic derivatives in the skin disease that treatment connection PROTEIN C X31 is mediated | |
| CN105085391B (en) | Cyclopropyl unsaturated quionoline compound and application as LTRA | |
| CN103483272A (en) | Resorcarenes-polysubstitution pyrimidine derivative as well as preparation method and application of derivative | |
| CN104725372B (en) | Tetracyclic indole alkaloid derivative as well as preparation method and application thereof | |
| CN104447702B (en) | A kind of amido replaces Bouchardatine derivant and its preparation method and application | |
| CN108976285A (en) | The warfarin of Gly-Pro-Arg-Pro-AA modification, synthesis, activity and application | |
| CN108840850A (en) | A kind of flavone derivative that treating osteoporosis and its pharmaceutical composition and application | |
| CN102060875B (en) | Quinazoline derivative, and preparation method and application thereof | |
| CN106389432A (en) | Application of nitidine chloride in preparing medicines for resisting osteoporosis and bone loss diseases | |
| CN102180941B (en) | Derivatives of betulonic acid, method for preparing same and application thereof | |
| WO2011096642A2 (en) | Pharmaceutical composition for preventing and treating inflammatory diseases | |
| CN101845052A (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof | |
| CN106176699A (en) | The neuroprotective purposes of Nootkatone | |
| CN103040813B (en) | Application of p-chloroaniline substituted pyranone in preparation of fungal infection resisting drugs | |
| CN103040811B (en) | Application of p-methoxyphenylamino pyranone in preparation of fungal infection resisting drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180420 |
|
| WW01 | Invention patent application withdrawn after publication |