CN107892687B - A kind of 2- acetic acid esters glyoxaline compound and its application in preventing medicine for treating osteoporosis - Google Patents
A kind of 2- acetic acid esters glyoxaline compound and its application in preventing medicine for treating osteoporosis Download PDFInfo
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- CN107892687B CN107892687B CN201810056718.0A CN201810056718A CN107892687B CN 107892687 B CN107892687 B CN 107892687B CN 201810056718 A CN201810056718 A CN 201810056718A CN 107892687 B CN107892687 B CN 107892687B
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention discloses a kind of 2 acetic acid esters glyoxaline compounds, structural formula is
Description
Technical field
The invention belongs to drug design and synthesis fields, are related to a kind of 2- acetic acid esters glyoxaline compound and its in prevention bone
Application in the loose drug of matter.
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, 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, in the age is more than 55 years old postclimacteric women, there is the people of half to suffer from the different bone of degree
Matter osteoporosis, and suffer from osteoporosis person in the elderly of over-65s and be up to 95% or more.With the reach of science and the mankind
Progress, the average life span constantly extend, and elderly population increase sharply, and the incidence of osteoporosis rapidly increases also with appearance.
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 70% or more.Osteoporosis cause it is 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
People’s lives quality is threatened again.
The osteoporosis epidemiological 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
Account for about 90% 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 inconvenient.This not only causes serious body and mind to patient and wrecks, while also increasing to family and society huge
Big manpower and financial resources burden.Therefore, prevention osteoporosis is anti-aging, 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 portion perimeter blood (spleen) monocyte and monokaryon of derived from bone marrow
The osteoclastic precursor of macrophage merges.Key link in bone remodeling is the bone information of osteoclast, normal stablizing
It is very important in bone homeostasis process.Some drugs such as bisphosphonates, calcitonin surround in anti-bone information drug
Osteoclast is unfolded, by inhibiting the activity of osteoclast to prevent or treat osteoporosis to reduce bone information.
Invention content
One of the objects of the present invention is to provide a kind of 2- acetic acid esters glyoxaline compound, structural formula is as follows：
。
Another object of the present invention is to provide a kind of application of compound in inhibiting osteoclast increment drug.
Another object of the present invention is to provide a kind of compounds to prepare prevention and/or treatment medicine for treating osteoporosis
In application.
Another object of the present invention is to provide a kind of synthetic routes of the compound to be：
。
Further, specific synthesis step is：
1) 3- phenyl-1-propanols (compound 1) generate methanesulfonic acid with generation sulfonylation under paratoluensulfonyl chloride low temperature
3- phenylpropyl acrylates (compound 2)；
2) compound 2 heats to react again with 1- (3- hy droxy furan -2- bases) second -1- ketone in the presence of an inorganic base generates 1-
(3- (3- phenyl-propoxies) furans -2- bases) second -1- ketone (compound 3)；
3) bromo-reaction generation 2- bromo- 1- (3- (the 3- benzene of carbonyl α-carbon occurs with pyrrolidones hydrobromate for compound 3
Base propoxyl group) furans -2- bases) second -1- ketone (compound 4)；
4) substitution reaction generation 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- of amine occur for compound 4
Base amino) ethane -1- ketone (compound 5)；
5) acylation reaction generation acetic acid (2- oxos -2- (3- (the 3- phenyl of amine occurs with acetic acid chloromethane acid anhydrides for compound 5
Propoxyl group) furans -2- bases) ethyl) (pyridine -2- bases) carbamic acid acid anhydride (compound 6)；
6) cyclization generation (4- (3- (3- phenyl-propoxies) furans -2- bases) -1- (pyridine -2- occur again for compound 6
Base) -1H- imidazoles -2- bases) acetic acid esters (compound 7).
Further, synthesis step 1) in low temperature range be 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 temperature be 50 DEG C -100 DEG C, preferably 85 DEG C.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific implementation mode
Embodiment：
The synthesis of 1-1 methanesulfonic acid 3- phenylpropyl acrylates：
3- phenyl-1-propanols (compound 1) (2.72g, 20mmol) are dissolved in dichloromethane (DCM) (25mL), are added
Triethylamine (TEA) (4.05g, 40mmol) obtains mixture, and mixture is then cooled to 0 DEG C.Under stiring, to the mixture
In be slowly added to paratoluensulfonyl chloride (MsCl) (5.72g, 30mmol), and reaction mixture is stirred 1 hour at 0 DEG C, so
It is stirred at room temperature afterwards 1 hour (being completed until detecting reaction by HPLC).After removing solvent, saturated sodium bicarbonate water is added
Solution.Product is extracted with EtOAc (3 × 30mL) and is washed with sodium bicarbonate solution and water, is then removed in a vacuum molten
Methanesulfonic acid 3- phenylpropyl acrylates (compound 2), 3.86g, yield 90.0% are obtained after agent.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- dimethyl formyls
In amine (DMF) (25mL), 1- (3- hy droxy furan -2- bases) second -1- ketone (2.27g, 18.01mmol) and potassium carbonate is then added
(7.47g, 54.03mmol).Mixture is heated into 18 hours (being completed until detecting reaction by HPLC) at 85 DEG C, 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
It is 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)
In, pyrrolidones hydrobromate (6.26g, 19.2mmol) is then added into this solution.Then by reaction mixture in nitrogen
It is stirred 4 hours at 0 DEG C under atmosphere, and is allowed to warm to room temperature and continues stirring until the reaction is complete (by TLC or HPLC detections
Display).Then solvent is removed in a vacuum, the isolated bromo- 1- of 4.48g yellow 2- (3- (the 3- phenyl third of flash column chromatography
Oxygroup) 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 conjunction of 1-4 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- bases amino) ethane -1- ketone
At：
2-aminopyridine (0.94g, 10mmol) is dissolved in anhydrous DMF (20mL), DIEA is then added into solution
(3.88g, 30mmol), stirring one after the meeting be added compound 4 (3.23g, 10mmol), by reaction mixture in a nitrogen atmosphere in
It stirs and (is completed until the reaction is complete by TLC or HPLC detection reactions) at room temperature.Then reaction mixture is diluted with cold water,
Dilution is extracted with ethyl acetate, combined organic layer is washed with brine and dried over sodium sulfate.Solvent is evaporated in vacuo
After obtain required product 1- (3- (3- phenyl-propoxies) furans -2- bases) -2- (pyridine -2- bases amino) ethane -1- ketone (change
Close object 5), crude product is purified by silica gel chromatography (2-4%MeOH/DCM) then, obtains purer compound 5,
2.64g, yield 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]。
1-5 acetic acid (2- oxos -2- (3- (3- phenyl-propoxies) furans -2- bases) ethyl) (pyridine -2- bases) amino first
The synthesis of acid anhydrides：
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 acetic acid chloromethane acid anhydrides (1.84g, 15mmol).In a nitrogen atmosphere by reaction mixture
It is stirred 4 hours at 0 DEG C, is then allowed to warm to room temperature, continued stirring and (detected until the reaction is complete by TLC or HPLC anti-
It should complete).Then it removes solvent under reduced pressure, obtains crude product acetic acid (2- oxos -2- (3- (3- phenyl-propoxies) furans -2- bases) second
Base) (pyridine -2- bases) carbamic acid acid anhydride (compound 6), with acetone and ethyl alcohol recrystallization, obtain 1.90g it is refined after compound
6, yield 90.1%.1H-NMR (400 MHz, CDCl3) δ: 2.05(m, 2H), 2.24(s, 3H), 2.77(t, 2H),
4.16(t, 2H), 6.31(d, 1H), 6.44(s, 2H), 6.88(d,1H), 7.14-7.26(m, 5H), 7.49(t,
1H), 7.86(t, 1H), 8.49(d, 1H), 8.71(d, 1H). 13C-NMR (125 MHz, CDCl3) δ: 20.93,
29.95, 34.34, 47.17, 70.26, 111.03, 117.61, 122.24, 126.17, 128.33, 129.22,
137.21, 137.91, 142.31, 146.41, 149.46, 150.78, 152.20, 157.15, 169.27,
179.97. LC-MS(ESI, pos, ion) m/z: 423[M+1]。
1-6 (4- (3- (3- phenyl-propoxies) furans -2- bases) -1- (pyridine -2- bases) -1H- imidazoles -2- bases) acetic acid esters
Synthesis：
Compound 6 (1.90g, 4.50mmol) obtained above is dissolved in acetic acid (20mL), then under stiring to
Ammonium acetate (6.94g, 90.00mmol) is added in upper solution, reaction mixture is stirred overnight at 95 DEG C.Then reaction is mixed
It closes object to be cooled to room temperature, saturated sodium bicarbonate solution is used in combination to neutralize.Then after being extracted with EtOAc, then passed through silica gel column layer
(4-6%MeOH/DCM elutions) purifying is analysed, product (4- (3- (3- phenyl-propoxies) furans -2- bases) -1- (pyridine -2- are obtained
Base) -1H- imidazoles -2- bases) acetic acid esters (compound 7) off-white powder 1.54g, yield 85%.1H-NMR (400 MHz,
CDCl3) δ: 2.05(m, 2H), 2.09(s, 3H), 2.77(t, 2H), 4.16(t, 2H), 6.00(d, 1H),
7.07(d, 1H), 7.15-7.26(m, 5H), 7.40(t, 1H), 7.90(d, 1H), 8.01(t, 1H), 8.51(d,
1H), 8.87(s, 1H). 13C-NMR (125 MHz, CDCl3) δ:20.67, 29.95, 34.34, 57.50,
70.26, 110.25, 123.60, 125.34, 126.17, 127.39, 128.33, 129.22, 133.51,
139.48, 142.30, 142.31, 142.68, 149.00, 149.03, 151.97, 152.25, 171.62. LC-MS
(ESI, pos, ion) m/z: 404[M+1]。
Test example 1：To the increment inhibiting effect of osteoclast
One, experimental method
1, 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% ethyl alcohol impregnates 2min, point
From femur, shin bone and humerus, the soft tissue of bone surface carefully to be removed, epiphysis is wiped out, diaphyseal portion is washed 2 times with α-MEM culture solutions,
It is put into cold α-MEM culture solutions, is cut off backbone stringer with microsurgical scissors, it is with scalpel that marrow inner cavity surface sclerotin is light
It gently scrapes in culture solution, then sclerotin fragment 2min is gently blown and beaten with round end suction pipe, the osteoclast being attached on bone cips is rushed
Enter in culture solution, stand 15s, draws upper cell suspension, it is about 10 that cell density, which is made,6The cell suspension of a/ml, is inoculated in
In 24 porocyte culture plates of preset coverslip, CO is set2Incubator（5% CO2, 37 DEG C）After cultivating 2h, the training in culture hole is sucked out
Nutrient solution removes not adherent heteroproteose cell, is gently rinsed 2 times with the α-MEM of pre-temperature, is grouped and continues after being administered according to grouping
Culture changes liquid 50% per 48h.Above-mentioned α-MEM culture solutions are purchased from Hyclone companies.
2, grouping 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 untested compound（It is corresponding real
Apply different compounds in example）α-MEM culture solutions, with the α-MEM cultures without containing 1 μm of ol/L untested compound in control group
Liquid.
3, osteoclast morphologic observation
Somatoscopy carried out to cell under inverted microscope after 48h, at the same each glass creep plate take at random 5 it is different
200 times of visuals field count apocyte（3 or 3 or more）Sum it is osteoclastic as the time point on each slide（Sample）Cell
Sum.
4, statistical disposition
As a result it is indicated 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.
5, experimental result
The counting of 1 osteoclast of table (a/piece,)
| Grouping | Number |
| Control group | 28.1±3.6 |
| Compound 6 | 20.8±3.4* |
| Compound 7 | 14.6±2.8* |
Note：Compared with the control group, * P ＜ 0.05
In embodiment it can be seen from upper table result prepared each compound compared with the control group, amount of osteoclast
There is different degrees of reduction, and somatoscopy is carried out to cell under inverted microscope and finds that control group osteoclast is visible
Cell space is very big, clear-cut, in oily egg shape, dumbbell shape, funnel type, chopper type etc. is decocted, has a large amount of pseudopodium to stretch around, cell
There are many core, generally 8~15.And there is cell space diminution in the osteoclast of compound 6 and compound 7 in experimental group, it is pseudo-
Foot disappears, the apoptosis phenomenon such as karyopycnosis.Illustrate that each compound of experimental group is inhibited to the increment of osteoclast.
Embodiment 2：To the preventive and therapeutic effect of vitamin A acid modeling osteoporosis rat
One, drug is prepared
1, vitamin A acid solution accurately weighs vitamin A acid 3.0g, adds 0.5% CMC-Na solution to 200ml, it is molten to obtain 15mg/ml
Liquid, it is spare；
2, Ipriflavone solution takes Ipriflavone 6.0g, adds DMSO 12ml, 0.5% CMC-Na solution is added to 300ml,
20mg/ml solution is obtained, it is spare；
3, testing compound solution is prepared by the compound in corresponding embodiment, accurately weighs 0.3g, add DMSO 4ml,
0.5% CMC-Na solution is added to 100ml, obtains 3mg/ml solution, it is spare.
Two, experimental method
Healthy female SD rats are randomly divided into 4 groups, respectively control group by weight（N=5）, model group（N=10）, sun
Property control group（Ipriflavone 100mg/kg, n=10）, several medicine groups to be measured（15mg/kg, n=10）.After experiment starts, often
Its morning 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 give equal bodies
Long-pending 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 measurement, is wrapped up with the wet gauze that physiological saline impregnates, in -20 DEG C of preservations after sealing
For measuring 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 furnaces again and is ashed 3h, 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 extract（It places 2 days and shakes up）, grey method measurement calcium, phosphorus content.
Three, experimental result
As a result it is indicated 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.
Influence of 2 the compounds of this invention of table to bone breaking force and bone calcium, bone phosphorus
Note：Compared with model group, * P ＜ 0.05
By upper table result it is found that rat to vitamin A acid modeling, the compounds of this invention 6 and compound 7 can increase fracture
The size of disconnected power, and increase the content of bone calcium and bone phosphorus, illustrate the compounds of this invention can have to osteoporosis prevent and/
Or therapeutic effect, osteoporosis new construction drug can be used as to carry out more in-depth study and exploitation.
Claims (3)
1. a kind of 2- acetic acid esters glyoxaline compound, structural formula are as follows：
。
2. compound as described in claim 1 is preparing the application in preventing and/or treating medicine for treating osteoporosis.
3. the synthetic route of compound as described in claim 1 is：
。
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