CN106279125B - Coumarin derivative and its preparation method - Google Patents
Coumarin derivative and its preparation method Download PDFInfo
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- CN106279125B CN106279125B CN201510296809.8A CN201510296809A CN106279125B CN 106279125 B CN106279125 B CN 106279125B CN 201510296809 A CN201510296809 A CN 201510296809A CN 106279125 B CN106279125 B CN 106279125B
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- umbelliferone
- formyl
- amino
- alanyl
- amino methylpyrimidine
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- GOJMGTGXOGLUAL-UHFFFAOYSA-N CC(C)CC(C[NH+](Cc1ncccn1)[O-])NC(CCNC(C(C(Oc1c2)=O)=Cc1ccc2O)=O)=O Chemical compound CC(C)CC(C[NH+](Cc1ncccn1)[O-])NC(CCNC(C(C(Oc1c2)=O)=Cc1ccc2O)=O)=O GOJMGTGXOGLUAL-UHFFFAOYSA-N 0.000 description 1
- ROSKZJGILXBSFM-UHFFFAOYSA-N NCc1ncccn1 Chemical compound NCc1ncccn1 ROSKZJGILXBSFM-UHFFFAOYSA-N 0.000 description 1
- CKZDPGZUVBLQSL-UHFFFAOYSA-N Oc(cc1)cc(O2)c1C=C(C=O)C2=O Chemical compound Oc(cc1)cc(O2)c1C=C(C=O)C2=O CKZDPGZUVBLQSL-UHFFFAOYSA-N 0.000 description 1
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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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to coumarin derivative and its preparation methods.Specifically, the invention discloses the novel umbelliferone -3- formyl-β with anti-inflammatory activity-alanylamino acyl -2- amino methylpyrimidine of logical formula (I), the AA=Ala in logical formula (I), Leu, Val, Met, Phe, Tyr, Asp (OBzl).Their preparation method is further related to, and further discloses its anti-inflammatory effect.Thus the invention discloses umbelliferone -3- formyl-β-potential applicability in clinical practice of the propionic acid as anti-inflammatory drug of 2- amino methylpyrimidine and amino acid modification.
Description
Invention field
The invention belongs to biomedicine fields, especially the present invention relates to the novel 7- hydroxyl tonka-bean with anti-inflammatory activity
Element -3- formyl-β-alanylamino acyl -2- amino methylpyrimidine (9a-g) preparation method and applications.
Background technique
Inflammation is a kind of protective defense reaction, and leads to the co-channel of many important human diseases, and join
With human infection, tumour, cardiovascular and cerebrovascular disease, Alzheimer's disease and the nervous system disease, anaphylactia, mental disease etc.
The occurrence and development process of other important diseases.Clinically, anti-inflammatory drug comes common drug second, is only second to anti-infective
Medicine, typical reaction is red, swollen, hot, pain and dysfunction etc..
Non-steroid anti-inflammatory drug (NSAIDS) and selective cyclooxygenase-2 (COX-2) inhibitor be for treat it is acute or
The conventional medicament of chronic inflammatory diseases, studies have found that NSAIDS can induce serious gastrointestinal side effect, including stomach and intestine
Gastrointestinal hemorrhage and induced ulcer, and Selective COX-2 inhibitor can increase patient and myocardial infarction occurs, cardiac sudden death and cerebral apoplexy
Risk.Therefore, developing new efficient, less toxic, anti-inflammatory drug is always one of important topic of new drug research, and cyclooxygenase
It is even more the emphasis studied with lipoxygenase COX/5-LOX double inhibitor.
Cumarin (Coumarin) is a kind of natural products with benzo α pyranone parent nucleus, is widely present in plant kingdom,
It is simultaneously also COX/5-LOX double inhibitor.It was once disclosed in document and reported that cumarin was shown well under 10 μm of ol/kg dosage
Anti-inflammatory activity.
Summary of the invention
A kind of compound of logical formula (I) of present disclosure：
Wherein AA is selected from Ala, Leu, Val, Met, Phe, Tyr or Asp (OBzl) in logical formula (I).
The coumarin derivative that the present invention obtains is respectively：
9a：Umbelliferone -3- formyl-β-alanyl alanyl -2- amino methylpyrimidine
9b：Umbelliferone -3- formyl-β-alanyl leucyl -2- amino methylpyrimidine
9c：Umbelliferone -3- formyl-β-alanyl valyl -2- amino methylpyrimidine
9d：Umbelliferone -3- formyl-β-alanyl methinyl -2- amino methylpyrimidine
9e：Umbelliferone -3- formyl-β-alanyl phenylalanyl -2- amino methylpyrimidine
9f：Umbelliferone -3- formyl-β-alanyl tyrosyl -2- amino methylpyrimidine
9g：Umbelliferone -3- formyl-β-alanyl aspartoyl benzyl ester -2- amino methylpyrimidine
The invention further relates to the preparation methods of logical formula (I), and this approach includes the following steps：
2,4- 4-dihydroxy benzaldehyde is condensed under piperidines catalysis with diethyl malonate and generates umbelliferone -3- carboxylic
Acetoacetic ester,
Obtained umbelliferone -3- the carboxylic acid, ethyl ester generates umbelliferone -3- carboxylic under concentrated hydrochloric acid effect
Acid,
Obtained umbelliferone -3- the carboxylic acid and beta-amino acids-OBzl is coupled to obtain umbelliferone -3- first
Acyl-Beta-alanine benzyl ester,
Obtained umbelliferone -3- formyl-Beta-alanine benzyl ester hydrogenolysis under the catalysis of palladium carbon generates 7- hydroxyl
Butylcoumariii -3- formyl-Beta-alanine,
Obtained umbelliferone -3- formyl-the Beta-alanine and l-amino acid benzyl ester is coupled to obtain 7- hydroxyl perfume
Legumin -3- formyl-β-alanylamino acid benzyl ester,
Obtained umbelliferone -3- formyl-β-alanylamino acid benzyl ester hydrogenolysis under the catalysis of palladium carbon is raw
It is sour at umbelliferone -3- formyl-β-alanylamino,
Obtained umbelliferone -3- formyl-β-alanylamino the acid is coupled to obtain with 2- amino methylpyrimidine
Umbelliferone -3- formyl-β-alanylamino acyl -2- amino methylpyrimidine,
It is coupled tertiary fourth oxygen amic acid and 2- amino methylpyrimidine to obtain tertiary fourth oxygen acyl aminoacyl -2- amino methylpyrimidine,
The obtained tertiary fourth oxygen acyl aminoacyl -2- amino methylpyrimidine generates N- aminoacyl-in HCl/EtOAc (4N) solution
2- amino methylpyrimidine,
N- aminoacyl -2- amino methylpyrimidine and umbelliferone -3- formyl-Beta-alanine are coupled to obtain 7- hydroxyl perfume
Legumin -3- formyl-β-alanylamino acyl -2- amino methylpyrimidine.
The present invention is further directed to evaluate their anti-inflammatory effect with the mouse ear swelling model that dimethylbenzene induces.
Thus the invention discloses Novel 2 Amino methylpyrimidines and the umbelliferone -3- formyl-β of amino acid modification-propionic acid to make
For the potential applicability in clinical practice of anti-inflammatory drug.
Further research through the invention, present inventors have recognized that, using 7- cumarin as lead compound, with β-ammonia
Umbelliferone -3- formyl-Beta-alanine after the modification of base propionic acid is parent nucleus, using amino acid as linking arm, with another tool
There is the cox 2 inhibitor 2- amino methylpyrimidine of stronger anti-inflammatory activity to stitch and fasten, can not only reduce clinically existingization
The toxic side effect of object is closed, while lead compound cumarin and 2- amino methylpyrimidine can be improved in organic solvent and water-soluble
The bad disadvantage of dissolubility in liquid, improves the bioavilability of compound, greatly reduces the oral dose of compound, enhancing
The anti-inflammatory activity of compound.By this modification, the compound with more preferable anti-inflammatory activity is obtained, there is good clinic to answer
Use prospect.
Detailed description of the invention
Fig. 1 shows 7- cumarin -3- formyl-β-propionic acid synthetic routes, wherein i) piperidines, diethyl oxalate；ii)
Concentrated hydrochloric acid, H2O；Iii) Beta-alanine-OBzl, 1- (3- dimethylaminopropyl) -3- ethyl-carbodiimide hydrochloride
(EDCHCl) I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), THF；Iv) 5%Pd, H2, methanol.
Fig. 2 indicates the synthetic route of logical formula (I) coumarin derivative (9a-g), wherein v) Boc-AA-OH, 1- (3- diformazan
Base aminopropyl) -3- ethyl-carbodiimide hydrochloride (EDCHCl), I-hydroxybenzotriazole (HOBt), N-methylmorpholine
(NMM), THF；vi)4N HCl/EtOAc；Vii) 1- (3- dimethylaminopropyl) -3- ethyl-carbodiimide hydrochloride
(EDCHCl), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), THF.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares umbelliferone -3- Ethyl formate (2)
At a temperature of 90 DEG C, weighs 2,4- 4-dihydroxy benzaldehyde (0.500g, 3.60mmol) and measure diethyl malonate
(0.70ml, 4.00mmol) is placed in 100ml eggplant bottle, is dissolved in 95% ethyl alcohol (20ml), and solution colour is rufous at this time
Transparency liquid；It adds piperidines (0.40ml, 4.00mmol), the green tinged coloured light of solution surface starts to flow back, molten after reacting about 6h
Liquid becomes dark-brown.It is cooled to room temperature, is concentrated under reduced pressure into red thick shape, compound 3 is obtained by filtration in ethyl alcohol recrystallization
(0.758g, 3.24mmol), character are faint yellow solid, yield 90%.ESI-MS m/z 233(M-1).
Embodiment 2 prepares umbelliferone -3- carboxylic acid (3)
At a temperature of 90 DEG C, Weigh Compound 3 (2.00g, 8.55mmol) is dissolved in water (20ml), and concentrated hydrochloric acid is added
After (6ml), flow back 8h.Reaction solution is cooled to room temperature, is filtered, washing obtains compound 4 (1.32g, 6.41mmol), character
For light red solid, yield 75%.ESI-MS m/z 205(M-1).
Embodiment 3 prepares umbelliferone -3- formyl-β-benzyl propionate (4)
It weighs 3 (1.00g, 4.85mmol) to be placed in 100ml eggplant bottle, tetrahydrofuran is added under ice bath cooling condition
(30ml) is sequentially added N- hydroxybenzotriazole (HOBt) (0.720g, 5.33mmol), 1- (3- dimethylaminopropyl) -3-
Ethyl-carbodiimide hydrochloride (EDCHCl) (1.02g, 5.33mmol) reacts 30 minutes.Addition tetrahydrofuran
The compound Tos Beta-alanine-OBzl (1.87g, 5.33mmol) of (20ml) dissolution, is added dropwise N-methylmorpholine (NMM)
(0.60ml) adjusts pH value to 8.Reaction is whole to carry out TLC detection, fully reacting in about 8 hours.Filtering, is concentrated to dryness, and is added
Ethyl acetate (100ml) dissolves residue, and solution is added in the separatory funnel of 250ml, successively uses unsaturated carbonate hydrogen
Sodium water solution washes (50mL × 3), saturated sodium-chloride water solution washes (50mL × 3), 5% aqueous potassium hydrogen sulfate wash (50mL × 3),
Saturated sodium-chloride water solution washes (50mL × 3), saturated sodium bicarbonate aqueous solution washes (50mL × 3), saturated sodium-chloride water solution is washed
Obtain three kinds of aqueous solutions are reused ethyl acetate and are stripped respectively by (50mL × 3), merge each ethyl acetate
Anhydrous Na is added in layer2SO4Dry about 30 minutes, filtering, concentrate filtrate to it is dry, using silica gel column chromatography to residue into
Row isolate and purify (methylene chloride: methanol=50: 1), obtaining midbody compound 4 (1.07g, 2.93mmol), character be it is yellowish
Color solid, yield 55%.ESI-MS m/z 364(M-1).
Embodiment 4 prepares umbelliferone -3- formyl-β-propionic acid (5)
4 (1.29g, 3.29mmol) are added in 50ml eggplant bottle, methanol (20ml) dissolution is added, adds Pd/C (5%)
(65mg) is passed through H after vacuumizing2Reaction at room temperature is carried out overnight, to monitor through TLC plate, fully reacting.Filtering, is concentrated under reduced pressure into
It is dry, it obtains compound 5 (620mg, 2.24mmol), character is faint yellow solid, yield 68%.ESI-MS m/z 276(M-
1)。
Embodiment 5 prepares tertiary fourth oxygen acyl alanyl -2- amino methylpyrimidine (7a)
It weighs Boc-A-OH (300mg, 3.03mmol) to be placed in 100ml eggplant bottle, tetrahydrofuran (40ml) dissolution, ice is added
It is sequentially added under bath N- hydroxybenzotriazole (HOBt) (405g, 3.03mmol), 1- (3- dimethylaminopropyl) -3- ethyl carbon
Change diimmonium salt hydrochlorate (EDCHCl) (573mg, 3.03mmol), N-methylmorpholine (NMM) (0.50ml) adjusting PH, which is added dropwise, is
8, it reacts 30 minutes.It weighs 2- amino methylpyrimidine hydrochloride (401mg, 2.50mmol) to be placed in small beaker, tetrahydro furan is added
Mutter (10ml) dissolution, while be added dropwise N-methylmorpholine (NMM) (0.20ml) adjust PH be 8.Eggplant is added in solution in small beaker
In bottle, room temperature reaction is monitored through TLC and is reacted, fully reacting in about 10 hours.Reaction solution is concentrated to dryness, 50ml second is added
Acetoacetic ester is extracted, and successively washes (30mL × 3) using saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washes (30mL
× 3), 5% aqueous potassium hydrogen sulfate washes (30mL × 3), saturated sodium-chloride water solution washes (30mL × 3), saturated sodium bicarbonate water
Solution washes (30mL × 3), saturated sodium-chloride water solution washes (30mL × 3), and obtain three kinds of aqueous solutions are reused ethyl acetate
Back extraction merges each ethyl acetate layer, and anhydrous Na is added2SO4About 30 minutes dry, filtering concentrates filtrate to
It is dry, residue is isolated and purified using silica gel column chromatography and (methylene chloride: methanol=40: 1), obtains compound 7a
(560mg, 2.00mmol), character are colorless oil, and yield is=72%.ESI-MS m/z 281(M+1).
Embodiment 6 prepares tertiary fourth oxygen acyl leucyl -2- amino methylpyrimidine (7b)
According to the operation of embodiment 5, by Boc-L-OH (500mg, 2.16mmol), HOBt (292mg, 2.16mmol) and
EDCHCl (413g, 2.16mmol) and 2- amino methylpyrimidine hydrochloride (287mg, 1.97mmol) are at anhydrous THF (50ml)
It is condensed to yield 7b (460mg, 1.43mmol), character is colorless oil, yield 70%.ESI-MS m/z 323(M+1).
Embodiment 7 prepares tertiary fourth oxygen acyl valyl -2- amino methylpyrimidine (7c)
According to the operation of embodiment 5, by Boc-V-OH (500mg, 2.30mmol), HOBt (311mg, 2.30mmol) and
EDCHCl (440mg, 2.30mmol) and 2- amino methylpyrimidine hydrochloride (305mg, 2.09mmol) are at anhydrous THF (50ml)
It is condensed to yield 7c (487mg, 1.58mmol), character is colorless oil, yield 75%.ESI-MS m/z 309(M+1).
Embodiment 8 prepares tertiary fourth oxygen acyl methinyl -2- amino methylpyrimidine (7d)
According to the operation of embodiment 5, by Boc-M-OH (500mg, 2.01mmol), HOBt (270mg, 2.00mmol) and
EDCHCl (382mg, 2.00mmol) and 2- amino methylpyrimidine hydrochloride (266mg, 1.83mmol) are at anhydrous THF (50ml)
It is condensed to yield 7d (440mg, 1.29mmol), character is colorless oil, yield 70%.ESI-MS m/z 341(M+1).
Embodiment 9 prepares tertiary fourth oxygen acyl phenylalanyl -2- amino methylpyrimidine (7e)
According to the operation of embodiment 5, by Boc-F-OH (500mg, 1.89mmol), HOBt (255mg, 1.88mmol) and
EDCHCl (360mg, 1.88mmol) and 2- amino methylpyrimidine hydrochloride (250mg, 1.72mmol) are at anhydrous THF (50ml)
It is condensed to yield 7e (320mg, 0.90mmol), character is colorless oil, yield 52%.ESI-MS m/z 357(M+1).
Embodiment 10 prepares tertiary fourth oxygen acyl tyrosyl -2- amino methylpyrimidine (7f)
According to the operation of embodiment 5, by Boc-Y-OH (500mg, 1.78mmol), HOBt (240mg, 1.78mmol) and
EDCHCl (340mg, 1.78mmol) and 2- amino methylpyrimidine hydrochloride (236mg, 1.62mmol) are at anhydrous THF (50ml)
It is condensed to yield 7f (379mg, 1.02mmol), character is colorless oil, yield 62%.ESI-MS m/z 373(M+1).
Embodiment 11 prepares tertiary fourth oxygen acyl benzyl ester aspartoyl -2- amino methylpyrimidine (7g)
According to the operation of embodiment 5, by Boc-D (OBzl)-OH (500mg, 1.55mmol), HOBt (209mg,
1.55mmol) with EDCHCl (296mg, 1.55mmol) and 2- amino methylpyrimidine hydrochloride (205mg, 1.41mmol) in nothing
Water THF (50ml) is condensed to yield 7g (380mg, 0.92mmol), and character is colorless oil, yield 65%.ESI-MS m/z
415(M+1)。
Embodiment 12 prepares umbelliferone -3- formyl-β-alanyl alanyl -2- amino methylpyrimidine (9a)
7a (742mg, 2.65mmol) is added in 100ml eggplant bottle, is added 4N HCl/EA (30ml), is reacted under ice bath,
TLC monitoring reacts about 3 hours completely.Decompressing and extracting solvent obtains compound 8a (286mg, 1.59mmol), is dissolved in
In tetrahydrofuran (40ml), it is 8 that N-methylmorpholine (NMM) (0.30ml), which is added dropwise, and adjusts PH.It is molten to weigh 5 (400mg, 1.44mmol)
Solution sequentially adds N- hydroxybenzotriazole (HOBt) (215mg, 1.59mmol), 1- (3- in tetrahydrofuran (30ml) under ice bath
Dimethylaminopropyl) -3- ethyl-carbodiimide hydrochloride (EDCHCl) (303mg, 1.59mmol), N- methyl is added dropwise
It is 8 that quinoline (NMM) (0.30ml), which adjusts PH, is reacted 30 minutes.Solution in small beaker is added in eggplant bottle, room temperature reaction, through TLC
Monitoring reaction, about 8h fully reacting.Reaction solution is concentrated to dryness, residue is isolated and purified using silica gel column chromatography
It (methylene chloride: methanol=20: 1), obtains target compound 9a (334mg, 0.76mmol), character is faint yellow solid, yield
It is=53%.Mp 252.6-254.4℃；[α]D 25=-12.1 (c=0.10, CH3OH)；IR(KBr)：3287,2875,1700,
1633,1567,1526,1439,1410,1365,1317,1216,1138,795,639cm-1；ESI-MS(m/e)438[M-H]-
；1H-NMR (300MHz, DMSO-d6)：δ/ppm 11.05 (s, 1H, O-H), 8.81 (t, J=6.0Hz, 1H, N-H), 8.78 (s,
1H, CH), 8.73 (d, J=5.1Hz, 2H, CH, CH), 8.35 (t, J=5.7Hz, 1H, N-H), 8.19 (d, J=7.8Hz, 1H,
N-H), 7.80 (d, J=8.7Hz, 1H, Ar-H), 7.35 (t, J=5.1Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=
2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-H), 4.60 (d, J=5.7Hz, 2H, CH2), 4.41 (m, 1H,
CH), 3.56-3.49 (m, 2H, CH2), 2.43 (t, J=6.6Hz, 2H, CH2), 1.24 (d, J=6.9Hz, 3H, CH3)；13C-NMR
(75MHz, DMSO-d6)：δ/ppm 172.81,170.80,167.13,164.07,161.89,161.34,157.75 (2C),
156.71,148.50,132.44,120.21,114.76,113.99,111.55,102.23,48.48,45.20,35.97,
35.30 18.73.
Embodiment 13 prepares umbelliferone -3- formyl-β-alanyl leucyl -2- amino methylpyrimidine (9b)
According to the operation of embodiment 12,7b (708mg, 2.20mmol) obtained in 4N HCl/EA (30ml) 8b (292mg,
1.32mmol), with HOBt (195mg, 1.45mmol), EDCHCl (276mg, 1.45mmol) and 5 (400mg, 1.44mmol)
It is condensed to yield 9b (221mg, 0.46mmol), character is faint yellow solid, and yield is=35%.Mp 215.3-216.8℃；
[α]D 25=-24.4 (c=0.10, CH3OH)；IR(KBr)：3296,2959,1700,1635,1566,1530,1437,1416,
1366,1321,1214,1144,794,637cm-1；ESI-MS(m/e)480[M-H]-；1H-NMR (300MHz, DMSO-d6)：δ/
Ppm 11.09 (s, 1H, O-H), 8.80 (m, 2H, N-H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH), 8.38 (t, J=
5.7Hz, 1H, N-H), 8.13 (d, J=8.4Hz, 1H, N-H), 7.82 (d, J=8.7Hz, 1H, Ar-H), 7.35 (t, J=
4.8Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-H),
4.42 (m, 3H, CH2, CH), 3.53 (m, 2H, CH2), 2.42 (m, 2H, CH2), 1.64-1.39 (m, 3H, CH2, CH), 0.82 (t,
J=6.0Hz, 6H, CH3, CH3)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 172.61,170.93,167.16,164.14,
161.88,161.33,157.71 (2C), 156.73,148.48,132.43,120.19,114.80,113.95,111.57,
102.24,51.33,45.27,41.35,36.08,35.40,24.65,23.49,21.98.
Embodiment 14 prepares umbelliferone -3- formyl-β-alanyl valyl -2- amino methylpyrimidine (9c)
According to the operation of embodiment 12,7c (611mg, 1.98mmol) obtained in 4N HCl/EA (30ml) 8c (248mg,
1.19mmol), with HOBt (161mg, 1.19mmol), EDCHCl (228mg, 1.19mmol) and 5 (300mg, 1.08mmol)
It is condensed to yield 9c (243mg, 0.52mmol), character is faint yellow solid, and yield is=48%.Mp 249.6-251.3℃；
[α]D 25=-10.2 (c=0.10, CH3OH)；IR(KBr)：3290,2968,1702,1636,1568,1527,1453,1370,
1218,1142,794,639cm-1；ESI-MS(m/e)466[M-H]-；1H-NMR (300MHz, DMSO-d6)：δ/ppm 11.07
(s, 1H, O-H), 8.83 (t, J=5.7Hz, 1H, N-H), 8.79 (s, 1H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH),
8.46 (t, J=5.4Hz, 1H, N-H), 7.99 (d, J=9.0Hz, 1H, N-H), 7.82 (d, J=8.7Hz, 1H, Ar-H), 7.36
(t, J=5.1Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.79 (d, J=1.8Hz, 1H, Ar-
H), 4.46 (t, J=5.4Hz, 2H, CH2), 4.30 (m, 1H, CH), 3.52 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.01 (m,
2H, CH2), 0.86 (t, J=6.9Hz, 6H, CH3, CH3)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 171.59,171.08,
167.25,164.09,161.85,161.33,157.71 (2C), 156.72,148.52,132.45,120.21,114.77,
113.96,111.55,102.24,58.01,45.30,36.11,35.30,30.94,19.71,18.44.
Embodiment 15 prepares umbelliferone -3- formyl-β-alanyl methinyl -2- amino methylpyrimidine (9d)
According to the operation of embodiment 12,7d (440mg, 1.33mmol) obtained in 4N HCl/EA (30ml) 8d (183mg,
0.80mmol), with HOBt (107mg, 0.80mmol), EDCHCl (152mg, 0.80mmol) and 5 (200mg, 0.72mmol)
It is condensed to yield 9d (155mg, 0.31mmol), character is faint yellow solid, and yield is=43%.Mp 219.0-221.2℃；
[α]D 25=-11.9 (c=0.10, CH3OH)；IR(KBr)：3279,2914,1694,1636,1515,1532,1450,1372,
1219,1144,794,639cm-1；ESI-MS(m/e)498[M-H]-；1H-NMR (300MHz, DMSO-d6)：δ/ppm 11.06
(s, 1H, O-H), 8.81 (t, J=5.7Hz, 1H, N-H), 8.78 (s, 1H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH),
8.43 (t, J=5.7Hz, 1H, N-H), 8.20 (d, J=8.1Hz, 1H, N-H), 7.81 (d, J=8.7Hz, 1H, Ar-H), 7.36
(t, J=4.8Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-
H), 4.55-4.38 (m, 3H, CH2, CH), 3.53 (m, 2H, CH2), 2.47 (m, 2H, CH2), 2.00 (s, 3H, CH3), 1.97-
1.78 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 171.72,171.15,167.13,164.08,
161.91,161.34,157.72 (2C), 156.73,148.48,132.43,120.22,114.77,114.01,111.56,
102.24,52.27,45.25,36.04,35.39,32.41,30.06,15.06.
Embodiment 16 prepares umbelliferone -3- formyl-β-alanyl phenylalanyl -2- amino methylpyrimidine (9e)
According to the operation of embodiment 12,7e (706mg, 1.98mmol) obtained in 4N HCl/EA (30ml) 8e (305mg,
1.19mmol), with HOBt (161mg, 1.19mmol), EDCHCl (228mg, 1.19mmol) and 5 (300mg, 1.08mmol)
It is condensed to yield 9e (319mg, 0.62mmol), character is faint yellow solid, and yield is=57%.Mp 194.3-195.7℃；
[α]D 25=-11.3 (c=0.10, CH3OH)；IR(KBr)：3270,2917,1694,1639,1614,1544,1452,1416,
1375,1225,1149,1118,850,794,640cm-1；ESI-MS(m/e)514[M-H]-；1H-NMR (300MHz, DMSO-
d6)：δ/ppm 11.04 (s, 1H, O-H), 8.76-8.71 (m, 4H, N-H, CH, CH, CH), 8.52 (t, J=5.7Hz, 1H, N-
H), 8.23 (d, J=8.7Hz, 1H, N-H), 7.81 (d, J=8.4Hz, 1H, Ar-H), 7.37 (t, J=4.8Hz, 1H, CH),
7.26-7.17 (m, 4H, Ar-H), 7.08 (m, 1H, Ar-H), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.79
(d, J=2.4Hz, 1H, Ar-H), 4.63 (m, 1H, CH), 4.48 (d, J=6.0Hz, 2H, CH2), 3.42 (m, 2H, CH2),
3.18-2.73 (m, 2H, CH2), 2.35 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 171.76,170.90,
167.09,164.07,161.84,161.25,157.76 (2C), 156.72,148.43,138.51,132.43,129.59
(2C), 128.38 (2C), 126.49,120.24,114.76,114.03,111.55,102.23,54.26,45.33,38.08,
35.93 35.29.
Embodiment 17 makes each umbelliferone -3- formyl-β-alanyl tyrosyl -2- amino methylpyrimidine (9f)
According to the operation of embodiment 12,7f (738mg, 1.98mmol) obtained in 4N HCl/EA (30ml) 8f (324mg,
1.19mmol), with HOBt (161mg, 1.19mmol), EDCHCl (228mg, 1.19mmol) and 5 (300mg, 1.08mmol)
It is condensed to yield 9f (244mg, 0.46mmol), character is faint yellow solid, and yield is=43%.Mp257.8-259.4℃；
[α]D 25=-11.2 (c=0.10, CH3OH)；IR(KBr)：3285,2982,1702,1625,1543,1516,1442,1419,
1370,1267,1216,1149,966,794,636cm-1；ESI-MS(m/e)530[M-H]-；1H-NMR (300MHz, DMSO-
d6)：δ/ppm 11.04 (s, 1H, O-H), 9.11 (s, 1H, O-H), 8.77 (m, 2H, N-H, CH), 8.74 (d, J=4.8Hz,
2H, CH, CH), 8.46 (t, J=5.7Hz, 1H, N-H), 8.16 (d, J=8.4Hz, 1H, N-H), 7.80 (d, J=8.7Hz, 1H,
Ar-H), 7.36 (t, J=4.8Hz, 1H, CH), 7.02 (d, J=8.4Hz, 2H, Ar-H), 6.87 (dd, J1=8.4Hz, J2=
2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-H), 6.59 (d, J=8.1Hz, 2H, Ar-H), 4.54 (m, 1H,
CH), 4.54 (m, 1H, CH), 4.47 (d, J=5.7Hz, 2H, CH2), 3.43 (m, 2H, CH2), 3.43 (m, 2H, CH2), 3.00-
2.94 (m, 2H, CH2), 2.35 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 171.87,170.87,
167.10,164.04,161.87,161.29,157.75 (2C), 156.73,156.13,148.46,132.43,130.51
(2C), 128.51,120.23,115.25 (2C), 114.73,114.01,111.56,102.24,54.64,45.30,37.32,
35.97 35.31.
Embodiment 18 prepares umbelliferone -3- formyl-β-alanyl aspartoyl benzyl ester -2- amino methylpyrimidine
(9g)
According to the operation of embodiment 12,7g (821mg, 1.98mmol) obtained in 4N HCl/EA (30ml) 8g (374mg,
1.19mmol), with HOBt (161mg, 1.19mmol), EDCHCl (228mg, 1.19mmol) and 5 (300mg, 1.08mmol)
It is condensed to yield 9g (241mg, 0.42mmol), character is faint yellow solid, and yield is=39%.Mp 213.7-215.5℃；
[α]D 25=-16.1 (c=0.10, CH3OH)；IR(KBr)：3287,2942,1706,1647,1616,1570,1525,1425,
1367,1326,1217,1178,1137,822,793,637cm-1；ESI-MS(m/e)530[M-H]-；ESI-MS(m/e)572
[M-H]-；1H-NMR (300MHz, DMSO-d6)：δ/ppm 11.08 (s, 1H, O-H), 8.82 (t, J=5.7Hz, 1H, N-H),
8.76 (s, 1H, CH), 8.72 (d, J=5.1Hz, 2H, CH, CH), 8.41 (d, J=8.1Hz, 1H, N-H), 8.34 (t, J=
5.7Hz, 1H, N-H), 7.79 (d, J=8.7Hz, 1H, Ar-H), 7.37-7.28 (m, 6H, Ar-H, CH), 6.87 (dd, J1=
8.7Hz, J2=2.1Hz, 1H, Ar-H), 6.77 (d, J=2.1Hz, 1H, Ar-H), 5.06 (s, 2H, CH2), 4.82 (m, 1H,
CH), 4.45 (t, J=6.0Hz, 2H, CH2), 3.60-3.50 (m, 2H, CH2), 2.91-2.59 (m, 2H, CH2), 2.44 (m, 2H,
CH2)；13C-NMR (75MHz, DMSO-d6)：δ/ppm 171.28,170.85,170.52,166.84,164.07,161.96,
161.30,157.72 (2C), 156.71,148.41,136.52,132.40,128.79 (2C), 128.35,128.23 (2C),
120.19,114.77,114.07,111.04,102.24,66.06,49.72,45.37,36.72,36.00,35.48.
The experiment of 1 anti-inflammatory effect of experimental example
1) experimental method
18-22g ICR male mice is randomly divided into blank control group, aspirin positive drug group, test-compound administration
Group, mouse use preceding tranquillization 1 day, and operation room is kept for 22 DEG C of room temperature, every group mouse 12.It is past after once daily 30 minutes
The left ear gabarit of small white mouse applies dimethylbenzene (0.03mL), and cervical dislocation is put to death after being anesthetized with ether mouse after 2 hours.It will be small
A left side for mouse, auris dextra are cut, and with the punch of diameter 7mm in the same position of two ears, are taken round auricle, are weighed respectively, find out two
The weight difference of circle auricle is as swelling.Swelling=left ear disk weight-auris dextra disk weight, inhibiting rate (%)=(blank
Group swelling-test-compound swelling)/blank group swelling.
2) medication and dosage
Administration mode is gastric infusion.Blank control：0.5% CMC, dosage 0.2mL/20g；Positive control：
Aspirin, dosage 1.11mmol/kg；The dosage of test-compound is 1umol/kg and 0.1umol/kg.
3) statistical method
This experimental data statistics is all made of t examine and variance analysis, swelling withIt indicates.
4) experimental result is included in table 1.
As can be seen from Table 1, dosage is in 1 μm of ol/kg, and test-compound removes 9a, outside 9g, remaining 6 targeted
Closing object has significant anti-inflammatory activity, there is statistical difference (p < 0.05)；For dosage in 0.1 μm of ol/kg, 9e and 9f are still
There is significant anti-inflammatory activity, there is statistical difference (p < 0.05), with the parent nucleus cumarin in document report at 10 μm of ol/kg
Anti-inflammatory activity (inhibiting rate 30.2%) quite, illustrate the effective dose of compound 9e and 9f down to 0.1 μm of ol/kg, this
Effective dose is than once 10 μm of ol/kg of effective dose of disclosed parent nucleus cumarin are 100 times low in document.
The mouse ear inflammation inhibitory activity of 1 dimethylbenzene of table induction
N=12.
A) compared with blank group (CMC), P < 0.05；
B) compared with blank group (CMC), P > 0.05.
Claims (5)
1. the compound of general formula (I)：
It is characterized in that it is selected from following compound,
9a:Umbelliferone -3- formyl-β-alanyl alanyl -2- amino methylpyrimidine,
9b:Umbelliferone -3- formyl-β-alanyl leucyl -2- amino methylpyrimidine,
9c:Umbelliferone -3- formyl-β-alanyl valyl -2- amino methylpyrimidine,
9d:Umbelliferone -3- formyl-β-alanyl methinyl -2- amino methylpyrimidine,
9e:Umbelliferone -3- formyl-β-alanyl phenylalanyl -2- amino methylpyrimidine,
9f:Umbelliferone -3- formyl-β-alanyl tyrosyl -2- amino methylpyrimidine,
9g:Umbelliferone -3- formyl-β-alanyl aspartoyl benzyl ester -2- amino methylpyrimidine,
2. the preparation method of the compound of general formula (I) according to claim 1, this approach includes the following steps：
2,4- 4-dihydroxy benzaldehyde is condensed under piperidines catalysis with diethyl malonate and generates umbelliferone -3- carboxylic acid second
Ester,
Obtained umbelliferone -3- the carboxylic acid, ethyl ester generates umbelliferone -3- carboxylic acid under concentrated hydrochloric acid effect,
Obtained umbelliferone -3- the carboxylic acid and β-the third amino acid-OBzl is coupled to obtain umbelliferone -3- first
Acyl-Beta-alanine benzyl ester,
It is fragrant that obtained umbelliferone -3- formyl-Beta-alanine benzyl ester hydrogenolysis under the catalysis of palladium carbon generates 7- hydroxyl
Legumin -3- formyl-Beta-alanine,
It is coupled tertiary fourth oxygen amic acid and 2- amino methylpyrimidine to obtain tertiary fourth oxygen acyl aminoacyl -2- amino methylpyrimidine,
The obtained tertiary fourth oxygen acyl aminoacyl -2- amino methylpyrimidine generates N- aminoacyl -2- ammonia in 4N HCl/EtOAc solution
Ylmethyl pyrimidine,
It is coupled N- aminoacyl -2- amino methylpyrimidine and umbelliferone -3- formyl-Beta-alanine to obtain 7- hydroxyl tonka-bean
Element -3- formyl-β-alanylamino acyl -2- amino methylpyrimidine.
3. compound according to claim 1 is synthesizing the application in pseudo- peptide.
4. application of the compound according to claim 1 in preparation treatment anti-inflammatory drug.
5. a kind of Pharmaceutical composition, it is characterised in that it includes the compound according to claim 1 for the treatment of effective dose
And pharmaceutically acceptable carrier.
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