CN107459560A - N α-imidazopyridine -6- formyl-N ω-AA-Lys- Glucosamines, it is synthesized, activity and application - Google Patents

N α-imidazopyridine -6- formyl-N ω-AA-Lys- Glucosamines, it is synthesized, activity and application Download PDF

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CN107459560A
CN107459560A CN201610391394.7A CN201610391394A CN107459560A CN 107459560 A CN107459560 A CN 107459560A CN 201610391394 A CN201610391394 A CN 201610391394A CN 107459560 A CN107459560 A CN 107459560A
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pyridine
imidazos
lys
formyls
boc
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CN107459560B (en
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赵明
彭师奇
王玉记
吴建辉
刘文超
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Capital Medical University
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    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
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Abstract

The invention discloses 16 kinds of (N of following formulaαThe formyl N of 3H imidazos [4,5 c] pyridine 6ωAA) Lys Glucosamines, disclose their preparation method, disclose their inhibitory action to tumour growth, disclose their anti-inflammatory activity.As a result show, they have antitumor and anti-inflammatory activity, have good potential applicability in clinical practice.

Description

N α-imidazopyridine -6- formyl-N ω-AA-Lys- Glucosamines, it is synthesized, activity and application
Technical field
The present invention relates to (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines, it is related to its preparation, It is related to its inhibitory action to tumour growth, further to its anti-inflammatory activity.As a result show, (Nα- 3H- imidazos [4,5-c] Pyridine -6- formyls-Nω- AA)-Lys- Glucosamines are that have antitumor and anti-inflammatory double activity compound.The invention belongs to life Thing field of medicaments.
Background technology
Cancer is the common name of one group of a variety of disease that can influence any position of body.The other terms used are malignant tumour and superfluous life Thing.Counted according to the World Health Organization, cancer is one of No.1 cause of the death in the world, especially in developing country.And the whole world Number of cancer deaths is estimated will to continue to rise, will be more than 13,100,000 to the year two thousand thirty.Therefore, new efficient, low toxicity, poison are developed The antineoplastic of Small side effects is always one of important topic of new drug research.
With the understanding to tumor characteristic and morbidity essence, inventor once disclosed lower 3H- imidazos [4,5-c] pyridine -6- formyls - AA-OBzl (wherein AA represents l-amino acid residue) shows antitumor activity under 1 μm of ol/kg dosage；Inventor once disclosed 3H- imidazos [4,5-c] pyridine -6- formyls-Met-AA-OBzl (wherein AA represents l-amino acid residue) of following formula is 0.02 Antitumor activity and anti-inflammatory activity are shown under μm ol/kg dosage.By further studying it was recognized by the inventor that using Glucosamine Modification imidazopyridine can not only improve antitumor activity, and can improve anti-inflammatory activity.Effective dose is 2nmol/kg.This It is unexpected technique effect.According to these understanding, the present invention is inventors herein proposed.
The content of the invention
First content of the present invention is to provide (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines,
AA is selected from L-Ala, L-Val, Gly, L-Phe, L-Trp, L-Ile, L-Leu, L-Pro, L-Met, L-Asn, L-Ser in formula, L-Thr,L-Glu,L-Arg(NO2), L-Asp (OBzl) and L-Tyr residues.
Second content of the present invention is to provide preparation (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- amino Portugal The synthetic method of grape sugar, this method include：
(1) L-Histidine carries out Pictet-Spengler condensation generation 6S-4,5,6,7- tetrahydrochysene -3H- miaows under dilute sulfuric acid catalysis with formaldehyde Azoles simultaneously [4,5-c] pyridine -6- carboxylic acids；
(2) 6S-4,5,6,7- tetrahydrochysenes -3H- imidazos [4,5-c] pyridine -6- carboxylic acids are converted into 6S-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] Pyridine -6- methyl formates；
(3) 6S-4,5,6,7- tetrahydrochysenes -3H- imidazos [4,5-c] pyridine -6- methyl formates are 3H- imidazos [4,5-c] with potassium permanganate oxidation Pyridine -6- methyl formates；
(4) 3H- imidazos [4,5-c] pyridine -6- methyl formates are saponified into 3H- imidazos [4,5-c] pyridine in NaOH solution (2N) - 6- formic acid；
(5) 3H- imidazos [4,5-c] pyridine -6- formic acid is coupled to obtain N with Lys (Boc)-OBzlα- 3H- imidazos [4,5-c] pyridine -6- Formyl-Lys (Boc)-OBzl；
(6) 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl are saponified into N in NaOH solution (2N)α- 3H- imidazoles And [4,5-c] pyridine -6- formyls-Lys (Boc)；
(7) 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) is coupled to obtain N with Glucosamineα- 3H- imidazos [4,5-c] pyrrole Pyridine -6- formyls-Lys (Boc)-Glucosamine；
(8)Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-Glucosamine obtains in 4N hydrogen chloride/ethyl acetate Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines；
(9)Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines and Boc-AA (AA is selected from L-Ala, L-Val in formula, Gly,L-Phe,L-Trp,L-Ile,L-Leu,L-Pro,L-Met,L-Asn,L-Ser,L-Thr,L-Glu,L-Arg(NO2), L-Asp (OBzl) and L-Tyr residues) coupling obtain (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA-Boc)-Lys- amino Glucose；
(10)(Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA-Boc)-Lys- Glucosamines are in 4N hydrogen chloride/acetic acid (N is obtained in ethyl esterα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines.
The 3rd content of the present invention is evaluation (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines To the inhibitory action of S180 mice tumors grews.
The 4th content of the present invention is evaluation (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines To the anti-inflammatory activity on ICR male mice ear swelling models.
Brief description of the drawings
Fig. 1 (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines synthetic route .i) HCHO, H2O,H2SO4,65℃；ii)MeOH,SOCl2,0℃；Iii) N,N-dimethylformamide (DMF), triethylamine, KMnO4；iv) NaOH,H2O,0℃；V) BTA-N, N, N', N'- tetramethylurea hexafluorophosphate (HBTU), N-methylmorpholine (NMM), N,N-dimethylformamide (DMF)；vi)NaOH,H2O,0℃；Vii) dicyclohexylcarbodiimide (DCC), 1- hydroxyl BTA (HOBt), N-methylmorpholine (NMM), N,N-dimethylformamide (DMF)；Viii) 4N hydrogen chloride/ethyl acetate, 0℃；Ix) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), N, N- dimethyl Formamide (DMF)；X) 4N hydrogen chloride/ethyl acetate, 0 DEG C.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments are entirely illustrative, and they are only For the present invention is specifically described, limitation of the present invention is not construed as.
Embodiment 1 prepares 6S-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids (1)
10.00g (64.5mmol) L-Histidine, 30mL water are mixed in 100mL eggplant bottles, added dropwise with constant pressure funnel under ice bath Enter the 2mL concentrated sulfuric acids, with the addition of the concentrated sulfuric acid, raw material is gradually dissolved, and after it is completely dissolved, 10mL is added into reaction solution 40% formalin, accelerate to react 5 hours at 65 DEG C of instrument of reaction in microwave.After completion of the reaction, dense ammonia is slowly added dropwise under ice bath Water adjusts pH value of solution 7, has a large amount of colourless precipitates to separate out, is filtered under diminished pressure, obtains 10.76g (99.2%) title compound, is colourless Solid.ESI-MS(m/z):168[M+H]+。
Embodiment 2 prepares 6S-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- methyl formates (2)
Add 15.6mL methanol under ice bath in 100mL eggplant bottles, 1.56mL thionyl chlorides, 30min is slowly added dropwise with constant pressure funnel Addition 1.00g (6mmol) 6S-4 afterwards, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids, after reacting at room temperature 3 days, TLC (methylene chloride/methanol=5:1) after monitoring reaction completely, reactant mixture is concentrated under reduced pressure into dry, and residue adds 10mL methanol Dissolve and be concentrated under reduced pressure, the operation is repeated 3 times to obtain white blister solid, adds 10mL ether and drains and is repeated 3 times without toner End, 0.58g (53%) title compound is finally recrystallized to obtain with methanol/ether, is colorless solid.ESI-MS(m/z):182[M +H]+。
Embodiment 3 prepares 3H- imidazos [4,5-c] pyridine -6- methyl formates (3)
Add 1.1g (6.1mmol) 6S-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- first under ice bath in 100mL eggplant bottles Sour methyl esters, DMF (DMF) is added to make dissolving.Triethylamine is added dropwise into the solution and adjusts pH value to 8, Divide 3 addition 1.2g (7.6mmol) potassium permanganate.After reacting 6h, TLC (dichloros/methane=3:1) monitoring reaction finishes. Reactant be concentrated under reduced pressure into it is dry, obtained black solid with 1N HCl solutions dissolve after be filtered to remove insoluble matter, 2N is added dropwise under ice bath NaOH solution adjusts pH value to separate out a large amount of colorless solids to 7.The solid is purified using methylene chloride/methanol as eluant, eluent with silicagel column (dichloro/methane=5:1) 0.68g (63%) title compound, is obtained, is colorless solid.ESI-MS(m/z):178[M+H]+。
Embodiment 4 prepares 3H- imidazos [4,5-c] pyridine -6- carboxylic acids (4)
Add 40mL 2N NaOH solutions under ice bath in 100mL eggplant bottles, 5.30g (29.9mmol) 3H- miaows are added after 10min Azoles simultaneously [4,5-c] pyridine -6- methyl formates, TLC shows that reaction finishes after reacting 3h, drips 2N HCl solutions under ice bath into reaction solution PH value is adjusted to 7, separates out a large amount of colorless solids.The solid purifies (dichloro using methylene chloride/methanol as eluant, eluent with silicagel column Methane/methanol=3:1) 1.50g (30%) title compound, is obtained, is colorless solid.ESI-MS(m/z):162[M-H]-；1H-NMR(300MHz,CD3OD)：δ/ppm=8.918 (s, 1H), 8.435 (s, 1H), 8.375 (s, 1H).
Embodiment 5 prepares Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl (5)
163mg (1mmol) 3H- imidazos [4,5-c] pyridine -6- formic acid is weighed in 100mL eggplant bottles, adds 15mL DMF. 397mg (1mmol) HBTU is added under ice bath and stirring, activates 30min.Weigh 450.5mg (1.2mmol) HClLys (Boc)-OBzl are in the small triangular flasks of 50mL, and after being dissolved with DMF, the solution then is added dropwise into the anti-of eggplant-shape bottle Answer in liquid, finally adjust reacting liquid pH value to 8 with NMM.It is stirred overnight at room temperature, TLC is shown after completion of the reaction, will be anti- Mixture is answered to be concentrated under reduced pressure into dry, residue adds 60mL ethyl acetate to dissolve, and is filtered to remove insoluble matter, filtrate layers are successively with full And NaHCO3Solution (20mL × 3) and saturation NaCl solution (20mL × 3) washing, organic layer anhydrous Na2SO4 Dry, filtering, filtrate decompression is concentrated to dryness, and obtained yellow oil purifies (methylene chloride/methanol=40 through silica gel column chromatography: 1) 145mg (30%) title compound, is obtained, is colorless solid.ESI-MS(m/z):482[M+H]+；1H-NMR(300 MHz,CD3OD):δ/ppm=9.002 (s, 1H), 8.496 (s, 1H), 8.368 (s, 1H), 7.357 (m, 5H), 5.219 (m, 2 ), H 4.745 (m, 1H), 3.021 (t, J=6.3Hz, 2H), 2.016 (m, 2H), 1.520 (m, 4H), 1.480 (s, 9H).
Embodiment 6 prepares Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) (6)
Weigh 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl 394mg and add 20mL first in 100mL eggplant bottles Alcohol, pH value is adjusted to 12 with 2N NaOH solutions under condition of ice bath, TLC (methylene chloride/methanol=10 after reaction 3 hours: 1) display reaction finishes, and saturation KHSO is added dropwise under ice bath into reaction solution4Solution adjusts pH value to 7, there is white precipitate analysis Go out, precipitation is filtered under diminished pressure, removal of solvent under reduced pressure produces title compound 280mg (90%).ESI-MS(m/z):392[M +H]+。
Embodiment 7 prepares Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-Glucosamine (7)
788mg (2mmol) 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OH are weighed in 100mL eggplant bottles, Add 50mL DMF.270mg (2mmol) HOBt and 494mg (2.4mmol) DCC is sequentially added under ice bath, Activate 30min.860mg (4mmol) HClGlucosamine (Glucosamine) is weighed in the small triangles of 100mL In bottle, after being dissolved with DMF, solution ph is adjusted to 7 with NMM under ice bath, the solution is then added dropwise to eggplant-shape bottle Reaction solution in, finally adjust reacting liquid pH value to 8 with NMM.Room temperature reaction is stayed overnight, TLC (methylene chloride/methanol= 3:1) display after completion of the reaction, reactant mixture be concentrated under reduced pressure into it is dry, residue add 60mL ethanol dissolve, be filtered to remove two Cyclohexyl urea (DCU), is concentrated under reduced pressure into dry, and obtained yellow oil is through C18Column chromatography purifies (methanol/water=60:1), Freeze-drying obtains 221mg (20.07%) title compound, is colorless solid.ESI-MS(m/z):553[M+H]+；1H-NMR(300MHz,CD3OD):δ/ppm=9.000 (s, 1H), 8.496 (s, 1H), 8.373 (s, 1H), 5.150 (d, J= 3.3Hz, 0.7H), 4.745 (d, J=3.3Hz, 0.3H), 4.725 (m, 1H), 3.886-3.634 (m, 4H), 3.336-3.315 (m, 2H),3.040(m,2H),2.087-1.804(m,2H),1.523(m,4H),1.480(s,9H)。
Embodiment 8 prepares Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines (8)
By 3g Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-Glucosamine is placed in 100mL eggplant bottles, Yu Bing Stirred under bath and add 30mL 4N hydrogen chloride/ethyl acetate, stirred 3.5h under ice bath, there is colorless solid precipitation.TLC (two Chloromethanes/methanol=3:1) after completion of the reaction, reaction solution is concentrated under reduced pressure under 37 DEG C of tepidarium for display.By residue nothing Water ether (10mL × 3) is concentrated under reduced pressure, and obtains 1.997g (80%) title compound, is colorless solid.ESI-MS(m/z): 453[M+H]+。
Embodiment 9 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ala-Boc)-Lys- Glucosamines (9a)
Weigh 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines are in 100mL eggplant bottles In, add 50mL DMF.270mg (2mmol) HOBt and 494mg (2.4mmol) are sequentially added under ice bath DCC, activate 30min.860mg (2.4mmol) Boc-Ala are weighed in the small triangular flasks of 100mL, it is molten with DMF Xie Hou, solution ph is adjusted to 7 with NMM under ice bath, then the solution is added dropwise in the reaction solution of eggplant-shape bottle, most Reacting liquid pH value is adjusted to 8 with NMM afterwards.Room temperature reaction is stayed overnight, TLC (methylene chloride/methanol=3:1) display reaction After, reactant mixture be concentrated under reduced pressure into it is dry, residue add 60mL methanol dissolve, be filtered to remove dicyclohexylurea (DCU) (DCU), It is concentrated under reduced pressure into dry, obtained yellow oil is through C18Column chromatography purifies (methanol/water=60:1), freeze-drying obtains 221 Mg (20.07%) title compound, it is colorless solid.ESI-MS(m/z):624[M+H]+。
Embodiment 10 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Val-Boc)-Lys- Glucosamines (9b)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 124mg (9.6%) title compound is obtained in glucose and 520mg (2.4mmol) Boc-Val, is colorless solid.ESI-MS (m/z):652[M+H]+。
Embodiment 11 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gly-Boc)-Lys- Glucosamines (9c)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 124mg (10%) title compound is obtained in glucose and 420mg (2.4mmol) Boc-Gly, is colorless solid.ESI-MS (m/z):610[M+H]+。
Embodiment 12 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Phe-Boc)-Lys- Glucosamines (9d)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 86mg (6.1%) title compound is obtained in glucose and 420mg (2.4mmol) Boc-Gly, is colorless solid.ESI-MS (m/z):700[M+H]+。
Embodiment 13 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Trp-Boc)-Lys- Glucosamines (9e)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 108mg (7.3%) title compound is obtained in glucose and 730mg (2.4mmol) Boc-Trp, is colorless solid.ESI-MS (m/z):739[M+H]+。
Embodiment 14 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ile-Boc)-Lys- Glucosamines (9f)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 108mg (8.1%) title compound is obtained in glucose and 554mg (2.4mmol) Boc-Ile, is colorless solid.ESI-MS (m/z):666[M+H]+。
Embodiment 15 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Leu-Boc)-Lys- Glucosamines (9g)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 98mg (7.36%) title compound is obtained in glucose and 554mg (2.4mmol) Boc-Leu, is colorless solid. ESI-MS(m/z):666[M+H]+。
Embodiment 16 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Pro-Boc)-Lys- Glucosamines (9h)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 66mg (5.08%) title compound is obtained in glucose and 516mg (2.4mmol) Boc-Pro, is colorless solid.ESI-MS (m/z):650[M+H]+。
Embodiment 17 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Met-Boc)-Lys- Glucosamines (9i)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 100mg (7.3%) title compound is obtained in glucose and 598mg (2.4mmol) Boc-Pro, is colorless solid.ESI-MS (m/z):684[M+H]+。
Embodiment 18 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Asn-Boc)-Lys- Glucosamines (9j)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 90mg (6.8%) title compound is obtained in glucose and 557mg (2.4mmol) Boc-Asn, is colorless solid.ESI-MS (m/z):657[M+H]+。
Embodiment 19 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ser-Boc)-Lys- Glucosamines (9k)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 78mg (6.1%) title compound is obtained in glucose and 492mg (2.4mmol) Boc-Ser, is colorless solid.ESI-MS (m/z):640[M+H]+。
Embodiment 20 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Thr-Boc)-Lys- Glucosamines (9l)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 60mg (5.0%) title compound is obtained in glucose and 526mg (2.4mmol) Boc-Thr, is colorless solid.ESI-MS (m/z):654[M+H]+。
Embodiment 21 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gln-Boc)-Lys- Glucosamines (9m)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 50mg (3.7%) title compound is obtained in glucose and 590mg (2.4mmol) Boc-Thr, is colorless solid.ESI-MS (m/z):681[M+H]+。
Embodiment 22 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω-Arg(NO2)-Boc)-Lys- Glucosamines (9n)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino Glucose and 766mg (2.4mmol) Boc-Arg (NO2) in obtain 50mg (3.3%) title compound, be colorless solid. ESI-MS(m/z):756[M+H]+。
Embodiment 23 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Asp (OBzl)-Boc)-Lys- Glucosamines (9o)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 68mg (4.47%) title compound is obtained in glucose and 775mg (2.4mmol) Boc-Asp (OBzl), is colourless solid Body.ESI-MS(m/z):760[M+H]+。
Embodiment 24 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Tyr-Boc)-Lys- Glucosamines (9p)
According to the method for embodiment 9, from 904mg (2mmol) Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- amino 120mg (8.4%) title compound is obtained in glucose and 674mg (2.4mmol) Boc-Tyr, is colorless solid.ESI-MS (m/z):716[M+H]+。
Embodiment 25 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ala)-Lys- Glucosamines (10a)
By 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ala-Boc)-Lys- Glucosamines are placed in 100mL eggplants In bottle, stirred under ice bath and add 20mL 4N hydrogen chloride/ethyl acetate, stirred 3.5h under ice bath, there is colorless solid analysis Go out.TLC (methylene chloride/methanol=3:1) after completion of the reaction, reaction solution is concentrated under reduced pressure under 37 DEG C of tepidarium for display. Residue is concentrated under reduced pressure with absolute ether (10mL × 3), obtains 40mg (80%) title compound, is colorless solid. ESI-MS(m/z):524[M+H]+；Mp:184~186 DEG C；[α]D 25=+50.5 (c=0.1, methanol)；IR(KBr,cm-1): 3260,2930,1642,1523,1460,1375,1299,1252,1032；1H-NMR(300MHz,CD3OD):δ/ppm= 8.990 (s, 1H), 8.486 (s, 1H), 8.378 (s, 1H), 5.150 (d, J=3.6Hz, 0.7H), 4.788 (d, J=3.6Hz, 0.3 H),4.718(m,1H),3.888-3.778(m,3H),3.761-3.611(m,2H),3.340-3.485(m,2H),3.240(m,2 ), H 2.034-1.863 (m, 2H), 1.560 (m, 4H), 1.310 (d, J=6.9Hz, 3H).
Embodiment 26 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Val)-Lys- Glucosamines (10b)
According to the method for embodiment 25, from 80mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Val-Boc)-Lys- ammonia Base glucose obtains title compound 50mg (75%), is colorless solid.ESI-MS(m/z):553[M+H]+；Mp: 163~165 DEG C；[α]D 25=+58.2 (c=0.1, methanol)；IR(KBr,cm-1):3231,2930,2858,1692,1646,1574, 1519,1453,1373,1299,1032,1H-NMR(300MHz,CD3OD):δ/ppm=8.992 (s, 1H), 8.511 (s, 1 ), H 8.380 (s, 1H), 5.151 (d, J=3.3Hz, 0.67H), 4.718 (d, J=3.3Hz, 0.33H), 4.718 (m, 1H), 3.976-3.634(m,4H),3.336-3.315(m,3H),3.240(m,2H),2.087-1.804(m,5H),1.523(m,2H), 1.420(m,3H),1.23(m,3H)。
Embodiment 27 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gly)-Lys- Glucosamines (10c)
According to the method for embodiment 25, from 75mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gly-Boc)-Lys- ammonia Base glucose obtains title compound 50mg (79%), is colorless solid.ESI-MS(m/z):524[M+H]+；Mp； 184~186 DEG C；[α]D 25=+50.3 (c=0.1, methanol)；IR(KBr,cm-1):3260,2930,1642,1523,1460,1375, 1299,1252,1032；1H-NMR(300MHz,CD3OD):δ/ppm=9.015 (s, 1H), 8.561 (s, 1H), 8.387 (s, 1 ), H 5.151 (d, J=3.3Hz, 0.5H), 4.720 (d, J=3.3Hz, 0.5H), 4.718 (m, 1H), 4.418 (m, 1H), 3.976-3.634(m,5H),3.336-3.315(m,2H),3.240(m,2H),1.823(m,2H),1.554(m,4H)。
Embodiment 28 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Phe)-Lys- Glucosamines (10d)
According to the method for embodiment 25, from 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Phe-Boc)-Lys- ammonia Base glucose obtains title compound 40mg (78%), is colorless solid.ESI-MS(m/z):600[M+H]+；Mp: 150~152 DEG C；[α]D 25=+42.6 (c=0.1, methanol)；IR(KBr,cm-1):3257,2926,1649,1521,1455,1032；1H-NMR(300MHz,CD3OD):δ/ppm=0.949 (s, 1H), 8.479 (s, 1H), 8.351 (s, 1H), 7.338-7.195 (m, 5H), 5.153 (d, J=3.3Hz, 0.7H), 4.725 (d, J=3.3Hz, 0.3H), 4.715 (m, 1H), 4.005-3.634 (m,4H),3.336-3.315(m,3H),3.140(m,2H),3.040(m,2H),2.087-1.804(m,2H),1.523(m,4 H)。
The preparation of embodiment 29 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Trp)-Lys- Glucosamines (10e)
According to the method for embodiment 25, from 50mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Trp-Boc)-Lys- ammonia Base glucose obtains title compound 30mg (70%), is colorless solid.ESI-MS(m/z):639[M+H]+；Mp: 183~185 DEG C；[α]D 25=+60.5 (c=0.1, methanol)；IR(KBr,cm-1):3258,2925,16469,1523,1458,1299, 1249,744,632；1H-NMR(300MHz,CD3OD):δ/ppm=8.912 (s, 1H), 8.519 (s, 1H), 8.364 (s, 1 ), H 7.575 (d, J=7.5Hz, 1H), 7.358 (d, J=8.1Hz, 1H), 7.135 (s, 1H), 7.056 (d, J=7.2Hz, 1 ), H 5.141 (d, J=3.3Hz, 0.5H), 4.835 (d, J=3.3Hz, 0.5H), 4.680 (m, 1H), 4.036 (m, 1H), 3.956-3.834(m,2H),3.815(m,2H),3.785-3.671(m,2H),3.584-3.471(m,2H),3.240(m,2H), 3.150(m,2H),1.959(m,1H),1.822(m,1H),1.427(m,4H)。
Embodiment 30 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ile)-Lys- Glucosamines (10f)
According to the method for embodiment 25, from 80mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ile-Boc)-Lys- amino Glucose obtains title compound 50mg (75%), is colorless solid.ESI-MS(m/z):566[M+H]+；Mp: 166~168 DEG C；[α]D 25=+46.8 (c=0.1, methanol)；IR(KBr,cm-1):3256,3078,2931,1649,1520,1461, 1382,1249,1033；1H-NMR(300MHz,CD3OD):δ/ppm=8.997 (s, 1H), 8.521 (s, 1H), 8.377 (s, 1H), 5.158 (d, J=3.3Hz, 0.5H), 4.788 (d, J=3.3Hz, 0.5H), 4.745 (m, 1H), 3.966-3.604 (m, 6 H),3.415(m,1H),3.240(m,2H),2.066-1.876(m,3H),1.617-1.458(m,5H),1.194(m,1H) 0.979-0.892(m,6H)。
Embodiment 31 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Leu)-Lys- Glucosamines (10g)
According to the method for embodiment 25, from 80mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Leu-Boc)-Lys- ammonia Base glucose obtains title compound 50mg (75%), is colorless solid.ESI-MS(m/z):566[M+H]+；Mp: 165~167 DEG C；[α]D 25=+50.3 (c=0.1, methanol)；IR(KBr,cm-1):3253,2938,1649,1520,1463,1032；1H-NMR(300MHz,CD3OD):δ/ppm=8.793 (s, 1H), 8.327 (s, 1H), 8.111 (s, 1H), 5.098 (d, J= 3.3Hz, 0.55H), 4.652 (d, J=3.3Hz, 0.45H), 4.489 (m, 1H), 3.813-3.534 (m, 5H), 3.336-3.315 (m,2H),3.040(m,2H),1.815(m,3H),1.450-1.348(m,6H),0.602(m,6H)。
Embodiment 32 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Pro)-Lys- Glucosamines (10h)
According to the method for embodiment 25, from 75mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Pro-Boc)-Lys- ammonia Base glucose obtains title compound 48mg (78%), is colorless solid.ESI-MS(m/z):550[M+H]+；Mp: 186~188 DEG C；[α]D 25=+14.2 (c=0.1, methanol)；IR(KBr,cm-1):3253,3076,2936,1650,1521,1460, 1377,1252,1033；1H-NMR(300MHz,CD3OD):δ/ppm=8.992 (s, 1H), 8.513 (s, 1H), 8.369 (s, 1H), 5.157 (d, J=3.3Hz, 0.5H), 4.750 (d, J=3.3Hz, 0.5H), 4.745 (m, 1H), 4.378 (m, 1H), 3.986-3.634(m,5H),3.336-3.315(m,3H),3.283(m,2H),2.407(m,1H),2.066-1.884(m,5H), 1.611(m,2H),1.515(m,2H)。
Embodiment 33 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Met)-Lys- Glucosamines (10i)
According to the method for embodiment 25, from 66mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Met-Boc)-Lys- ammonia Base glucose obtains title compound 45mg (80%), is colorless solid.ESI-MS(m/z):584[M+H]+；Mp: 160~162 DEG C；[α]D 25=+58.1 (c=0.1, methanol)；IR(KBr,cm-1):3257,3076,2924,1650,1520,1463, 1251,1034；1H-NMR(300MHz,CD3OD):δ/ppm=8.998 (s, 1H), 8.520 (s, 1H), 8.381 (s, 1H), 5.157 (d, J=3.3Hz, 0.6H), 4.720 (d, J=3.3Hz, 0.4H), 4.718 (m, 1H), 3.986-3.734 (m, 4H), 3.336-3.315 (m, 3H), 3.340 (m, 2H), 2.541 (t, J=4.5Hz, 2H), 2.114-2.077 (m, 2H), 2.081 (s, 3 H),2.077-1.808(m,2H),1.621(m,2H),1.539(m,2H)。
Embodiment 34 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Asn)-Lys- Glucosamines (10j)
According to the method for embodiment 25, from 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Asn-Boc)-Lys- ammonia Base glucose obtains title compound 39mg (76%), is colorless solid.ESI-MS(m/z):557[M+H]+；Mp: 170~172 DEG C；[α]D 25=+54.6 (c=0.1, methanol)；IR(KBr,cm-1):3260,2925,1650,1523,1463,1375, 1299,1252,1032；1H-NMR(300MHz,CD3OD):δ/ppm=8.765 (s, 1H), 8.308 (s, 1H), 8.101 (s, 1H), 5.124 (d, J=3.3Hz, 0.4H), 4.655 (d, J=3.3Hz, 0.6H), 4.465 (m, 1H), 4.101 (m, 1H), 3.886-3.534(m,4H),3.222(m,2H),3.211(m,1H),3.081(m,1H),2.702(m,2H),1.847(m,2 H),1.465(m,2H),1.365(m,2H)。
Embodiment 35 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ser)-Lys- Glucosamines (10k)
According to the method for embodiment 25, from 50mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Ser-Boc)-Lys- ammonia Base glucose obtains title compound 30mg (70%), is colorless solid.ESI-MS(m/z):540[M+H]+；Mp: 193~195 DEG C；[α]D 25=+30.7 (c=0.1, methanol)；IR(KBr,cm-1):3282,2925,1649,1537,1467,1336, 1250,1032；1H-NMR(300MHz,CD3OD):δ/ppm=9.000 (s, 1H), 8.509 (s, 1H), 8.377 (s, 1H), 5.159 (d, J=3.3Hz, 0.7H), 4.755 (d, J=3.3Hz, 0.7H), 4.745 (m, 1H), 3.941-3.894 (m, 3H), 3.839-3.729(m,4H),3.336-3.315(m,2H),3.240(m,2H),2.087-1.804(m,2H),1.523(m,2H), 1.193(m,2H)。
Embodiment 36 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Thr)-Lys- Glucosamines (10l)
According to the method for embodiment 25, from 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Thr-Boc)-Lys- ammonia Base glucose obtains title compound 40mg (80%), is colorless solid.ESI-MS(m/z):554[M+H]+；Mp: 166~168 DEG C；[α]D 25=+64.5 (c=0.1, methanol)；IR(KBr,cm-1):3252,2931,1649,1520,1462,1032；1H-NMR(300MHz,CD3OD):δ/ppm=8.759 (s, 1H), 8.294 (s, 1H), 8.086 (s, 1H), 5.110 (d, J= 3.3Hz, 0.5H), 4.650 (d, J=3.3Hz, 0.5H), 4.445 (m, 1H), 3.886-3.634 (m, 6H), 3.336-3.215 (m, 2H),3.140(m,2H),1.887-1.704(m,2H),1.503(m,2H),1.363(m,2H),1.006(m,3H)。
Embodiment 37 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gln)-Lys- Glucosamines (10m)
According to the method for embodiment 25, from 56mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Gln-Boc)-Lys- ammonia Base glucose obtains title compound 38mg (80%), is colorless solid.ESI-MS(m/z):581[M+H]+；Mp: 158~160 DEG C；[α]D 25=+12.4 (c=0.1, methanol)；IR(KBr,cm-1):3258,2938,1656,1520,1461,1254, 1050；1H-NMR(300MHz,CD3OD):δ/ppm=9.033 (s, 1H), 8.626 (s, 1H), 8.426 (s, 1H), 5.154 (d, J=3.3Hz, 0.5H), 4.715 (d, J=3.3Hz, 0.5H), 4.700 (m, 1H), 3.929-3.752 (m, 5H), 3.536-3.385(m,2H),3.269(m,2H),2.431(m,2H),2.129-1.834(m,4H),1.623(m,2H),1.527 (m,2H)。
Embodiment 38 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω-Arg(NO2))-Lys- Glucosamines (10n)
According to the method for embodiment 25, from 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls -Nω-Arg(NO2)-Boc)-Lys- Glucosamines obtain title compound 42mg (82%), it is colorless solid.ESI-MS(m/z): 656[M+H]+；Mp:182~184 DEG C；[α]D 25=+40.8 (c=0.1, methanol)；IR(KBr,cm-1):3231,2931,1638, 1575,1521,1455,1380,1261,1033；1H-NMR(300MHz,CD3OD):δ/ppm=8.807 (s, 1H), 8.309 (s, 1H), 8.095 (s, 1H), 5.131 (d, J=3.3Hz, 0.6H), 4.500 (d, J=3.3Hz, 0.4H), 4.488 (m, 1H), 3.886-3.634(m,5H),3.336-3.315(m,3H),3.040(m,1H),2.835(m,2H),1.804(m,2H),1.825 (m,2H),1.480-1.373(m,6H)。
Embodiment 39 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Asp (OBzl))-Lys- Glucosamines (10o)
According to the method for embodiment 25, from 80mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls -Nω- Asp (OBzl)-Boc)-Lys- Glucosamines obtain title compound 55mg (80%), and it is colorless solid.ESI-MS (m/z):660[M+H]+；Mp:173~175 DEG C；[α]D 25=+40.9 (c=0.1, methanol)；IR(KBr,cm-1):3306,2926, 1649,1574,1522,1457,1381,1299,1255；1H-NMR(300MHz,CD3OD):δ/ppm=8.993 (s, 1H), 8.496 (s, 1H), 8.374 (s, 1H), 7.340 (m, 5H), 5.150 (d, J=3.3Hz, 0.7H), 5.116 (s, 2H), 4.712 (d, J=3.3Hz, 0.3H), 4.711 (m, 1H), 3.926-3.634 (m, 5H), 3.436-3.375 (m, 2H), 3.198 (m, 2H), 2.792 (dd, J=7.2Hz, J=12.0Hz, 1H), 2.692 (dd, J=7.2Hz, J=12.0Hz, 1H), 1.923 (m, 2H), 1.545(m,4H)。
Embodiment 40 prepares (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Tyr)-Lys- Glucosamines (10p)
According to the method for embodiment 25, from 60mg (Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- Tyr-Boc)-Lys- ammonia Base glucose obtains title compound 39mg (75%), is colorless solid.ESI-MS(m/z):616[M+H]+；Mp: 184~186 DEG C；[α]D 25=+50.4 (c=0.1, methanol)；IR(KBr,cm-1):3260,2930,1642,1523,1460,1375, 1299,1252,1032；1H-NMR(300MHz,CD3OD)：δ/ppm=8.937 (s, 1H), 8.481 (s, 1H), 8.335 (s, 1 ), H 7.020 (d, J=5.4Hz, 2H), 6.755 (d, J=5.4Hz, 2H), 5.158 (d, J=3.6Hz, 0.45H), 4.723 (d, J=3.6Hz, 0.55H), 4.713 (m, 1H), 3.966-3.634 (m, 5H), 3.436-3.375 (m, 2H), 3.198 (m, 2H), 2.891 (dd, J=4.5Hz, J=9.0Hz, 1H), 2.960 (dd, J=4.5Hz, J=9.0Hz, 1H), 1.948 (m, 2H), 1.497(m,4H)。
Experimental example 1 determines the CDCC of compound
1) compound of the invention is configured to required concentration with the culture medium containing 0.1%DMSO.
2) tumour cell of experiment is MCF-7 (human breast cancer cell), K562 (human leukemia chronic granulocyte), A549 (human lung cancers Cell line), HaCa-T (people's epidermis immortalized cells).
3) experimental method
MCF-7, HL-60, K562 and S180 cell select RPMI-1640 culture mediums；Contain 10% tire through inactivation in culture medium Cow's serum and 1 × 105U/L penicillin and 100mg/L streptomysins.
The culture of the attached cell of attached cell MCF-7, A549, HaCa-T half:It is respectively that growth conditions are good, given birth in logarithm Long-term cell is with 3 × 104Individual/mL density is inoculated in 96 orifice plates, per the μ L of hole 100, is placed in 37 DEG C and 5%CO2Cell incubate Educate and cultivated in case 4 hours, then add the compound 10a-p of sterilized processing and containing 0.1%DMSO's by default concentration gradient The solution that culture medium is configured to, per the μ L of hole 25, control group adds the solvent of isometric sample dissolution.Continue culture 48 hours Afterwards, the MTT solution that 25 μ L concentration are 5mg/mL is added per hole, is placed in 37 DEG C and 5%CO2Cell incubation case in culture it is 4 small When.100 μ L DMSO is added after careful removing supernatant per hole, vibration about 10min dissolving purple powders (first a ceremonial jade-ladle, used in libation) are vertical I.e. in detection O.D. (absorbance) value, wavelength 570nm on ELIASA.
Suspension cell K562 culture:Respectively that growth conditions are good, the cell in exponential phase is with 5 × 104Individual/mL's is close Degree is inoculated in 96 orifice plates, per the μ L of hole 100, then adds the compound 10a-p of sterilized processing with containing by default concentration gradient The solution that 0.1%DMSO culture medium is configured to, per the μ L of hole 25, control group adds the solvent of isometric sample dissolution, puts In 37 DEG C and 5%CO2Cell incubation case in cultivate 48 hours after, per hole add 25 μ L concentration be 5mg/mL MTT it is molten Liquid, it is 37 DEG C and 5%CO to continue to be placed in condition2Cell incubation case in cultivate 4 hours.2500rpm centrifuges 10min, carefully Supernatant is suctioned out, 100 μ L DMSO, vibration about 10min dissolving purple powders (first a ceremonial jade-ladle, used in libation), immediately in enzyme mark are added per hole O.D. (absorbance) value, wavelength 570nm are detected on instrument.
The activity that compound under each concentration suppresses tumor cell proliferation is obtained as the following formula:
Cell propagation (%)=(the average O.D. values of the average O.D. values/control group of compound group) × 100%, experiment is repeated 3 times, with Cell propagation is mapped to drug concentration, and IC is obtained by graphing method50(half effective inhibition concentration) value.
4) it the results are shown in Table 1.As a result show all there is no toxicity to tumour cell or non-tumor cell 10a-p.This is to expect not The technique effect arrived.
The 10a-p of table 1 extracorporeal anti-tumor cell-proliferation activity (IC50, μM, n=3)
Experimental example 2 evaluates the activity that 10a-p suppresses tumour growth
1) 10a-p physiological saline solutions of the present invention, adriamycin (ADR) are used as positive control, physiological saline by the use of physiological saline solution (NS) it is used as negative control；
2) 10a-p, physiological saline and adriamycin are intraperitoneal administration, and 10a-p dosage is 2nmol/kg, the dosage of physiological saline For 0.2mL/20g, adriamycin dosage is 2 μm of ol/kg, successive administration 10 days, is administered 10 times altogether.
3) experimental animal is ICR male mices (cleaning grade), 20 ± 2g of body weight, every group of 12 mouse.
4) knurl source is mouse S 180 sarcoma, and purchased from Department Of Medicine, Peking University's animal experimental center, voluntarily passage maintains.
5) animal model and treatment
Extracted under aseptic condition and be inoculated with eugonic S180 ascites tumors knurl liquid, with normal saline dilution into (1:2) liquid is abundant Mixing, 0.2% Trypan Blue of tumor cell suspension Fresh is counted after mixing by white blood cell count(WBC) method, dye is blue Color person is dead cell, and tinter is not living cells, and cell concentration and cell survival rate is calculated as follows.
Viable count/4 × 10 in the block plaid of cell concentration=44× extension rate=cell number/mL
Cell survival rate=viable count/(viable count+dead cell number) × 100%
Knurl liquid of the survival rate more than 90% is prepared into 2.0 × 10 with homogenate method7Individual/mL cell suspension, in mouse armpit notch graft Kind, 0.2mL/ only, manufactures S180 tumor-bearing mices.After tumor inoculation 24h, compound is injected intraperitoneally in treatment group mouse daily 5a, 5b, dosage are 100nmol/kg and 20nmol/kg.The life of 0.2mL tween 80s is injected intraperitoneally in naive mice daily Manage salt solution.Adriamycin is injected intraperitoneally in positive controls mouse daily, and dosage is 2 μm of ol/kg.Experiment was carried out to the 10th day, was claimed Mouse weight, etherization, take off cervical vertebra and put to death mouse, then fix the right armpit tumor location of mouse with tweezers, cut off skin, Exposure tumour, blunt separation, weighs, tumour inhibiting rate is calculated as follows：Tumour inhibiting rate %=(average knurl weight-the changes of negative control group The average knurl weight of compound group) average knurl weight × 100% of/negative control group.Experimental data using t examine and variance analysis, knurl weight with Represent.It the results are shown in Table 2.As can be seen from Table 2, under 100nmol/kg dosage, compound 5a, 5b tumour The knurl weight of mouse is significantly less than the knurl weight of the saline-treated mice of tween 80, illustrates compound 5a, 5b effective dose It is low to reach 100nmol/kg.This effective dose is than inventor once disclosed 3H- imidazos [4,5-c] pyridine -6- formyls-AA-OBzl 1 μm of ol/kg of effective dose of (wherein AA represents tryptophane or other l-amino acid residues remove proline) is low 10 times.
Influences of the 10a-p of table 2 to S180 tumor-bearing mice tumour growths
N=10；A) p is compared with physiological saline<0.05；B) p is compared with physiological saline<0.01.
As can be seen from Table 2, under 2nmol/kg dosage, the knurl weight of 10a-p treatment mouse is significantly less than physiological saline and controlled Treat the knurl weight of mouse.Effective dose is low to reach 2nmol/kg.This effective dose is than inventor's once disclosed 3H- imidazos [4,5-c] Pyridine -6- formyls-AA-OBzl (wherein AA represents l-amino acid residue) 1 μm of ol/kg of effective dose is low 500 times；Than invention Once disclosed 3H- imidazos [4,5-c] pyridine -6- formyls-Met-AA-OBzl (wherein AA represents l-amino acid residue) has people It is low 10 times to imitate 0.02 μm of ol/kg of dosage.This is unexpected technique effect.
Experimental example 3 evaluates the anti-inflammatory activity of compound
1) experimental method
18-22g ICR male mices are randomly divided into blank control group, aspirin (ASP) positive drug group, compound 10a-p Administration group, physiological saline (NS) negative control group, mouse use preceding tranquillization 1 day, and operation room keeps 22 DEG C of indoor temperature, often Group mouse 10.Once daily applies dimethylbenzene (0.03mL) after 30 minutes toward the left ear gabarit of small white mouse, by mouse after 2 hours Cervical dislocation is put to death after being anesthetized with ether.By a left side for mouse, auris dextra is cut, with diameter 7mm card punch two ears phase Same position, circular auricle is taken, is weighed respectively, obtain the weight difference of two circle auricles as swelling.Swelling=left ear disk Weight-auris dextra disk weight.
2) medication and dosage
Administering mode is gastric infusion.Blank control：Physiological saline (NS), dosage 0.2mL/20g；Positive control： Aspirin, dosage 1.11mmol/kg；The dosage of compound is 2nmol/kg.
3) statistical method
This experimental data statistics using t examine and variance analysis, swelling withRepresent.
4) experimental result is included in table 3.
As can be seen from Table 3,10a-p treats the ear swelling degree of mouse under 2nmol/kg dosage and is significantly lower than saline therapy The ear swelling degree of mouse.Illustrate that they have obvious antiinflammatory action.Effective dose is low to reach 2nmol/kg.This effective dose is than hair A person of good sense's once disclosed 3H- imidazos [4,5-c] pyridine -6- formyls-Met-AA-OBzl (wherein AA represents l-amino acid residue) 0.02 μm of ol/kg of effective dose is low 10 times.Show unexpected technique effect.
The 10a-p of table 3 anti-inflammatory activity
N=10；A) p is compared with physiological saline<0.05p<0.05；B) p is compared with physiological saline<0.01.

Claims (4)

1. (the N of following formulaα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines,
AA is selected from L-Ala, L-Val, Gly, L-Phe, L-Trp, L-Ile, L-Leu, L-Pro, L-Met, L-Asn, L-Ser in formula, L-Thr,L-Glu,L-Arg(NO2), L-Asp (OBzl) and L-Tyr residues.
2. (the N of claim 1α- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines preparation method, This method includes：
(1) L-Histidine carries out Pictet-Spengler condensation generation 6S-4,5,6,7- tetrahydrochysene -3H- miaows under dilute sulfuric acid catalysis with formaldehyde Azoles simultaneously [4,5-c] pyridine -6- carboxylic acids；
(2) 6S-4,5,6,7- tetrahydrochysenes -3H- imidazos [4,5-c] pyridine -6- carboxylic acids are converted into 6S-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] Pyridine -6- methyl formates；
(3) 6S-4,5,6,7- tetrahydrochysenes -3H- imidazos [4,5-c] pyridine -6- methyl formates are 3H- imidazos [4,5-c] with potassium permanganate oxidation Pyridine -6- methyl formates；
(4) 3H- imidazos [4,5-c] pyridine -6- methyl formates are saponified into 3H- imidazos [4,5-c] pyridine in NaOH solution (2N) - 6- formic acid；
(5) 3H- imidazos [4,5-c] pyridine -6- formic acid is coupled to obtain N with Lys (Boc)-OBzlα- 3H- imidazos [4,5-c] pyridine -6- Formyl-Lys (Boc)-OBzl；
(6) 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl are saponified into N in NaOH solution (2N)α- 3H- imidazoles And [4,5-c] pyridine -6- formyls-Lys (Boc)；
(7) 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) is coupled to obtain N with Glucosamineα- 3H- imidazos [4,5-c] pyrrole Pyridine -6- formyls-Lys (Boc)-Glucosamine；
(8)Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-Glucosamine obtains in 4N hydrogen chloride/ethyl acetate To Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines；
(9)Nα- 3H- imidazos [4,5-c] pyridine -6- formyl-Lys- Glucosamines are coupled to obtain (N with Boc-AAα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA-Boc)-Lys- Glucosamines；
(10)(Nα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA-Boc)-Lys- Glucosamines are in 4N hydrogen chloride/acetic acid (N is obtained in ethyl esterα- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines.
3. (the N of claim 1α- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines prepare it is antitumor Application in medicine.
4. (the N of claim 1α- 3H- imidazos [4,5-c] pyridine -6- formyls-Nω- AA)-Lys- Glucosamines are preparing anti-inflammatory agent Application in thing.
CN201610391394.7A 2016-06-03 2016-06-03 N alpha-imidazopyridine-6-formyl-N omega-AA-Lys-glucosamine, and synthesis, activity and application thereof Expired - Fee Related CN107459560B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103450329A (en) * 2012-05-29 2013-12-18 首都医科大学 3H-imidazo[4,5-c]pyridine-6-formyl-amido acid benzyl esters and their synthesis, anti-tumor activity and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103450329A (en) * 2012-05-29 2013-12-18 首都医科大学 3H-imidazo[4,5-c]pyridine-6-formyl-amido acid benzyl esters and their synthesis, anti-tumor activity and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘俊朋: "氨基葡萄糖拟肽类衍生物的合成", 《中国优秀硕士学位论文全文数据库(电子期刊)_工程科技I辑》 *

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