CN106242987A - One prevents and treats diabetes and medicine for treating diabetic nephropathy and synthetic method thereof and application - Google Patents
One prevents and treats diabetes and medicine for treating diabetic nephropathy and synthetic method thereof and application Download PDFInfo
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Abstract
The invention discloses one and prevent and treat diabetes and medicine for treating diabetic nephropathy and synthetic method thereof and application, this medicine is the derivant of caffeic acid phenylalanine, its structure shown in formula I, wherein, R1、R2For H, OH, OCH3、OCOCH3, 3 methyl fourth 2 thiazolinyl or isopentene groups；R3For H, CH3、Bn、OCH3、OCOCH3、BnCH2, i Pr, t Bu or adamantyl；N is 0 or 1.The rat diabetes model induced by STZ; show that this derivant can significantly reduce the blood glucose of diabetic model rats; diabetic nephropathy model mice there is certain protective effect simultaneously; confirm the blood sugar reducing function of this derivant and the effect of protection renal, the related drugs of diabetes and diabetic nephropathy can be prepared.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the application in blood sugar lowering and protection renal of the caffeic acid-phenylalanine derivative,
It is specifically related to described derivant purposes in preparing the related drugs such as anti-diabetic and complication thereof.
Background technology
Caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound (Caffeoyl-N-phenylalanine), chemical name is (instead)-3-
(3,4-dihydroxy phenyl) acrylic acid-L-phenylalanine, is widely present in various coffee bean, as Coffea Arabica, middle fruit coffee,
In Robusta's coffee etc., this compound is in nineteen fifty-five, by Klaus Peter Adam seminar first from Himalaya hoof lid
Herba pteridii latiusculi (Athyrium filix-femina) separates and identifies structure.Research subsequently finds successively, and this compound is at other
Plant is also widely present.
With the CAPE compounds in propolis seemingly, caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound also has the widest
General biological activity.Research in early days shows, it all has stronger inhibitory action to gram positive bacteria and negative bacterium；And should
Compounds has certain mitigation to A beta-amyloyd fibrosis.Xu et al. finds, this compound is to neuraminidase influenza
Having good inhibiting effect, it is respectively 39.6 and 37.4uM to the IC50 of H9N2 and H1N1 virus, by structure of modification, and this change
The analog of compound can be greatly improved activity, and its IC50 reaches 7.2uM and 8.5uM, and biological activity improves about 5 times.Andreas
Hensel et al. is found by cell experiment, and this compound is made by reducing the adhesion of the BabA outer membrane protein of helicobacter pylori
With, thus reach suppression or reduce the purpose of stomach cancer cell hypertrophy, the application for this compounds provides new thinking.Up-to-date
Research show, caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound and derivant thereof are likely to become new elder generation in terms of anti HIV-1 virus
Lead compound.Caffeic acid-caffeic acid-tartaric acid derivatives, i.e. chicoric acid (CAS:70831-56-0, chemical name (2r, 3r)-
2,3-bis [[E-3-(3,4-dihydroxyphenyl) prop-2-enoyl] oxy] butanedioic acid) inhibition of HIV
Suppression ratio IC50=15.7mM.
Along with going deep into of research, original method from natural product extraction compound can not meet activity and structure effect
The needs of relation research, it is the most necessary for studying new synthetic method, meanwhile, deeper into research caffeic acid-phenylalanine
The biologic activity of amide compound and the like, provides new application for it, the particularly application in terms of medicine and pharmacology, also
It is the most significant.
Summary of the invention
It is an object of the invention to provide one and prevent and treat diabetes and medicine for treating diabetic nephropathy and synthetic method thereof and application.
For reaching above-mentioned purpose, present invention employs techniques below scheme:
One prevents and treats diabetes and medicine for treating diabetic nephropathy, and this medicine is caffeic acid-phenylalanine derivative, described derivative
The structure of thing is shown in formula I:
Wherein, R1And R2For H, OH, OCH3、OCOCH3, 3-methyl but-2-ene base or isopentene group；R3For H, CH3、Bn、
OCH3、OCOCH3、BnCH2, i-Pr, t-Bu or adamantyl；N is 0 or 1, and during n=1, for naphthalene derivative, has α and β two kinds
Different substituting group positions.
A kind of synthetic method preventing and treating diabetes and medicine for treating diabetic nephropathy, comprises the following steps:
1) raw material A being dissolved in organic solvent to obtain solution I, described raw material A is caffeic acid or caffeic acid derivative；
2) in solution I, add organic amine, be subsequently placed in ice-water bath stirring and be cooled to 0 DEG C, obtain solution II；
3) under ice-water bath and stirring condition, in solution II, it is sequentially added into condensing agent and raw material B, obtains reactant liquor；Add
It is spaced 20～40min between condensing agent and addition raw material B (to be intended to make condensing agent and raw material A react and generate more active centre
Product), described raw material B is phenylalanine or phenylalanine derivative, reacts 12～48 in 40～80 DEG C after being heated up by reactant liquor
Hour, reaction terminates rear rotary evaporation and removes solvent；
4) adding ethyl acetate in gained residue after rotary evaporation removing solvent, then mix homogeneously sucking filtration, right
Organic facies in sucking filtration gained filtrate is dried with anhydrous sodium sulfate after washing, and then rotary evaporation removing solvent obtains and slightly produces
Thing, described crude product obtains purpose product by column chromatography purification.
Described organic solvent be selected from non-proton organic solvent, as dichloromethane, chloroform, acetone, oxolane, toluene,
Trichloroethane etc.；Described organic amine is selected from tertiary amine or secondary amine, such as triethylamine, diisopropylamine, diisopropyl ethyl amine etc.；
(amount of material is another kind of than for 1:1～1:3, i.e. one of which in the active esters condensing agent two kinds of described condensing agent
1～3 times of consumption), such as DCC and DMAP, NMM and IBCF, EDCI and HOBt, EDCI and DMAP etc..
The structure of described caffeic acid derivative is:
Wherein, R1And R2For H, OH, OCH3、OCOCH3, 3-methyl but-2-ene base or isopentene group；
The structure of described phenylalanine derivative shown in following structural formula or as described in the structure of phenylalanine derivative
For the form of salt or the form of free alkali of following structural formula, the form of described salt is hydrochlorate or sulfate:
Wherein, R3For H, CH3、CH2CH3、i-Pr、t-Bu、Bn、OCH3、OCOCH3Or adamantyl；N is 0 or 1, and n=1
Time, for naphthalene derivative, there are two kinds of different substituting group positions of α with β.
Based on the amount ratio of material, the usage ratio of described raw material A and organic amine is 1:1～1:3, raw material A and condensing agent (with
The summation meter of two kinds of active esters condensing agents) usage ratio be 1:1～1:4, the usage ratio of raw material A and raw material B be 1:1～
1:2。
Concretely comprising the following steps of described washing: successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt pair of mass fraction 5%
Organic facies in filtrate carries out washing (each 5～10mL, 2～3 times).
In described column chromatography, according to normal hexane: volume ratio=10:1～2:1 of acetone carries out gradient elution, column chromatography has
Concrete conditions in the establishment of a specific crime is:
Column chromatography silica gel model is 100～300 mesh；Consumption is 10～100 times of crude product quality；
Crude product adds the column chromatography silica gel of twice (mass ratio), after stirring, fills post.
Gradient elution is:
Gradient I, normal hexane: acetone=10:1 (volume ratio), cumulative volume (unit: milliliter) be crude product quality (unit:
Gram) 5～10 times；
Gradient II, normal hexane: acetone=5:1 (volume ratio), cumulative volume (unit: milliliter) be crude product quality (unit:
Gram) 10～20 times；
Gradient III, normal hexane: acetone=2:1 (volume ratio), cumulative volume (unit: milliliter) be crude product quality (unit:
Gram) 5～10 times；
After every test tube collection 5mL, TLC (GF254) identifies same chromatographic peak, collect, merge ,-0.08MPa, 45 DEG C of rotations
Evaporation of solvent.
Described cumulative volume is different because of the difference of purpose product concrete structure to the multiple of crude product quality.
Described preparation method is further comprising the steps of: described R1And R2During for hydroxyl, in step 1) front, to R1And R2
Protect, and in step 4) after carry out deprotection.Protection group used, such as benzyl, silicon ether, alkoxyl etc., with
Eliminate the issuable side reaction of active hydrogen.
Above-mentioned prevent and treat the application in preparation prevents and treats the medicine of diabetes of diabetes and medicine for treating diabetic nephropathy.
Above-mentioned prevent and treat diabetes and medicine for treating diabetic nephropathy preparation preventing and treating diabetic nephropathy medicine in application.
Beneficial effects of the present invention is embodied in:
The synthetic method of caffeic acid-phenylalanine derivative of the present invention is simple, and synthesis material is easy to get, and passes through diabetes
The experiment in vivo of animal pattern, demonstrates the significant hypoglycemic activity of caffeic acid-phenylalanine derivative, zymetology and tissue slice
Research demonstrates its protective effect to kidney, and the preparation and the activity research that are not only such compound provide new thinking,
And anti-diabetic can be prepared as active constituents of medicine, improve carbohydrate metabolism and the medicine of auxiliary treatment diabetic complication.
The present invention, on the basis of existing document is reported, optimizes synthetic route, improves productivity, and product can be easily separated pure
Changing, extend the scope of application of substrate simultaneously, substrate substituted to various functional groups all has the preferable suitability.
Accompanying drawing explanation
Fig. 1 is kidney cell paraffin section (× 400 times): A-blank group, B-model group, C-CP5 group, D-positive group, arrow
The leader note obvious injury region of cell.
Detailed description of the invention
With embodiment, the present invention is elaborated below in conjunction with the accompanying drawings.
Caffeic acid of the present invention-phenylalanine derivative synthesis is with caffeic acid (or caffeic acid derivative) and phenylpropyl alcohol ammonia
Acid (or phenylalanine derivative) is obtained by condensation reaction.
The structure of this caffeic acid-phenylalanine derivative is shown in formula I:
Wherein, R1And R2For H, OH, OCH3、OCOCH3, 3-methyl but-2-ene base or isopentene group；R3For H, CH3、Bn、
OCH3、OCOCH3、BnCH2, i-Pr, t-Bu or adamantyl.N is 0 or 1.This synthetic method is also applied for preparing caffeic acid-benzene
Ala amide compound.
The present invention uses the rat diabetes model that STZ induces, and evaluates synthetic product (caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide
Compound and caffeic acid-phenylalanine derivative) on impact glycometabolic in diabetic model rats body, evaluate relative to other
Model, it is possible to reflect the carbohydrate metabolism environment of diabetes patient more really, improves druggability.Experimental data shows this compounds
There is preferable hypoglycemic activity；Zymetology and tissue slice by diabetic nephropathy model animal are studied, and find that it has kidney and protects
Protect effect.
(1) synthesis example
The synthesis of example 1 caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound (being called for short CP1, as shown in Formula II)
1) weigh caffeic acid 90mg (0.5mmol) and add in 10mL round-bottomed flask, in round-bottomed flask, drip 5mL tri-chloroethene
Alkane, dissolves caffeic acid；
2) in round-bottomed flask, add 208 μ L (about 1.5mmol) triethylamine, stir 10min under ice-water bath, make system
Temperature reaches 0 DEG C；
3) under ice-water bath and stirring condition, in round-bottomed flask, add EDCI (1-ethyl-(3-dimethylamino third
Base) phosphinylidyne diimmonium salt hydrochlorate) 143mg (0.75mmol) and DMAP (4-dimethylamino pyridine) 91.5mg (0.75mmol),
Adding L-phenylalanine hydrochlorate 101mg (0.5mmol) after 20min in round-bottomed flask, temperature rises to 40 DEG C, continues at and stir
React 24 hours under the conditions of mixing；
4) reaction terminates rear decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent, adds 20mL ethyl acetate and shakes
Even, sucking filtration, filtrate organic facies at the middle and upper levels is successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt washing of mass fraction 5%
(10mL*2), anhydrous sodium sulfate is dried, and decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent obtains Light brown solid and slightly produces
Thing, (the described cumulative volume multiple to solid crude product quality: gradient I is 10 times, gradient II is 20 times to column chromatography, and gradient III is
5 times) after caffeic acid-phenylalanine (73.8mg, productivity 45%).Structural Identification data are as follows: LC-MS:328.1 (M+1+)。1HNMR (400MHz, CDCl3) δ: 8.29 (1H, d, J=8Hz), 7.24 (d, 1H, J=16Hz), 7.21-7.33 (m, 5H),
6.96 (d, 1H, J=2Hz), 6.85 (dd, 1H, J=8Hz, 2Hz), 6.76 (d, 1H, J=2Hz), 6.42 (d, 1H, J=
16Hz),4.57(m,1H),3.16(m,1H),2.99(m,1H)。
The synthesis of example 2 ferulic acids-phenylalanine isopropyl ester (being called for short CP2, as shown in formula III)
1) weigh ferulic acid 97mg (0.5mmol) and add in 10mL round-bottomed flask, in round-bottomed flask, drip 6mL DCM
(dichloromethane), dissolves ferulic acid；
2) in round-bottomed flask, add 205 μ L (about 1.5mmol) diisopropylamine, stir 15min under ice-water bath, make body
The temperature of system reaches 0 DEG C；
3) under ice-water bath and stirring condition, in round-bottomed flask, add NMM (N-methylmorpholine) 101mg (1mmol)
With IBCF (isobutyl chlorocarbonate) 135mg (1mmol), in round-bottomed flask, after 40min, add L-phenylalanine isopropyl ester salt
Hydrochlorate 101mg (1mmol), temperature rises to 80 DEG C, continues at and reacts 18 hours under stirring condition；
4) reaction terminates rear decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent, adds 15mL ethyl acetate and shakes
Even, sucking filtration, filtrate organic facies at the middle and upper levels is successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt washing of mass fraction 5%
(10mL*2), anhydrous sodium sulfate is dried, and decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent obtains brown solid crude product,
Column chromatography (the described cumulative volume multiple to solid crude product quality: gradient I is 7 times, gradient II is 20 times, and gradient III is 5 times)
After ferulic acid-phenylalanine isopropyl ester (119.6mg, productivity 62%).Structural Identification data are as follows: LC-MS:384.2 (M+1+)。1HNMR (400MHz, CDCl3) δ: 8.33 (1H, d, J=8Hz), 7.23 (d, 1H, J=16Hz), 7.20-7.32 (m, 5H),
6.96 (d, 1H, J=2Hz), 6.82 (dd, 1H, J=8Hz, 2Hz), 6.77 (d, 1H, J=2Hz), 6.44 (d, 1H, J=
16Hz), 4.93 (m, 1H), 4.55 (m, 1H), 3.16 (m, 1H), 2.99 (m, 1H), 1.41 (d, 3H, J=6.6Hz), 1.36 (d,
3H, J=6.6Hz).
The synthesis of example 3 3-acetyl group-caffeic acid-β-naphthylalanine benzyl ester (being called for short CP3, as shown in formula IV)
1) weigh raw material 3-acetyl group-caffeic acid (structural formula is as follows) 111mg (0.5mmol) and add 10mL round-bottomed flask
In, in round-bottomed flask, drip 5mL toluene, by material dissolution；
2) in round-bottomed flask, add 70 μ L (about 0.5mmol) triethylamine, stir 20min under ice-water bath, make system
Temperature reaches 0 DEG C；
3) add in round-bottomed flask under ice-water bath and stirring condition EDCI 95mg (0.5mmol) and
HOBt67.3mg (0.5mmol), adds β-L-naphthylalanine benzyl ester 183mg (0.6mmol) in round-bottomed flask after 30min,
Temperature rises to 60 DEG C, continues at and reacts 48 hours under stirring condition；
4) reaction terminates rear decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent, adds 20mL ethyl acetate and shakes
Even, sucking filtration, filtrate organic facies at the middle and upper levels is successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt washing of mass fraction 5%
(5mL*3), anhydrous sodium sulfate is dried, and decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent obtains brown oil crude product,
After column chromatography (the described cumulative volume multiple to crude product quality: gradient I is 10 times, gradient II is 15 times, and gradient III is 5 times)
Obtain 3-acetyl group-caffeic acid-β-naphthylalanine benzyl ester (166mg, productivity 65%).Structural Identification data are as follows: LC-MS:510.2
(M+1+)。1HNMR (400MHz, CDCl3) δ: 8.33 (s, 1H), 7.7-7.94 (m, 4H), 7.63 (d, 1H, J=16Hz), 7.44-
7.54 (m, 3H), 7.30-7.35 (m, 5H), 6.96 (d, 1H, J=2Hz), 6.85 (dd, 1H, J=8Hz, 2Hz), 6.76 (d,
1H, J=2Hz), 6.40 (d, 1H, J=16Hz), 5.07-5.11 (m, 2H), 4.33 (m, 1H), 3.30 (m, 2H), 2.28 (s,
3H)。
Example 4 3-(3,5-bis-(3-methyl but-2-ene) phenyl) acrylic acid-phenyalanine methyl ester (is called for short CP4, such as formula V
Shown in) synthesis
1) raw material 3-(3,5-bis-(3-methyl but-2-ene) phenyl) acrylic acid (structural formula is as follows) 150mg is weighed
(0.5mmol) add in 25mL round-bottomed flask, in round-bottomed flask, drip 10mL acetone, by material dissolution；
2) in round-bottomed flask, add 205 μ L (about 1.5mmol) triethylamine, stir 10min under ice-water bath, make system
Temperature reaches 0 DEG C；
3) under ice-water bath and stirring condition, in round-bottomed flask, EDCI 190mg (1mmol) and DMAP120mg is added
(1mmol), adding L-phenylalanine methyl ester hydrochloride 65mg (0.6mmol) after 25min in round-bottomed flask, temperature rises to 55
DEG C, continue at and react 40 hours under stirring condition；
4) reaction terminates rear decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent, adds 20mL ethyl acetate and shakes
Even, sucking filtration, filtrate organic facies at the middle and upper levels is successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt washing of mass fraction 5%
(10mL*2), anhydrous sodium sulfate is dried, and decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent obtains dark-brown oily and slightly produces
Thing, column chromatography (the described cumulative volume multiple to crude product quality: gradient I is 10 times, gradient II is 12 times, and gradient III is 5 times)
After 3-(3,5-bis-(3-methyl but-2-ene) phenyl) acrylic acid-phenyalanine methyl ester (90mg, productivity 39%).Structural Identification
Data are as follows: LC-MS:462.3 (M+1+)。1HNMR (400MHz, CDCl3) δ: 7.56 (d, 1H, J=16Hz), 7.20-7.32
(m, 5H), 7.13-7.20 (m, 2H), 6.28 (d, 1H, J=16Hz), 5.31-5.35 (m, 2H), 4.06 (m, 1H), 3.82 (s,
3H),3.28-3.42(m,4H),3.08(m,2H),1.91(m,6H),1.82(m,6H)。
Example 5 3-(4-hydroxyl-3-isopentene group phenyl) acrylic acid-α-naphthylalanine (is called for short CP5, as shown in formula VI)
Synthesis
1) weigh raw material 3-(4-hydroxyl-3-isopentene group phenyl) acrylic acid (structural formula is as follows) 116mg (0.5mmol) to add
Enter in 10mL round-bottomed flask, in round-bottomed flask, drip 5mL THF (oxolane), by material dissolution；
2) in round-bottomed flask, add 140 μ L (about 1mmol) triethylamine, stir 15min under ice-water bath, make the temperature of system
Degree reaches 0 DEG C；
3) add in round-bottomed flask under ice-water bath and stirring condition EDCI 143mg (0.75mmol) and
DMAP91.5mg (0.75mmol), adds α-L-naphthylalanine hydrochlorate 75.3mg in round-bottomed flask after 20min
(0.6mmol), temperature rises to 75 DEG C, continues at and reacts 12 hours under stirring condition；
4) reaction terminates rear decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent, adds 20mL ethyl acetate and shakes
Even, sucking filtration, filtrate organic facies at the middle and upper levels is successively with sodium bicarbonate aqueous solution and the saturated aqueous common salt washing of mass fraction 5%
(10mL*2), anhydrous sodium sulfate is dried, and decompressing and extracting (rotary evaporation ,-0.08MPa, 45 DEG C) solvent obtains brown solid crude product,
(the described cumulative volume multiple to solid crude product quality: gradient I is 5 times, gradient II is 20 times to column chromatography, and gradient III is 10
3-(4-hydroxyl-3-isopentene group phenyl) acrylic acid-α-naphthylalanine (92.5mg, productivity 43%) is obtained after again).Structural Identification number
According to as follows: LC-MS:430.2 (M+1+)。1HNMR(400MHz,CDCl3)δ:8.38(s,1H),7.60-7.80(m,4H),7.28-
7.52 (m, 4H), 7.19-7.25 (m, 2H), 6.77 (d, 1H, J=8Hz), 6.25 (d, 1H, J=16Hz), 6.83 (d, 1H, J=
15Hz), 6.32 (d, 1H, J=15Hz), 4.30 (m, 1H), 3.28 (m, 2H), 2.40 (m, 1H), 0.86-0.92 (m, 6H).
(2) diabetes model of STZ induced rat and the blood sugar reducing function of medicine
Model construction and the standard method of drug screening method list of references report, sketch and be: take SD Mus 40, lottery
It is divided into model group (n=35) and Normal group (n=5).Injection STZ40mg/ in left lower quadrant chamber after water 12h is can't help in model group fasting
Kg (0.01mol/L, pH 4.2), 1 time/d, continuous 5d.Water 12h pneumoretroperitoneum injection equal volume amounts Chinese holly is can't help in Normal group fasting
Rafter acid buffer, 1 time/d, continuous 5d.After last injection in 1 week, docking every day takes blood and measures blood glucose.3d blood glucose continuously >
16.7mmol/L person is diabetes rat, within the 4th day, carries out medicament screening experiment.
Medicament screening experiment: taking the successful rat of modeling, fasting 12h, with 2g/kg (concentration is as 0.4g/mL) body weight
Glucose dose gavage, simultaneously gastric infusion.With blood glucose meter respectively the most upon administration 0,0.5,1,1.5,2h measure blood glucose (BG)；With
Area under the drug-time curve (AUC) reflects carbohydrate tolerance.
Administering mode
(1) blank group (being called for short blank group): organize isopyknic normal saline (20mL/kg) with other；
(2CP1～CP5 experimental group (is called for short CP group, CP1～CP5 concentration is identical): according to 15 μm ol/kg gastric infusions；
(3) positive control medicine group (being called for short positive group): metformin is dissolved in ultra-pure water, and final concentration is 10g/L, presses
According to 15 μm ol/kg gastric infusions；
Often group laboratory animal 5, totally 35, Roche blood glucose meter (ease ejector half, correct) tail vein blood measures；Often organize reality
Test data to average, do Drug-time curve figure.
Test result and data analysis (the results are shown in Table 1)
(1) compared to blank group (22.2,45.0,35.3,29.1,26.5), CP group and positive group all can in various degree
Reducing blood glucose, in 2h, the hypoglycemic effect of positive group (i.e. metformin 22.9,33.4,29.1,27.2,23.2) is best；
(2) compared with positive group, the blood sugar lowering ability of the compound prepared by examples detailed above is below or near to metformin, its
(i.e. (4-hydroxyl-3-is different for 3-(3,5-bis-(3-methyl but-2-ene) phenyl) acrylic acid-phenyalanine methyl ester and 3-for middle CP4 and CP5
Pentenyl phenyl) acrylic acid-α-naphthylalanine) blood sugar lowering ability and metformin closely, simultaneously to original hyperglycemia
Phenomenon has certain mitigation (being reduced to 21.6 and 21.2 from 25.2 and 23.0 respectively), and further long-term experiment shows can
Blood glucose value is reduced to normal level.
(3) CP5 with CP4 compares, and its AUC area is essentially identical, but CP5 has blood sugar lowering ability more smoothly, to body
The regulation of interior blood glucose is more mild, the most further antidiabetic medicine preclinical study.
Therefore consider result, compound prepared by examples detailed above (caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound and
Caffeic acid-phenylalanine derivative) there is obvious blood sugar lowering ability, wherein compound CP5 is more suitable for being developed into novel resisting
Diabetes medicament.
The SD rat diabetes model result of table 1.STZ induction
(3) CP5 (in CP1～CP5, CP5 is that effect is best) protective effect to kidney in diabetic nephropathy mice
Model construction and the standard method of drug screening method list of references report, sketch and be: male mouse of kunming, body weight
24～26g, raising temperature is 23 DEG C ± 2 DEG C, humidity 60%, alternately illumination in every 12 hours, experiment prospective adaptation feed 3 days, from
By taking food drinking-water；Feedstuff is divided into chow diet and model feedstuff.Modeling and medicament protection time are 30 days.Triglyceride (TG),
T-CHOL (TC), high density lipoprotein (HDL-C), the detection of low density lipoprotein, LDL (LDL-C) use full-automatic biochemical analysis
Instrument (HITACHI 7600) measures；The mensuration of N-acetyl-β-D-glucosaminidase (NAG) uses corresponding reagent box according to giving
Method of determining measures.
Administering mode is as follows:
(1) blank group (being called for short blank group): feeding chow diet, gastric infusion organizes equal-volume normal saline with other
(20mL/kg)；
(2) diabetic nephropathy model matched group (abbreviation model group): feed high fat height sugar and the model feedstuff containing cadmium, gavage
It is administered and other groups equal-volume normal saline (20mL/kg)；
(3) 3-(4-hydroxyl-3-isopentene group phenyl) acrylic acid-α-naphthylalanine protection group (being called for short CP5 group): feed height
Fat height sugar and the model feedstuff containing cadmium, gastric infusion (physiological saline solution, a small amount of DMSO hydrotropy), dosage 10 μm ol/kg/day；
(4) positive control medicine group (being called for short positive group): avosentan (avosentan) is dissolved in ultra-pure water, DMSO
Hydrotropy, final concentration is 10mg/mL, gastric infusion, dosage 10 μm ol/kg/day；
The biochemistry detection result of table 2. diabetic nephropathy model mice
Test result and data analysis (the results are shown in Table 2)
(1) compared to model group, CP5 group and the positive group the most protected effect of every biochemical indicator to kidney, can be effective
The damage of protection kidney；Wherein, the content of TG can be down to normal level substantially；CP5 is relative to avosentan, and TC is had more preferably by it
Normalizing effect, about 140% (model group is about 234%) of normal level can be down to；
(2) compared to model group, CP5 and avosentan all have extraordinary protective effect to LDL-C, can be greatly reduced
The content of LDL-C；Protective effect to HDL-C is essentially identical simultaneously；
(3) NAG very important index during being kidney injury and normalization, result shows, CP5 in experimentation
NAG can be made to be down to normal level.
Tissue slice electron microscope experiment is as follows:
Sample preparation and operation, according to standard operating instructions, are sketched and are: mice strength of breaking is put to death, and takes fresh renal tissue, good fortune
After you Malin soaks and be fully fixing, it is cut into the fritter of 5mm × 5mm；Flowing water rinses, and ethanol carries out soaking dehydration and dimethylbenzene is molten
After liquid transparence, paraffin embedding, H&E dyes；Germany's Lycra positively fixed type DM2500M microscope is observed.
Seeing Fig. 1, the electron microscopic picture of renal tissue section shows the normal and kidney microcosmic of damage the most intuitively
Structure, CP5 and avosentan have certain protective effect to kidney injury simultaneously, and the protective effect of CP5 and positive drug base
This is identical.
In a word, caffeic acid-(.+-.)-.alpha.-Aminobenzenepropanamide compound and caffeic acid-phenylalanine derivative proposed by the invention
Having blood sugar reducing function, compared to hypoglycemic medicine used by clinic, its blood sugar lowering ability is slightly below metformin, but, to original high
Blood glucose phenomenon has certain mitigation, can be as prevention and the lead compound for the treatment of diabetes medicament.Meanwhile, glycosuria is passed through
The model of sick nephropathy and medicament protection experiment, Preliminary screening has gone out compound CP5, can more effectively protect kidney under experimental conditions
Dirty damage, can be as the lead compound of medicine for treating diabetic nephropathy.
Claims (9)
1. prevent and treat diabetes and medicine for treating diabetic nephropathy for one kind, it is characterised in that；This medicine is that caffeic acid-phenylalanine derives
Thing, the structure of described derivant shown in formula I:
Wherein, R1And R2For H, OH, OCH3、OCOCH3, 3-methyl but-2-ene base or isopentene group；R3For H, CH3、Bn、OCH3、
OCOCH3、BnCH2, i-Pr, t-Bu or adamantyl；N is 0 or 1, and during n=1, for naphthalene derivative, has α with β two kinds different
Substituting group position.
2. the synthetic method preventing and treating diabetes and medicine for treating diabetic nephropathy, it is characterised in that: comprise the following steps:
1) raw material A being dissolved in organic solvent to obtain solution I, described raw material A is caffeic acid or caffeic acid derivative；
2) in solution I, add organic amine, be subsequently placed in ice-water bath stirring and be cooled to 0 DEG C, obtain solution II；
3) under ice-water bath and stirring condition, in solution II, it is sequentially added into condensing agent and raw material B, obtains reactant liquor；Add condensation
Being spaced 20～40min between agent and addition raw material B, described raw material B is phenylalanine or phenylalanine derivative, by reactant liquor liter
Reacting 12～48 hours in 40～80 DEG C after temperature, reaction terminates rear rotary evaporation and removes solvent；
4) after rotary evaporation removing solvent, gained residue adds ethyl acetate, then mix homogeneously sucking filtration, to sucking filtration
Organic facies in gained filtrate is dried with anhydrous sodium sulfate after washing, and then rotary evaporation removes solvent and obtains crude product, institute
State crude product and obtain purpose product by column chromatography purification.
3. according to the prevented and treated diabetes of claim 2 and the synthetic method of medicine for treating diabetic nephropathy, it is characterised in that: described organic
Solvent is selected from non-proton organic solvent；Described organic amine is selected from secondary amine or tertiary amine；Described condensing agent is selected from active esters
Condensing agent.
Prevent and treat the synthetic method of diabetes and medicine for treating diabetic nephropathy the most according to claim 2, it is characterised in that: described coffee
The structure of coffee acid derivative is:
Wherein, R1And R2For H, OH, OCH3、OCOCH3, 3-methyl but-2-ene base or isopentene group；
The structure of described phenylalanine derivative shown in following structural formula or as described in the structure of phenylalanine derivative be with
The form of the salt of lower structural formula or the form of free alkali, the form of described salt is hydrochlorate or sulfate:
Wherein, R3For H, CH3、CH2CH3、i-Pr、t-Bu、Bn、OCH3、OCOCH3Or adamantyl；N is 0 or 1, and during n=1,
For naphthalene derivative, there are two kinds of different substituting group positions of α with β.
Prevent and treat the synthetic method of diabetes and medicine for treating diabetic nephropathy the most according to claim 2, it is characterised in that: by material
Amount than meter, the usage ratio of described raw material A and organic amine is 1:1～1:3, the usage ratio of raw material A and condensing agent be 1:1～
1:4, raw material A is 1:1～1:2 with the usage ratio of raw material B.
Prevent and treat the synthetic method of diabetes and medicine for treating diabetic nephropathy the most according to claim 2, it is characterised in that wash described in:
That washs concretely comprises the following steps: sodium bicarbonate aqueous solution and saturated aqueous common salt with mass fraction 5% are to the organic facies in filtrate successively
Wash.
Prevent and treat the synthetic method of diabetes and medicine for treating diabetic nephropathy the most according to claim 2, it is characterised in that: described post
The condition of gradient elution of chromatography includes: normal hexane: volume ratio=10:1～2:1 of acetone.
8. prevent and treat diabetes and medicine for treating diabetic nephropathy as claimed in claim 1 in preparation prevents and treats the medicine of diabetes for one kind
Application.
9. prevent and treat diabetes and the medicine for treating diabetic nephropathy medicine at preparation preventing and treating diabetic nephropathy as claimed in claim 1 for one kind
In application.
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| CN1646480A (en) * | 2002-04-15 | 2005-07-27 | 财团法人牧岩生命工学研究所 | Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition |
| CN102405079A (en) * | 2009-02-13 | 2012-04-04 | 雀巢产品技术援助有限公司 | Products comprising n-phenylpropenoyl amino acid amides and uses thereof |
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| CN1646480A (en) * | 2002-04-15 | 2005-07-27 | 财团法人牧岩生命工学研究所 | Derivatives of hydroxyphenyl, a method for preparing thereof and their pharmaceutical composition |
| CN102405079A (en) * | 2009-02-13 | 2012-04-04 | 雀巢产品技术援助有限公司 | Products comprising n-phenylpropenoyl amino acid amides and uses thereof |
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| CN115960020A (en) * | 2021-10-08 | 2023-04-14 | 深圳枫语生物医药科技有限公司 | Caffeic acid nitrone compound and preparation method and application thereof |
| CN115960020B (en) * | 2021-10-08 | 2024-04-09 | 深圳枫语生物医药科技有限公司 | Caffeic acid nitrone compound and preparation method and application thereof |
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