CN114573476A - Linear head-tail diamine bridged compound and application thereof in preparing medicament for treating glycometabolism disorder diseases - Google Patents
Linear head-tail diamine bridged compound and application thereof in preparing medicament for treating glycometabolism disorder diseases Download PDFInfo
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- CN114573476A CN114573476A CN202210225334.3A CN202210225334A CN114573476A CN 114573476 A CN114573476 A CN 114573476A CN 202210225334 A CN202210225334 A CN 202210225334A CN 114573476 A CN114573476 A CN 114573476A
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- diamine
- benzyl
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Abstract
The invention discloses a linear head-tail diamine bridged compound, a preparation method thereof and application thereof in preparing a medicament for treating glycometabolism disorder diseases. The compound of the invention has obvious inhibitory activity to aldose reductase and certain oxidation resistance. The application of the compound in preparing the medicine for treating the glucose metabolism disorder diseases, the medicine for treating diabetic complications and the diseases caused by oxidative stress is reported for the first time. Compared with other prior art, the compound has novel structure, simple preparation process and better curative effect than a positive control drug epalrestat.
Description
The application is a divisional application of Chinese patent application with the application number of '202010959328.1', the application date of the original application is '9-14.2020', and the invention name is 'a compound and a preparation method thereof and application thereof in preparing a medicament for treating glycometabolism disorder diseases'.
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a linear head-tail diamine bridged compound, a preparation method thereof and application thereof in preparing a medicament for treating glycometabolism disorder diseases.
Background
Diabetes Mellitus (DM) is an endocrine metabolic syndrome characterized primarily by hyperglycemia and Diabetes, due to insufficient insulin secretion or insulin resistance in the body. Diabetic patients are prone to induce diabetic complications when being in a hyperglycemic state for a long time, and the diabetic complications are mainly classified into three types: retinopathy, such as: glaucoma, cataract, and the like; peripheral neuropathies, such as: peripheral neuritis, foot ulcer, etc.; kidney disorders, such as: renal microangiopathy, which in severe cases can lead to renal failure, uremia, etc.
In addition, the heart and cerebral vessels are possibly diseased, and stroke, cardiac hypertrophy, congestive heart failure and the like can be caused. These complications are all caused by long-term hyperglycemia of the body, which damages the vascular wall and peripheral nerves and greatly increases the risk of cardiovascular diseases.
Although diabetes has always plagued patients' health, it is really life threatening to be a series of complications due to the persistent hyperglycemia in the body. These complications occur in association with excessive activation of Aldose Reductase (AR) in high sugar environments.
Inhibition of AR has been shown to be an effective approach for the treatment of diabetic complications. According to literature research, although many AR inhibitors have been developed, few aldose reductase inhibitors are available for clinical use, which are effective and have fewer adverse reactions. Among the aldose reductase inhibitors that are commercially available and chemically synthesized are epalrestat (epalrestat), astatin (alrestatin), ponalrestat (ponalrestat), sorbinil (sorbinel) and tolrestat (tolrestat). These drugs are also not ideal. The development of aldose reductase inhibitors with definite therapeutic effect and safety is urgent.
The Chinese patent of invention ZL201410723116.8 and ZL201710372369.9 both disclose a compound having aldose reductase inhibitory activity, but the compound of patent ZL201410723116.8 has less AR inhibitory activity than that of the positive control drug Epasitah and has less antioxidant activity than Trolox; although the patent ZL201710372369.9 found candidate compounds with good AR inhibitory activity and antioxidant activity, its stability and bioavailability were deficient and further improvement was needed.
Disclosure of Invention
In view of the above, the primary object of the present invention is to provide a novel linear head-to-tail diamine bridged compound having both aldose reductase inhibitory activity and antioxidant activity.
Another object of the present invention is to provide a process for producing the above compound.
The invention also aims to provide the application of the compound in preparing medicaments for treating glucose metabolism disorder diseases, in particular to the application in preparing medicaments for treating diabetic complications.
The purpose of the invention is realized by the following technical scheme:
a linear head-to-tail diamine bridged compound having a structure represented by formula I:
in the structure of formula I, the X group has a structure as shown in formula II-1, formula II-2 or formula II-3:
in the structures shown in the formula II-1, the formula II-2 and the formula II-3, R is monohydroxy substituent, dihydroxy substituent or hydroxy and hydroxymethyl substituent;
preferably, when R is monohydroxy, the substitution position in the formula II-1 can be 5-, 6-, 7-, 8-, preferably 6-; the substitution positions in the formulae II-2 and II-3 can be 5-, 6-, 7-, 8-, preferably 7-.
Preferably, R is a dihydroxy substitution, or when hydroxy and hydroxymethyl are disubstituted, an ortho substitution is provided;
further preferably, when R is a dihydroxy group, the substitution position in the formula II-1, the formula II-2 and the formula II-3 may be 5,6-, 6, 7-or 7, 8-;
further preferably, when R is a hydroxyl group and a hydroxymethyl group, the substitution position in the formula II-1 is preferably 6-hydroxyl-7-hydroxymethyl; the substitution position thereof in the formulae II-2 and II-3 is preferably 6-hydroxymethyl-7-hydroxy.
In the structure shown in the formula I, p is 1-6;
the Z group is methyl, isopropyl or cyclopropyl.
Preferably, the compounds of the present invention are specific compounds as shown in table 1:
TABLE 1
The invention also claims pharmaceutically acceptable salts of the compounds having the structure shown in the formula I and the specific compounds shown in the table 1.
The invention also claims synthetic intermediates (or prodrugs) of compounds of the structure shown in formula I and specific compounds shown in Table 1.
A method for preparing a compound having a structure represented by formula I, comprising the steps of:
(1) preparation of N-t-Butoxyacyl protected substituted acyl diamine: dissolving carboxylic acid in a solvent, adding a coupling reagent with the molar weight of 1.0-3.0 times of that of the carboxylic acid, stirring and reacting for 10-40 min at the temperature of-20-0 ℃, then adding head and tail diamine with one end protected by N-tert-butoxy acyl and the organic base with the molar weight of 1.0-3.0 times of that of the carboxylic acid, stirring and reacting for 30-60 min at the temperature of-20-0 ℃, heating to 30-60 ℃, and continuing stirring and reacting for 24-36 h; after the reaction is finished, removing the solvent by rotary evaporation, and purifying the concentrate by silica gel column chromatography to obtain acyl head-tail diamine protected by one end of N-tert-butoxy acyl;
the carboxylic acid has a structure shown in a formula II-1 ', a formula II-2 ' or a formula II-3 ':
the head and tail diamine protected by one end of N-tert-butoxy acyl has a structure shown in a formula III-1':
(2) mono-acyl head-to-tail diamine at one end: dissolving acyl head and tail diamine protected by one end of N-tert-butoxy acyl in a solvent, slowly adding a 4M hydrochloric acid solution of which the molar weight is 5-20 times that of the acyl head and tail diamine protected by one end of N-tert-butoxy acyl, and stirring and reacting for 3-6 hours at 0-40 ℃; after the reaction is finished, removing the solvent by rotary evaporation, and freeze-drying to obtain end-to-end monoacyl diamine;
(3) preparation of N-acylated-O-benzyl-D-serine: adding an acylation reagent with the molar weight of 1.0-5.0 times that of O-benzyl-D-serine into O-benzyl-D-serine, stirring and reacting for 4-9 h at 50-100 ℃, removing the solvent by rotary evaporation, and separating and purifying the concentrate by using high performance liquid chromatography to obtain N-acylation-O-benzyl-D-serine;
(4) preparation of a compound of the structure of formula I: dissolving N-acylation-O-benzyl-D-serine in a solvent, adding a coupling reagent with the molar weight of 1.0-3.0 times that of the N-acylation-O-benzyl-D-serine, and stirring and reacting at-20-0 ℃ for 10-40 min to obtain a solution A; dissolving the monoacyl end-to-end diamine prepared in the step (2) in a solvent, adding organic alkali with the molar weight 3.0-5.0 times that of the monoacyl end-to-end diamine, cooling to below-30 ℃, dropwise adding the solution A under stirring, keeping the temperature after dropwise adding, and stirring for 1-3 hours; heating to room temperature, and continuing to react for 20-40 h; after the reaction is finished, removing the solvent by rotary evaporation; purifying the concentrate by silica gel column chromatography to obtain a compound with a structure shown in formula I;
the solvent used in the steps (1) and (4) is N, N-Dimethylformamide (DMF) or Dichloromethane (DCM)/DMF mixed solution with the volume ratio of 10: 1.
The coupling reagent used in the steps (1) and (4) can be one of ethyl chloroformate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), N-diisopropyl carbodiimide (DIC) and benzotriazole-1-yl-oxy-tripyrrolidinyl phosphorus hexafluorophosphate (PyBOP) and N-hydroxybenzotriazole (HOBt) mixed according to a molar ratio of 1: 1.
The organic base used in steps (1) and (4) is triethylamine or Diisopropylethylamine (DIPEA).
The solvent used in the step (2) is one of methanol, ethanol and DMF.
The acylating agent used in the step (3) is acid anhydride or acyl chloride.
In the step (4), the molar ratio of the N-acylated-O-benzyl-D-serine to the one-end monoacyl head-tail diamine is 1 (1-3), and preferably 1.0: 1.1.
In still another aspect, the invention also provides the application of the compounds (the compounds with the structure shown in the formula I and the compounds listed in the table 1) in the preparation of medicines for treating glucose metabolism disorder diseases, in particular to the application in the preparation of medicines for treating diabetic complications. These diabetic complications include diabetic retinopathy, diabetic peripheral neuropathy, and diabetic senile dementia.
The present invention has demonstrated that the above-mentioned compounds (structural compounds of formula I and compounds listed in Table 1) have excellent inhibitory activity against aldose reductase using the following experiments: the inhibition rate of alpha-cyano-3, 4-dihydroxycinnamic acid derivatives (namely the compounds of the invention) on the enzymatic hydrolysis activity of aldose reductase is determined by taking D, L-glyceraldehyde as a substrate, and Epalrestat (Epalrestat), a clinical drug, is taken as a positive control. The results showed that (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (. alpha. -cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G) had the best inhibitory activity against human aldose reductase, IC50The value was 12.26. + -. 0.85nmol/L, which is greater than the epalrestat level (IC)5075.64 +/-4.22 nmol/L) and is stronger than CHR-532R (IC) reported by patent CN 201410723116.85089.71 +/-3.51 nmol/L) which is stronger than CHR-5N-D (IC) reported in patent CN201710372369.95041.02 ± 2.83 nmol/L). Other compounds of the invention also exhibit certain inhibitory activity against aldose reductase in vitro.
The compound (the compound with the structure shown in the formula I and the compound listed in the table 1) is inspected to eliminate the free radical generated by 1, 1-diphenyl-2-trinitrophenyl hydrazine (DPPH), and CHR-5N-F is found to show excellent antioxidation, and the half clearing concentration EC is50The concentration is 8.81 +/-0.51 mu M and is obviously stronger than that of a positive control drug Trolox (EC)5014.39 ± 0.23 μ M). Other compounds of the invention also exhibit some free radical scavenging ability.
The effect of CHR-5N-G as a test agent and Epalrestat as a positive control agent and Edaravone as an antioxidant on chick embryo survival, mortality, neural tube teratogenesis, and chick embryo morphology and body weight under a high sugar environment (0.4 mmol/eg) was examined by reference to experimental methods reported in the literature (Zhang L, Li YF, Yuan S, et al, scientific Reports,2016,6: 24942). The results show that the survival rate, the death rate, the total aberration rate and the body weight of the chick embryos treated by the CHR-5N-G are 78.8 percent, 20.7 percent, 11.3 percent and 243.2mg respectively at the concentration of 500 nM; the survival rate, the death rate, the total distortion rate and the body weight of the chick embryos treated by the epalrestat are 69.6 percent, 29.8 percent, 27.9.0 percent and 231.4mg respectively; the survival rate, the death rate, the total distortion rate and the body weight of the chicken embryos treated by the edaravone are 71.2 percent, 30.4 percent, 22.3 percent and 228.5mg respectively. The result shows that the effect of the tested medicament CHR-5N-G is generally superior to that of epalrestat and edaravone.
Meanwhile, the compound has specific inhibitory activity on AR, shows obvious enzyme inhibitory activity on ALR2, is superior to a positive control drug, and has consistent in-vitro activity result with the result of the in-vitro activity; the ALR1 does not show obvious inhibitory activity to the isozyme, so that the target compound has high selectivity on inhibiting AR. The compound remarkably inhibits the polyalcohol pathway of glucose metabolism by inhibiting the activity of AR, and prevents the generation of a metabolite sorbitol of the pathway. The in vivo antioxidant experiment also shows that the compound can obviously inhibit the formation of oxidation product MDA in embryoid bodies, and the ORAC level shows that the compound has good free radical scavenging capacity. The experiments strongly prove that the compound CHR-5N-G can play a good role in protecting the chicken embryonic neural tube deformity induced by high sugar, and secondly, the in-vivo enzyme inhibition activity and the in-vivo antioxidant activity of the compound are outstanding, which are consistent with the in-vitro experiments, and meanwhile, the expression of the regulatory protein Pax 3 can be obviously improved.
A diabetic peripheral neuropathy rat model is established according to a reference document (Neural Regeneration Research 2016,11(2),345 and 351), and CHR-5N-G has an obvious therapeutic effect on high-sugar induced peripheral neuropathy.
Therefore, the compounds (the structural compound of the formula I and the compounds listed in the table 1, and the pharmaceutically acceptable salts and synthetic intermediates thereof) can be used for preparing medicaments for treating glucose metabolism disorder diseases, and particularly can be used for preparing medicaments for treating diabetic complications such as diabetic retinopathy, diabetic senile dementia, nerve ending disorder and the like; the compounds can be used for preparing medicaments for treating diseases caused by oxidative stress, especially diabetic complications.
Compared with the prior art, the invention has the following advantages and effects:
the inhibitory activity of the compound on aldose reductase and the application of the compound in preparing medicaments for treating glycometabolism disorder diseases, medicaments for treating diabetic complications and diseases caused by oxidative stress are reported for the first time. Compared with other prior art, the compound has novel structure, simple preparation process and better curative effect than a positive control drug epalrestat.
Drawings
FIG. 1 is a diagram of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (alpha-cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G)1H NMR spectrum.
FIG. 2 is a diagram of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (alpha-cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G)13C MRC map.
FIG. 3 is an HR-ESI-MS spectrum of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (. alpha. -cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G).
FIG. 4 is a bar graph of the in vitro ALR2 enzyme inhibition rates of a portion of the compounds.
FIG. 5 is a bar graph of free radical scavenging rates for different concentrations of Trolox, CHR-5N-G, CHR-5N-F.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
(E) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (4-hydroxyphenyl) acrylamide (CHR-5F-B) comprising the following five steps:
(1) synthesis of (E) - α -cyano-4-hydroxycinnamic acid: 122.1mg (1.0mmol) of 4-hydroxybenzaldehyde is weighed into a dry 50mL round bottom flask, 85mg (1.0mmol) of cyanoacetic acid and 15.4mg (0.2mmol) of ammonium acetate are added, 48mg (0.8mmol) of glacial acetic acid is weighed into the reaction system by a syringe, 10mL of toluene is added as a solvent, and a small-sized water separator, a condenser tube and a drying tube are connected onto a reaction bottle. The reaction was stirred and refluxed for 18h in an oil bath at 120 ℃. Cooling to room temperature after the reaction is finished, standing at low temperature, filtering, and adding dichloromethane into filter cakeWashed three times with DCM to give a yellow solid in 92.8% yield.1H NMR(300MHz,CD3OD)δ:9.66(s,1H,Ar-OH),8.21(s,1H,＝CH-),7.46(d,2H,J＝8.3Hz,Ar-H),6.88(d,J＝8.3Hz,2H,Ar-H)；ESI-MS(m/z):188.3[M-H]-。
(2) Preparation of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-4-hydroxycinnamamide: 1.89g (10.0mmol) of alpha-cyano-4-hydroxycinnamic acid was added to a 100mL round bottom flask, 30mL of DCM/DMF (10:1 (V/V)) was added and dissolved with stirring, 1.15g (11.0mmol) of weighed EDC & HCl was added to the flask, and the reaction was stirred at 0 ℃ for 10min, then 0.82g (11.0mmol) of weighed HOBt was added to the reaction flask and the reaction was stirred at 0 ℃ for 10min to activate the free carboxyl group sufficiently. After the carboxyl group was sufficiently activated, 2.29g (11.0mmol) of 4-N-Boc-aminoaniline and 4.6mL (26.4mmol) of DIPEA were measured by syringe, and injected into the reaction flask in sequence, stirred at 0 ℃ for reaction for about 30min, slowly warmed to room temperature, and reacted for 24 h. After the reaction, the solvent was removed, and the residue was separated and purified by silica gel column chromatography (chloroform: methanol: 40:1) to obtain 3.29g of a yellow solid, which was obtained in 86.7% yield.1H NMR(400MHz,DMSO-d6)δ:10.03(s,Ar-NH),9.34(s,Ar-NH),8.75(s,Ar-OH),8.45(s,＝CH),7.75(m,4H,Ar),7.45(d,J＝8.3Hz,2H,Ar-H),6.46(d,J＝8.3Hz,2H,Ar-H),1.48(CH3,9H)；13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9,79.5,28.4。
(3) Preparation of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamamide: (E) -N- (N-Boc-4-aminophenyl) - α -cyano-4-hydroxycinnamamide 1.14g (3.0mmol) was dissolved in 30mL of dry methanol, transferred to a 50mL round-bottomed flask, and 7.5mL of a 4mol/L HCl solution (30mmol) was slowly added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. The solvent was removed to give a pale yellow solid in 97.3% yield.1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H,Ar-NH),8.75(s,1H,Ar-OH),8.45(s,1H,＝CH),7.45(d,J＝8.3Hz,2H,Ar-H),7.38(d,J＝8.1Hz,2H,Ar-H),6.58(d,J＝8.3Hz,2H,Ar-H),6.32(d,J＝8.1Hz,2H,Ar-H),4.53(br,2H,Ar-NH2)；13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9。
(4) N-acetyl-O-benzyl-preparation of D-serine: 195.2mg (1.0mmol) of O-benzyl-D-serine is weighed into a 50mL round-bottom flask, dissolved in 10mL redistilled methanol, 0.3mL (about 3mmol) of acetic anhydride and 0.5mL (about 3mmol) of DIEA are weighed into a syringe and added into the reaction system, and the reflux reaction is carried out for 7h at 70 ℃. After the reaction, methanol in the reaction solution was removed under reduced pressure, and unreacted acetic anhydride was removed by freeze-drying. HPLC preparation (mobile phase methanol: water 50:50, 0.05% TFA, uv 254nm) gave a colorless oil, 74.5% yield.1H NMR(400MHz,CDCl3)δ:11.63(s,1H,-COOH),7.26(m,5H,Ar-H),7.04(d,J＝7.8Hz,1H,-CO-NH-),4.79-4.67(m,1H,-N-CH-),4.47(s,2H,Ar-CH2-O-),3.82-3.78(m,2H,-CH2-O-),2.01(s,3H,-CO-CH3)；13C NMR(75MHz,CDCl3)δ172.98,171.69,137.45,128.61,128.09,127.90,73.53,69.66,52.91,22.92.ESI-MS(m/z):236.7[M-H]-。
(5) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (4-hydroxyphenyl) acrylamide: weighing 118.7mg (0.5mmol) of N-acetyl-O-benzyl-D-serine in a penicillin bottle, sequentially adding 101.5mg (0.75mmol) of HOBt and 144mg (0.75mmol) of EDC & HCl, and 3-10 mL of DCM/DMF (10:1, V/V) as solvents, and stirring for reaction for 10min to obtain solution A. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) -alpha-cyano-4-hydroxycinnamamide is further weighed and dissolved in 3-10 mL of DCM/DMF, 0.4mL (2.2mmol) of DIPEA is added, the mixture is cooled to-30 ℃, the solution A is dropwise added under stirring, and after the dropwise addition is finished, the temperature is kept and the stirring is carried out for 1 hour. Then, the reaction was allowed to warm to room temperature and continued for 23 h. After the reaction is finished, the solvent is removed by rotary evaporation. The resulting extract was subjected to silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to obtain 181.1mg of a pale yellow solid with a yield of 66.1%.1H NMR(300MHz,DMSO-d6)δ:9.67(s,1H),8.17(d,J＝8.0Hz,3H),7.37–7.23(m,11H,＝CH,Ar-H),6.52(d,J＝8.7Hz,2H),4.65(d,J＝7.9Hz,1H),4.50(d,J＝3.8Hz,2H),3.61(s,1H),3.12(s,1H),1.88(s,3H,CH3)；13C NMR(101MHz,DMSO-d6)δ:171.80,169.49,167.79,144.76,138.32,138.21,128.37,128.36,127.67,127.65,127.62,127.59,121.25,114.12,72.19,70.13,69.75,53.79,53.34,52.44,42.02,22.68,22.51,18.27,16.92,12.63.ESI-MS(m/z):499.2for C28H26N4O5([M+H]+)；
(C＝1,CH3OH)。
The above data confirm that the compound is (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) -alpha-cyano-3- (4-hydroxyphenyl) acrylamide (CHR-5F-B), and the structure is shown below.
Example 2
(E) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) - α -cyano-3- (4-hydroxyphenyl) acrylamide (CHR-5F-E) comprising the following five steps.
(1) Preparation of (E) -alpha-cyano-4-hydroxycinnamic acid. Same procedure as in (1) of example 1
(2) Preparation of (E) -N- (N-Boc-4-aminocyclohexyl) - α -cyano-4-hydroxycinnamamide: the procedure was as in (2) of example 1. 2.29g (11.0mmol) of 4-N-Boc-aminocyclohexylamine was changed to 2.36g (11.0mmol) of 4-N-Boc-aminocyclohexylamine, giving 2.29g of a pale yellow solid in 59.5% yield.1H NMR(300MHz,DMSO-d6)δ:10.50(s,1H,Ar-OH),8.31(s,1H),8.15(s,1H),7.85(s,1H),7.77(d,J＝8.2Hz,2H),6.94(d,J＝8.2Hz,2H),3.70(m,1H),3.43(m,1H),1.66(m,4H),1.51(m,4H),1.38(s,9H)；13C NMR(75MHz,DMSO-d6)δ:161.64,160.97,154.91,150.00,132.72,122.95,117.31,116.18,101.68,77.46,46.97,28.29,28.08,26.84。
(3) Preparation of (E) -N- (4-aminocyclohexyl) - α -cyano-4-hydroxycinnamamide: the procedure was as in (3) of example 1. The (E) -N- (N-Boc-4-aminocyclohexyl) - α -cyano-4-hydroxycinnamamide obtained in the above step was added to give 1.67g of a light brown solid, yield 89.6%.1H NMR(300MHz,DMSO-d6)δ:10.50(s,1H,Ar-OH),8.33(s,1H),8.17(s,1H),7.52(d,J＝8.1Hz,2H),6.63(d,J＝8.1Hz,2H),3.65(m,1H),2.58(m,1H),1.73(m,4H),1.52(br,2H),1.47(m,4H)；13C NMR(75MHz,DMSO-d6)δ:161.65,160.96,150.01,132.73,122.97,117.33,116.17,101.69,46.98,28.32,28.10。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) - α -cyano-3- (4-hydroxyphenyl) acrylamide: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamamide was replaced by 156.9mg (0.55mmol) of (E) -N- (4-aminocyclohexyl) - α -cyano-4-hydroxycinnamamide. The resulting mixture was subjected to silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to obtain 174.3mg of a pale yellow solid with a yield of 62.8%.1H NMR(300MHz,CDCl3)δ:9.72(s,1H,Ar-OH),8.32(br,2H),8.16(s,1H),8.13(br,1H),7.89(d,J＝8.7Hz,2H,Ar-H),7.40-7.28(m,5H,Ar-H),6.98(d,J＝8.7Hz,2H,Ar-H),4.75(m,1H),4.63(s,2H),4.03-3.84(m,3H),3.64-3.46(m,2H),2.05(s,3H,CH3),1.74(m,4H),1.51(m,4H)；13C NMR(75MHz,CDCl3)δ:161.4,160.7,154.9,150.7,149.4,143.2,137.5,132.8,128.6,122.4,117.7,116.8,101.8,77.3,69.7,57.3,50.6,46.9,28.7,26.9.ESI-MS(m/z):503.6for C28H32N4O5([M-H]+)；
(C＝2,CH3OH)。
The above data confirmed that this compound is (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) - α -cyano-3- (4-hydroxyphenyl) acrylamide (CHR-5F-E), and the structure is shown below.
Example 3
(E) Preparation of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (. alpha. -cyano-3- (4-hydroxyphenyl) acryloyl) piperazine (CHR-5F-G) comprising the following five steps:
(1) preparation of (E) -alpha-cyano-4-hydroxycinnamic acid. Same procedure as in (1) of example 1
(2) Preparation of (E) -4-Boc-1- (α -cyano-4-hydroxycinnamoyl) piperazine: the procedure was as in (2) of example 1. 2.29g (11.0mmol) of 4-N-Boc-aminoaniline was changed to 2.05g (11.0mmol) of N-Boc-piperazine. 1.89g of light yellow solid is obtained, and the yield is 52.9%.1H NMR(400MHz,CDCl3)δ:9.68(s,1H),8.12(s,1H),7.83(d,J＝8.7Hz,2H),6.97(d,J＝8.7Hz,2H),3.55-3.51(m,8H),1.48(s,9H)；13C NMR(101MHz,CDCl3)δ:163.97,160.14,154.43,152.81,132.69,124.48,116.60,116.15,101.31,80.56,50.91,48.82,28.21。
(3) Preparation of (E) - α -cyano-4-hydroxycinnamoylpiperazine: the procedure was as in (3) of example 1. The (E) -4-Boc-1- (alpha-cyano-4-hydroxycinnamoyl) piperazine obtained in the above step was charged to give 1.23g of a light brown solid, and the yield was 90.5%.1H NMR(400MHz,CDCl3)δ:9.69(s,1H),8.13(s,1H),7.82(d,J＝8.7Hz,2H),6.96(d,J＝8.7Hz,2H),3.36(m,4H),2.87(m,4H),1.23(br,1H)；13C NMR(101MHz,CDCl3)δ:164.12,154.45,152.83,133.21,124.53,116.62,116.17,101.35,80.56,51.62,47.13。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (α -cyano-3- (4-hydroxyphenyl) acryloyl) piperazine: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamoyl amide was replaced with 141.5mg (0.55mmol) of (E) - α -cyano-4-hydroxycinnamoyl piperazine. Purifying by silica gel column chromatography (chloroform: methanol: 40:1, V: V) with gradient elution to obtain light yellow solid 132.6mg with yield of 50.6%.1H NMR(400MHz,DMSO-d6)δ:9.72(s,1H,Ar-OH),8.56(s,1H),8.15(s,1H),7.52(d,J＝8.7Hz,2H),7.42(m,5H,Ar-H),6.69(d,J＝8.7Hz,2H),4.76(m,1H),4.63(s,2H),3.62(m,1H),3.53(m,4H),3.41(m,4H),3.32(m,2H),2.04(s,3H,CH3)；13C NMR(101MHz,DMSO-d6)δ:171.73,169.75,168.12,157.87,151.43,144.25,138.52,129.61,128.82,127.40,124.70,115.80,115.60,106.90,72.30,70.0,54.80,49.40,48.90,22.90；ESI-MS(m/z):499.5for C26H28N4O5([M+Na]+)；
(C＝2,CH3OH).
The above data demonstrate that the compound is (E) -4- (N-acetyl-O-benzyl-D-serinyl) -1- (α -cyano-3- (4-hydroxyphenyl) acryloyl) piperazine (CHR-5F-G), having the structure:
example 4
(E) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (3, 4-dihydroxyphenyl) acrylamide (CHR-5N-B) comprising the following five steps:
(1) synthesis of (E) - α -cyano-3, 4-dihydroxycinnamic acid: 138mg (1.0mmol) of 3, 4-dihydroxybenzaldehyde is weighed into a dry 50mL round bottom flask, 85mg (1.0mmol) of cyanoacetic acid and 15.4mg (0.2mmol) of ammonium acetate are added, 48mg (0.8mmol) of glacial acetic acid is weighed into the reaction system by a syringe, 10mL of toluene is added as a solvent, and a small-sized water separator, a condenser tube and a drying tube are connected onto a reaction bottle. The reaction was stirred and refluxed for 18h in an oil bath at 120 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, then allowed to stand at a low temperature, filtered, and the filter cake was washed three times with Dichloromethane (DCM) to obtain 196.3mg of a yellow solid with a yield of 95.7%.1H NMR(300MHz,CD3OD)δ:9.52(s,2H,Ar-OH),8.21(s,1H,＝CH-),7.64(d,J＝8.3Hz,1H),7.36(s,1H,Ar-H),6.88(d,J＝8.3Hz,1H,Ar-H)；ESI-MS(m/z):204.3for C10H6NO4([M-H]-)。
(2) Preparation of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-3, 4-dihydroxycinnamamide: the same procedure as in (2) of example 1 was repeated except for replacing 1.89g (10.0mmol) of α -cyano-4-hydroxycinnamic acid with 2.05g (10.0mmol) of α -cyano-3, 4-dihydroxycinnamic acid. 2.82g of a yellow solid was obtained with a yield of 71.3%.1H NMR(400MHz,DMSO-d6)δ:10.03(s,1H),9.34(s,1H,Ar-NH),8.75(s,2H,2×Ar-OH),8.45(s,1H,＝CH),7.75(m,4H,Ar),7.66(d,J＝8.3Hz,1H),7.38(s,1H,Ar-H),6.89(d,J＝8.3Hz,1H,Ar-H),1.49(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:163.8,157.7,152.5,150.4,143.2,133.6,133.2,124.7,121.8,115.8,106.9,79.5,28.4。
(3) Preparation of (E) -N- (4-aminophenyl) - α -cyano-3, 4-dihydroxycinnamamide: the procedure was the same as in example 1, step (3), except that 1.14g (3.0mmol) of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-4-hydroxycinnamide was replaced with 1.19g (3.0mmol) of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-3, 4-dihydroxycinnamamide. Pale yellow solid was obtained in 96.4% yield.1H NMR(400MHz,DMSO-d6)δ:10.05(s,1H,Ar-NH-),8.77(s,2H,2×Ar-OH),8.46(s,1H,＝CH),7.76(d,J＝7.6Hz,2H,Ar-H),7.65(d,J＝8.3Hz,1H),7.36(s,1H,Ar-H),6.87(d,J＝8.3Hz,1H,Ar-H),6.53(d,J＝7.6Hz,2H,Ar-H),4.56(br,2H)；13C NMR(101MHz,DMSO-d6)δ:163.9,151.8,150.2,142.6,133.4,132.8,124.6,121.7,115.6,106.8。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (3, 4-dihydroxyphenyl) acrylamide: 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamide was replaced with 162.4mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-3, 4-dihydroxycinnamamide, the procedure was as in example 1, step (5). The resulting product was purified by silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to obtain 152.2mg of a pale yellow solid (yield: 53.8%).1H NMR(300MHz,DMSO-d6)δ:10.18(s,1H,-CONH-Ar),9.62(s,1H,Ar-NHCO-),9.47(s,2H,2×Ar-OH),8.34(d,J＝18.2Hz,1H),7.96(s,1H,＝CH),7.65(d,J＝6.2Hz,2H),7.59(d,J＝6.2Hz,2H),7.51(d,J＝8.5Hz,1H),7.25(m,5H,Ar-H),7.11(s,1H),6.85(d,J＝8.5Hz,1H),5.05(d,J＝13.1Hz,1H,CO-CH-N),4.65(s,2H,Ar-CH2-O),3.55(s,1H,O-CH2),3.07(s,1H,O-CH2),1.80(s,3H,CH3)；13C NMR(75MHz,DMSO-d6)δ:172.81,171.23,163.92,150.56,146.92,144.76,137.53,134.31,133.42,129.33,128.62(2),127.87,127.65,127.62,123.20,121.25(4),117.29,115.76,115.32,109.51,72.29,69.75,56.63,22.92.ESI-MS(m/z):545.7for C28H26N4O6([M+Na]+).
(C＝2，CH3OH)。
The above data demonstrate that the compound is (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) -alpha-cyano-3- (3, 4-dihydroxyphenyl) acrylamide (CHR-5N-B) and has the following structure:
example 5
(E) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acrylamide (CHR-5N-C) comprising the following five steps:
(1) synthesis of (E) - α -cyano-3-hydroxymethyl-4-hydroxycinnamic acid: the procedure was carried out in the same manner as in example 4, step (1) except for replacing 138mg (1.0mmol) of 3, 4-dihydroxybenzaldehyde with 152.1mg (1.0mmol) of 3-hydroxymethyl-4-hydroxybenzaldehyde. 204.9mg of a yellow solid are obtained with a yield of 93.5%.1H NMR(300MHz,CD3OD)δ:9.62(s,H,Ar-OH),8.26(s,1H,＝CH-),7.54(d,J＝8.3Hz,1H),7.32(d,J＝8.3Hz,1H,Ar-H),7.14(s,1H,Ar-H),7.02(br,1H),4.63(s,2H)；ESI-MS(m/z):218.4for C11H8NO4([M-H]-)。
(2) Preparation of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-3-hydroxymethyl-4-hydroxycinnamamide: the same procedure as in example 1, step (2), was repeated except for replacing 1.89g (10.0mmol) of α -cyano-4-hydroxycinnamic acid with 2.19g (10.0mmol) of α -cyano-3-hydroxymethyl-4-hydroxycinnamic acid. 3.01g of a yellow solid was obtained in a yield of 73.2%.1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H,-CO-NH-Ar),9.84(s,1H,Ar-NH-Boc-),9.72(s,1H,Ar-OH),8.45(s,1H,＝CH),7.75(m,4H,Ar),7.66(d,J＝8.3Hz,1H),7.38(d,J＝8.3Hz,1H,Ar-H),7.14(s,1H,Ar-H),7.06(br,1H),4.63(s,2H,Ar-CH2-O),1.51(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:163.8,156.13,153.06,150.51,133.62,133.25,129.60,128.83,128.18,126.20,121.76(4),115.84,107.11,79.53,61.12,29.05(3)。
(3) Preparation of (E) -N- (4-aminophenyl) - α -cyano-3-hydroxymethyl-4-hydroxycinnamamide: the same procedure as in example 1, step (2), was repeated except for replacing 1.14g (3.0mmol) of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-3-hydroxymethyl-4-hydroxycinnamide with 1.23g (3.0mmol) of (E) -N- (N-Boc-4-aminophenyl) - α -cyano-4-hydroxycinnamide. This gave 88.7mg of a pale yellow solid, yield 95.6%.1H NMR(400MHz,DMSO-d6)δ:10.15(s,1H,Ar-NH-),9.77(s,1H,Ar-OH),8.21(s,1H,＝CH),7.52(d,J＝7.6Hz,1H,Ar-H),7.43(d,J＝8.3Hz,2H),7.37(d,J＝7.6Hz,1H,Ar-H),7.21(s,1H,Ar-H),6.33(d,J＝8.3Hz,2H,Ar-H),4.56(br,2H)；13C NMR(101MHz,DMSO-d6)δ:163.9,156.14,150.52,133.63,133.26,129.63,128.85,128.17,126.22,121.78(4),115.85,107.12,61.13。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acrylamide: 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamide was replaced with 170.1mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-3-hydroxymethyl-4-hydroxycinnamide, and the procedure was the same as in step (5) of example 1. After silica gel column chromatography (chloroform: methanol: 40:1, V: V), the mixture was separated and purified by gradient elution to obtain 157.8mg of a pale yellow solid, which was obtained in 54.3% yield.1H NMR(300MHz,DMSO-d6)δ:10.13(s,1H,-CONH-Ar),9.71(s,1H,Ar-NHCO-),9.57(s,1H,Ar-OH),8.33(d,J＝18.2Hz,1H),8.16(s,1H,＝CH),7.66(d,J＝6.2Hz,2H),7.57(d,J＝6.2Hz,2H),7.53(d,J＝8.5Hz,1H),7.25(m,5H,Ar-H),7.14(s,1H),7.05(br,1H,Bn-OH),6.86(d,J＝8.5Hz,1H),5.07(d,J＝13.1Hz,1H,CO-CH-N),4.68(s,2H,Ar-CH2-O-),4.63(s,2H,Ar-CH2-O),3.56(s,1H,O-CH2),3.08(s,1H,O-CH2),1.82(s,3H,CH3)；13C NMR(75MHz,DMSO-d6)δ:172.83,171.23,164.01,154.87,138.02,134.21,133.34,129.56,128.74,128.63(2),128.06,127.82,127.45(2),126.14,121.85(4),115.12,107.11,72.32,69.11,61.25,57.14,53.34,22.93.ESI-MS(m/z):551.8for C29H28N4O6Na([M+Na]+).
(C＝2，CH3OH)。
The above data demonstrate that this compound is (E) -N- (4- (N-acetyl-O-benzyl-D-seryl) aminophenyl) - α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acrylamide (CHR-5N-C), and has the following structure:
example 6
(E) Preparation of-4- (N-acetyl-O-benzyl-D-seryl) -1- (α -cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G) comprising the following five steps:
(1) the procedure was as in (1) of example 4.
(2) Preparation of (E) -4-Boc-1- (α -cyano-3, 4-dihydroxycinnamoyl) piperazine: the procedure was as in (2) of example 4. 2.29g (11.0mmol) of 4-N-Boc-aminoaniline was changed to 2.05g (11.0mmol) of N-Boc-piperazine. 2.34g of pale yellow solid is obtained with a yield of 62.7%.1H NMR(400MHz,CDCl3)δ:9.57(s,2H,2×OH),8.15(s,1H,＝CH),7.52(d,J＝8.3Hz,1H,Ar-H),7.03(s,1H,Ar-H),6.86(d,J＝8.3Hz,1H,Ar-H),3.55-3.52(m,4H,CH2),3.39(m,4H,CH2),1.40(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:163.59,153.98,150.95,146.56,145.84,128.85,124.72,123.81,117.22,116.00,106.17,79.47,51.21(2),49.03(2),28.22(3)。
(3) Preparation of (E) - α -cyano-3, 4-dihydroxycinnamoyl piperazine: the procedure was as in (3) of example 1. The (E) -4-Boc-1- (alpha-cyano-3, 4-dihydroxycinnamoyl) piperazine obtained in the above step was charged to give 1.60g of a light brown solid, and the yield was 93.4%.1H NMR(400MHz,CDCl3)δ:9.63(s,2H,2×OH),8.16(s,1H),7.61(d,J＝8.7Hz,1H),7.03(s,1H,Ar-H),6.93(d,J＝8.7Hz,1H),3.36(m,4H),2.87(m,4H),1.23(br,1H)；13C NMR(101MHz,CDCl3)δ:166.52,150.93,146.55,145.83,128.84,124.73,123.82,117.23,116.00,106.17,51.21(2),47.03(2)。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure is as in (4) of example 1.
(5) Preparation of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (α -cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamide was replaced by 150.3mg (0.55mmol) of (E) - α -cyano-3, 4-dihydroxycinnamoylpiperazine. The resulting product was subjected to silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to obtain 145.7mg of a pale yellow solid, which was obtained in 53.8% yield.1H NMR(400MHz,DMSO-d6)δ:9.52(s,2H,2×Ar-OH),8.36(s,1H,Ac-NH-),8.13(s,1H,Ar-CH＝),7.53(d,J＝8.1Hz,1H),7.33(m,5H,Ar-H),7.08(s,1H,Ar-H),6.95(d,J＝8.1Hz,1H),4.75(m,1H,-CO-CH-N-),4.67(s,2H,Ar-CH2 O-),3.62(m,1H),3.53(m,4H),3.39(m,4H),3.33(m,1H),1.86(s,3H,CH3-CO-) (see fig. 1);13C NMR(101MHz,DMSO-d6)δ:172.61,170.13,168.04,151.22,146.63,145.92,138.05,129.31,128.64(2),127.81,127.47(2),123.18,116.97,115.92,115.17,107.15,72.33,69.98,54.91,49.53(2),48.95(2),22.94.ESI-MS(m/z):493.4C26H29N4O6([M+H]+) (see FIG. 2); HR-ESI-MS (m/z):493.2087 (see FIG. 3);
(C＝2,CH3OH).
the above data demonstrate that the compound is (E) -4- (N-acetyl-O-benzyl-D-serinyl) -1- (α -cyano-3- (3, 4-dihydroxyphenyl) acryloyl) piperazine (CHR-5N-G) and has the following structure:
example 7
(E) Preparation of-4- (N-acetyl-O-benzyl-D-seryl) -1- (α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acryloyl) piperazine (CHR-5N-H) comprising the following five steps:
(1) the procedure was as in (1) of example 5.
(2) Preparation of (E) -4-Boc-1- (α -cyano-3-hydroxymethyl-4-hydroxycinnamoyl) piperazine: the procedure was as in (2) of example 5. 2.29g (11.0mmol) of 4-N-Boc-aminoaniline was changed to 2.05g (11.0mmol) of N-Boc-piperazine. 2.55g of light yellow solid is obtained with a yield of 65.8%.1H NMR(400MHz,CDCl3)δ:9.63(s,1H,Ar-OH),8.13(s,1H,＝CH),7.48(d,J＝8.2Hz,1H,Ar-H),7.31(d,J＝8.2Hz,1H,Ar-H),7.13(s,1H,Ar-H),7.05(s,1H,Ar-H),4.65(s,2H,O-CH2-Ar),3.36(m,4H,CH2),3.32(m,4H,CH2),1.43(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:167.52,155.46,154.81,150.65,129.85,128.73,128.15,126.32,117.22,116.07,115.85,106.94,79.86,51.03(2),48.81(2),28.52(3)。
(3) Preparation of (E) - α -cyano-3-hydroxymethyl-4-hydroxycinnamoylpiperazine: the procedure was as in (3) of example 1. The (E) -4-Boc-1- (alpha-cyano-3-hydroxymethyl-4-hydroxycinnamoyl) piperazine obtained in the above step was charged to give 1.75g of a light brown solid in a yield of 92.5%.1H NMR(400MHz,CDCl3)δ:9.65(s,1H,Ar-OH),8.16(s,1H,＝CH),7.45(d,J＝8.2Hz,1H,Ar-H),7.29(d,J＝8.2Hz,1H,Ar-H),7.12(s,1H,Ar-H),7.04(s,1H,Ar-H),4.62(s,2H,O-CH2-Ar),3.25(m,4H,CH2),2.82(m,4H,CH2),1.08(br,1H)；13C NMR(101MHz,DMSO-d6)δ:167.71,155.47,150.58,129.93,128.81,128.09,126.26,116.05,115.83,106.96,51.62(2),47.33(2)。
(4) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of (E) -4- (N-acetyl-O-benzyl-D-seryl) -1- (α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acryloyl) piperazine: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamoyl amide was replaced with 158.1mg (0.55mmol) of (E) - α -cyano-3-hydroxymethyl-4-hydroxycinnamoyl piperazine. After silica gel column chromatography (chloroform: methanol: 40:1, V: V), the mixture was separated and purified by gradient elution to obtain 153.8mg of a pale yellow solid with a yield of 55.2%.1H NMR(400MHz,DMSO-d6)δ:9.63(s,1H,Ar-OH),8.33(s,1H,Ac-NH-),8.12(s,1H,Ar-CH＝),7.49(d,J＝8.2Hz,1H),7.33(m,5H,Ar-H),7.29(d,J＝8.2Hz,1H),7.05(s,1H,Bn-OH),4.76(m,1H,-CO-CH-N-),4.66(s,2H,Ph-CH2O-),4.63(s,2H,Ar-CH2O-),3.59(m,1H),3.48(m,4H),3.36(m,4H),3.32(m,1H),1.87(s,3H,CH3-CO-)；13C NMR(101MHz,DMSO-d6)δ:170.73,169.84,167.23,155.45,150.56,137.52,129.61,128.75,128.62(2),128.03,127.83,127.52(2),126.18,116.06,115.83,107.13,72.35,70.02,60.51,54.93,49.46(2),48.94(2),22.95.ESI-MS(m/z):507.6C27H31N4O6([M+H]+)；
(C＝2,CH3OH).
The above data demonstrate that this compound is (E) -4- (N-acetyl-O-benzyl-D-serinyl) -1- (α -cyano-3- (3-hydroxymethyl-4-hydroxyphenyl) acryloyl) piperazine (CHR-5N-H), having the structure:
example 8
The preparation of N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) -6-hydroxy-beta-naphthamide (CHR-5Y-E1) comprising the following four steps:
(1) preparation of N- (N-Boc-4-aminocyclohexyl) -6-hydroxy- β -naphthylamide: the procedure was as in (2) of example 2. 1.89g (10.0mmol) of 4-hydroxy-alpha-cyanocinnamic acid was changed to 1.88g (10.0mmol) of 6-hydroxy-beta-naphthoic acid to give 3.63g of a pale yellow solid with a yield of 94.5%.1H NMR(300MHz,DMSO-d6)δ:9.99(s,1H,OH),8.33(s,1H,＝CH-CO),8.07(m,1H,Ar-H),7.85(m,2H,Ar-H),7.72(m,2H),7.46(m,1H),7.26(m,1H),3.88(m,1H),3.46(m,1H),1.78(s,4H,CH2),1.59(s,4H,CH2),1.39(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:166.95,157.73,154.99,134.94,131.48(2),130.92,129.09,127.41,126.65,125.75,124.70,119.32,108.62,77.44,53.76,51.61,28.71(2),28.63(2),28.41(3)。
(2) Preparation of N- (4-aminocyclohexyl) -6-hydroxy- β -naphthylamide: the procedure was as in (3) of example 1. The N- (N-Boc-4-aminocyclohexyl) -6-hydroxy-beta-naphthamide obtained in the above step was added to give a light brown solid (2.45 g), yield 91.2%.1H NMR(300MHz,DMSO-d6)δ:9.28(s,1H,OH),8.31(s,1H),8.08(m,1H,Ar-H),7.83(m,2H,Ar-H),7.72(m,1H),7.46(s,1H),7.28(m,1H),3.88(m,1H),3.55(m,1H),2.58(m,1H),1.78(m,2H,CH2),1.73(m,2H),1.54(m,2H),1.51(m,2H)；13C NMR(101MHz,DMSO-d6)δ:167.23,158.13,133.54,131.81,131.32,130.93,128.29,126.67,124.73,118.35,109.14,51.65,50.32,31.41(2),28.73(2)。
(3) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(4) Preparation of N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) -6-hydroxy- β -naphthylamide: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamamide was replaced by 156.4mg (0.55mmol) of N- (4-aminocyclohexyl) -6-hydroxy- β -naphthamide. The resulting extract was subjected to silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to obtain 181.4mg of a pale yellow solid with a yield of 65.5%.1H NMR(300MHz,CDCl3)δ:10.06(s,1H,OH),8.34(s,1H,Ac-NH-),8.31(s,1H,Ar-H),8.14(d,J＝7.4Hz,1H,-NH-CO-),8.08(d,J＝8.7Hz,1H,Ar-H),7.81(m,2H,Ar-H),7.72(d,J＝8.7Hz,1H,Ar-H),7.45(s,1H,Ar-H),7.34(m,5H,Ar-H),7.26(m,1H,Ar-H),4.67(m,1H,CO-CH-NH),4.62(s,2H,Ar-O-CH2-),3.58(m,1H),3.53(m,2H),3.34(m,1H),1.88(s,3H,CH3-CO-),1.81(m,2H),1.76(m,2H),1.53(m,2H),1.49(m,2H)；13C NMR(101MHz,DMSO-d6)δ:171.42,170.69,167.18,158.14,138.25,135.95,130.49,129.07,128.20,127.45,126.62,125.75,124.76,119.36,108.63,72.03,70.29,52.49,46.84,45.22,28.01,27.47,22.56.ESI-MS(m/z):526.7C29H33N3O5([M+Na]+)；
(C＝2,CH3OH)。
The above data confirm that this compound is N- (4- (N-acetyl-O-benzyl-D-seryl) aminocyclohexyl) -6-hydroxy- β -naphthamide (CHR-5Y-E1), the structure of which is shown below.
Example 9
The preparation of 4- (N-acetyl-O-benzyl-D-seryl) -1- (6-hydroxy- β -naphthoyl) piperazine (CHR-5Y-G) comprises the following four steps:
(1) preparation of 4-Boc-1- (6-hydroxy- β -naphthoyl) piperazine: the procedure was as in (2) of example 3. 1.89g (10.0mmol) of 4-hydroxy-alpha-cyanocinnamic acid was replaced with 1.88g (10.0mmol) of 6-hydroxy-beta-naphthoic acid to give 2.34g of a pale yellow solid in 65.8% yield.1H NMR(400MHz,CD3OD)δ:9.23(s,1H,OH),8.31(s,1H,Ar-H),8.08(d,J＝8.5Hz,1H,Ar-H),7.77(d,J＝9.7Hz,1H,Ar-H),7.69(d,J＝8.5Hz,1H,Ar-H),7.41(s,1H,Ar-H),7.26(d,J＝9.7Hz,1H，Ar-H),3.61(m,4H,CH2),3.35(m,4H),1.47(s,9H,3×CH3)；13C NMR(101MHz,CD3OD)δ:172.87,157.82,155.95,136.89,131.81,131.32,130.89,128.47,126.59,125.12,120.26,118.33,109.70,81.39,50.92(2),49.81(2),28.39。
(2) Preparation of 6-hydroxy- β -naphthoylpiperazine: the procedure was as in (3) of example 1. The 4-Boc-1- (6-hydroxy-. beta. -naphthoyl) piperazine obtained in the above step was charged to give 1.55g of a pale brown solid, yield 91.8%.1H NMR(400MHz,CD3OD)δ:9.21(s,1H,OH),8.29(s,1H,Ar-H),8.10(d,J＝8.3Hz,1H,Ar-H),7.79(d,J＝9.5Hz,1H,Ar-H),7.68(d,J＝8.3Hz,1H,Ar-H),7.43(s,1H,Ar-H),7.28(d,J＝9.5Hz,1H，Ar-H),3.48(m,4H,CH2),2.92(m,4H)；13C NMR(101MHz,CD3OD)δ:169.02,158.23,134.04,131.78,131.29,130.89,128.36,126.65,124.80,118.33,109.20,52.67(2),47.11(2)。
(3) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(5) Preparation of 4- (N-acetyl-O-benzyl-D-seryl) -1- (6-hydroxy- β -naphthoyl) piperazine: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamamide was replaced with 141.0mg (0.55mmol) of 6-hydroxy- β -naphthoylpiperazine. The resulting product was subjected to silica gel column chromatography (chloroform: methanol: 40:1, V: V) and gradient elution to separate and purify the product, to obtain 136.8mg of a pale yellow solid, with a yield of 52.3%.1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H,Ar-OH),8.35(d,J＝8.1Hz,1H,Ar-H),8.30(s,1H,Ar-H),8.25(d,J＝8.2Hz,1H,Ar-H),7.84(d,J＝8.6Hz,1H,Ar-H),7.68(d,J＝8.2Hz,1H),7.32(m,5H,Ar-H),7.28(d,J＝8.6Hz,1H,Ar-H),4.75(m,1H,-CO-CH-N-),4.62(s,2H,Ar-CH2-O),3.58(m,1H),3.61(m,4H),3.52(m,4H),3.35(m,1H),1.85(s,3H,CH3CO-)；13C NMR(101MHz,DMSO-d6)δ:170.59,169.72,168.85,158.19,137.56,134.07,131.18,130.93,128.65(2),128.27,127.61,127.53,127.46,126.90,126.71,126.13,124.87,119.43,108.66,72.19,69.64,50.02(2),49.42(2),22.93.ESI-MS(m/z):474.5C27H29N3O5([M-H]+)；
(C＝2,CH3OH).
The above data demonstrate that this compound is 4- (N-acetyl-O-benzyl-D-seryl) -1- (6-hydroxy- β -naphthoyl) piperazine (CHR-5Y-G) and has the following structure:
example 10
The preparation of 3-N- (N-acetyl-O-benzyl-D-seryl) -7-hydroxy-3-quinolinecarboxylatepropanediamine (CHR-5H) comprises the following four steps:
(1) preparation of N- (3-N-Boc-aminopropyl) -7-hydroxy-3-quinolinecarboxamide: the procedure was as in (2) of example 1. 1.89g (10.0mmol) of 4-hydroxy- α -cyanocinnamic acid was replaced by 1.89g (10.0mmol) of 7-hydroxy-3-quinolinecarboxylic acid; 2.29g (11.0mmol) of 4-N-Boc-aminoaniline was replaced with N-Boc-1,3-propanediamine 1.92g (11.0mmol) gave 2.51g of a pale yellow solid in a yield of 72.7%.1H NMR(400MHz,DMSO-d6)δ:9.42(s,1H,Ar-OH),8.83(s,1H,-C-CH＝C-),8.63(s,1H,-N＝CH-),8.35(m,1H，ArCO-NH-),7.90(d,J＝8.9Hz,1H,NH),7.47(m,2H,Ar-H),6.80(m,1H,-NH-Boc),3.21(m,4H),1.78(m,2H),1.37(s,9H,3×CH3)；13C NMR(101MHz,DMSO-d6)δ:166.1,160.5,156.1,149.7,146.5,136.3,131.6,125.9,124.6,119.1,110.5,79.7,39.6,37.3,28.8,28.5(3)。
(2) Preparation of N- (3-aminopropyl) -7-hydroxy-3-quinolinecarboxamide: the procedure was as in (3) of example 1. The N- (3-N-Boc-aminopropyl) -7-hydroxy-3-quinolinecarboxamide obtained in the above step was charged to give 1.54g of a light brown solid in a yield of 95.3%.1H NMR(400MHz,DMSO-d6)δ:9.39(s,1H,Ar-OH),8.81(s,1H,-C-CH＝C-),8.64(s,1H,-N＝CH-),8.34(m,1H,ArCO-NH-),7.87(d,J＝8.9Hz,1H,NH),7.45(m,2H,Ar-H),3.19(m,2H),2.69(m,2H),1.89(m,2H)；13C NMR(101MHz,DMSO-d6)δ:165.8,160.3,149.6,146.4,136.1,131.7,125.8,124.5,119.2,110.6,39.2,35.8,28.6。
(3) Preparation of N-acetyl-O-benzyl-D-serine: the procedure was as in (4) of example 1.
(4) Preparation of 3-N- (N-acetyl-O-benzyl-D-seryl) -7-hydroxy-3-quinolinecarboxylatepropanediamine: the procedure was as in (5) of example 1. 153.6mg (0.55mmol) of (E) -N- (4-aminophenyl) - α -cyano-4-hydroxycinnamamide was replaced by 134.9mg (0.55mmol) of N- (3-aminopropyl) -7-hydroxy-3-quinolinecarboxamide. After silica gel column chromatography (chloroform: methanol: 40:1, V: V), the mixture was separated and purified by gradient elution to obtain 167.8mg of a pale yellow solid with a yield of 65.7%.1H NMR(400MHz,DMSO-d6)δ:10.49(s,1H,OH),9.13(s,1H,＝CH-CO),8.65(s,1H,-N＝CH-),8.43(s,1H,ArCO-NH-),8.33(m,1H,Ac-NH-),8.03(m,1H,-NH-CO),7.90(d,J＝8.8Hz,1H,Ar-H),7.47(m,2H,Ar-H),7.32(m,5H),4.74(m,1H,CO-CH-N),4.61(s,2H,-CH2-OAr),3.61(m,1H),3.32(m,1H),3.17(m,4H),2.36(m,2H),1.85(s,3H,CH3CO-)；13C NMR(101MHz,DMSO-d6)δ:173.32,170.91,165.73,160.22,150.65,149.16,137.90,136.15,131.64,128.56(2),127.69,127.42(2),125.48,124.38,120.88,119.06,110.11,73.00,70.11,57.44,39.52,37.35,28.67,22.25.ESI-MS(m/z):465.6C25H28N4O5([M+H]+)；
(C＝2,CH3OH).
The above data demonstrate that this compound is 3-N- (N-acetyl-O-benzyl-D-seryl) -7-hydroxy-3-quinolinecarboxylatepropanamine (CHR-5H), and has the following structure:
according to the synthetic routes and methods of the compounds of formula I disclosed in the present application, and the synthetic methods of the specific compounds of examples 1-10, those skilled in the art can adjust the raw materials involved in the synthetic methods according to the structures of the target products, so as to synthesize other compounds listed in table 1, which are not listed here.
Example 11
Inhibitory Activity of Compounds in Table 1 against aldose reductase
In the present invention, Aldose Reductase (AR), reduced coenzyme II (NADPH), DL-glyceraldehyde were purchased from Sigma; epalrestat (Epalrestat) was purchased from tokyo chemical industry co.
The experimental steps are as follows: the enzyme reaction system is carried out on a 96-well plate, and comprises: PBS buffer (pH 6.2)100 μ L, 1.5mmol/L NADPH 20 μ L, 100mmol/L DL-glyceraldehyde 20 μ L, different concentration (Epalrestat or test sample) solutions 20 μ L, AR dilutions 20 μ L, distilled water 20 μ L. The experimental setup was blank control, standard control, enzyme metabolism group as in table 2-1.
TABLE 2-1 grouping and dosing
Note: all volume units above are μ L.
After the liquid is incubated for 5min at 37 ℃,20 mu L of AR is added into each group except a blank solvent group to start reaction, a 96-well plate is rapidly placed into a fluorescence microplate reader, the temperature is 37 ℃, the detection wavelength is 340nm, the change condition of NADPH absorbance is continuously detected, the detection is carried out once every 30s, and the total detection time is 30 min.
According to the results measured by the experiment, the descending values A of blank group NADPH absorbance are respectively calculated0Decrease in enzyme Activity group (No sample) NADPH Absorbance A1NADPH absorbance decrease values A of the Epalrestat group and the test sample groupEPS、A2. The inhibition rate was determined by using the change in NADPH absorbance of each group:
sample inhibition rate for AR/% - [1- (a)2-A0)/(A1-A0)]×100％。
According to the enzyme reaction experiment result, the final concentration of the sample is used as the abscissa, the inhibition rate is used as the ordinate, an inhibition curve is drawn, and the IC of different samples is calculated according to the kinetic curve50. All data are used
Data statistics are shown to be processed by the SPSS10.0 software, with the inter-group comparisons tested with t. IC of positive control Epalrestat was determined5075.64 + -4.22. Obtaining IC of target end product by the above method50The results are shown in Table 2-2:
TABLE 2-2 IC of the target Compounds50Value of
As can be seen from Table 2-2 and FIG. 4, the compound CHR-5N-G has the best inhibitory activity on aldose reductase in vitro, which is significantly stronger than the positive control drug epalrestat, and is also significantly stronger than the compound CHR-532R reported in patent CN 201410723116.8 and the compound CHR-5N-D reported in patent CN 201710372369.9;
except that the compounds CHR-5N-E, CHR-5Y-1 and CHR-5H-E, CHR-5H-G, CHR-5H-H showed weaker enzyme inhibitory activity than the positive drug epalrestat, the in vitro inhibitory activity of other compounds on aldose reductase is stronger than that of the positive control drug.
Example 12
In vitro antioxidant Activity of the Compounds in Table 1
In this embodiment, Trolox (6-Hydroxy-2,5,7, 8-tetramethylhydroxychroman-2-carboxylic acid); 1, 1-diphenylyl-2-piperidinylhydrazyl (DPPH) was purchased from Sigma.
The experimental steps are as follows: the reaction system was performed in a 96-well plate, and 40. mu.L of each sample solution was added to the 96-well plate, and then 160. mu.L of DPPH solution was added in parallel to each well. A control group (40. mu.L methanol + 160. mu.L DPPH) and a blank group (40. mu.L test sample + 160. mu.L methanol) were also set. Shaking for 1min to mix well, standing 96-well plate in dark condition for 0.5 hr, quickly placing the plate in microplate reader, and detecting wavelength at 517 nm. The final absorbance (A) values were measured and each sample was run in triplicate and averaged. The clearance rate is calculated as follows:
radical scavenging rate (%) ═ aControl of－(ASample(s)－ABlank space))/AControl×100％
AControl ofAbsorbance of control group without sample;
Asample (I)Is the absorbance of the reaction solution after the test sample is added;
Ablank spaceAbsorbance of blank group.
All data are used
Data statistics are shown to be processed by the SPSS10.0 software, with the t-test for inter-group comparisons. The results are shown in Table 3-1.
TABLE 3-1 inhibition of DPPH by the target Compounds at a concentration of 100. mu.M
The inhibition of DPPH by the compounds examined at 100. mu.M is shown in Table 3-1. As can be seen from Table 3-1, all the compounds examined showed a certain degree of free radical scavenging rate, wherein the in vitro antioxidant activity of CHR-5Y-2, CHR-5Y-3 and CHR-5Y-E2 is stronger than that of the positive control Trolox.
For compounds with outstanding inhibitory activity and positive controls, to facilitate comparison of their inhibitory activity, a histogram of concentration-inhibition at three concentrations of 25 μ M, 12.5 μ M, 6.25 μ M is generated as shown in FIG. 5:
the half clearing concentration of Trolox, CHR-5Y-2 and CHR-5Y-3, namely EC is obtained by linear regression analysis of the logarithm of the concentration and the inhibition rate of the compound50The results are shown in Table 3-2.
TABLE 3-2 Compounds correspond to EC50Value of
As can be seen from the results of Table 3-2, the compounds CHR-5Y-2 and CHR-5Y-3 are superior in oxidation resistance and stronger than the positive drug Trolox.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A linear head-to-tail diamine bridged compound characterized by having the structure shown in formula I:
in the structure of formula I, the X group has a structure as shown in formula II-1, formula II-2 or formula II-3:
in the structures shown in the formula II-1, the formula II-2 and the formula II-3, R is monohydroxy substituent, dihydroxy substituent or hydroxy and hydroxymethyl substituent;
the Z group is methyl, isopropyl or cyclopropyl.
2. The compound of claim 1, wherein: r is a dihydroxy substitution or when hydroxy and hydroxymethyl are disubstituted, ortho substitution is performed.
3. The compound of claim 1, wherein: in the structure shown in the formula I, p is 1-6.
4. The compounds shown in table 1:
TABLE 1
5. A pharmaceutically acceptable salt of a compound of any one of claims 1 to 4.
6. A process for the preparation of a compound according to claims 1-3, characterized in that it comprises the following steps:
(1) preparation of N-t-Butoxyacyl protected substituted acyl diamine: dissolving carboxylic acid in a solvent, adding a coupling reagent with the molar weight of 1.0-3.0 times that of the carboxylic acid, stirring and reacting for 10-40 min at-20-0 ℃, then adding a head-tail diamine with one end protected by N-tert-butoxy acyl and an organic base with the molar weight of 1.0-3.0 times that of the carboxylic acid, stirring and reacting for 30-60 min at-20-0 ℃, heating to 30-60 ℃, and continuing stirring and reacting for 24-36 h; after the reaction is finished, removing the solvent by rotary evaporation, and purifying the concentrate by silica gel column chromatography to obtain acyl head-tail diamine protected by one end of N-tert-butoxy acyl;
the carboxylic acid has a structure shown in a formula II-1 ', a formula II-2 ' or a formula II-3 ':
the head and tail diamine protected by one end of N-tert-butoxy acyl has a structure shown in a formula III-1':
(2) mono-acyl head-to-tail diamine at one end: dissolving acyl head and tail diamine protected by one end of N-tert-butoxy acyl in a solvent, slowly adding a 4M hydrochloric acid solution of which the molar weight is 5-20 times that of the acyl head and tail diamine protected by one end of N-tert-butoxy acyl, and stirring and reacting for 3-6 hours at 0-40 ℃; after the reaction is finished, removing the solvent by rotary evaporation, and freeze-drying to obtain end-to-end monoacyl diamine;
(3) preparation of N-acylated-O-benzyl-D-serine: adding an acylation reagent with the molar weight of 1.0-5.0 times that of O-benzyl-D-serine into O-benzyl-D-serine, stirring and reacting for 4-9 h at 50-100 ℃, removing the solvent by rotary evaporation, and separating and purifying the concentrate by using high performance liquid chromatography to obtain N-acylation-O-benzyl-D-serine;
(4) preparation of a compound of the structure of formula I: dissolving N-acylation-O-benzyl-D-serine in a solvent, adding a coupling reagent with the molar weight of 1.0-3.0 times that of the N-acylation-O-benzyl-D-serine, and stirring and reacting at-20-0 ℃ for 10-40 min to obtain a solution A; dissolving the monoacyl end-to-end diamine prepared in the step (2) in a solvent, adding organic alkali with the molar weight 3.0-5.0 times that of the monoacyl end-to-end diamine, cooling to below-30 ℃, dropwise adding the solution A under stirring, keeping the temperature after dropwise adding, and stirring for 1-3 hours; heating to room temperature, and continuing to react for 20-40 h; after the reaction is finished, removing the solvent by rotary evaporation; purifying the concentrate by silica gel column chromatography to obtain a compound with a structure shown in formula I;
the acylating agent used in the step (3) is acid anhydride or acyl chloride.
7. Use of a compound according to any one of claims 1 to 4 or a salt according to claim 5 for the manufacture of a medicament for the treatment of disorders of carbohydrate metabolism.
8. Use of a compound according to any one of claims 1 to 4 or a salt according to claim 5 for the manufacture of a medicament for the treatment of a disease caused by oxidative stress.
9. Use of a compound according to any one of claims 1 to 4 or a salt according to claim 5 in the manufacture of a medicament for the treatment of diabetic complications.
10. Use according to claim 9, characterized in that: the diabetic complications comprise diabetic retinopathy, diabetic nerve ending disorder and diabetic senile dementia.
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