CN110156872B - Tegafur derivative and preparation method and application thereof - Google Patents

Tegafur derivative and preparation method and application thereof Download PDF

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CN110156872B
CN110156872B CN201910443687.9A CN201910443687A CN110156872B CN 110156872 B CN110156872 B CN 110156872B CN 201910443687 A CN201910443687 A CN 201910443687A CN 110156872 B CN110156872 B CN 110156872B
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tegafur
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CN110156872A (en
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刘爱芹
白著双
许士琪
郝超
朱礼岩
于胜海
庞靖祥
王风玲
初海平
王丹丹
袁晔
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Wuhan Jiuzhou Yumin Medical Technology Co ltd
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Abstract

The invention relates to a medicine for treating tumors, and belongs to the field of medicines. The tegafur derivative or the pharmaceutically acceptable salt thereof has the advantages that amino acid groups necessary for human health are introduced into drug molecules, the selectivity on tumor cells is improved, the solubility and the penetrability of drugs are enhanced, the toxicity of the drugs on the cells is relieved, the metabolism is weakened, the slow release performance is shown compared with tegafur drug molecules, and meanwhile, the safety problem of amino acid modified prodrugs is controllable due to the safety of amino acids.

Description

Tegafur derivative and preparation method and application thereof
Technical Field
The invention relates to a medicinal compound, in particular to a tegafur derivative and a preparation method and application thereof.
Background
The malignant tumor is a chronic disease and a disease threatening the health of human, the incidence rate and the mortality rate of the cancer in the world are on the rising trend year by year since the second half of the 20 th century, and according to the statistics of the annual report of tumor registration in 2015, 312 ten thousand cases of cancer are newly added in the country, and 6 people are diagnosed as cancer every minute. The incidence of cancer is not only gradually increasing, but the age of onset also tends to be younger. The world health organization predicts that cancer will be the "first killer" in humans in the 21 st century. Tumors are worldwide diseases and one of the most fierce killers of human health, and many researchers at home and abroad carry out various researches on early diagnosis and treatment of the tumors. With the rise of metabonomics, the metabolic characteristics of tumors are more and more emphasized. The tumor tissue has obvious metabolic abnormal conditions which are mainly reflected in the enhancement of the protein synthesis and the weakening of the amino acid decomposition of the tumor tissue, and the conditions are adapted to the vigorous growth of tumor cells. Amino acids are protein synthesis raw materials and catabolites, and changes in their composition and concentration reflect the metabolic status of the patient. The rapid growth of tumor tissue and the unlimited proliferation of cells require the uptake and consumption of large amounts of amino acids, resulting in defects in the amino acid metabolism of the body. Studies have shown that tumor amino acid metabolism is specific and presents inconsistencies in serum amino acid levels in patients with esophageal carcinoma, osteosarcoma, lymphoma, soft tissue sarcoma, and metastatic tumors. In addition, staging of tumors can also affect amino acid levels in vivo, with decreased liver storage function, and increased concentrations of tyrosine, methionine, and phenylalanine in liver cancer patients.
Malignant tumor is a common disease and frequently occurring disease which seriously threatens human health, and the mortality of human caused by the malignant tumor accounts for the second place of all the mortality, and is only second to cardiovascular and cerebrovascular diseases. Since the development of 5-fluorouracil (5-Fu), it has occupied an important position in tumor therapy. While 5-Fu inhibits tumor cell proliferation, it is also highly toxic to normal cells, mainly manifested as bone marrow suppression and gastrointestinal discomfort. In order to search for 5-Fu derivatives with small toxic and side effects and high activity, people carry out a great deal of structural modification work and pharmacodynamic research on 5-Fu, and successively develop various derivatives of 5-Fu such as tegafur, carmofur and the like, which are used for improving the lipid solubility of medicines, reducing the toxicity and improving the bioavailability.
During the growth of tumor, the tumor tissue continuously transports various essential amino acids and nonessential amino acids in the plasma of the body to the tumor tissue and cells in order to meet the requirements of self-synthesis of protein and cell proliferation. Based on the special requirement of tumor cells on amino acid, amino acid derivatives have been widely used as antitumor drugs, and many researchers use amino acid to structurally modify various antitumor drugs by combining the structural characteristics and structure-activity relationship of the antitumor drugs so as to search for the antitumor drugs with high efficiency and good selectivity. The action mode of the amino acid as the anticancer drug is (1) the antitumor drug taking the amino acid as a carrier, such as phenylalanine mustard gas, L-valine, L-glutamic acid, L-lysine and phenylenediamine mustard co-conjugate. (2) The amino acid derivative is used as structural analogue of amino acid required by tumor cell to reach the aim of resisting tumor, such as S-carbamoyl-L-cysteine. (3) The amino acid derivative is used as an antitumor drug of an enzyme inhibitor. For example, N-acetyl-L-aspartate is an inhibitor of aspartate aminotransferase, which can interrupt the pyrimidine nucleotide synthesis pathway to achieve the anti-tumor purpose. (4) Amino acid derivatives as intermediate products for tumor inhibitors. (5) Amino acid derivatives that reverse cancer cells.
At present, 5-Fu derivative tegafur is used as a parent body for structural modification, (1) rhein and the tegafur derivative are coupled to synthesize a novel bone-targeted rhein derivative, and the xanthic acid-N-beta-hydroxyethyl tegafur ester has good bone affinity. (2) The imide structure is introduced, and the antitumor activity of part of tegafur derivatives is improved compared with tegafur. (3) Seleno-phospholipid (ester) -tegafur conjugate is synthesized, and has the characteristic of easy penetration of cell membranes.
Disclosure of Invention
The invention aims to provide a tegafur derivative, and solves the problems of high toxicity and low bioavailability of tegafur and derivatives at present.
Technical scheme
A tegafur derivative or a pharmaceutically acceptable salt thereof, having the following structural formula:
Figure RE-GDA0002106364440000031
wherein R-H is an amino acid or an amino acid derivative or a peptide chain of 2-8 amino acid aggregates, and the R-H forms an amido bond with a carbonyl group in the formula I through an amino group in an amino acid or a derivative molecule thereof.
Further, R-H is selected from:
natural L-configuration alpha-amino acid and corresponding D-configuration alpha-amino acid, and ester derivatives corresponding to the amino acids;
or unnatural alpha-amino acid with L configuration and corresponding alpha-amino acid with D configuration, and ester derivatives corresponding to the amino acids;
or various non-natural beta-amino acids, gamma-amino acids, amino acids with amino groups separated from carboxyl groups by no more than 10 carbon atoms, corresponding amino acids with D configuration, and ester derivatives corresponding to the amino acids.
Further, R-H is selected from natural L-configuration alpha-amino acid and corresponding D-configuration alpha-amino acid, and derivatives thereof, and common natural L-configuration alpha-amino acid is mainly selected from the following amino acids:
a. alkyl amino acids: including L-phenylalanine (L-Phe), alanine (L-Ala), glycine (Gly), leucine (L-Leu), isoleucine (L-Ile), valine (L-Val);
b. amino acid containing amino groups, including: histidine (L-His), arginine (L-Arg), glutamine (L-Gln), lysine (L-Lys), proline (L-Pro), asparagine (L-Asn), tryptophan (L-Trp);
c. amino acids containing two carboxyl groups: mainly comprises aspartic acid (L-Asp) and glutamic acid (L-Glu);
d. thiol-containing amino acids: mainly comprises cysteine (L-Cys) and methionine (L-Met);
e. hydroxyl group-containing amino acids: the method mainly comprises the following steps: serine (L-Ser), tyrosine (L-Tyr) and threonine (L-Thr).
The amino acid structure is as follows:
Figure RE-GDA0002106364440000041
further, the ester derivative corresponding to the amino acid means that a carboxyl group in the amino acid molecule is converted into a methyl ester or an ethyl ester.
Furthermore, enantiomers of the natural L-configuration amino acid and the amino acid ester derivative.
Further, the non-natural L-configuration α -amino acid is preferably:
Figure RE-GDA0002106364440000051
further, the above-mentioned unnatural α -amino acid in D configuration is preferably:
Figure RE-GDA0002106364440000052
further, the unnatural β -amino acids, γ -amino acids, and amino acids having an amino group separated from a carboxyl group by no more than 10 carbon atoms have the formula:
Figure RE-GDA0002106364440000053
further, the alpha amino acids R-H are preferably selected from one of the following amino acid esters or amino acids or their corresponding amino acid esters of opposite configuration or corresponding amino acids of opposite configuration:
Figure RE-GDA0002106364440000061
further, the R-H is selected from one of the following amino acid methyl esters or corresponding amino acids or corresponding amino acid ethyl esters:
Figure RE-GDA0002106364440000062
a process for producing the tegafur derivative described above, comprising: (1) reacting tegafur with chloroacetic ester under strong alkaline condition; (2) hydrolyzing the obtained product under alkaline condition to obtain carboxylic acid; (3) the carboxylic acid and the amino acid ester react under the condition of a condensing agent to obtain the tegafur amino acid ester derivative. The derivatives of amino acids can be obtained by further processing the product obtained by the reaction of carboxylic acid and amino acid ester. For example, carboxylic acids can be obtained by direct alkaline conditional hydrolysis of the amino acid esters obtained. For their salts, they are obtained by reacting carboxylic acids with the corresponding bases. The general reaction formula is as follows:
Figure RE-GDA0002106364440000071
where R1 ═ Me, Et, where R — H represent the various amino acids described above, i.e.:
natural L-configuration alpha-amino acid and corresponding D-configuration alpha-amino acid, and their derivatives;
non-natural L-configuration alpha-amino acids and corresponding D-configuration alpha-amino acids, and derivatives thereof;
various non-natural beta-amino acids, gamma-amino acids and their corresponding D-configuration amino acids, and their derivatives;
a pharmaceutical composition comprising: tegafur derivatives represented by general formula (I) and pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.
The tegafur derivative shown in the general formula I and the application of the pharmaceutically acceptable salt thereof in preparing the medicines for treating various tumor diseases. Preferably, the compounds are used for the treatment of prostate, lung, breast, liver, stomach, cervical, colon and epithelial cancers.
Advantageous effects
The invention introduces amino acid group essential to human health into drug molecules, improves the selectivity to tumor cells, enhances the solubility and penetrability of the drug, relieves the toxicity of the drug to cells, weakens the metabolism, shows slow release performance compared with tegafur drug molecules, and simultaneously has controllable safety problem of amino acid modified prodrug due to the safety of the amino acid. In a subsequent biological activity experiment, the tegafur amino acid derivative provided by the technical scheme has a better tumor cell apoptosis induction effect, is higher in bioavailability, and has a medical application prospect compared with tegafur.
Detailed Description
The invention will be further illustrated with reference to the following specific examples.
Amino acids are the most basic substances in life activities and the material basis of life metabolism, and the amino acid metabolism generally exists in various tissues and cells of the body and has important physiological functions of participating in the synthesis of proteins, energy metabolism and the like of the body. The amino acid requirements of tumor cells are much greater than for normal tissues. During the growth of tumor, the tumor tissue continuously transports various essential amino acids and nonessential amino acids in the plasma of the body to the tumor tissue and cells in order to meet the requirements of self-synthesis of protein and cell proliferation. Therefore, the transport rate of malignant tumor cells to amino acid can be increased, and the amino acid is introduced into anti-tumor drug molecules, so that the selectivity of the anti-tumor drug molecules to tumor cells can be improved, and the aim of killing tumor tissues and cells is fulfilled.
Therefore, the amino acid is introduced into the anti-tumor drug molecules, so that the selectivity of the drug to tumor cells is improved, the lipid solubility of the drug is enhanced, and the toxicity of the drug to the cells is relieved. More and more pharmaceutical researchers use amino acids to modify the structure of various anti-cancer drugs in sequence, and study the in vivo and in vitro anti-tumor activity and toxicity of the anti-cancer drugs so as to provide high-efficiency and low-toxicity anti-tumor drugs for clinic.
The present invention provides various preparation examples of tegafur amino acid derivatives, and the compounds of the present invention and the preparation methods thereof will be better understood from the following examples:
Figure RE-GDA0002106364440000091
wherein R-H is selected from amino acids, esters and derivatives thereof.
Example 1: preparation of Compound 5a
Figure RE-GDA0002106364440000092
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), glycine methyl ester hydrochloride (1.00mmol,125.55mg,1.00eq) were stirred at room temperature for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain white solid 5 n.
1H NMR(400MHz,DMSO)8.64(t,J＝5.8Hz,1H),8.02(d,J＝6.7Hz,1H),5.99–5.90(m,1H),4.46(s,2H), 4.32–4.24(m,1H),3.88(d,J＝5.8Hz,2H),3.83(dd,J＝15.0,7.3Hz,1H)3.64(s,3H),2.31–2.21(m,1H),2.06– 1.89(m,3H).13C NMR(101MHz,DMSO)170.6,167.1,156.8(d,J＝26.1Hz),149.1,139.8(d,J＝228.3Hz), 124.5(d,J＝33.8Hz),87.8,70.1,52.23,43.4,41.3,32.1,24.0.
MS：330.0(M+H)
Example 2: preparation of Compound 5b
Figure RE-GDA0002106364440000101
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-alanine methyl ester hydrochloride (1.00mmol,139.60mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 a.
1H NMR(400MHz,DMSO)8.64(d,J＝7.0Hz,1H),8.02(d,J＝6.7Hz,1H),5.99–5.92(m,1H),4.44(q, J＝16.0Hz,2H),4.33–4.23(m,2H),3.82(q,J＝7.4Hz,1H),3.63(s,3H),2.33–2.18(m,1H),2.05–1.88(m, 3H),1.28(d,J＝7.2Hz,3H).13C NMR(100MHz,DMSO)173.3,166.3,156.8(d,J＝26.1Hz),149.1,139.8(d, J＝228.2Hz),124.5(d,J＝33.9Hz),87.8,70.1,52.4,48.1(d,J＝3.9Hz),43.2,32.1,24.0,17.6.
MS：344.0(M+H)
Example 3: preparation of Compound 5c
Figure RE-GDA0002106364440000102
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.50mL), L-valine methyl ester hydrochloride (1.00mmol,167.63mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 e.
1H NMR(400MHz,DMSO)8.56(d,J＝8.3Hz,1H),8.02(d,J＝6.6Hz,1H),5.96(m,1H),4.56-4.42(m, 2H),4.27(dd,J＝13.0,6.3Hz,1H),4.21(dd,J＝11.9,7.0Hz,1H)3.82(q,J＝7.3Hz,1H),3.65(s,3H),2.32– 2.20(m,1H),2.12–1.84(m,4H),0.92–0.84(m,6H).13C NMR(101MHz,DMSO)172.3,166.7,156.7(d,J＝ 26.2Hz),149.1,139.8(d,J＝228.3Hz),124.5(d,J＝34.6Hz),87.8,70.0,57.8(d,J＝3.7Hz),52.2,43.2,32.1, 30.7,24.0,19.4,18.6.
MS：372.0(M+H)
Example 4: preparation of Compound 5d
Figure RE-GDA0002106364440000111
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-leucine methyl ester hydrochloride (1.00mmol,181.55mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution.Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain orange yellow solid 5 c.
1H NMR(400MHz,DMSO-D6)8.53(t,J＝7.8Hz,1H),7.97(d,J＝6.6Hz,1H),5.94–5.88(m,1H),4.40 (s,2H),4.32–4.18(m,2H),3.78(q,J＝7.4Hz,1H),3.59(s,3H),2.30–2.12(m,1H),2.03–1.80(m,3H),1.49 (m,3H),0.85(d,J＝6.4Hz,3H),0.80(d,J＝6.3Hz,3H).13C NMR(101MHz,DMSO-D6)173.3,166.6,156.8 (d,J＝29.1Hz),149.2(s),139.9(d,J＝229.2Hz),124.5(d,J＝31.3Hz),87.9,70.1,52.4,50.9,50.8,43.4,43.3, 32.2,24.7,24.7,24.1,24.1,23.2,21.9,21.8.
MS：386.1(M+H)
Example 5: preparation of Compound 5e
Figure RE-GDA0002106364440000121
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-isoleucine methyl ester hydrochloride (1.00mmol,181.66mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 d.
1H NMR(400MHz,DMSO)8.58(d,J＝7.8Hz,1H),8.02(d,J＝6.6Hz,1H),6.02–5.88(m,1H),4.56– 4.38(m,2H),4.33–4.16(m,2H),3.89–3.74(m,1H),3.64(d,J＝9.1Hz,3H),2.32–2.20(m,1H),2.04–1.90 (m,3H),1.84–1.73(m,1H),1.49–1.32(m,1H),1.26–1.11(m,1H),0.85(t,J＝6.0Hz,7H).13C NMR(100 MHz,DMSO)172.3,172.3,166.7,156.8(d,J＝26.0Hz),156.8(d,J＝26.1Hz),149.1,139.8(d,J＝228.3Hz), 139.8(d,J＝228.4Hz),124.5(d,J＝33.6Hz),124.5(d,J＝33.7Hz),87.8,70.1,56.8(d,J＝2.5Hz),52.2,52.2,43.2,43.2,32.1,32.1,25.1,25.1,24.0,24.0,11.6.
MS：386.1(M+H)
Example 6: preparation of Compound 5f
Figure RE-GDA0002106364440000122
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-phenylalanine methyl ester hydrochloride (1.00mmol,215.68mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain yellow solid 5 b.
1H NMR(400MHz,DMSO-D6)8.65(d,J＝7.4Hz,1H),8.07–7.89(m,1H),7.33–7.09(m,5H),5.92–5.86 (m,1H),4.44–4.33(m,3H),4.26–4.15(m,1H),3.78(dd,J＝14.7,7.4Hz,1H),3.55(s,3H),3.07–2.76(m,2H), 2.30–2.15(m,1H),2.04–1.80(m,3H).13C NMR(101MHz,DMSO)172.1,166.6,156.7(d,J＝26.2Hz), 149.1,139.8(d,J＝229.3Hz),129.6,128.8,127.1,124.5(d,J＝33.6Hz),87.8,70.1,54.3,52.3,43.3,37.2,32.1,24.0.
MS：420.1(M+H)
Example 7: preparation of Compound 5g
Figure RE-GDA0002106364440000131
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-phenylglycine methyl ester hydrochloride (1.00mmol,201.65mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin drying to obtain 5 o.
1H NMR(400MHz,DMSO-D6)9.10(t,J＝4.6Hz,1H),7.97(d,J＝6.4Hz,1H),7.61–7.12(m,5H),5.97 –5.86(m,1H),5.39(dd,J＝6.9,3.6Hz,1H),4.49(ddd,J＝20.1,16.2,4.6Hz,2H),4.35–4.18(m,1H),3.85– 3.71(m,1H),3.59(d,J＝4.1Hz,3H),2.28–2.14(m,1H),2.00–1.82(m,3H).13C NMR(101MHz,DMSO-D6) 171.3,166.5,156.8(d,J＝25.5Hz),149.2,139.9(d,J＝228.6Hz),136.6,136.6,124.6(d,J＝33.9Hz),87.9, 70.1,56.8,52.9,43.3,32.2,24.1.
MS：406.1(M+H)
Example 8: preparation of Compound 5h
Figure RE-GDA0002106364440000132
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-proline methyl ester hydrochloride (1.00mmol,165.50mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 i.
1H NMR(400MHz,DMSO-D6)8.02–7.95(m,1H),5.99–5.88(m,1H),4.86–4.62(m,1H),4.61–4.46 (m,1H),4.31–4.16(m,2H),3.85–3.74(m,1H),3.70–3.31(m,5H),2.34–2.06(m,2H),2.01–1.76(m,6H).13C NMR(101MHz,DMSO-D6)172.6,164.7,156.7(d,J＝26.1Hz),149.1,139.8(d,J＝228.6Hz),124.7(d,J ＝33.6Hz),124.58(d,J＝33.5Hz),87.9,70.1,70.1,59.1,52.3,46.3,43.0,32.2,32.1,29.1,24.9,24.2,24.1.
MS：370.0(M+H)
Example 9: preparation of Compound 5i
Figure RE-GDA0002106364440000141
L-aspartic acid (1.00mmol, 133.00mg, 1.00eq) and anhydrous methanol (40mL) were stirred in an ice-water bath, after cooling, thionyl chloride (2.00mmol,238.00mg,2.00eq) was slowly added dropwise and stirring continued for 19 h. The solvent was spin dried to give a white granular solid.
Figure RE-GDA0002106364440000142
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-aspartic acid dimethyl ester hydrochloride (1.00mmol,233.00mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin drying to obtain 5 s.
1H NMR(400MHz,DMSO)8.74(dd,J＝7.9,3.4Hz,1H),8.02(d,J＝6.7Hz,1H),6.01–5.86(m,1H), 4.70–4.57(m,1H),4.49–4.37(m,2H),4.27(dd,J＝14.0,6.2Hz,1H),3.82(q,J＝7.4Hz,1H),3.63(s,3H),3.62 (s,3H),2.87–2.68(m,2H),2.31–2.19(m,1H),2.06–1.86(m,3H).13C NMR(101MHz,DMSO)171.3,170.8, 166.6,156.7(d,J＝26.0Hz),149.1,139.8(d,J＝226.7Hz),124.6(d,J＝33.6Hz),87.8,70.1,52.7,52.2,49.0, 43.3,36.2,32.1,24.0.
MS：402.3(M+H)
Example 10: preparation of Compound 5j
Figure RE-GDA0002106364440000151
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-glutamic acid dimethyl ester hydrochloride (1.00mmol,211.64mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin drying to obtain 5 t.
1H NMR(400MHz,DMSO)8.64(t,J＝7.4Hz,1H),8.02(d,J＝6.7Hz,1H),5.99–5.90(m,1H),4.53–4.40(m,2H),4.35–4.20(m,2H),3.89–3.77(m,1H),3.64(d,J＝1.2Hz,3H),3.60(s,3H),2.38(td,J＝7.6,3.2 Hz,2H),2.30–2.22(m,1H),2.06–1.90(m,4H),1.88–1.79(m,1H).13C NMR(101MHz,DMSO)173.1, 172.3,172.3,166.8,166.8,156.8(d,J＝26.1Hz),156.8(d,J＝26.1Hz),149.1,139.9(d,J＝228.3Hz),139.8(d,J ＝228.3Hz),124.5(d,J＝33.5Hz),87.9,87.9,70.1,52.5,52.5,51.6(d,J＝3.8Hz),43.4,43.3,32.1,29.9,26.7, 24.0.
MS：416.1(M+H)
Example 11: preparation of Compound 5k
Figure RE-GDA0002106364440000152
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), L-methionine methyl ester hydrochloride (1.00mmol,199.70mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain a light yellow solid 5 j.
1H NMR(400MHz,DMSO)8.64(t,J＝7.8Hz,1H),8.02(d,J＝6.6Hz,1H),5.99–5.91(m,1H),4.43 (ddd,J＝11.4,10.9,5.2Hz,3H),4.33–4.20(m,1H),3.89–3.77(m,1H),3.65(d,J＝1.1Hz,3H),2.53–2.41(m, 2H),2.32–2.18(m,1H),2.04(d,J＝0.7Hz,3H),2.03–1.81(m,5H).13C NMR(101MHz,DMSO)172.1, 172.1,166.4,166.4,156.4(d,J＝26.1Hz),156.4(d,J＝26.1Hz),148.7,139.5(d,J＝228.3Hz),139.4(d,J＝ 228.4Hz),124.1(d,J＝33.6Hz),87.5,87.5,69.7,69.7,52.1,52.1,51.0,50.9,43.0,42.9,39.5,31.7,31.7,30.8, 29.4,23.6,14.6.
MS：404.1(M+H)
Example 12: preparation of Compound 5l
Figure RE-GDA0002106364440000161
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.50mL), L-tyrosine methyl ester hydrochloride (1.00mmol,231.68mg,1.00eq) were taken. Stirring at room temperatureThe reaction is carried out for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. And adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain 5l of light yellow oily liquid.
1H NMR(400MHz,DMSO)9.30(s,1H),8.66(d,J＝7.5Hz,1H),8.02(d,J＝6.6Hz,1H),6.99(dd,J＝8.3, 1.4Hz,2H),6.67(d,J＝8.0Hz,2H),5.95(dd,J＝4.1,2.6Hz,1H),4.44(s,2H),4.41–4.34(m,1H),4.26(dt,J＝ 11.8,6.1Hz,1H),3.88–3.72(m,1H),3.59(d,J＝1.5Hz,3H),2.98–2.66(m,2H),2.34–2.19(m,1H),1.94(dt, J＝13.6,6.6Hz,3H).13CNMR(101MHz,DMSO)172.3,166.5,156.7(d,J＝26.1Hz),156.5,149.1,139.8(d,J ＝228.3Hz),130.5,127.3,124.5(d,J＝33.8Hz),115.5,87.8,70.1,54.6(d,J＝2.0Hz),52.3(s),43.2(d,J＝3.9 Hz),36.6,32.1,24.0.
MS：436.2(M+H)
Example 13: preparation of Compound 5m
Figure RE-GDA0002106364440000171
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), D-alanine methyl ester hydrochloride (1.00mmol,139.60mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain white solid 5 a'.
1H NMR(400MHz,DMSO)8.66(d,J＝7.1Hz,1H),8.02(d,J＝6.7Hz,1H),6.04–5.90(m,1H),4.53– 4.37(m,2H),4.32–4.20(m,2H),3.83(q,J＝7.4Hz,1H),3.63(d,J＝1.2Hz,3H),2.35–2.19(m,1H),2.07– 1.87(m,3H),1.29(d,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)173.3,166.4,156.8(d,J＝26.0Hz),149.1, 139.8(d,J＝228.3Hz),124.51(d,J＝33.7Hz),87.8,70.1,52.4,48.1(d,J＝3.8Hz),43.2,32.1,24.0,17.6.
MS：344.0(M+H)
Example 14: preparation of Compound 5n
Figure RE-GDA0002106364440000172
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), D-phenylalanine methyl ester hydrochloride (1.00mmol,215.68mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain pale yellow solid 5 b'.
1H NMR(400MHz,DMSO)8.73(d,J＝7.5Hz,1H),8.02(d,J＝6.7Hz,1H),7.37–7.14(m,5H),5.99– 5.92(m,1H),4.45(m,3H),4.32–4.22(m,1H),3.89–3.76(m,1H),3.60(d,J＝1.5Hz,3H),3.59–3.52(m,1H), 3.08–2.87(m,2H),2.36–2.16(m,1H),2.09–1.87(m,3H).13CNMR(101MHz,DMSO)172.1,166.6,156.7 (d,J＝26.1Hz),149.1,139.8(d,J＝228.4Hz),137.3,129.4(d,J＝45.9Hz),128.8,127.1,124.5(d,J＝33.8Hz), 87.8,70.1,55.4,54.3,54.3,52.3,52.3,37.2,32.1,24.0.
MS：420.1(M+H)
Example 15: preparation of Compound 5o
Figure RE-GDA0002106364440000181
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), D-proline methyl ester hydrochloride (1.00mmol,165.50mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 i'.
1H NMR(400MHz,DMSO-D6)8.02–7.96(m,1H),5.93–5.89(m,1H),4.85–4.58(m,1H),4.58–4.32 (m,1H),4.30–4.13(m,2H),3.78(q,J＝7.4Hz,1H),3.70–3.33(m,5H),2.31–2.07(m,2H),2.03–1.77(m, 6H).13C NMR(101MHz,DMSO-D6)172.6,164.7,156.7(d,J＝26.0Hz),149.1,139.8(d,J＝228.5Hz),124.7 (d,J＝33.7Hz),124.6(d,J＝33.4Hz),87.9,70.1,59.1,52.3,46.3,43.1,32.2,32.1,29.1,24.9,24.2,24.1.
MS：370.0(M+H)
Example 16: preparation of Compound 5p
Figure RE-GDA0002106364440000191
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), D-tyrosine methyl ester hydrochloride (1.00mmol,231.68mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain light yellow solid 5 l'.
1H NMR(400MHz,DMSO-D6)9.21(s,1H),8.59(d,J＝7.6Hz,1H),7.97(d,J＝6.6Hz,1H),6.94(d,J＝8.2 Hz,2H),6.62(d,J＝8.4Hz,2H),5.99–5.81(m,1H),4.38(s,1H),4.35–4.29(m,1H),4.26–4.17(m,1H),3.78 (q,J＝7.4Hz,1H),2.84–2.73(m,2H),2.31–2.17(m,1H),2.05–1.83(m,3H).13C NMR(101MHz,DMSO) 172.3,166.5,162.8,156.7(d,J＝26.1Hz),156.5,149.1,139.8(d,J＝228.3Hz),130.5,127.3,124.5(d,J＝33.7Hz),115.5,87.8,70.0,54.6,52.3,43.3,36.6,32.1,24.0.
MS：436.2(M+H)
Example 17: preparation of Compound 5q
Figure RE-GDA0002106364440000192
Beta-aminopropionic acid (1.00mmol, 89.09mg, 1.00eq) and anhydrous methanol (40mL) were stirred in an ice-water bath, after cooling, thionyl chloride (2.00mmol,238.00mg,2.00eq) was slowly added dropwise and stirring was continued for 19 h. The solvent was spin dried to give a white granular solid.
Figure RE-GDA0002106364440000193
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), β -aminopropionic acid methyl ester hydrochloride (1.00mmol,139.58mg,1.00eq) were taken, stirred at room temperature and reacted for 16h, after the reaction was completed, a small amount of water and saturated NaHCO were added3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain white solid 5 w.
1H NMR(400MHz,DMSO)8.27(t,J＝5.4Hz,1H),8.01(d,J＝6.7Hz,1H),5.97–5.93(m,1H),4.37(s, 2H),4.26(td,J＝14.4,6.4Hz,1H),3.88–3.77(m,1H),3.61(s,3H),3.29(dd,J＝12.6,6.6Hz,2H),2.47(t,J＝ 6.8Hz,2H),2.32–2.20(m,1H),2.06–1.87(m,3H).13CNMR(101MHz,DMSO)172.2,166.5,156.8(d,J＝ 26.0Hz),149.2,139.9(d,J＝228.2Hz),124.5(d,J＝33.7Hz),87.8,70.1,51.9,43.5,35.3,34.0,32.1,24.0.
MS：344.1(M+H)
Example 18: preparation of Compound 5r
Figure RE-GDA0002106364440000201
Stirring gamma-amino acid (1.00mmol,103.12mg,1.00eq) and anhydrous methanol (40mL) in an ice-water bath, cooling, slowly adding thionyl chloride (2.00mmol,238.00mg,2.00eq) dropwise, and continuing stirring for 19 h. The solvent was spin dried to give a white granular solid.
Figure RE-GDA0002106364440000202
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), gamma-amino acid methyl ester hydrochloride (1.00mmol,153.61mg,1.00eq) were taken. At room temperatureThe reaction was stirred for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin drying to obtain 5 z.
1H NMR(400MHz,DMSO-D6)8.08(t,J＝5.2Hz,1H),7.97(d,J＝6.7Hz,1H),5.96–5.85(m,1H),4.32 (s,2H),4.27–4.17(m,1H),3.78(q,J＝6.5Hz,1H),3.55(s,3H),3.03(q,J＝6.7Hz,2H),2.26(td,J＝7.6,1.6Hz, 2H),2.25–2.15(m,1H),2.03–1.95(m,1H),1.95–1.84(m,2H),1.67–1.54(m,2H).13C NMR(101MHz, DMSO-D6)173.6,166.44,156.9(d,J＝26.2Hz),149.3,140.0(d,J＝227.6Hz),124.5(d,J＝33.3Hz),87.9, 70.1,51.8,43.7,38.4,32.2,31.1,24.9,24.1.
MS：358.1(M+H)
Example 19: preparation of Compound 5s
Figure RE-GDA0002106364440000211
5-amino valeric acid (1.00mmol,117.15mg,1.00eq) and anhydrous methanol (40mL) were stirred in an ice-water bath, after cooling, thionyl chloride (2.00mmol,238.00mg,2.00eq) was slowly added dropwise, and stirring was continued for 19 h. The solvent was spin dried to give a white granular solid.
Figure RE-GDA0002106364440000212
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), 5-aminovaleric acid methyl ester hydrochloride (1.00mmol,167.63mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin-drying to obtain 5 x.
1H NMR(400MHz,DMSO)8.11(t,J＝5.5Hz,1H),8.01(d,J＝6.7Hz,1H),6.07–5.86(m,1H),4.35(s, 2H),4.27(dd,J＝14.0,6.2Hz,1H),3.82(q,J＝7.4Hz,1H),3.58(s,3H),3.04(dd,J＝13.1,6.3Hz,2H),2.27(m, 3H),2.14–1.88(m,3H),1.56–1.45(m,2H),1.45–1.32(m,2H).13C NMR(101MHz,DMSO)173.7,166.2, 156.9(d,J＝26.0Hz),149.2(s),139.9(d,J＝228.0Hz),124.5(d,J＝33.7Hz),87.8,70.1,55.4,51.7,43.6,38.7, 33.3,32.1,28.9,24.0,22.3.
MS：372.1(M+H)
Example 20: preparation of Compound 5t
Figure RE-GDA0002106364440000221
Taking 7-aminoheptanoic acid (1.00mmol, 145.20mg, 1.00eq) and absolute methanol (40mL), stirring in an ice-water bath, cooling, slowly dropwise adding thionyl chloride (2.00mmol,238.00mg,2.00eq) and continuing stirring for reaction for 19h, and spin-drying the solvent to obtain a white granular solid.
Figure RE-GDA0002106364440000222
3(1.00mmol,258.00mg,1.00eq), 1-hydroxybenzotriazole (1.11mmol,150.00mg,1.11eq), EDC & HCl (1.11mmol,213.00mg,1.11eq), DIPEA (3.05mmol,532.00mg,3.05eq), DMF (7.5mL), 7-aminoheptanoic acid methyl ester hydrochloride (1.00mmol,195.70mg,1.00eq) were taken. The reaction was stirred at rt for 16 h. After the reaction is finished, adding a small amount of water and saturated NaHCO3The solution was extracted 3 times with ethyl acetate and the ester layer was washed 2 times with saturated NaCl solution. Adding anhydrous sodium sulfate, drying for 0.5h, and spin drying to obtain 5 y.
1H NMR(400MHz,DMSO)8.07(t,J＝5.4Hz,1H),8.01(d,J＝6.7Hz,1H),5.98–5.89(m,1H),4.35(s, 2H),4.26(dt,J＝16.1,8.1Hz,1H),3.82(dd,J＝15.0,7.4Hz,1H),3.58(s,3H),3.10–2.94(m,2H),2.28(td,J＝ 16.3,8.5Hz,3H),2.11–1.85(m,3H),1.59–1.46(m,2H),1.36(d,J＝6.7Hz,2H),1.30–1.18(m,4H).13C NMR (101MHz,DMSO)173.4,172.9,165.7,156.4(d,J＝26.1Hz),148.7,139.4(d,J＝228.1Hz),124.0(d,J＝33.6 Hz),87.4,69.6,59.7,54.9,51.2,43.1,39.5,38.5,33.4,33.2,31.7,28.8,28.1,25.9,24.4,24.4,23.5,14.2.
MS：400.3(M+H)。
Activity assay:
the invention selects the prepared tegafur derivative to carry out activity test, takes tegafur as a positive control group, and comprises the steps of taking exponential growth phase A549, MCF7, HepG2 and Hela cells, and adjusting the cell density to 1 × 10 by RPMI1640 culture solution containing 10% fetal calf serum5/mL, inoculating to 96-well culture plate, setting solvent control and test sample group, inoculating to 100 μ L per group with at least 2 wells, and placing 5% CO2The culture was carried out in an incubator at 37 ℃ for 24 hours. Discarding original culture solution, precisely weighing the sample, adding DMSO, dissolving, diluting with 10% fetal calf serum-containing RPMI1640 culture solution to 100, 20, 4, 0.8, 0.16 μ g/L, adding into 96-well plate, respectively, adding fresh cell culture solution into negative control group, setting 5% CO in each well to 100 μ L2Culturing in an incubator for 48h, observing cell morphology under a microscope, adding 10 mu L of 0.5% MTT solution into each well, culturing for 4h at 37 ℃, discarding the solution in the well, adding 150 mu L of LDMSO solution into each well, measuring absorbance at the wavelength of 570nm of an enzyme labeling instrument, and calculating the activity of the compound (1-OD test sample/OD negative control) × 100%, wherein the activity test results of the compound are as follows:
Figure RE-GDA0002106364440000231
note: "-" indicates no cell viability assay.
According to the results of the activity test of the tegafur derivative, the synthesized compound has stronger apoptosis induction capability on specific tumor cell lines and has obvious technical application value in antitumor drugs.

Claims (4)

1. A tegafur derivative or a pharmaceutically acceptable salt thereof, having a structural formula:
Figure FDA0002608311570000011
wherein R-H is an amino acid derivative, and the R-H forms an amido bond with carbonyl in the formula I through amino in the molecule of the amino acid derivative; the amino acid derivatives are selected from Gly-OMe and L-Glu-OMe、L-Met-OMe、D-Phe-OMe、NH2(CH2)2CO-OMe。
2. A process for preparing the tegafur derivative of claim 1, comprising the steps of:
(1) reacting tegafur with chloroacetic ester under strong alkaline condition; (2) hydrolyzing the obtained product under alkaline condition to obtain carboxylic acid; (3) reacting carboxylic acid with amino acid ester under the condition of a condensing agent to obtain tegafur amino acid ester derivative; the reaction route comprises:
Figure FDA0002608311570000012
r1 ═ Me, Et, R — H represent various amino acid derivatives.
3. A pharmaceutical composition comprising the tegafur derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 1 and a pharmaceutically acceptable auxiliary, diluent or carrier.
4. The use of the tegafur derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for the treatment of lung cancer, breast cancer, liver cancer, and cervical cancer.
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