CN111233955B - Thiazolone formyl cytosine derivative and pharmaceutical application thereof - Google Patents

Thiazolone formyl cytosine derivative and pharmaceutical application thereof Download PDF

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CN111233955B
CN111233955B CN202010129983.4A CN202010129983A CN111233955B CN 111233955 B CN111233955 B CN 111233955B CN 202010129983 A CN202010129983 A CN 202010129983A CN 111233955 B CN111233955 B CN 111233955B
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李飞
李伦家
陈睿泽
夏奕
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Nanjing Yuanju Pharmaceutical Technology Co ltd
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Abstract

A thiazolone formyl cytosine derivative and a pharmaceutical application thereof are disclosed, wherein the chemical structure of the thiazolone formyl cytosine derivative conforms to a general formula (I):
Figure DDA0002395536570000011
wherein: r1Is CH, CF, C (CF)3) Or N, R2、R3is-H or-OH, R4、R5is-H, -OH or-F. The thiazolone formyl cytosine derivative can release pyrimidine anti-tumor active ingredients under the environment of high free radicals of tumors, and generates stronger cytotoxicity. Has excellent antitumor effect and good safety, and can be used for preparing medicine for treating tumor.

Description

Thiazolone formyl cytosine derivative and pharmaceutical application thereof
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to thiazolone formyl cytosine derivatives and pharmaceutical application thereof.
Background
5-fluorouracil (fluorouracil) is a common clinical antitumor drug. 5-Fu itself has no anti-tumor activity and must be metabolised to active products such as fluorouracil monophosphate (FUMP), fluorouracil deoxynucleoside triphosphate (FdUTP) by Orotate Phosphoribosyltransferase (OPRT) in tissues. Since the expression of OPRT is higher in tumor tissues than in normal tissues, 5-Fu has a certain selectivity for tumors. However, 5-Fu was injected intravenouslyThereafter, 85% of 5-Fu is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) to the inactive product β -ureido-2-fluoropropionic acid, further to 2-fluoro- β -alanine, urea, etc., and only 15% of 5-Fu has an opportunity to enter the tissue. Too fast a metabolic rate, resulting in 5-Fu with little clinical value.
Figure BDA0002395536560000011
In order to improve the drug metabolism property of 5-Fu and increase the concentration of 5-Fu in tumor tissues, 5-fluorouracil prodrugs such as 5-fluorodeoxyuridine (floxuridine), trofluridine (trifluridine), doxifluridine (doxifluridine), tegafur (tegafur) and the like are developed, and the prodrugs have no antitumor effect but can be metabolized into 5-fluorouracil under the action of Thymidine Phosphorylase (TP) to generate drug effect. Since the expression of TP enzyme in tumor tissues is far higher than that in normal tissues, the prodrugs have better safety.
Figure BDA0002395536560000012
Capecitabine (capecitabine) is another form of a 5-Fu prodrug. Capecitabine produces 5 ' -deoxy-5-fluoro-cytosine nucleoside (5 ' -DFCR) under the action of Carboxylesterase (CE) in the liver, 5 ' -DFCR is deaminated by cytosine deaminase (CYD) to produce 5 ' -deoxy-5-fluoro-pyrimidine nucleotide (5 ' -DFUR), which is metabolized to 5-Fu in tumor tissues under the action of Thymine Phosphorylase (TP) to produce an antitumor effect.
Figure BDA0002395536560000021
Cytosine antineoplastic drugs such as cytarabine (cytarabine), gemcitabine (gemcitabine), decitabine (decitabine), azacitibine (azacitibine) and the like are easily deaminated and inactivated by cytosine deaminase in vivo, and the action time can be prolonged by aminoacylation of the cytosine deaminase, but the targeting of the drugs to tumor cells cannot be solved.
Figure BDA0002395536560000022
Because the tumor rapidly grows and the concentration of free radicals in tumor tissues or tumor cells is higher, if the antitumor drug can be modified into a prodrug without or with lower activity, an active ingredient with stronger activity is released under the action of the free radicals, so that the toxicity of the drug to normal cells can be reduced while the high antitumor activity is maintained. The invention provides thiazolone formyl cytosine derivatives, which adopt a urea bond form to acidylate the amino of cytosine, and the urea bond is stable and difficult to be hydrolyzed and metabolized in liver, so that higher blood concentration can be maintained, and the action time can be prolonged. Active ingredients with stronger activity can be quickly released in tumor tissues or tumor cells with higher free radical concentration, so that the targeting property to the tumor can be realized while high anti-tumor activity is kept, and the active ingredients are released at the tumor part, so that the catabolism of dihydropyrimidine dehydrogenase (DPD) of the liver is reduced, a better drug effect can be obtained under a smaller dose, a better treatment effect is obtained, and the method is safer and more effective.
Disclosure of Invention
The technical problem to be solved is as follows: the thiazolone formyl cytosine derivative can release uracil antitumor active ingredients under the environment of high free radicals of tumors, and generates stronger cytotoxicity. Has excellent antitumor effect and good safety, and can be used for preparing medicine for treating tumor.
The technical scheme is as follows: a thiazolone formyl cytosine derivative has a chemical structure which conforms to a general formula (I):
Figure BDA0002395536560000031
wherein: r1Is CH, CF, C (CF)3) Or N, R2、R3is-H or-OH, R4、R5is-H, -OH or-F.
The thiazolone formyl cytosine derivative has a preferable structure shown as follows:
Figure BDA0002395536560000032
the thiazolone formyl cytosine derivative or the pharmaceutically acceptable salt thereof is applied to preparing the medicines for treating tumors.
The medicine for treating tumor contains the thiazolone formyl cytosine derivative or its pharmaceutically acceptable salt as effective component.
It should be noted that our studies found that: the compound of the embodiment can exist stably under normal conditions, and can maintain higher blood concentration. Under high free radical environment, the example compound has reduced stability and degrades rapidly. The cytotoxicity of the compound of the embodiment under the condition of pre-scavenging free radicals is obviously lower than that under the normal condition, and the fact that the antitumor activity of the medicine is closely related to the existence of the free radicals is suggested.
Taking the example compound 1 as an example, the antitumor effect and safety of the target compound were examined, and the compound 1 showed better tumor growth inhibition (see table 4, table 5) and better safety (see table 6) than gemcitabine.
Taking the example compound 2 as an example, the antitumor effect and safety of the target compound were examined, and the compound 2 had better efficacy and safety compared to the capecitabine group (see table 7).
Has the advantages that: the thiazolone formyl cytosine derivative obtained by the invention has better stability and can maintain higher blood concentration. Has less cytotoxicity under the condition of no free radicals, and can quickly release more cytotoxic components under the environment of high free radicals. Because the concentration of free radicals of tumor cells is higher, the thiazolone formyl cytosine derivative obtained by the invention can specifically play an anti-tumor role on tumors in a tumor area, and reduce toxic and side effects on other tissues. Better drug effect and better treatment effect can be obtained under the condition of smaller dosage, and the traditional Chinese medicine is safer and more effective.
Detailed Description
The following examples are given to enable a person skilled in the art to fully understand the invention, but do not limit it in any way.
Example 1: synthesis of target Compound
1.1 Synthesis of Thiazolone formyl Gemcitabine (Compound 1)
Figure BDA0002395536560000041
Gemcitabine hydrochloride (500mg,1.67mmol) was dissolved in dry DMF (5mL), imidazole (398mg,5.85mmol), tert-butyldimethylsilyl chloride (TBS-Cl, 301mg,2.0mmol) were added, stirring was carried out at room temperature for 12 hours, the solvent was evaporated off under reduced pressure, ethyl acetate (50mL) was added, washing was carried out with water (50mL), the aqueous phase was extracted 2 times with EtOAc (50mL), the combined organic phases were washed with saturated brine (150mL), MgSO4And (5) drying. The crude product was purified by silica gel chromatography (eluent: dichloromethane: methanol 10:1) to obtain 552mg (yield 88%) of a white solid compound (gemcitabine-TBSO).1H NMR(400MHz,DMSO)δ7.63(d,1H),7.38(s,2H),6.31(d,1H),6.14(t,1H),5.76(d,1H),4.19-4.06(m,1H),3.95(d,1H),3.90-3.77(m,2H),0.90(s,9H),0.09(d,6H).
Gemcitabine-TBSO (100mg,0.27mmol) was dissolved in dry tetrahydrofuran (2.5mL) and pyridine (61. mu.L, 0.75mmol) at 4 ℃ and 1, 3-thiazolone formyl chloride (89.4mg,0.54mmol) was added dropwise and stirred for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel chromatography (eluent: dichloromethane: methanol volume ratio: 30:1) to give a white solid compound (gemcitabine-TBSO-S) 94.4mg, yield 69%.1H NMR(500MHz,MeOD)δ8.30(d,1H),7.29(d,1H),6.25(t,1H),4.33-4.24(m,1H),4.10(d,1H),4.03-3.85(m,4H),3.45–3.30(m,2H),0.98(s,9H),0.17(s,6H).
Gemcitabine-TBSO-S (50.7mg,0.1mmol) in 75% (w/w) aqueous tetrabutylammonium fluoride (TBAF) (0.15mmol) was dissolved in dry tetrahydrofuran (3mL), stirred at room temperature for 12 hours, the solvent was evaporated off under reduced pressure, and the crude product was purified by silica gel chromatographyThe reaction mixture was dissolved (eluent: dichloromethane: methanol volume ratio 15:1) to obtain a white solid (compound 1, 24.3mg, yield 62%).1H NMR(400MHz,DMSO)δ11.06(s,1H),8.25(d,1H),7.08(d,1H),6.30(d,1H),6.16(t,1H),5.29(t,1H),4.25-4.13(m,1H),4.00–3.85(m,2H),3.89(dt,1H),3.84-3.63(m,2H),3.45–3.30(m,2H).
1.2 Synthesis of Compound 2
Figure BDA0002395536560000051
2 ', 3 ' -di-O-acetoxy-5 ' -deoxy-5-fluoro-cytidine (1.65g,0.05mmol) was dissolved in dichloromethane (5mL) and pyridine (1.0mL) at-15 deg.C, 1, 3-thiazolone formyl chloride (0.89mg,0.054mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Methanol (3mL) was added, the solvent was evaporated under reduced pressure, the crude product was stirred in ether (10mL) at room temperature for 1 hour, filtered, the filter cake was washed with ether, and the filtrate was concentrated to give a white solid (1.95g, yield 85%). Methanol (2mL) was added to 1.5g, a 2mol/L sodium hydroxide solution was added dropwise at-15 ℃ to adjust pH10-11, the mixture was reacted for 1 hour, the pH was adjusted to 5-6 with hydrochloric acid, methylene chloride was added for extraction, the mixture was concentrated, the solid was dissolved by heating with ethyl acetate (4mL), n-hexane (4mL) was added dropwise, and the mixture was cooled to obtain Compound 2(0.73g, yield 60%) as white crystals. Compound 21H NMR(400MHz,DMSO)δ8.06(s,1H),5.67(d,1H),5.43(d,1H),5.06(d,1H),4.07(d,1H),4.00–3.85(m,2H),3.45–3.30(m,2H),1.32(s,3H).
1.2 Synthesis of Compounds 3,4,5
Compound 3 was synthesized with 2 ', 3 ' -di-O-acetoxy-5 ' -deoxy-5-trifluoromethyl-cytosine nucleoside and 1, 3-thiazolone formyl chloride, according to the synthesis method of compound 2.1H NMR(400MHz,DMSO)δ8.10(s,1H),6.09(t,1H),5.46(d,1H),5.09(d,1H),4.08(d,1H),4.02–3.86(m,2H),3.46–3.31(m,2H),1.34(s,3H).
Compound 4 was synthesized with 1- (tetrahydro-2-furanyl) -5-fluoro-cytosine and 1, 3-thiazolone formyl chloride, according to the synthesis method of compound 2.1H NMR(400MHz,DMSO)δ8.11(s,1H),6.07(t,1H),5.87-5.83(m,1H),4.16(d,1H),4.00–3.83(m,2H),3.74(dd,1H),3.45–3.29(m,2H),2.22-2.09(m,1H),2.01-1.83(m,3H)
Compound 5 was synthesized with 1- (tetrahydro-2-furanyl) -5-trifluoromethyl-cytosine and 1, 3-thiazolecarbonyl chloride, according to the synthesis of compound 2.1H NMR(400MHz,DMSO)δ8.12(s,1H),5.88-5.84(m,1H),4.17(d,1H),4.00–3.85(m,2H),3.75(dd,1H),3.45–3.30(m,2H),2.22-2.11(m,1H),2.02-1.86(m,3H)
1.2 Synthesis of Compounds 6,7,8
Compound 6 was synthesized with cytarabine and 1, 3-thiazolone formyl chloride, according to the synthesis method of Compound 1.1H NMR(400MHz,DMSO)δ7.57(d,1H),δ7.07(b,1H),δ7.00(b,1H),δ6.03(d,1H),δ5.66(d,1H),δ5.38(t,2H),4.99(t,1H),4.00–3.85(m,4H),3.73(dd,1H),3.59–3.56(m,2H),3.45–3.30(m,2H)
Compound 7 was synthesized with decitabine and 1, 3-thiazolone formyl chloride, according to the synthesis method of compound 1.1H NMR(400MHz,DMSO)δ8.50(s,1H),δ7.50(s,1H),δ7.48(s,1H),δ6.03(t,1H),δ5.22(d,1H),δ5.03(t,1H),4.22(t,1H),4.00–3.85(m,4H),3.81(d,1H),3.62–3.52(m,2H),3.45–3.30(m,2H)，2.20–2.11(m,1H)
Compound 8 was synthesized with azacitidine and 1, 3-thiazolone formyl chloride, according to the synthesis method of Compound 1.1H NMR(400MHz,DMSO)δδ8.58(s,1H),δ7.54(s,1H),δ7.52(s,1H),δ5.66(d,1H),δ5.43(d,1H),δ5.12(t,1H),δ5.03(d,1H),4.08-4.06(m,1H),4.01–3.84(m,4H),3.68–3.67(m,2H),3.56(s,1H),3.45–3.30(m,2H)
Example 2: target compound in Normal Environment and H2O2Stability survey in an environment
Normal environment: 1.0mL of acetonitrile solution of a target compound 1 of 40 mu moL/L, 4.0mL of PBS buffer solution of pH7.4, uniformly mixing, and measuring the peak area of the target compound 1 by adopting high performance liquid chromatography; after standing at room temperature for 6 and 12 hours, the peak area of the target compound 1 was measured by high performance liquid chromatography and compared with the peak area at 0 hour. A relative value is obtained.
H2O2Environment: 100. mu. moL/L acetonitrile solution of the objective Compound 1 (1.0mL) was added thereto 250. mu. moL/L H2O24.0mL of the PBS buffer solution (pH7.4), uniformly mixing, and measuring the peak area of the target compound 1 by adopting high performance liquid chromatography; after standing at room temperature for 0.5 and 1 hour, the peak area of the target compound 1 was measured by high performance liquid chromatography and compared with the peak area at 0 hour. A relative value is obtained.
TABLE 1 target Compounds at 6 hours under Normal Environment and H2O2Stability study at ambient 0.5 hours
Compound numbering Normal environment for 6 hours H2O2Ambient 0.5 hours
1 98％ 25％
2 99％ 34％
3 98％ 30％
4 98％ 33％
5 99％ 34％
6 98％ 29％
7 98％ 28％
8 98％ 28％
The above experimental results show that: the target compound was stable in PBS buffer at pH7.4 and was not easily hydrolyzed. At H2O2Is unstable under environmental conditions and is rapidly degraded.
Example 3: research on in-vitro inhibition effect of target compound on tumor cell proliferation under normal state and state of removing free radicals in advance
Taking human tumor cells (human lung adenocarcinoma cell A549, human acute lymphoblastic leukemia CCRF-CEM cell, and human pancreatic adenocarcinoma cell BxPC-3 cell) in logarithmic growth phase, adding 0.25% pancreatin for digestion for 3min, suspending the cells with 10% calf serum RPMI-1640, counting, and adjusting cell concentration to 1 × 105One cell per mL, 100. mu.L/well inoculated in a Top-count special 96-well cell culture plate at 37 ℃ in 5% CO2And (5) incubating for 24 h. The cells were then divided into experimental and control groups, and the experimental group was added with the target compound solution, each concentration was four replicates per well, and 200 μ L of each well volume was made up. Continuously culturing for 72 hr after each group is added with sample, and adding into each well before culturing3H-TdR 3×105Bq, determining CPM (count per minute) value of each well by using Top-count. Calculating the half Inhibition Concentration (IC) of each experimental group drug to cell proliferation50)。
Removing free radical groups in advance: collecting logarithmic growth phase human tumor cells (human lung adenocarcinoma cell A549, human acute stranguria)Barkeleukemia CCRF-CEM cells, human pancreatic adenocarcinoma cells BxPC-3 cells), adding 0.25% pancreatin for 3min, suspending the cells with 10% calf serum RPMI-1640, counting, and adjusting cell concentration to 1 × 105One cell per mL, 100. mu.L/well inoculated in a Top-count special 96-well cell culture plate at 37 ℃ in 5% CO2And (5) incubating for 24 h. Then, the cells were pretreated with a free radical scavenger, N-acetylcysteine (NAC, 20mmoL/L), for 1 hour, and divided into an experimental group and a control group, and the experimental group was added with a target compound solution, each concentration was four-fold, and each pore volume was made up to 200. mu.L. Continuously culturing for 72h, respectively, adding into each well before culturing3H-TdR 3×105Bq, determining CPM (count per minute) value of each well by using Top-count. Calculating the half Inhibition Concentration (IC) of each experimental group drug to cell proliferation50)。
TABLE 2 half maximal Inhibitory Concentration (IC) of the target compound against tumor cell proliferation (72 hours) in the normal, pre-radical deprived state50，μg/mL)
Figure BDA0002395536560000071
The above experimental results show that: the compounds 1,6,7 and 8 in the examples have obvious difference on the in-vitro inhibition effect on the proliferation of the tumor cells in a normal state and a state of removing free radicals in advance, and the in-vitro inhibition effect on the proliferation of the tumor cells of the medicines is suggested to depend on the existence of the free radicals.
Examples compound 2,3,4,5 as a prodrug of 5-Fu, the above compound was not tested for its cellular activity in vitro, since 5-Fu itself has no antitumor activity and must be metabolically converted to an active product by orotate phosphoribosyl transferase (OPRT) in tissues.
EXAMPLE 4 determination of the plasma concentration (AUC) of the object Compound in vivo
The same dose of compound 1 and gemcitabine was administered intravenously (i.v.8.5mg/kg) to C57 mice, and blood was taken at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, and 24h after administration, plasma was separated, and the concentration of the target compound in the plasma was determined by hplc-ms. The pharmacokinetic parameters AUC of the target compound were calculated using DAS software.
Table 3 plasma concentration AUC (mg.h.l) of the compounds of the examples-1)
Compound 1 Gemcitabine
AUC0-t 2.4±0.11 0.13±0.03
AUC0-inf 2.6±0.10 0.14±0.03
The result of in vivo blood concentration measurement shows that: the plasma concentration (AUC) of compound 1 was significantly higher (more than 10-fold) than gemcitabine after the same dose injection. It is suggested that compound 1 is more stable than gemcitabine and is able to maintain higher blood levels.
Example 5: growth inhibition of Compound 1 on human BxPC-3 nude mouse subcutaneous transplantation tumor
Taking BxPC-3 human pancreatic cancer cells in logarithmic growth phase at 5 × 106Individual cell 0.2mL-1Only a-1The concentration of (2) is inoculated subcutaneously on the back of a nude mouse, and after the length and the diameter of the transplanted tumor of the nude mouse are all more than or equal to 5mm, the similar volume of the tumor body is calculated according to the length and the diameter of the transplanted tumor. Arranged in order according to the size of the tumor volume, and the score is set by random area groupsThe preparation method divides the nude mice into 5 groups.
Administration protocol 50 model animals were randomly divided into a negative control group, a low dose group (compound 1, 0.1mmol/kg), a high dose group (compound 1, 0.4mmol/kg), and gemcitabine hydrochloride group (0.2mmol/kg), administered intraperitoneally (2 times/week) for 3 weeks, and the nude mice were sacrificed while the animal body weights were measured.
The inhibitory effects are shown in tables 4 and 5, and the body weight changes are shown in table 6.
TABLE 4 growth inhibition of compound 1 of interest in nude mice against subcutaneous transplantable tumors of human BxPC-3 nude mice (tumor volume mm)3)
Figure BDA0002395536560000081
TABLE 5 growth inhibition of Compound 1 of interest on human BxPC-3 nude mice subcutaneous transplantable tumors in nude mice
Figure BDA0002395536560000082
After administration, each group showed significant tumor growth inhibition, and the compound 1 low-dose group, medium-dose group, and high-dose group all showed better therapeutic effects than the gemcitabine group.
TABLE 6 influence of object Compound 1 on body weight of nude mice animal model for subcutaneous transplantation of human BxPC-3 nude mice
Figure BDA0002395536560000091
After administration, the body weight of the nude mice in all test groups is less than that of the compound 1 low dose group, the body weight of the middle dose group and the body weight of the control group, and the body weight of the high dose group and the body weight of the control group are reduced to a certain extent, which indicates that the nude mice have a certain toxic effect. The high dose group weighed more than gemcitabine, indicating less toxicity than gemcitabine.
The above experimental results suggest: compared with gemcitabine, compound 1 has better efficacy and safety.
Example 6: growth inhibition effect of compound 2 on human colon cancer HCT-116 cell nude mouse subcutaneous transplantation tumor
Taking human colon cancer HCT-116 cells of logarithmic growth phase at 5X 106Individual cell 0.2mL-1Only a-1The concentration of (2) is inoculated to the subcutaneous back of a nude mouse, and after the length and diameter of the transplanted tumor of the nude mouse are all more than or equal to 5mm, the similar volume of the tumor body is calculated according to the length and diameter of the transplanted tumor. The mice were divided into 5 groups by randomized block design assignment.
Administration protocol 50 model animals were randomly divided into a negative control group, a low dose group (compound 2, 150mg/kg), a medium dose group (compound 2, 300mg/kg), a high dose group (compound 2, 600mg/kg), and a capecitabine group (300mg/kg), and were administered by intraperitoneal injection (2 times per week), respectively, for 3 weeks, while measuring the animal body weight. The results are shown in Table 7.
TABLE 7 growth inhibitory Effect of Compound 2 of interest on human Colon cancer HCT-116 cell nude mouse subcutaneous transplantation tumor
Figure BDA0002395536560000092
After administration, each group showed significant tumor growth inhibition, the compound 2 low-dose group and the capecitabine group showed equivalent curative effects, and the medium-dose group and the high-dose group showed better therapeutic effects than the capecitabine group.
After administration, the body weight of all the nude mice in the test groups is less than that of the low-dose group and the control group of the compound 2, and the body weight of the nude mice in the middle-dose group, the high-dose group and the control group are not obviously different, so that the body weight of the nude mice in the middle-dose group, the high-dose group and the control group are reduced to a certain extent, and a certain toxic effect is suggested. The high dose group was heavier than the capecitabine group, indicating less toxicity than the capecitabine group.
The above experimental results suggest: compared with the capecitabine group, the compound 2 has better drug effect and safety.
The above examples are only for illustrating the technical idea and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (4)

1. A thiazolone formyl cytosine derivative is characterized in that the chemical structure of the thiazolone formyl cytosine derivative conforms to the general formula (I):
Figure FDA0002395536550000011
wherein: r1Is CH, CF, C (CF)3) Or N, R2、R3is-H or-OH, R4、R5is-H, -OH or-F.
2. The thiazolone formylcytosine derivative of claim 1, wherein the structure is as follows:
Figure FDA0002395536550000012
3. the use of a thiazolone formylcytosine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for treating tumors.
4. The medicine for treating tumor is characterized in that the effective component is thiazolone formyl cytosine derivatives or pharmaceutically acceptable salts thereof according to claim 1 or 2.
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