Naphthopyrimidino-fused heteroazasugar derivatives, methods of synthesis and use thereof

Abstract

This invention provides a naphthopyrimidine-fused-acid sugar derivative, its synthesis method, and its application, belonging to the field of pharmaceutical technology. The naphthopyrimidine-fused-acid sugar derivative has the structures shown in formulas (I) to (IV). These compounds are obtained by one-step cyclization via a condensation reaction with 1,8-diaminonaphthalene in an organic solvent under the catalysis of a trifluoromethanesulfonate catalyst, using a propionyl-protected and p-toluenesulfonated sugar as the starting material. The preparation method is efficient and simple. The compounds of this invention exhibit good anti-proliferative activity against colon cancer tumor cells.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a naphthopyrimidine and fused azazose derivative, its synthesis method, and its application. Background Technology

[0002] Tumors are growths formed by the abnormal proliferation of certain cells in an organism under the influence of tumorigenic factors. The metastasis and spread of malignant tumors can develop into cancer, which has become one of the major health challenges plaguing humanity in the 21st century. Therefore, the research and application of antitumor drugs has always been a hot topic in new drug development. Currently, most antitumor drugs are modified from natural alkaloids, such as camptothecin, vinblastine, and evodiamine, all of which possess good antitumor activity. In recent years, some synthetic nitrogen-containing hybrid compounds, such as tetrahydroquinoline derivatives and phenanthroline derivatives, have also shown excellent tumor cell inhibitory activity (Noaman, E., et al., Eur. J. Med. Chem., 2010, 45, 1849-1853). Therefore, designing and synthesizing novel and unique nitrogen-containing hybrid compounds and studying their antitumor cell proliferation activity is of great significance for the development of antitumor drugs.

[0003] Azoses, also known as iminosaccharides, are sugars obtained by replacing oxygen atoms in the inner rings of carbohydrate compounds with nitrogen atoms. They are widely found in plants and microorganisms in nature. Polycyclic (three or more rings) fused azoses are an important branch of azoses. The nitrogen heterocycles they contain enrich their structure and activity, while the polyhydroxy structures endow them with good water solubility and bioavailability, attracting widespread attention in drug synthesis and medicine. Although the synthesis of polycyclic (three or more rings) fused azoses has been reported (Baskaran, S., et al., J. Org. Chem., 2018, 83, 9604-9618), their antitumor activity has been rarely reported. Summary of the Invention

[0004] The purpose of this invention is to provide a naphthopyrimidine-fused azasaccharide derivative, the chemical structure of which is shown in formulas (I) to (IV):

[0005]

[0006] The method for synthesizing the above-mentioned naphthopyrimidine-fused azasaccharide derivative includes the following steps:

[0007] Starting with a propylidene-protected and p-toluenesulfonated sugar and 1,8-diaminonaphthalene, the starting materials were dissolved in an organic solvent and reacted under stirring in the presence of a trifluoromethanesulfonate catalyst. After the reaction was completed, the reaction solution was dissolved in an organic alcohol solvent, the solvent was removed by vacuum evaporation, and the compounds were obtained by column chromatography.

[0008] Preferably, the organic solvent is a toluene / methanol mixed solvent or toluene solvent; the trifluoromethanesulfonate catalyst is scandium trifluoromethanesulfonate or nickel trifluoromethanesulfonate; and the organic alcohol solvent is methanol.

[0009] Preferably, the molar ratio of the propylene-protected and p-toluenesulfonated sugar to the trifluoromethanesulfonate catalyst is 1:0.1.

[0010] More preferably, the synthetic route for the compound shown in formula (I) is as follows:

[0011]

[0012] More preferably, the synthetic route for the compound shown in formula (II) is as follows:

[0013]

[0014] More preferably, the synthetic route for the compound shown in formula (III) is as follows:

[0015]

[0016] More preferably, the synthetic route for the compound shown in formula (IV) is as follows:

[0017]

[0018] Preferably, in the synthesis of the compound shown in formula (II), the molar ratio of compound 1b to compound 2 is 1:1.2.

[0019] Preferably, in the synthesis of the compounds shown in formula (I), formula (III) or formula (IV), the molar ratio of compound 1a, compound 1b or compound 1c to compound 2 is 1:0.8.

[0020] Preferably, the volume ratio of toluene to methanol in the toluene / methanol mixed solvent is 5:1.

[0021] Preferably, in the synthesis of the compound shown in formula (II), the mobile phase for column chromatography separation is V. 二氯甲烷 :V 乙酸乙酯 = (3~6):1, the silicone column is a 200-300 mesh silicone column.

[0022] Preferably, in the synthesis of the compounds shown in formula (I), formula (III) or formula (IV), the mobile phase for column chromatography separation is V. 二氯甲烷 :V 甲醇 = (10~20):1, the silicone column is a 200-300 mesh silicone column.

[0023] The present invention also provides the use of the above-mentioned naphthopyrimidine and fused azahexasaccharide derivatives in the preparation of antitumor cell drug formulations, especially in the preparation of anti-colon cancer (HCT116) tumor cell inhibitor drugs.

[0024] Experiments have shown that the naphthopyrimidine and fused azahexasaccharide derivative of this invention has good anti-HCT116 tumor cell proliferation activity. When uniformly mixed with a pharmacologically permissible carrier, it can be prepared into various forms of pharmaceutical formulations for tumor-related diseases using conventional formulation methods.

[0025] If the compound of the present invention is the active ingredient, it can be combined with water, sucrose, sorbitol sugar, fructose and other components to prepare an oral liquid preparation; or combined with excipients (lactose, glucose, sucrose, mannitol sugar), disintegrants (starch), lubricants (stearic acid, talc), binders (gelatin, polyvinyl alcohol) and other components to prepare tablets or capsules.

[0026] The compounds of this invention, as active ingredients, can also be combined with physiological saline, glucose solution, or a mixed carrier consisting of saline and glucose to prepare an injection solution.

[0027] The recommended effective dosage for clinical use of this invention is 10–20 mg / person / day, 2–3 times daily. Physicians may also determine the dosage based on individual patient differences.

[0028] Beneficial effects:

[0029] This invention provides a novel naphthopyrimidine-fused-acid sugar derivative and its synthetic method. The method innovatively uses p-toluenesulfonated sugar and 1,8-diaminonaphthalene as starting materials, and obtains the crude naphthopyrimidine-fused-acid sugar derivative of this invention through a single-step cyclization reaction in the presence of a trifluoromethanesulfonate catalyst. The synthetic method is efficient and simple, and the compound and its isomers can be obtained in pure form by column chromatography.

[0030] This invention is the first to study the antitumor activity of polycyclic (three or more rings) fused azahexasaccharide compounds. The experiment shows that the naphthopyrimidine and fused azahexasaccharide derivatives provided by this invention have excellent anti-HCT116 tumor cell proliferation activity, in order to provide more drug options for the clinical treatment of tumor-related diseases. Detailed Implementation

[0031] The present invention will be further described below with reference to the embodiments. The embodiments described below are for illustration only and do not limit the scope of protection of the present invention in any way.

[0032] The processes and methods not described in detail in the following embodiments are conventional methods known in the art. All reagents used in the embodiments are analytical grade or chemically pure, and can be commercially available or prepared by methods known to those skilled in the art. The following embodiments all achieve the purpose of the present invention.

[0033] Example 1

[0034] Synthesize (7aR,8S,9R,10R)-6-isopropyl-7,7a,8,9,10,11-hexahydropyridine[1,2-a]pyrimidine-8,9,10-triol [abbreviated as compound (I)].

[0035] The chemical reaction process is as follows:

[0036]

[0037] The specific method is as follows:

[0038] Weigh 344.4 mg (1 mmol) of p-toluenesulfonated (Ts-substituted) D-ribose (commercially available) or prepared using D-ribose as a starting material according to the literature method (Aravind, A., et al., Eur. J. Org. Chem., 2011, 83, 6980-6988) and 1,8-diaminonaphthalene (126.6 mg, 0.8 equivalents, commercially available) into a 50 mL reaction tube. Add nickel trifluoromethanesulfonate (35.7 mg, 0.1 equivalents) and a toluene / methanol mixed solvent (V... 甲苯 :V 甲醇 =5:1) 6 mL of solution was stirred and dissolved. The mixture was heated to 70℃ in an oil bath and reacted. After 8 hours, TLC monitoring showed that the starting material 1,8-diaminonaphthalene had reacted completely. The reaction solution was dissolved in methanol, the solvent was removed by vacuum distillation, and the mixture was separated by 200-300 mesh silica gel column chromatography (V 二氯甲烷 :V 甲醇 =10:1), yielding a yellow oily compound (I).

[0039] Compound (I): Yellow oily substance, yield 12%. (c 0.1,CH3OH); 1 H NMR (400MHz, CDCl3) δ (ppm): 7.36–7.19 (m, 4H), 6.65 (dd, J = 6.0, 2.0Hz, 1H), 4.28 (d, J = 8.8Hz, 1H), 4.20 (s, 1H) ,4.05–3.98(m,1H),3.88(dd,J=12.0,4.8Hz,1H),3.65(dd,J=8.8,2.4Hz,1H),3.11–2.98(m,2H),1.30(s,6H); 13C NMR (150MHz, CDCl3) δ (ppm): 141.9, 135.1, 133.1, 126.0, 125.0, 124.3, 118. 6,118.4,114.5,104.6,71.5,70.8,66.8,66.2,46.0,26.9,22.5;MS(ESI):C 18 H 22 N₂O₃([M+H)) + ):315.2.

[0040] Example 2

[0041] Synthesize (7aR,8R,9S,10S)-2,2-dimethyl-7,7a,8,9,10,11-hexahydropyrido[1,2-a]pyrimidine-8,9,10-triol [abbreviated as compound (II)].

[0042] The chemical reaction process is as follows:

[0043]

[0044] The specific method is as follows:

[0045] Weigh 344.4 mg, 1 mmol (commercially available) of propionyl-protected and p-toluenesulfonated (Ts-treated) L-ribose (or L-ribose prepared according to the literature method (Aravind, A., et al., Eur. J. Org. Chem., 2011, 83, 6980-6988) and 1,8-diaminonaphthalene (189.8 mg, 1.2 equivalents, commercially available) into a 50 mL reaction tube. Add scandium trifluoromethanesulfonate (49.2 mg, 0.1 equivalents) and 6 mL of toluene, stirring to dissolve. Heat the mixture in an oil bath to 70 °C and react for 4 hours. TLC monitoring showed that the L-ribose reaction was complete. Dissolve the reaction mixture in methanol, remove the solvent under reduced pressure, and separate the solutions by 200-300 mesh silica gel column chromatography (V...). 二氯甲烷 :V 乙酸乙酯 =3:1), yielding a gray oily compound (II).

[0046] Compound (II): Gray oily substance, yield 17%. (c 0.1,CH3OH); 1H NMR (600MHz, CDCl3) δ (ppm): 7.49 (d, J=7.8Hz, 1H), 7.41–7.30 (m, 3H), 6.94 (dd, J=7.2, 1.2Hz, 1H), 6.67 (d, J=7.2Hz, 1H), 4.71– 4.67(m,1H),4.31(d,J=3.0Hz,1H),4.18–4.10(m,2H),3.95(t,J=3.6Hz,1H),2.87(d,J=12.6Hz,1H),1.73(s,3H),1.27(s,3H); 13 C NMR (150MHz, CDCl3) δ (ppm): 142.8, 138.1, 134.6, 126.8, 126.4, 122.5, 118.8, 118.4,115.4,104.2,98.8,76.3,72.0,69.1,67.9,47.2,30.5,27.4;MS(ESI):C 18 H 20 N₂O₃([M+H)) + ):313.2.

[0047] Example 3

[0048] Synthesize (7aR,8R,9S,10S)-6-isopropyl-7,7a,8,9,10,11-hexahydropyrido[1,2-a]pyrimidine-8,9,10-triol [abbreviated as compound (III)].

[0049] The chemical reaction process is as follows:

[0050]

[0051] The specific method is as follows:

[0052] Compound (III) was synthesized by weighing 344.4 mg, 1 mmol of commercially available, or L-ribose protected with propionyl group and p-toluenesulfonated (Ts-substituted) according to the method in the literature (Aravind, A., et al., Eur. J. Org. Chem., 2011, 83, 6980-6988).

[0053] Compound (III): Yellow oil, 9% yield. (c 0.1,CH3OH); 1H NMR (400MHz, CD3OD) δ (ppm): 7.33–7.15 (m, 4H), 6.75 (d, J = 7.6Hz, 1H), 4.21 (d, J = 8.8Hz, 1H), 4.15 (t, J = 2.4Hz, 1H), 3.98 (ddd, J = 1 1.2,5.2,2.8Hz,1H),3.83(dd,J=11.6,5.2Hz,1H),3.63(dd,J=9.2,2.8Hz,2H),3.13(m,1H),3.00(t,J=11.6Hz,1H),1.34(s,6H); 13 C NMR(100MHz,CD3OD)δ(ppm):143.0,136.2,133.3,125.6,123.7,123.5,117.9, 117.3,114.4,104.0,71.6,71.3,66.9,66.3,45.7,26.6,21.6,21.5; MS(ESI):C 18 H 22 N₂O₃([M+H)) + ):315.2.

[0054] Example 4

[0055] Synthesize (7aR,8R,9S,10R)-6-isopropyl-7,7a,8,9,10,11-hexahydropyridine[1,2-a]pyrimidine-8,9,10-triol [abbreviated as compound (IV)].

[0056] The chemical reaction process is as follows:

[0057]

[0058] The specific method is as follows:

[0059] Compound (IV) was synthesized according to the method of Example 1. 344.4 mg, 1 mmol of D-lythose (commercially available or prepared from D-lythose as a starting material) that is protected by propionyl group and p-toluenesulfonated (Ts-substituted).

[0060] Compound (IV): Yellow oily substance, yield 8%. (c 0.1,CH3OH); 1H NMR (400MHz, CD3OD) δ (ppm): 7.33–7.16 (m, 4H), 6.73 (d, J = 7.6Hz, 1H), 4.11 (s, 1H), 4.10 (d, J = 2.8Hz ,1H),4.06–4.03(m,1H),3.85(dd,J=12.7,2.5Hz,1H),3.63(s,1H),3.18–3.07(m,2H),1.32(s,6H); 13 C NMR (150MHz, CDCl3) δ (ppm): 148.0, 139.8, 137.0, 130.9, 129.3, 127.5, 122.3, 122.2,119.2,108.5,78.3,74.7,73.1,70.6,66.9,54.1,26.0,25.6;MS(ESI):C 18 H 22 N₂O₃([M+H)) + ):315.2.

[0061] Example 5

[0062] Tests on the anti-proliferative activity of the compounds of this invention against HCT116 tumor cells.

[0063] Test Method: Cell Counting Kit-8 (CCK-8) was purchased from Sigma and used to measure cell viability. The experiment consisted of a blank group, a control group, and a sample group, with three replicates per group. HCT116 tumor cells were seeded into 96-well plates at a density of 3000-5000 cells / well, with 100 μL of culture medium. The test compound was added to the wells at different concentrations, and the plates were incubated at 37°C for 48 and 96 hours, respectively. After 48 and 96 hours of treatment, 10 μL of CCK-8 reagent was added to each well of the plate in the dark. Cell viability was assessed by measuring the absorbance at 450 nm using a microplate reader. Inhibition rate (%) was calculated using the formula: 100 - [(sample group OD...] 450nm / Blank Group OD 450nm (×100).

[0064] As shown in Table 1, compounds (I), (II), (III), and (IV) of the present invention exhibit strong inhibitory activity against the proliferation of HCT116 tumor cells, especially compound (II), which shows even stronger inhibitory activity and an IC50 of 100% for inhibiting the proliferation of HCT116 tumor cells. 50 The concentration reached 3.91 μM, demonstrating good anti-tumor cell proliferation activity. This is the first report of a naphthopyrimidine-fused heteroazosaccharide compound as an inhibitor of HCT116 tumor cells, which is of great significance for the design and synthesis of subsequent highly active antitumor drugs.

[0065] Table 1. Inhibitory activity of compounds (I) to (IV) of the present invention against HCT116 tumor cell proliferation

[0066]

[0067] Example 6

[0068] Take 5 mg of compound (II) prepared in Example 2, 60 mg of lactose, 30 mg of potato starch, 2 mg of polyvinyl alcohol, and 1 mg of magnesium stearate, and prepare oral tablets.

[0069] The embodiments listed in this invention are intended to illustrate the preparation method of naphthopyrimidine and fused azahesaccharide derivatives and the inhibitory activity of such compounds on HCT116 tumor cell proliferation enzymes. The embodiments are not only used to illustrate the specific synthesis method of the compounds described therein and their anti-HCT116 tumor cell proliferation activity, but also to illustrate the synthesis of homologues and analogues by changing the types and quantities of raw materials, without constituting any limitation on the scope of this invention.

Claims

1. Naphthopyrimidine and fused azasaccharide derivatives shown in formulas (I) to (IV): 。 2. The method for synthesizing the naphthopyrimidine-fused azazose derivative according to claim 1, characterized in that, Includes the following steps: Starting with a propylidene-protected and p-toluenesulfonated sugar and 1,8-diaminonaphthalene, the starting materials were dissolved in an organic solvent and reacted under the action of a trifluoromethanesulfonate catalyst. After the reaction was completed, the reaction solution was dissolved in an organic alcohol solvent, the solvent was removed by vacuum distillation, and the compounds were obtained by column chromatography. The synthetic route for the compound represented by formula (I) is as follows: ； The synthetic route for the compound represented by formula (II) is as follows: ； The molar ratio of compound 1b to compound 2 is 1:1.

2. The synthetic route for the compound represented by formula (III) is as follows: ； The synthetic route for the compound represented by formula (IV) is as follows: ； In the synthesis of the compounds shown in formula (I), formula (III) or formula (IV), the molar ratio of compound 1a, compound 1b or compound 1c to compound 2 is 1:0.

8.

3. The synthesis method according to claim 2, characterized in that, The molar ratio of the propylidene-protected and p-toluenesulfonated sugar to the trifluoromethanesulfonate catalyst is 1:0.

1.

4. The synthesis method according to claim 2, characterized in that, The volume ratio of toluene to methanol in the toluene / methanol mixed solvent is 5:

1.

5. The synthesis method according to claim 2, characterized in that, In the synthesis of the compound shown in formula (II), the mobile phase used for column chromatography separation is V. 二氯甲烷 :V 乙酸乙酯 =(3~6) :1, the silicone column is a 200-300 mesh silicone column.

6. The synthesis method according to claim 2, characterized in that, In the synthesis of compounds represented by formula (I), (III), or (IV), the mobile phase used for column chromatography separation is V. 二氯甲烷 :V 甲醇 = (10~20):1, the silica gel column is a 200-300 mesh silica gel column.

7. The use of the naphthopyrimidine and fused azazose derivative of claim 1 in the preparation of anti-colon cancer tumor cell drug formulations.

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