Use of chiral bisphosphonate diamine compound

Abstract

The use of the chiral bisphosphonate diamine compound in the preparation of anti-cancer reagents is inhibitory activity as shown in tests against the type of liver cancer cells SMMC -7721, and the che

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit and priority of Chinese Patent Publication No. 113546085 filed with the China National Intellectual Property Administration (CNIPA) on July 19, 2021 and entitled "USE OF CHIRAL BISPHOSPHONATE DIAMINE COMPOUND", the disclosure of which is incorporated by reference herein in its entirety as part of the present application. TECHNICAL FIELD

[0002] The present disclosure relates to use of a chiral compound, in particular to use of a chiral bisphosphonate diamine compound. 23 10 24 BACKGROUND

[0003] Chiral phosphine oxazoline and metal complexes have shown desirable asymmetric catalytic activity and high enantioselectivity in various reactions such as Didls-Alder diene cycloaddition, Michael condensation, Friedel-Crafts condensation, Aldol, Henry reaction, and nitrile silicification, thereby receiving extensive attention[1’13].

[0004] (l)Glos, M.; Reiser, O. Org. Lett.2000, 2(14), 2045.

[0005] (2)Braga, A. L. Vargas, F.; Sehnem, J.A.; Braga, R. C. J. Org. Chern. 2005, 70(22), 9021.

[0006] (3)Breit, B., Schmidt, Y.; Chem. Rev. 2008, 108(8), 2928. (d) McManus, H. A.; Guiiy, P. J. J. Org. Chem.2002, 67(24), 8566.

[0007] (4)Wang, W.B.; Fang, J.M.J.Org.Chem.1998, 63, 1356.

[0008] (5)Fu, G.C.Acc.Chem.Res.2006, 39(11), 853.

[0009] (6)Hargaden, G. C.; Patrick J. Guiry, P. J. Chem.Rev.2009, 109(6), 2505.

[0010] (7)McManu, H. A.; Guiry, P. J. Chem.Rev.2004, 104(9), 4151.

[0011] (8)Takamichi, Y.; Masatoshi, O.; Takahiro, K.; Dai, M.; Kiyoshi, S.; Motowo, Y. Tetrahedron: Asymmetry 2003, 14, 3275.

[0012] (9)Cristina G. -Y., P. J.; Frank R.; Gunter, H. Organometallics 2004, 23, 5459.

[0013] (lO)Delphine, F.; Montserrat, G., Francisco, J., Guillermo, M.; Merce, R., Miguel, A. M.,; Jose, M. Organometallics 2004, 23(13), 3197.

[0014] (ll)Koch, G ; Guy, C.; Loiseleur, O.; Pfaltz, A.; Pretot, R ; Schaffner, S.; Schnider, P.; VonMatt, P. Recueil des Travaux Chimiques des Pays-Bas 1995, 114(4 / 5), 206.

[0015] (12)Sprinz, J.; Helmchen, G. Tetra. Lett. 1993, 34(11), 1769.

[0016] (13)Franco, D.; Gomez, M.; Jimenez, F.; Muller, G.; Rocamora, M.; Maestro, M.A.; Mahia, J. Organometallics2004, 23(13), 3197.

[0017] The applicant has been engaged in the development of asymmetric compounds for a long time, and has applied for patents successively, including ZL200610096004.X, CN101016311A, CN101099936A, 200810020198.4, CN101279954A, 200810022278.3, and 200910116614.5. SUMMARY

[0018] The present disclosure aims to provide a high-efficiency chiral anti-cancer agent in the field of asymmetric synthesis, especially in preparation of a chiral drug compound. A technical problem to be solved by the present disclosure is to select the chiral drug compound as an optimal anti-liver cancer agent.

[0019] In the present disclosure, a chiral phosphine compound has a chemical name of , with a chemical formula as follows:

[0021] in the chemical formula, R is phenyl (-Ph).

[0022] A synthesis method of the chiral phosphine compound includes two steps. In step I, 2-cyanoaniline (2-aminobenzonitrile) and L-phenylglycol are reacted to prepare an intermediate 2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolinyl]aniline. In step II, a target product is synthesized by a reaction of the intermediate with phenylphosphonic dichloride [(Ph)POC12]. A flow chart is as follows:

[0023]

[0024] The L-phenylglycol is L-(+)-a-phenylglycinol. The L-phenylglycinol and the 2-cyanoaniline undergo a ring-closing reaction to form oxazolinyl, and an R group carried in the L-phenylglycinol is -Ph.

[0025] A synthesis method of the chiral phosphine compound refers to preparing an intermediate and then synthesizing a target product, including reaction, separation, and purification. The 2-cyanoaniline and the L-phenylglycininol are refluxed in a chlorobenzene solvent for 24 h in the presence of anhydrous ZnCh as a catalyst under anhydrous and anaerobic conditions, and then separated and purified to obtain the intermediate. The chlorobenzene is removed after the reaction is completed, an obtained reaction product is dissolved in water and then extracted with chloroform, and a resulting extract phase is desolvated and then purified by column chromatography. The intermediate and the phenylphosphonic dichloride are refluxed for 24 h in a mixed solvent of toluene and triethylamine under anhydrous and anaerobic conditions, and then separated and purified. That is, the mixed solvent is removed after the reaction, and a remaining substance is purified by column chromatography to obtain the target product.

[0026] For this compound, a synthesis and preparation method of a target compound has been applied in 2010. An application number is: 201010238319.X. At present, it is found that the compound shows a certain inhibitory effect in anti-liver cancer, with an index half maximal inhibitory concentration (IC50) reaching 10.26=0.24. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows ’HNMR of a target compound 1;

[0028] FIG. 2 shows 13CNMR of the target compound 1; and

[0029] FIG. 3 shows 31PNMR of the target compound 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] (I) Preparation of an intermediate 1

[0031] 1. Preparation of the intermediate 1

[0032] In a 100 mL two-necked flask, 60 mg (0.37 mmol) of anhydrous ZnCk, 40 mL of chlorobenzene, 1.0 g (8.47 mmol) of 2-cyanoaniline, and 3 g of L-phenylglycinol were added under anhydrous and anaerobic conditions. A resulting mixture was refluxed at a high temperature for 24 h, and the solvent was removed under reduced pressure. A resulting residue was dissolved in water and extracted with CHCL (20 mL 2). An obtained organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and an obtained crude product was subjected to column chromatography with petroleum ether / dichloromethane (4:1) to obtain 1.1 g of a colorless oily liquid with a yield of 58%; [a]5 = +195.8°(c=0.25, CHCk): ’HNMR (500 MHz, CDCI3, 27°C), 8 (ppm)=7.74 (d, J=7.5 Hz, 1H), 7.28-7.37 (m, 6H), 6.68-6.72 (m, 1H), 6.13 (s, 2H), 5.45 (t, 1H), 4.68 (t, 1H), 4.12 (t, J=0.5 Hz, 1H).

[0033] 2. Synthesis of a compound bis{N-2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolinyl]-diphenyl-phenylphosphorodiamidate:

[0034] In a 100 mL two-necked flask, 40 mL of toluene, 1.4 g (6.42 mmol) of 2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl]aniline (intermediate la), 20 mL of tri ethylamine, and 0.6 mL (3.00 mmol) of phenylphosphonic dichloride were added under anhydrous and anaerobic conditions. A resulting mixture was heated to allow refluxing for 24 h, and the solvent was removed under reduced pressure. An obtained crude product was subjected to column chromatography with petroleum ether / dichloromethane (1:9) to obtain a light yellow liquid with a yield of 45%. [a]5D = +172.3°(c=0.85, CHCL); 1HNMR (500 MHz, CDCh, 27°C) 8 (ppm)=11.92(d, J=12 Hz, 1H), 7.67-7.87(m, 6H), 6.88-7.26(m, 17H), 5.27(t, J=0.5Hz, 1H), 5.08(t, J=0.5Hz, 1H), 4.56-4.68(m, 3H), 4.00-4.10(m, 1H). 13CNMR(125 MHz, CDCI3, 27°C)165.02(x2), 143.52, 143.34, 141.90, 141.84, 132.71(x2), 132.07(x2), 131.54, 131.44,129.55(x2), 128.80(x2), 128.72(x2), 128.61(x2), 127.57, 127.46, 126.46, 126.36, 120.00(x2), 119.92(x2), 118.42, 118.38, 118.06, 118.02, 73.12, 73.02, 69.62, 69.53. 13PNMR(300 MHz, CDCI3, 27°C), 8 (ppm)=5.474. IR(KBr): 3062, 2957, 2924, 2853, 1633, 1602, 1584, 1499, 1455, 1437, 1361, 1301, 1265, 1218, 1164, 1136, 1122, 1065, 1047, 954, 910, 752, 731, 697, 645, 621, 514, 475; HRMS(EI): m / z(%): calcd for C36H31N4O3P: 598.2134; found: 598.2131.

[0035] (III) Use of this compound in anti-liver cancer

[0036] In the present disclosure, the compound (I) synthesized according to the target design showed a strong inhibitory activity (EDso<lO.O ug / mL) in a liver cancer cell (SMMC-7721) test. This test was conducted with reference to a method described in [J. Natl. Cancer Inst. 1990, 82(13): 1107-1112], Briefly, human cancer cells used (such as DU145, PC-3, A549, KB, and KB-Vin) were placed in a single medium (RPMI-1640 containing 10% (v / v) calf serum), and morphological characteristics and growth status of the cells in the medium were examined with a microscope. The cells were cultured in a 2.5 cm2 culture dish at 37°C under a humidified atmosphere containing 5% CO2. A cell line grew adherently. The sample preparation and dilution, as well as inoculation of the sample in a cell fluid should be conducted aseptically. Test samples were generally dissolved in DMSO and stored at -70°C. In a 96-well culture plate, test samples of different concentrations and about 5,000 to 20,000 cells were placed in each well for 72 h. IC50 values for inhibition of cancer cell growth were determined by a sulforhodamine B (SRB) method.

[0037] Table 1 showed the test results of some anticancer activities of the compound in the present disclosure.

[0038] Table 1 Anti cancer activity data (IC50 value) of compound (I)

[0039] Cell line Sample Liver cancer cell SMMC-7721 IC50+SD (pm) Average Standard deviation Chiral bisphosphonate diamine compound (I) 10.26 ±0.24

[0040] IC50 represented an effective concentration that inhibited the growth of half of cancer cells, indicating the anti-cancer activity. NA indicated no inhibitory activity. The human cancer cells used in this test were purchased from ATCC, USA.

[0041] The above descriptions are merely preferred implementations of the present disclosure. It should be noted that a person of ordinary skill in the art may further make several improvements and modifications without departing from the principle of the present disclosure, but such improvements and modifications should be deemed as falling within the protection scope of the present disclosure.

Claims

1. Use of a chiral bisphosphonate diamine compound in preparation of an anti-cancer agent, wherein the anti-cancer agent shows an inhibitory activity in an SMMC-7721 cancer cell type test of liver cancer; and the chiral bisphosphonate diamine compound has a chemical formula as follows:in the chemical formula, R is -Ph.

2. The use according to claim 1, wherein the anti-cancer agent is an anti-liver cancer agent.

3. Use of a chiral bisphosphonate diamine compound in anti-liver cancer, wherein the chiral bisphosphonate diamine compound has a chemical formula as follows:; and in the chemical formula, R is -Ph.

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