WO2023001124A1 - Use of chiral bisphosphonate diamine compound - Google Patents
Use of chiral bisphosphonate diamine compound Download PDFInfo
- Publication number
- WO2023001124A1 WO2023001124A1 PCT/CN2022/106366 CN2022106366W WO2023001124A1 WO 2023001124 A1 WO2023001124 A1 WO 2023001124A1 CN 2022106366 W CN2022106366 W CN 2022106366W WO 2023001124 A1 WO2023001124 A1 WO 2023001124A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chiral
- compound
- bisphosphonate
- diamine compound
- liver cancer
- Prior art date
Links
- -1 bisphosphonate diamine compound Chemical class 0.000 title claims abstract description 6
- 229940122361 Bisphosphonate Drugs 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 206010019695 Hepatic neoplasm Diseases 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 3
- 239000003183 carcinogenic agent Substances 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 6
- 230000001093 anti-cancer Effects 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 2
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 2
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- IBDMRHDXAQZJAP-UHFFFAOYSA-N dichlorophosphorylbenzene Chemical compound ClP(Cl)(=O)C1=CC=CC=C1 IBDMRHDXAQZJAP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 1
- NHFAABIHBNXKDT-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;phosphane Chemical class P.C1CN=CO1 NHFAABIHBNXKDT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000006842 Henry reaction Methods 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the use of a chiral compound, in particular to the use of a chiral bisphosphonamide compound.
- the invention aims to provide a high-efficiency chiral anti-cancer reagent for the field of asymmetric synthesis, especially for the preparation of chiral drug compounds.
- the technical problem to be solved is to select the chiral compound as the best anti-liver cancer reagent.
- the chiral phosphine compound referred to in the present invention is bis ⁇ N-2-[(4S)-4,5-dihydrogenated-4-phenyl-2-oxazolinyl]-diphenyl-phenyl Phosphonamide, having the following chemical structure:
- R is selected from -Ph(phenyl).
- the synthetic method of this chiral phosphine compound is two steps, the first step prepares intermediate 2-[(4S)-4,5- Dihydro-4-phenyl- 2 -oxazolinyl] aniline, the second step above-mentioned intermediate and phenylphosphonic acid dichloride [(Ph)POCl ] to synthesize the target product, the flow chart is as follows:
- L-amino alcohol is selected from L-phenylglycine.
- L-phenylglycinol reacts with 2-cyanoaniline, the ring is closed to form an oxazoline group, and the R group carried by it is -Ph.
- the synthetic method of this chiral phosphine compound is to prepare the intermediate first and then synthesize the target product, including reaction, separation and purification.
- Reflux reaction in chlorobenzene solvent for 24 hours in the presence of catalyst anhydrous ZnCl then separate and purify, slough off chlorobenzene after the reaction, dissolve with water and extract with chloroform, and purify with column chromatography after desolventizing the extract phase;
- the reaction of synthesizing the target product is that the prepared intermediate and diphenylphosphonyl chloride are refluxed in a mixed solvent of toluene and triethylamine under anhydrous and oxygen-free conditions for 24 hours, and then separated and purified, that is, the solvent is removed after the reaction , purified by column chromatography.
- the compound has applied for the synthesis and preparation method of the target compound in 2010.
- the compound shows a certain inhibitory effect on anti-tumor liver cancer, and its index IC 50 value reaches 10.26 ⁇ 0.24.
- Fig. 1 is the 1 HNMR of target compound 1;
- Fig. 2 is the 13 CNMR of target compound 1;
- FIG. 3 is a 31 PNMR chart of target compound 1.
- the compound (I) synthesized according to the target design of the present invention shows strong inhibitory activity (ED 50 ⁇ 10.0 ⁇ g/mL) in the test of liver cancer cells (SMMC-7721).
- This test was carried out with reference to the method described in [J. Natl. Cancer Inst. 1990, 82(13): 1107-1112]. Briefly, the human cancer cells used (DU145, PC-3, A549, KB, KB-VIn, etc.) were placed in a single medium (RPMI-1640 containing 10% (v/v) calf serum) A microscope examines the morphological characteristics and growth of cells in culture. Cells were cultured in a 2.5 cm 2 culture dish at 37°C in a humidified atmosphere containing 5% CO 2 .
- Test samples are usually dissolved in DMSO and stored at -70°C. In a 96-well culture plate, test samples of different concentrations and about 5,000-20,000 cells were placed in each well for 72 hours. The IC 50 value of inhibiting the growth of cancer cells was determined by the SRB (sulforhodamine B) method.
- Table 1 shows the test results of some anticancer activities of the compounds of the present invention.
- IC 50 is the effective concentration that inhibits the growth of half of cancer cells, indicating anticancer activity.
- NA No inhibitory activity.
- the above-mentioned human cancer cells used in this experiment were purchased from ATCC in the United States.
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 chemical formula aa thereof is as follows: in the formula, R is selected from a -Ph (phenyl) group.
Description
本申请要求于2021年07月19日提交中国专利局、申请号为202110814325.3、发明名称为“一种手性双膦酰二胺化合物的用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of a Chinese patent application submitted to the China Patent Office on July 19, 2021 with the application number 202110814325.3 and the title of the invention "A Use of a Chiral Bisphosphonamide Compound", the entire content of which is incorporated by reference incorporated in this application.
本发明涉及一种手性化合物的用途，具体地说是一种手性双膦酰二胺化合物的用途。The present invention relates to the use of a chiral compound, in particular to the use of a chiral bisphosphonamide compound.
手性膦噁唑啉及金属的配合物在Didls-Alder(狄乐斯-艾而特)二烯环加成反应、Michael(米歇尔)缩合反应、Friedel-Crafts(傅瑞德-克拉佛兹)缩合反应、Aldol(醇醛)、亨利反应、腈硅化等反应等许多反应中表现出良好的不对称催化活性和高对映选择性，因而受到广泛的关注[1-13]。Chiral phosphine oxazoline and metal complexes in Didls-Alder (Diles-Elt) diene cycloaddition reaction, Michael (Michel) condensation reaction, Friedel-Crafts (Friedel-Crafts) Condensation reaction, Aldol (aldol), Henry reaction, nitrile silicification and many other reactions have shown good asymmetric catalytic activity and high enantioselectivity, so they have received extensive attention [1-13].
(1)Glos，M.；Reiser，O.Org.Lett.2000，2(14)，2045.(1) Glos, M.; Reiser, O. Org. Lett. 2000, 2(14), 2045.
(2)Braga，A.L.Vargas，F.；Sehnem，J.A.；Braga，R.C.J.Org.Chem.2005，70(22)，9021.(2) Braga, A.L. Vargas, F.; Sehnem, J.A.; Braga, R.C.J.Org.Chem. 2005, 70(22), 9021.
(3)Breit，B.；Schmidt，Y.；Chem.Rev.2008，108(8)，2928.(d)McManus，H.A.；Guiry，P.J.J.Org.Chem.2002，67(24)，8566.(3) Breit, B.; Schmidt, Y.; Chem.Rev.2008, 108(8), 2928. (d) McManus, H.A.; Guiry, P.J.J.Org.Chem.2002, 67(24), 8566.
(4)Wang，W.B.；Fang，J.M.J.Org.Chem.1998，63，1356.(4) Wang, W.B.; Fang, J.M.J.Org.Chem. 1998, 63, 1356.
(5)Fu，G.C.Acc.Chem.Res.2006，39(11)，853.(5) Fu, G.C. Acc. Chem. Res. 2006, 39(11), 853.
(6)Hargaden，G.C.；PatrickJ.Guiry，P.J.Chem.Rev.2009，109(6)，2505.(6) Hargaden, G.C.; Patrick J. Guiry, P. J. Chem. Rev. 2009, 109(6), 2505.
(7)McManu，H.A.；Guiry，P.J.Chem.Rev.2004，104(9)，4151.(7) McManu, H.A.; Guiry, P.J. Chem. Rev. 2004, 104(9), 4151.
(8)Takamichi，Y.；Masatoshi，O.；Takahiro，K.；Dai，M.；Kiyoshi，S.；Motowo，Y.Tetrahedron：Asymmetry 2003，14，3275.(8) Takamichi, Y.; Masatoshi, O.; Takahiro, K.; Dai, M.; Kiyoshi, S.; Motowo, Y. Tetrahedron: Asymmetry 2003, 14, 3275.
(9)Cristina G.-Y.，P.J.；Frank R.；Günter，H.Organometallics 2004，23，5459.(9) Cristina G.-Y., P.J.; Frank R.; Günter, H. Organometallics 2004, 23, 5459.
(10)Delphine，F.；Montserrat，G.，Francisco，J.，Guillermo，M.；Mercè，R.，Miguel，A.M.，；José，M.Organometallics 2004，23(13)，3197.(10) Delphine, F.; Montserrat, G., Francisco, J., Guillermo, M.; Mercè, R., Miguel, A.M.,; José, M. Organometallics 2004, 23(13), 3197.
(11)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.(11) Koch, G.; Guy, C.; Loiseleur, O.; Pfaltz, A.; Pretot, R.; Schaffner, S.; 1995, 114(4/5), 206.
(12)Sprinz，J.；Helmchen，G.Tetra.Lett.1993，34(11)，1769.(12) Sprinz, J.; Helmchen, G. Tetra. Lett. 1993, 34(11), 1769.
(13)Franco，D.；Gomez，M.；Jimenez，F.；Muller，G.；Rocamora，M.；Maestro，M.A.；Mahia，J.Organometallics2004，23(13)，3197。(13) Franco, D.; Gomez, M.; Jimenez, F.; Muller, G.; Rocamora, M.;
申请人长期从事不对称化合物的研制，并陆续申请了发明专利，ZL200610096004.X、CN101016311A、CN101099936A、200810020198.4、CN101279954A、200810022278.3、200910116614.5。The applicant has been engaged in the development of asymmetric compounds for a long time, and has successively applied for invention patents, ZL200610096004.X, CN101016311A, CN101099936A, 200810020198.4, CN101279954A, 200810022278.3, 200910116614.5.
发明内容Contents of the invention
本发明旨在为不对称合成领域特别是制备手性药物化合物提供一种高效手性抗癌试剂，所要解决的技术问题是遴选该手性化合物作为最佳的抗肝癌试剂。The invention aims to provide a high-efficiency chiral anti-cancer reagent for the field of asymmetric synthesis, especially for the preparation of chiral drug compounds. The technical problem to be solved is to select the chiral compound as the best anti-liver cancer reagent.
本发明所称的手性膦化合物是化学名称为双{N-2-[(4S)-4,5-二氢化-4-苯基-2-噁唑啉基]-二苯基-苯基膦酰二胺，具有以下化学结构式：The chiral phosphine compound referred to in the present invention is bis{N-2-[(4S)-4,5-dihydrogenated-4-phenyl-2-oxazolinyl]-diphenyl-phenyl Phosphonamide, having the following chemical structure:
式中R选自-Ph(苯基)。In the formula, R is selected from -Ph(phenyl).
本手性膦化合物的合成方法为两步，第一步以2-氰基苯胺(2-氨基苯腈)和L-苯甘基醇反应制备中间体2-[(4S)-4,5-二氢化-4-苯基-2-噁唑啉基]苯胺，第二步上述中间体与苯基膦酰二氯[(Ph)POCl
2]合成目标产物，流程示意如下：
The synthetic method of this chiral phosphine compound is two steps, the first step prepares intermediate 2-[(4S)-4,5- Dihydro-4-phenyl- 2 -oxazolinyl] aniline, the second step above-mentioned intermediate and phenylphosphonic acid dichloride [(Ph)POCl ] to synthesize the target product, the flow chart is as follows:
所述的L-氨基醇选自L-苯甘氨醇。L-苯甘氨醇与2-氰基苯胺反应时闭环形成噁唑啉基，其携带的R基是-Ph。Described L-amino alcohol is selected from L-phenylglycine. When L-phenylglycinol reacts with 2-cyanoaniline, the ring is closed to form an oxazoline group, and the R group carried by it is -Ph.
本手性膦化合物的合成方法是先制备中间体后合成目标产物，包括反应、分离和纯化，制备中间体的反应由2-氰基苯胺和L-苯甘氨醇在无水无氧条件下和催化剂无水ZnCl
2存在时于氯苯溶剂中回流反应24小时，然后分离、纯化，即反应结束后脱去氯苯，加水溶解后用氯仿萃取，萃取相脱溶后用柱层析纯化；合成目标产物的反应是所制备的中间体与二苯基膦酰氯在无水无氧条件下于甲苯和三乙胺混合溶剂中回流反应24小时，然后分离、纯化，即反应结束后脱去溶剂，用柱层析纯化。
The synthetic method of this chiral phosphine compound is to prepare the intermediate first and then synthesize the target product, including reaction, separation and purification. Reflux reaction in chlorobenzene solvent for 24 hours in the presence of catalyst anhydrous ZnCl, then separate and purify, slough off chlorobenzene after the reaction, dissolve with water and extract with chloroform, and purify with column chromatography after desolventizing the extract phase; The reaction of synthesizing the target product is that the prepared intermediate and diphenylphosphonyl chloride are refluxed in a mixed solvent of toluene and triethylamine under anhydrous and oxygen-free conditions for 24 hours, and then separated and purified, that is, the solvent is removed after the reaction , purified by column chromatography.
该化合物已在2010年申请目标化合物的合成及制备方法。申请号：201010238319.X。目前，发现该化合物在抗肿瘤肝癌中显示了一定的抑制作用，其指标IC
50值达到10.26±0.24。
The compound has applied for the synthesis and preparation method of the target compound in 2010. Application number: 201010238319.X. At present, it is found that the compound shows a certain inhibitory effect on anti-tumor liver cancer, and its index IC 50 value reaches 10.26±0.24.
图1是目标化合物1的
1HNMR；
Fig. 1 is the 1 HNMR of target compound 1;
图2是目标化合物1的
13CNMR；
Fig. 2 is the 13 CNMR of target compound 1;
图3是目标化合物1的
31PNMR图。
FIG. 3 is a 31 PNMR chart of target compound 1.
(一)中间体1的制备(1) Preparation of Intermediate 1
1、中间体1的制备1. Preparation of Intermediate 1
在100mL两口瓶中，无水无氧条件下，加入无水ZnCl
260mg(0.37mmol)，40mL氯苯，2-腈基苯胺1.0g(8.47mmol)，L-苯甘氨醇3g，将混合物在高温下回流24h，停止反应，减压以除去溶剂，将剩余物用水溶解，并用CHCl
3(20mL×2)萃取，有机相用无水硫酸钠干燥，旋 转除去溶剂，将粗产品用石油醚/二氯甲烷(4：1)柱层析，得无色油状液体1.1g，产率58％；[a]
5＝+195.8°(c＝0.25，CHCl
3)：
1HNMR(500MHz，CDCl
3，27℃)，δ(ppm)＝7.74(d，J＝7.5Hz，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＝0.5Hz，1H)。
In a 100mL two-necked flask, under anhydrous and anaerobic conditions, add 60mg (0.37mmol) of anhydrous ZnCl 2 , 40mL of chlorobenzene, 1.0g (8.47mmol) of 2-cyanoaniline, and 3g of L-phenylglycinol. Reflux at high temperature for 24h, stop the reaction, remove the solvent under reduced pressure, dissolve the residue in water, and extract with CHCl 3 (20mL×2), dry the organic phase with anhydrous sodium sulfate, spin to remove the solvent, and dilute the crude product with petroleum ether /dichloromethane (4:1) column chromatography to obtain 1.1 g of colorless oily liquid, yield 58%; [a] 5 =+195.8° (c = 0.25, CHCl 3 ): 1 HNMR (500 MHz, CDCl 3 , 27℃), δ(ppm)=7.74(d, J=7.5Hz, 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=0.5Hz, 1H).
2.化合物双N-2-[(4S)-4,5-二氢化-4-(苯基)-2-噁唑啉基]二苯基-二苯基膦酰胺的合成：2. Synthesis of compound bis-N-2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl]diphenyl-diphenylphosphonamide:
在100mL两口瓶中，无水无氧条件下，加入40mL甲苯，2-[(4S)-4,5-二氢化-4-(苯基)-2-噁唑啉基]苯胺(中间体1a)1.4g(6.42mmol)，三乙胺20mL，苯基膦酰二氯0.6mL(3.00mmol)，将混合物加热回流24h，停止反应，减压以除去溶剂，将粗产品用石油醚/二氯甲烷(1：9)柱层析，得淡黄色液体，产率45％；[a]
5
D＝+172.3°(c＝0.85，CHCl
3)；
1HNMR(500MHz，CDCl
3，27℃)δ(ppm)＝11.92(d，J＝12Hz，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(125MHz，CDCl
3，27℃)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(300MHz，CDCl
3，27℃)，δ(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 C
36H
31N
4O
3P：598.2134；found：598.2131。
In a 100mL two-necked flask, under anhydrous and oxygen-free conditions, add 40mL of toluene, 2-[(4S)-4,5-dihydro-4-(phenyl)-2-oxazolinyl]aniline (intermediate 1a ) 1.4g (6.42mmol), triethylamine 20mL, phenylphosphonic dichloride 0.6mL (3.00mmol), the mixture was heated to reflux for 24h, the reaction was stopped, and the solvent was removed under reduced pressure, and the crude product was washed with petroleum ether/dichloro Methane (1:9) column chromatography gave a light yellow liquid with a yield of 45%; [a] 5 D =+172.3°(c=0.85, CHCl 3 ); 1 HNMR (500MHz, CDCl 3 , 27°C)δ (ppm)=11.92(d, J=12Hz, 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). 13 CNMR (125MHz, CDCl 3 , 27℃) 165.02(x2), 143.52, 143.34, 141.90, 141.84, 132.71 (x2) 132.07(x2) 131.54 131.44 , 118.42, 118.38, 118.06, 118.02, 73.12, 73.02, 69.62, 69.53. 13 PNMR (300MHz, CDCl 3 , 27°C), δ (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 C 36 H 31 N 4 O 3 P: 598.2134; found: 598.2131.
(三)本化合物在抗肿瘤肝癌中的用途(3) The purposes of this compound in antitumor liver cancer
本发明依据目标设计合成的化合物(I)在肝癌细胞(SMMC-7721)试验中均显示出较强的抑制活性(ED
50＜10.0μg/mL)。参照[J.Natl.Cancer Inst.1990，82(13)：1107-1112]中所述的方法进行本试验。简言之，将所用的人体癌细胞(DU145，PC-3，A549，KB，KB-VIn等)置于单一培养基(RPMI-1640含10％(v/v)小牛血清)中，用显微镜对细胞在培养液中 的形态特征和生长状况进行检查。细胞置于2.5cm
2的培养皿中，37℃，含5％CO
2潮湿空气中培养。细胞系贴壁生长。样品配制和稀释及将其接种于细胞液中的过程应为无菌操作。测试样品通常用DMSO溶解，-70℃保存。在96孔培养板中，每个孔置于不同浓度的测试样品和约5000-20000个细胞，放置72小时。抑制癌细胞生长的IC
50值由SRB(sulforhodamine B)方法确定。
The compound (I) synthesized according to the target design of the present invention shows strong inhibitory activity (ED 50 <10.0 μg/mL) in the test of liver cancer cells (SMMC-7721). This test was carried out with reference to the method described in [J. Natl. Cancer Inst. 1990, 82(13): 1107-1112]. Briefly, the human cancer cells used (DU145, PC-3, A549, KB, KB-VIn, etc.) were placed in a single medium (RPMI-1640 containing 10% (v/v) calf serum) A microscope examines the morphological characteristics and growth of cells in culture. Cells were cultured in a 2.5 cm 2 culture dish at 37°C in a humidified atmosphere containing 5% CO 2 . Cell lines grow adherently. The process of sample preparation and dilution and its inoculation in cell fluid should be performed aseptically. Test samples are usually dissolved in DMSO and stored at -70°C. In a 96-well culture plate, test samples of different concentrations and about 5,000-20,000 cells were placed in each well for 72 hours. The IC 50 value of inhibiting the growth of cancer cells was determined by the SRB (sulforhodamine B) method.
本发明化合物的部分抗癌活性测试结果见表1。Table 1 shows the test results of some anticancer activities of the compounds of the present invention.
表1.(I)的抗癌活性数据(IC
50值)
Table 1. Anticancer activity data ( IC50 values) of (I)
IC
50是抑制半数癌细胞生长的有效浓度，表示抗癌活性。NA：无抑制活性。本试验所用的上述人体癌细胞从美国ATCC购买。
IC 50 is the effective concentration that inhibits the growth of half of cancer cells, indicating anticancer activity. NA: No inhibitory activity. The above-mentioned human cancer cells used in this experiment were purchased from ATCC in the United States.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.
Claims (3)
- 一种手性双膦酰二胺化合物在制备抗癌试剂中的用途，所述的抗癌试剂是针对肝癌SMMC-7721癌症细胞种类试验中均显示出抑制活性，所述手性双膦酰二胺化合物的化学式如下：A use of a chiral bisphosphonodiamine compound in the preparation of an anticancer agent, the anticancer agent exhibits inhibitory activity against liver cancer SMMC-7721 cancer cell types, and the chiral bisphosphonodiamide The chemical formula of the amine compound is as follows:
式中R选自-Ph。In the formula, R is selected from -Ph. - 根据权利要求1所述的用途，其特征在于，所述的抗癌试剂为抗肝癌试剂。The use according to claim 1, characterized in that the anti-cancer agent is an anti-liver cancer agent.
- 一种手性双膦酰二胺化合物在抗肿瘤肝癌中的用途，其特征在于，所述手性双膦酰二胺化合物的化学式如下：A use of a chiral bisphosphonamide compound in anti-tumor liver cancer, characterized in that the chemical formula of the chiral bisphosphonamide compound is as follows:
式中R选自-Ph。In the formula, R is selected from -Ph.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2316418.9A GB2620096A (en) | 2021-07-19 | 2022-07-19 | Use of chiral bisphosphonate diamine compound |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110814325.3 | 2021-07-19 | ||
| CN202110814325.3A CN113546085B (en) | 2021-07-19 | 2021-07-19 | Application of chiral diphosphonic diamide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023001124A1 true WO2023001124A1 (en) | 2023-01-26 |
Family
ID=78132083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2022/106366 WO2023001124A1 (en) | 2021-07-19 | 2022-07-19 | Use of chiral bisphosphonate diamine compound |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN113546085B (en) |
| GB (1) | GB2620096A (en) |
| WO (1) | WO2023001124A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113546085B (en) * | 2021-07-19 | 2023-04-25 | 合肥工业大学 | Application of chiral diphosphonic diamide compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607970A (en) * | 2009-07-24 | 2009-12-23 | 合肥工业大学 | A kind of chiral bi-phosphono-diamine compound and synthetic method thereof |
| CN102382138A (en) * | 2011-07-28 | 2012-03-21 | 罗梅 | Chiral diphosphonic diamine compound and applications thereof |
| CN113546085A (en) * | 2021-07-19 | 2021-10-26 | 合肥工业大学 | Application of chiral diphosphonic diamide compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5227508A (en) * | 1992-01-24 | 1993-07-13 | Mayo Foundation For Medical Education And Research | 3-deoxy-3-substituted analogs of phosphatidylinositol |
| TW201100441A (en) * | 2009-06-01 | 2011-01-01 | Osi Pharm Inc | Amino pyrimidine anticancer compounds |
| CN108003111A (en) * | 2017-12-14 | 2018-05-08 | 华东理工大学 | Double target spot inhibitor of a kind of HDAC1 and IDO1 and its preparation method and application |
-
2021
- 2021-07-19 CN CN202110814325.3A patent/CN113546085B/en active Active
-
2022
- 2022-07-19 GB GB2316418.9A patent/GB2620096A/en active Pending
- 2022-07-19 WO PCT/CN2022/106366 patent/WO2023001124A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607970A (en) * | 2009-07-24 | 2009-12-23 | 合肥工业大学 | A kind of chiral bi-phosphono-diamine compound and synthetic method thereof |
| CN102382138A (en) * | 2011-07-28 | 2012-03-21 | 罗梅 | Chiral diphosphonic diamine compound and applications thereof |
| CN113546085A (en) * | 2021-07-19 | 2021-10-26 | 合肥工业大学 | Application of chiral diphosphonic diamide compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113546085A (en) | 2021-10-26 |
| GB202316418D0 (en) | 2023-12-13 |
| CN113546085B (en) | 2023-04-25 |
| GB2620096A (en) | 2023-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2023001124A1 (en) | Use of chiral bisphosphonate diamine compound | |
| JP2010509393A5 (en) | ||
| JP6745823B2 (en) | Methods for the synthesis of rapamycin derivatives | |
| CN101607970A (en) | A kind of chiral bi-phosphono-diamine compound and synthetic method thereof | |
| CN116888133A (en) | Method for preparing organic tin compound | |
| CN109704926B (en) | Anticancer active molecular skeleton 1, 4-eneyne compound and preparation method and application thereof | |
| KR20140117450A (en) | Method for producing farnesal using vanadium complex | |
| CN107686452B (en) | 6-bromoisovanillin long-chain organic amine Schiff base and preparation method thereof | |
| CN110283078A (en) | Polysubstituted 1, 4-diene compound and preparation method thereof | |
| CN101591356A (en) | A kind of chiral phosphoramide compound and synthetic method thereof | |
| EP3611170A1 (en) | Antianxiety deuterated compounds and medical use thereof | |
| CN105949118B (en) | A kind of preparation method of 2- aryl quinoline derivatives | |
| CN104892682A (en) | Synthesis method of metal-coordination polymer containing sulfanilic acid and catalytic activity of metal-coordination polymer | |
| CN102382138B (en) | Chiral diphosphonic diamine compound and applications thereof | |
| CN107118180A (en) | A kind of nitrogenous octatomic ring alkyne derivatives and preparation method thereof | |
| CN111393478A (en) | Synthetic method of medicine for treating pneumonia infected by new coronavirus COVID-19 | |
| CN107021969B (en) | The method that catalysis oxidation prepares biotin precursor ketone acid | |
| CN106083534B (en) | A kind of method of the aryl boric acid phenol of visible light catalytic | |
| Signore et al. | Synthesis of N, N-disubstituted phosphoramidates via a Lewis acid-catalyzed phosphorimidate rearrangement | |
| Taylor et al. | Spontaneous dehydrocoupling in peri-substituted phosphine–borane adducts | |
| CN108250241B (en) | N, N, N coordination trivalent dicyclic phosphide, synthesis method and catalytic application thereof | |
| CN107082788B (en) | The synthetic method that one kind is efficiently esterified with imines catalysis P (O)-OH class compound and alcohol | |
| CN101838210A (en) | The method of the metal complex of preparation polydentate beta-ketoiminates | |
| CN102070669A (en) | Chiral phosphamide compound | |
| CN101538280A (en) | Chiral phosphine compound and synthesis method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22845289 Country of ref document: EP Kind code of ref document: A1 |
|
| ENP | Entry into the national phase |
Ref document number: 202316418 Country of ref document: GB Kind code of ref document: A Free format text: PCT FILING DATE = 20220719 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 22845289 Country of ref document: EP Kind code of ref document: A1 |