Akr1c3-activated dna alkylating agent, and medical application thereof
AssigneeAscentawits Pharmaceuticals, Ltd.
InventorsAnrong LI, Jianxin DUAN, Fanying MENG, Tianyang QI, Teng MENG, Mengyun ZHANG
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Abstract
An AKR1C3-activated DNA alkylating agent having any one of the following structural formulae (A, B, C), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, or an isotopic variant thereof, and an anticancer medical application thereof.
Claims25
A compound with any one of the following structural formulae, or a pharmaceutically acceptable salt, a prodrug, a solvate, or an isotopic variant thereof:
(canceled)
8-13. (canceled)
A method for preparing any one of the compounds with the following structures, comprising subjecting compound I-1, I-2, or I-3 to a ring-closure reaction to obtain the corresponding compound A, B, or C, respectively:
- wherein Xs are each independently fluorine, chlorine, bromine, or iodine;
- preferably, silver oxide or silver nitrate is used as a catalyst in the ring-closure reaction, with or without the addition of an organic base;
- preferably, Xs are both bromine;
- preferably, the organic base is N,N-diisopropylethylamine or triethylamine.
17-19. (canceled)
A compound with any one of the following structures:
- wherein Xs are each independently fluorine, chlorine, bromine, or iodine.
(canceled)
A method for preparing any one of the compounds with the following structures, comprising performing the first reaction of compound II-1, II-2, or II-3 as the starting reactant with phosphorus oxyhalide to obtain an intermediate, respectively, then performing the second reaction of the intermediate with haloethylamine or haloethylamine hydrohalide, and finally obtaining the corresponding compound I-1, I-2, or I-3, respectively:
- wherein the two Xs in compound I-1, I-2, or I-3 are each independently fluorine, chlorine, bromine, or iodine;
- wherein the phosphorus oxyhalide is selected from phosphorus oxyfluoride, phosphorus oxychloride, phosphorus oxybromide, and phosphorus oxyiodide, and is preferably phosphorus oxychloride;
- wherein the halogen atoms in the phosphorus oxyhalide and the two Xs in compound I-1, I-2, or I-3 may be the same or different.
A compound with any one of the following structures:
A method for preparing any one of the compounds with the following structures, wherein compound III-3 is reacted with TMSCF3 in contact and hydrolyzed after deprotection to obtain racemic alcohol II-1, and chiral resolution operation is performed on racemic alcohol II-1 to obtain chiral alcohol II-2 and chiral alcohol II-3, respectively;
(canceled)
A method for preparing any one of the deuterated compounds with the following structures, comprising subjecting compounds IV-1 to IV-21 to a ring-closure reaction to obtain the corresponding deuterated compounds V-1 to V-15, respectively:
- wherein the two X atoms in any one of compounds IV-1 to IV-21 are each independently fluorine, chlorine, bromine, or iodine, preferably bromine;
- wherein silver oxide or silver nitrate is used as a catalyst in the ring-closure reaction, with or without the addition of a base.
A method for preparing any one of the compounds with the following structures, comprising the following steps:
- reacting compound
- as the starting material to obtain compound
- then reacting the compound
- with formula I-7-1, I-7-2, or I-7-3 to obtain the corresponding compound of formula A, B, or C, respectively:
- wherein Y1 and Y2 are halogen or OM, and M is hydrogen, sodium, potassium, magnesium, or calcium, and halogen is preferably bromine.
Dependencies are inferred from the claim text.