CN-122010969-A - Aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecin derivative, and preparation method and application thereof

CN122010969ACN 122010969 ACN122010969 ACN 122010969ACN-122010969-A

Abstract

The invention belongs to the technical field of organic synthesis and medicine, and particularly relates to an aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecin derivative, and a preparation method and application thereof. The derivative is a compound with a structure shown in a formula (I), wherein R is Wherein X is N is an integer of 3-10, Z is selected from (I.e., amine group substitution). The novel aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecine derivative provided by the invention has good in-vitro and in-vivo antitumor activity, can be used for preparing camptothecine medicines for preventing or treating tumors, and has the advantages of easiness in operation, simplicity and convenience in post-treatment, low-cost and easily-obtained reaction initial raw materials, strong designability of reaction substrates, higher reaction efficiency and stronger practicability.

Inventors

LI QINGYONG
ZHANG BOSHI
WANG WENCHAO
LI LEI
YANG YAN
WANG HONG

Assignees

浙江工业大学

Dates

Publication Date: 20260512
Application Date: 20260126

Claims (13)

1. An aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivative, characterized by a compound having the structure represented by formula (I): in the formula (I), R is ; Wherein X is N is an integer of 3 to 10; Z is selected from Wherein each R 1 、R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-30 alkyl, substituted or unsubstituted C 3-12 alkenyl, substituted or unsubstituted C 1-10 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-20 ether, substituted or unsubstituted C 1-10 ester, substituted or unsubstituted C 3-10 alkoxy, substituted or unsubstituted C 1-10 silyl, substituted or unsubstituted C 3-10 alkylthio, substituted or unsubstituted C 3-10 alkylthio, substituted or unsubstituted C 3-10 alkylimino, substituted or unsubstituted C 7-10 alkenylamino, substituted or unsubstituted C 7-10 alkenylimino, substituted or unsubstituted C 10-30 adamantanes; the alkyl, alkenyl, alkynyl, alkoxy, ether, alkylthio, alkyl nitrogen, alkyl imino, alkenyl amino and alkenyl imino are straight chain, branched chain or cyclic structure.
2. The aminated 20 (S) -10, 11-difluoromethylenedioxycamptothecin derivative according to claim 1, wherein Z is selected from the group consisting of substituted or unsubstituted C 3-10 cycloalkylamine, substituted or unsubstituted C 10-30 adamantane-like amine, substituted or unsubstituted C 3-12 cycloalkenylamine, substituted or unsubstituted arylamine, substituted or unsubstituted C 3-20 ethercyclylamine, or substituted or unsubstituted aromatic heterocyclylamine; preferably, the aromatic heterocyclic group is selected from an amine-substituted pyridine ring, furan ring, thiophene ring, pyrazole ring, indole ring, benzopyrazole ring, piperidine ring, morpholine ring, thiomorpholine ring, naphthalene ring or triazole ring.
3. The aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivative according to claim 1 or 2, wherein when R 1 、R 2 is a substituted structure, the substituted groups are each independently selected from halogen, C 1-10 straight or branched alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-12 cycloalkyl, C 1-10 alkoxy, C 1-10 alkylthio, C 1-10 alkylsilyl, C 1-10 haloalkoxy, C 1-10 ester, 3-12 membered heterocyclyl, C 6-14 aryl, oxy C 6-14 aryl, oxy C 6-14 arylheteroaryl, nitrogen C 6-14 aryl, nitrogen C 5-14 arylheteroaryl, 5-14 membered heteroaryl, -CN, -NO 2 、-CF 2 H、-CF 2 OH、-CF 3 or-OCF 3 .
4. The aminated 20 (S) -10, 11-difluoromethylenedioxycamptothecin derivative according to claim 1, wherein each R 1 、R 2 is independently selected from H, halogen, C 1-10 straight or branched alkyl, substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted C 1-10 alkoxy, substituted or unsubstituted C 3-10 alkylene oxide, C 1-10 silyl, C 1-10 ester, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 10-16 adamantane, substituted or unsubstituted C 7-10 alkenylamine, or substituted or unsubstituted C 7-10 alkenylimine; Preferably, the substituted or unsubstituted C 1-10 alkoxy is C 1-10 haloalkoxy and/or the substituted or unsubstituted C 7-10 alkenylimino is a substituted or unsubstituted C 7-10 alkyl C 7-10 alkenylimino; More preferably, the Z is selected from any one of the following groups: 。
5. A process for the preparation of an aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivative according to any one of claims 1 to 4, characterized by the following synthetic route: the method comprises the following steps: (1) Adding a raw material of 5-amino-2, 2-difluoro-1, 3-benzodioxole and bromoC 3-10 alkyl nitrile into an organic solvent A, adding Lewis acid into an inert atmosphere, and reacting to obtain an intermediate I; (2) Adding the intermediate I, tricyclic ketone and a catalyst into an organic solvent B for complete dissolution, spin-drying the organic solvent to obtain a solid, and carrying out a vacuum solid-solid reaction in heating to obtain an intermediate II; (3) And adding the intermediate II and an amine compound into an organic solvent C, and adding an alkaline compound for reaction to obtain the aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecin derivative.
6. The process according to claim 5, wherein the molar ratio of 5-amino-2, 2-difluoro-1, 3-benzodioxole, brominated C 3-10 -alkylnitrile to Lewis acid is from 1:0.1 to 5:1 to 50, preferably from 1:0.45 to 0.5:18 to 22; And/or the molar ratio of the intermediate I, the tricyclic ketone and the catalyst is 1:0.1-5:0.1-5, preferably 1:0.5-1.2:0.1-0.6; and/or the molar ratio of the intermediate II, the amine compound and the alkaline compound is 1:0.1-15:0.1-10, preferably 1:5-10:3-5.
7. The preparation method according to claim 5, wherein in the step (1), the reaction temperature is 80-95 ℃, the reaction progress is monitored by TLC, and after the reaction is finished, an acidic aqueous solution is added to quench the reaction; And/or in step (2) the reaction is carried out under vacuum and/or the temperature of the reaction is 60-150 ℃ for 0.5-20 hours, preferably the temperature of the reaction is 115 ℃ for 1 hour; and/or in step (3), the temperature of the reaction is 30-70 ℃ for 2-30 h hours, preferably the temperature of the reaction is 50 ℃ and the time is 5 h; preferably, the acidic aqueous solution is an acidic aqueous solution having a concentration of 1-10mol/mL, preferably 3mol/mL HCl aqueous solution.
8. The method according to claim 5, wherein the Lewis acid is selected from the group consisting of boron trichloride, boron trifluoride, aluminum trichloride, gallium trichloride, trimethylaluminum, ferric chloride and ferric bromide; And/or the catalyst is selected from any one of Lewis acid, iodine, dodecyl sulfate, ferric chloride hexahydrate, sulfamic acid, 2,4, 6-trichloro-1, 3, 5-triazine, bismuth triflate, yttrium triflate, lithium bis (trifluoromethanesulfonyl) imide, magnesium bis (trifluoromethanesulfonyl) imide and paratoluenesulfonic acid or hydrate thereof, preferably paratoluenesulfonic acid hydrate; The basic compound is selected from one or more of N, N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide and triethylamine, preferably N, N-diisopropylethylamine, sodium bicarbonate, potassium carbonate and triethylamine, and more preferably N, N-diisopropylethylamine or sodium bicarbonate.
9. The process according to claim 5, wherein the organic solvent A is selected from one or more of dichloroethane, dichloromethane, methanol and acetonitrile; And/or the organic solvent B is selected from methanol, ethanol, n-butanol, ethyl acetate, acetone, dichloromethane and dichloroethane, preferably dichloromethane and methanol, and more preferably dichloromethane; and/or the organic solvent C is selected from ethanol, methanol, dichloromethane, DMF, preferably dichloromethane, DMF, more preferably DMF.
10. Use of an aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivative according to any one of claims 1 to 4 for the preparation of a medicament for the prevention and/or treatment of cancer.
11. The use according to claim 10, wherein the cancer is any one of bladder cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, colon cancer, stomach cancer, liver cancer, esophageal cancer, kidney cancer, throat cancer, thyroid cancer, testicular cancer, brain cancer, bone cancer and blood cancer, preferably bladder cancer.
12. A pharmaceutical formulation comprising a therapeutically effective amount of any one of the aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivatives, or active metabolites, prodrugs, stereoisomers, pharmaceutically acceptable salts, polymorphs, solvates or conjugates thereof according to any one of claims 1-4, and a pharmaceutically acceptable carrier.
13. The pharmaceutical formulation of claim 12, wherein the pharmaceutical formulation is a conjugated drug comprising an aminated 20 (S) -10, 11-difluoromethylenedioxycamptothecin derivative, an active metabolite, prodrug, stereoisomer, pharmaceutically acceptable salt, polymorph, solvate or conjugate thereof as a cytotoxic agent, and wherein the conjugated drug further comprises one or more of an antibody, a polypeptide, a nucleic acid and a small molecule.

Description

Aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecin derivative, and preparation method and application thereof Technical Field The invention belongs to the technical field of organic synthesis and medicine, and particularly relates to an aminated 20 (S) -10, 11-difluoro methylenedioxy camptothecin derivative, and a preparation method and application thereof. Background Camptothecin (CPT) is a natural source quinoline alkaloid in camptotheca and has significant antitumor activity by inhibiting DNA topoisomerase I (TOPO I), its derivatives topotecan, irinotecan and belotecan have been approved for clinical treatment of colon cancer, small cell lung cancer and ovarian cancer. The anti-tumor structure-activity relationship shows that the camptothecine modification can obviously influence the anti-tumor activity of the camptothecine, and the camptothecine is an optimal site for further developing novel high-activity anti-tumor medicines. Camptothecin cannot be used in clinic directly due to its poor water solubility and toxicity under physiological conditions. The invention patent CN110590796A discloses a camptothecin derivative, a preparation method and application thereof, and the compound provided by the invention is a novel camptothecin derivative with a novel structure, wherein methylenedioxy is introduced into 10,11 positions and different substituent groups are introduced into 7-positions of a parent ring, the preparation method has the advantages of easily available raw materials, simple synthesis method, simple and quick purification mode, and excellent in-vitro cytotoxicity and excellent in-vivo anti-tumor effect. The invention patents WO2005009347A2 and WO0149291 disclose methods of forming camptothecin compounds that are potent antitumor compounds that inhibit the enzyme topoisomerase I and that can alkylate the DNA of the related topoisomerase I-DNA cleavable complex. Chinese patent application CN117777153A discloses a 20 (S) -10, 11-difluoro methylenedioxy camptothecine derivative, a preparation method and application thereof, and the derivative has good solubility, anti-inflammatory activity, in-vivo and in-vitro anti-tumor activity and cell transmembrane transport capacity. The prior art represented by the foregoing documents has at least the following technical problems or drawbacks that have not been solved: Currently, camptothecin derivatives approved for anticancer use are susceptible to interactions of several mechanisms that cause cancer cells to be resistant to chemotherapy, and drug resistance and toxicity remain the bottleneck of patent drugs for such compounds. There is still a need to develop new camptothecin derivatives, especially those that are more potent, less toxic, have good permeability and overcome tumor resistance. In addition, the preparation method of the compound has complex reaction procedures, low yield, high cost and difficult mass preparation when the substituent groups are introduced, and the steric hindrance and the conjugated system cause extremely difficult electronegativity formation of the introduced positions due to the fact that the substituent groups are introduced into a parent structure in the last step of reaction in the synthetic route, so that the preparation method needs to be further improved. Disclosure of Invention Aiming at the key problem that the drug resistance and toxicity of the existing camptothecin derivative still prevent the patent medicine, the invention prepares a novel camptothecin derivative by introducing different kinds of amine groups into the 7-position of the framework, the series of derivatives have novel anti-tumor mechanism, can target Topo I and RNA helicase DDX5 (p 68) simultaneously, regulate the expression of DDX5 in tumor cells while targeting Topo I to induce the DNA damage of the tumor cells to cause apoptosis, block the DNA damage repair path started by DDX5, overcome the tumor drug resistance risk caused by Topo I inhibitor and reduce the toxicity. The partial compound provided by the invention has an amino active site at seven positions and can be used for drug toxic load of ADC. The invention optimizes the synthetic route of the derivative aiming at the problems of complex preparation method, low yield and the like, has simple synthetic route, low cost and high yield, and is suitable for mass preparation. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: In a first aspect, the present invention provides an aminated 20 (S) -10, 11-difluoromethylenedioxy camptothecin derivative, which is a compound having the structure represented by formula (I): in the formula (I), R is ; Wherein X isN is an integer of 3 to 10; Z is selected from Wherein each R 1、R2 is independently selected from H, halogen, substituted or unsubstituted C 1-30 alkyl, substituted or unsubstituted C 3-12 alkenyl, substituted or unsubstituted C 1-10 alkynyl, substituted or unsubstituted aryl, subst