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CN-121991059-A - Phenanthroindolizidine alkaloid derivative and preparation method, pharmaceutical composition and application thereof

CN121991059ACN 121991059 ACN121991059 ACN 121991059ACN-121991059-A

Abstract

The invention belongs to the technical field of medicines, and discloses a phenanthroindolizidine alkaloid derivative, a preparation method, a pharmaceutical composition and application thereof. Relates to a compound shown as a general formula I-a, I-b or I-c, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicines for treating human glioma, in particular glioblastoma. The preferred compound of the invention can inhibit proliferation, invasion and metastasis of glioblastoma cells, has obvious curative effect on various drug-resistant glioblastomas, has lower toxicity and good in-vitro pharmacokinetic properties, shows potential of overcoming in-vivo drug resistance, and has wide clinical application prospect.

Inventors

  • YU SHISHAN
  • WANG ZHIPENG
  • WANG RUBING
  • JI MING
  • Feng Zifan
  • LI MI
  • ZHU SHANSHAN
  • XU TAO
  • Dang Chenyu
  • DENG JIALING

Assignees

  • 中国医学科学院药物研究所

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. A compound having the general formula I-a, I-b or I-c, racemates, stereoisomers or pharmaceutically acceptable salts thereof: Wherein R 1 is selected from benzyl which is unsubstituted or optionally substituted by one, two or more R 1a , R 2 、R 3 is the same or different and is selected from hydrogen, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy which is unsubstituted or optionally substituted by one, two or more R 2a , each R 1a is the same or different and is selected from CN, hydroxy, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, each R 2a is the same or different and is selected from CN, hydroxy, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy.
  2. 2. The compound of claim 1, wherein R 2 、R 3 is the same or different and is selected from the group consisting of hydrogen, halogen, hydroxy, unsubstituted or optionally substituted with one, two or more R 2a , C 1-6 alkyl, C 1-6 alkoxy; Preferably, R 2 、R 3 , which are identical or different, are selected independently of one another from hydrogen, halogen, hydroxy, unsubstituted or optionally substituted by one, two or more R 2a , C 1-3 alkyl or C 1-3 alkoxy.
  3. 3. The compound according to any one of claim 1 or 2, wherein each R 1a is the same or different and is selected independently from CN, hydroxy, amino, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, each R 2a is the same or different and is selected independently from CN, hydroxy, amino, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl or C 1-3 alkoxy; Preferably, each R 1a , which are the same or different, are independently selected from CN, F, cl, methyl, methoxy, trifluoromethyl, trifluoromethoxy; preferably, each R 2a , which is the same or different, is independently selected from CN, hydroxy, halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
  4. 4. A compound according to any one of claims 1 to 3, wherein R 1 is selected from 4-methoxybenzyl, 4-trifluoromethylbenzyl, 2-fluoro-4-cyanobenzyl, 4-fluorobenzyl, 3, 4-dimethoxybenzyl, 2, 6-dimethylbenzyl or benzyl, a racemate, a stereoisomer or a pharmaceutically acceptable salt thereof.
  5. 5. The compound according to any one of claims 1 to 4, wherein R 2 、R 3 , which are identical or different, are independently selected from C 1-3 alkyl or C 1-3 alkoxy; Preferably, R 2 、R 3 are identical or different and are selected independently of one another from methyl or methoxy.
  6. 6. The compound according to any one of claims 1 to 5, wherein the compound is selected from the group consisting of:
  7. 7. a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 6, racemates, stereoisomers or pharmaceutically acceptable salts thereof; preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  8. 8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of a tablet, a capsule, a pill, an injection, a sustained release formulation, a controlled release formulation, and various microparticle delivery systems.
  9. 9. Use of a compound according to any one of claims 1-6, a racemate, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 7 or 8, for the manufacture of a medicament for the treatment and/or prevention of a neoplastic disease.
  10. 10. The use according to claim 9, wherein the tumour is selected from gliomas; preferably, the glioma is selected from glioblastoma; preferably, the glioblastoma is selected from primary drug resistant glioblastomas and/or acquired drug resistant glioblastomas.

Description

Phenanthroindolizidine alkaloid derivative and preparation method, pharmaceutical composition and application thereof Technical Field The invention belongs to the technical field of medicines, and in particular relates to a phenanthroindolizidine alkaloid derivative shown in a general formula I-a, I-b or I-c, a preparation method thereof, a pharmaceutical composition containing the same and application of the same in preparation of medicines for treating and/or preventing human glioma-related diseases. Background Glioblastoma (Glioblastoma, GBM) is a common intracranial tumor, has the characteristics of high morbidity, high malignancy, high mortality, low cure rate and the like, and the special morbidity position and high invasiveness cause that the operation treatment can not completely eradicate the focus, so that the glioblastoma is considered as one of tumors with highest treatment difficulty and worst prognosis effect in systemic tumors. At present, cytotoxic drugs such as temozolomide (Temozolomide, TMZ) which are first-line chemotherapeutics used for auxiliary treatment have better effects only on patients newly diagnosed with GBM, but are extremely easy to generate drug resistance. Thus, there is an urgent need to develop new drugs for clinical treatment of recurrent, drug resistant GBM. The (S) -3-pivaloyloxy-6, 7-dimethoxy phenanthroindolizidine (CAT 3) is an active molecule obtained by the applicant on the basis of deep biological activity research and structural modification of several phenanthroindolizidine alkaloid natural products on the basis of a parent compound PF 403. The compound can penetrate the blood brain barrier and has good therapeutic effect on glioma (Cancer Lett.2016,381, 391-403). The applicant realizes the mass preparation of the compound and a specific crystal form (CN 110294752A, CN110117279A, CN 110117280A) by optimizing the synthesis process, but the research on the in-vivo drug effect of animals discovers that the compound is easy to generate gastrointestinal toxicity and low in bioavailability, and the activity is further enhanced by structural modification, so that the toxicity is reduced, and the drug property is improved. According to the molecular splicing principle, PF403 is connected with triazole groups with high biocompatibility and rich pharmacological activity, so that a novel compound with higher drug resistance brain glioblastoma proliferation activity, lower toxicity and good pharmacokinetic property than CAT3 is obtained. Disclosure of Invention The technical problem to be solved by the invention is to provide a compound shown as a general formula I-a, I-b or I-c, a racemate, a stereoisomer or a pharmaceutically acceptable salt thereof. Yet another technical problem to be solved by the present invention is to provide a process for preparing a compound having the general formula I-a, I-b or I-c, racemate, stereoisomer or pharmaceutically acceptable salt thereof. A further technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising at least one compound of the general formula I-a, I-b or I-c, its racemate, stereoisomer or its pharmaceutically acceptable salt, and a further technical problem to be solved by the present invention is to provide the use of a compound of the general formula I-a, I-b or I-c, its racemate, stereoisomer or its pharmaceutically acceptable salt for the manufacture of a medicament for the treatment and/or prevention of tumor-related diseases. In order to solve the technical problems, the invention adopts the following technical scheme: The present invention relates to compounds having the general formula I-a, I-b or I-c: Wherein R 1 is selected from benzyl which is unsubstituted or optionally substituted by one, two or more R 1a, R 2、R3 is the same or different and is selected from hydrogen, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy which is unsubstituted or optionally substituted by one, two or more R 2a, each R 1a is the same or different and is selected from CN, hydroxy, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, each R 2a is the same or different and is selected from CN, hydroxy, amino, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy. Preferred compounds according to the invention include: According to an embodiment of the invention, the compounds of the invention also include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include inorganic and organic salts. The inorganic acid comprises hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid and the like. Organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, aspartic acid, and tartaric acid. Also provided according to the invention are methods of preparing the compounds of the invention. The invention also relat