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CN-121974920-A - Nathidine derivative for DHODH inhibitor, and preparation method and application thereof

CN121974920ACN 121974920 ACN121974920 ACN 121974920ACN-121974920-A

Abstract

The invention belongs to the technical field of medicines, relates to a narcotine derivative for a DHODH inhibitor, a preparation method and application thereof, and in particular relates to synthesis of a narcotine derivative and application of the narcotine derivative serving as a novel DHODH inhibitor in treatment of malignant tumors, autoimmune diseases, infectious diseases such as viruses and parasites. The invention discloses the application of the known narcotine derivatives as DHODH inhibitors for the first time, and expands the application scenes of the narcotine derivatives. On the basis, a series of novel derivatives are continuously synthesized, and the novel derivatives also show good DHODH inhibitory activity. The disclosed compounds have outstanding DHODH inhibitory activity and exhibit a distinct mitochondrial membrane participation in binding patterns from existing DHODH inhibitors.

Inventors

  • ZHANG YONGQIANG
  • YIN QIANQIAN
  • LIU CHUANXU
  • SHI HAOLIANG
  • LU JIE
  • ZHANG DEJIN

Assignees

  • 华东理工大学
  • 上海科技大学

Dates

Publication Date
20260505
Application Date
20251210

Claims (10)

  1. 1.A narcotine derivative or a pharmaceutically acceptable salt thereof for a DHODH inhibitor is characterized in that the narcotine derivative has a structural general formula shown as (I) or (II), ; (I) In the general structural formula (I), n is 0-3;X and is Se, S or O, the R 1 group represents C1-C10 cycloalkyl, the R 2 group represents C1-C6 alkyl and branched alkyl, and the R 3 group represents C1-C6 alkyl and branched alkyl or benzyl; ; (II) in the general structural formula (II), n is 0-3;R and represents alkyl, branched alkyl, substituted alkyl and branched alkyl, cycloalkyl, oxacycloalkyl and azacycloalkyl, fluoro cycloalkyl and bridged cycloalkyl.
  2. 2. A narcotine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein n in the general structural formula (I) is 2, x is Se or S, the R 1 group represents a C4-C8 cycloalkyl group, the R 2 group represents a C1-C3 alkyl group and a branched alkyl group, and the R 3 group represents a C1-C3 alkyl group and a branched alkyl group or a benzyl group.
  3. 3. A narcotine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein n in the general structural formula (II) is 0-3;R groups representing C1-C7 alkyl, branched alkyl, substituted alkyl and branched alkyl, C3-C7 cycloalkyl, oxacycloalkyl and azacycloalkyl, and C1-C12 fluorocycloalkyl and bridged cycloalkyl.
  4. 4. A narcotine derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein n in the general structural formula (II) is 0-3;R groups representing C1-C3 alkyl, branched alkyl, oxaalkyl and branched alkyl, C3-C7 cycloalkyl, oxacycloalkyl and azacycloalkyl, and C3-C12 fluorocycloalkyl and bridged cycloalkyl.
  5. 5. A narcotine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the narcotine derivative has the structure: ; ; ; ; 。
  6. 6. the process for producing a narcotine derivative as set forth in claim 5, The preparation method of S1 is as follows: ; 1) Bromine solution (Br 2 ) is taken as a brominating reagent, and under the action of hydrobromic acid (HBr), the 9' position of the narcotine 1 is brominated to obtain an intermediate 2; 2) Cycloheptyl acetic acid 3 is reduced by lithium aluminum hydride (LiAlH 4) to generate an intermediate 4; 3) Intermediate 4 reacts with phosphorus tribromide (PBr 3) to obtain intermediate 5; 4) Nickel iodide (NiI 2) is used as a catalyst, 4 '-di-tert-butyl-2, 2' -bipyridine (dtbpy) is used as a ligand, zinc powder (Zn), magnesium chloride (MgCl 2) and Pyridine (Pyridine) are used for performing a coupling reaction on the intermediate 2 and the intermediate 5 at 50 ℃ to generate S1.
  7. 7. The process for producing a narcotine derivative as claimed in claim 5, wherein the process for producing S2 is as follows: ; 1) 4, 4-difluoro cyclohexyl acetic acid 6 is reduced by lithium aluminum hydride (LiAlH 4) to generate an intermediate 7; 2) Intermediate 7 is reacted with phosphorus tribromide (PBr 3) to afford intermediate 8; 3) Nickel iodide (NiI 2) is used as a catalyst, 4 '-di-tert-butyl-2, 2' -bipyridine (dtbpy) is used as a ligand, zinc powder (Zn), magnesium chloride (MgCl 2) and Pyridine (Pyridine) are used for performing a coupling reaction on the intermediate 2 and the intermediate 8 at 50 ℃ to generate S2.
  8. 8. The process for producing a narcotine derivative as claimed in claim 5, wherein the process for producing S3 is as follows: ; 1) The cycloheptyl formic acid 9 is reduced by lithium aluminum hydride (LiAlH 4) to generate an intermediate 10; 2) Intermediate 10 is reacted with phosphorus tribromide (PBr 3) to afford intermediate 11; 3) Nickel iodide (NiI 2) is used as a catalyst, 4 '-di-tert-butyl-2, 2' -bipyridine (dtbpy) is used as a ligand, zinc powder (Zn), magnesium chloride (MgCl 2) and Pyridine (Pyridine) are used for performing a coupling reaction on the intermediate 2 and the intermediate 11 at 50 ℃ to generate S3.
  9. 9. The process for producing a narcotine derivative as claimed in claim 5, wherein the process for producing S4-S13 is as follows: ; Nickel iodide (NiI 2) is used as a catalyst, 4 '-di-tert-butyl-2, 2' -bipyridine (dtbpy) is used as a ligand, zinc powder (Zn), magnesium chloride (MgCl 2) and Pyridine (Pyridine) are used for carrying out coupling reaction on the intermediate 2 and various commercially available halogenated hydrocarbons at 50 ℃ to generate S4-S13.
  10. 10. Use of a narcotine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of malignant tumors, autoimmune diseases, and infectious diseases of viruses and parasites.

Description

Nathidine derivative for DHODH inhibitor, and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, relates to a narcotine derivative for a DHODH inhibitor, a preparation method and application thereof, and in particular relates to synthesis of a narcotine derivative and application of the narcotine derivative serving as a novel DHODH inhibitor in treatment of malignant tumors, autoimmune diseases, infectious diseases such as viruses and parasites. Background Dihydroorotate dehydrogenase (DHODH) is an iron-containing flavin-dependent enzyme present in the inner mitochondrial membrane and is the rate-limiting enzyme in the de novo pyrimidine nucleotide synthesis pathway. Studies have shown that DHODH is overexpressed in a variety of malignancies, including Acute Myeloid Leukemia (AML), breast cancer, colorectal cancer, melanoma, and the like. DHODH has also been shown to be a potent target for autoimmune diseases and infectious diseases such as viruses, fungi, and the like. DHODH inhibitors currently marketed include Leflunomide (Leflunomide) and its metabolite teriflunomide (Teriflunomide, 2012), which were approved by the FDA in 1998, both of which are used clinically mainly for the treatment of autoimmune diseases such as rheumatoid arthritis. However, the two DHODH inhibitors have poor activity, low target selectivity and obvious toxic and side effects, and restrict further application. Among them, the FDA in 2010 warns the leflunomide of a black frame for liver injury. In this context, some novel DHODH inhibitors were developed. For example, PTC299 is an oral study drug with a novel dual mechanism of action, which can target DHODH and VEGF simultaneously, has broad-spectrum antiviral activity, and is also in clinical phase II study for treatment of Acute Myelogenous Leukemia (AML). ASLAN003 is also a potent DHODH inhibitor, which can induce the differentiation of primary AML cells, exhibit good proliferation inhibitory activity, and are effective in vivo, and enter the clinical phase I/II research stage in 2018, and there are studies on anti-hepatitis e virus using the compound at present. BAY 2402234 is a selective potent DHODH inhibitor from bayer medicine that induces AML cell differentiation, inhibiting its proliferation. In addition, malignant proliferation of a variety of other malignant tumor cells (e.g., IDH mutant glioma cells) can be inhibited. However, the clinical trials of BAY 2402234 for the treatment of leukemias and gliomas are currently being terminated. In addition, other DHODH inhibitors entering the clinical trial phase of anti-tumor include Olorofim (treatment of invasive fungal infection, entry into clinical phase I/II study, in progress), AG-636 (treatment of lymphoma, entry into clinical phase I study, completion), JNJ-74856665 (treatment of AML, clinical phase I, completion), IMU-935 (treatment of prostate cancer, clinical phase I study, terminated), brequinar (treatment of AML and neocrown, clinical phase I/II study, terminated), and the like, further demonstrating the potential of such inhibitors for use in the treatment of a variety of diseases. However, in the whole, most of the defects of large toxic and side effects and poor curative effect exist, so that clinical tests are slow to progress, and future development prospects are unclear. Narcotine (Noscapine) is a tetrahydroisoquinoline alkaloid derived from poppy, and is contained in a content inferior to morphine. Although the source is the same as morphine, the medicament has no side effects of addiction and respiratory depression, is clinically used as an over-the-counter cough medicament for a long time, and has the advantages of good safety, oral administration, easy passage through blood brain barrier and the like. It has also been found in recent years that they have moderate antitumor activity, the mechanism of action being mainly tubulin inhibitors. A series of antitumor seleno-and thionarcotine derivatives at the 9' position are reported in patents CN118994182A and CN 111909162B. The present study further explored the potential of a portion of the preferred compounds as highly potent DHODH inhibitors. It is pointed out that the mitochondrial membrane is involved in the binding of this class of compounds to DHODH and the unique mode of action makes it potentially less off-target and toxic. Based on the above, 9' substituent is changed, a class of narcotine derivatives with novel structures is synthesized, and the narcotine derivatives also have good DHODH inhibitory activity, and are expected to be developed into medicines for treating infectious diseases such as tumors, autoimmune diseases, viruses and the like. Disclosure of Invention The invention discloses the application of a part of known narcotine derivatives in general formula (I) or (II) in preparing DHODH inhibitor medicines, in particular to the application in treating malignant tumors, aut