Search

CN-121974974-A - Proteolytic targeting chimeric for treating multiple myeloma, preparation method and application thereof

CN121974974ACN 121974974 ACN121974974 ACN 121974974ACN-121974974-A

Abstract

The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a proteolytic targeting chimeric for treating multiple myeloma, and a preparation method and application thereof. Dissolving a compound 2, a compound 3 and HATU in THF, adding DIPEA, stirring for reaction, adding water for stopping reaction, extracting, washing, drying, and performing column chromatography to obtain a product 4, dissolving the product 4 in dichloromethane under the protection of argon, adding trifluoroacetic acid for reaction, adding toluene, distilling under reduced pressure to obtain a product 5, dissolving the product 5, a compound 6, HATU and DIPEA in THF, stirring for reaction, adding water for stopping reaction, extracting, washing, drying, and performing column chromatography to obtain the protein hydrolysis targeting chimeric for treating multiple myeloma. The proteolytic targeting chimeric for treating the multiple myeloma has remarkable antiproliferative activity on the RPMI-8266 cells of the multiple myeloma, has simple preparation process and is suitable for industrial production.

Inventors

  • SHU YING
  • SANG FENG

Assignees

  • 山东理工大学

Dates

Publication Date
20260505
Application Date
20260407

Claims (10)

  1. 1. A proteolytic targeting chimera for use in the treatment of multiple myeloma characterized by the following structural formula: 。
  2. 2. A method of preparing a proteolytically targeted chimera for use in the treatment of multiple myeloma according to claim 1, comprising the steps of: (1) Dissolving a compound 2, a compound 3 and 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate in tetrahydrofuran, adding N, N-diisopropylethylamine, stirring for reaction, adding water for terminating reaction, extracting, washing, drying, and performing column chromatography to obtain a product 4; (2) Under the protection of argon, the product 4 is dissolved in dichloromethane, and then trifluoroacetic acid is added for reaction, toluene is added, and reduced pressure distillation is carried out to obtain a product 5; (3) Under the protection of argon, the product 5, the compound 6, the 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine are dissolved in tetrahydrofuran to react under stirring, and then water is added to terminate the reaction, extraction, washing, drying and column chromatography are carried out, thus obtaining the proteolytic targeted chimera for treating the multiple myeloma.
  3. 3. The method for preparing a proteolytically targeted chimera for multiple myeloma treatment according to claim 2, characterized in that the structural formula of compound 2 in step (1) is as follows: ; The structural formula of compound 3 is as follows: ; the structural formula of product 4 is as follows: ; The ratio of the compound 2 to the compound 3 to the compound 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate to tetrahydrofuran is 1:0.9-1.2:1-1.4:3-5, wherein the compound 2 to the compound 3 to the compound 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are calculated in mmol, the tetrahydrofuran is calculated in mL, the mol ratio of N, N-diisopropylethylamine to the compound 2 is 3-5:1, the volume ratio of the tetrahydrofuran to water is 1:3.8-4.5, and the extraction is carried out by using ethyl acetate.
  4. 4. The method for preparing the proteolytic targeting chimera for treating multiple myeloma according to claim 2, wherein the end point of the stirring reaction in the step (1) is monitored by thin layer chromatography to completely disappear the compound 2, the developing agent of the thin layer chromatography is a mixed solution of methylene dichloride and methanol, wherein the volume ratio of the methylene dichloride to the methanol is 8-12:1, the detection mode of the thin layer chromatography is ultraviolet detection, the temperature of the stirring reaction is 20-30 ℃, and the washing is carried out by using sodium chloride solution.
  5. 5. The method of preparing a proteolytically targeted chimera for use in the treatment of multiple myeloma according to claim 2, characterized in that the structural formula of product 5 in step (2) is as follows: ; the ratio of the product 4 to the dichloromethane to the trifluoroacetic acid is 1:6-7.1:2.5-3.5, wherein the product 4 is calculated by mmol, the dichloromethane and the trifluoroacetic acid are calculated by mL, and the volume ratio of the dichloromethane to the toluene is 1.3-1.7:1.
  6. 6. The method for preparing the proteolytic targeting chimera for treating multiple myeloma according to claim 2, wherein the temperature of adding trifluoroacetic acid in the step (2) is-5 ℃, the reaction temperature is-5 ℃, the end point of the reaction is monitored by thin layer chromatography to completely disappear the product 4, the developing agent of the thin layer chromatography is a mixed solution of dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 1.8-2.2:1, the detection mode of the thin layer chromatography is ultraviolet detection or iodine fumigation detection, the reduced pressure distillation pressure is-0.1-0.06 MPa, and the reduced pressure distillation temperature is 55-65 ℃.
  7. 7. The method for preparing a proteolytically targeted chimera for multiple myeloma treatment according to claim 2, characterized in that the structural formula of compound 6 in step (3) is as follows: ; the ratio of the product 5, the compound 6, the 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, the N, N-diisopropylethylamine and the tetrahydrofuran is 1:0.89-1:1.2-1.8:0.6-1.0:7-9, wherein the product 5, the compound 6 and the 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are calculated in mmol, and the N, N-diisopropylethylamine and the tetrahydrofuran are calculated in mL.
  8. 8. The method for preparing the proteolytic targeting chimera for treating multiple myeloma according to claim 2, wherein the end point of the stirring reaction in the step (3) is monitored by thin layer chromatography to completely disappear the compound 6, the developing agent of the thin layer chromatography is a mixed solution of methylene dichloride and methanol, the volume ratio of the methylene dichloride to the methanol is 8-12:1, the detection mode of the thin layer chromatography is ultraviolet detection or iodine fumigation detection, and the temperature of the stirring reaction is 20-30 ℃.
  9. 9. The method for preparing the proteolytic targeting chimera for treating multiple myeloma according to claim 2, wherein the volume ratio of tetrahydrofuran to water in the step (3) is 1:11-13.5, the extraction is extraction by using ethyl acetate, and the washing is sequentially carried out by using hydrochloric acid, saturated sodium bicarbonate solution and sodium chloride solution.
  10. 10. Use of a proteolytic targeting chimera for the treatment of multiple myeloma according to claim 1, characterized by the use in the preparation of a medicament for the treatment of multiple myeloma.

Description

Proteolytic targeting chimeric for treating multiple myeloma, preparation method and application thereof Technical Field The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a proteolytic targeting chimeric for treating multiple myeloma, and a preparation method and application thereof. Background Proteolysis targeting chimeras (Proteolysis TARGETING CHIMERAS, PROTACS) are a class of heterobifunctional molecules that induce degradation of the target protein, the concept of which was first proposed by r.j. Deshaies and c.m. Crews et al. The chemical structure of PROTACs comprises three key parts, namely a target protein ligand (target protein ligand), a connecting chain (Linker) and an E3 ubiquitin ligase ligand, wherein the action mechanism of PROTACs is different from the 'occupation driving' mode of the traditional small molecule inhibitor, and the effect is exerted through the 'event driving' mode, namely the target protein ligand in PROTACs molecules is combined with the target protein (target protein) while the E3 ubiquitin ligase ligand recruits E3 ubiquitin ligase to form a target protein-PROTACs-E3 ubiquitin ligase ternary complex, and PROTACs realizes ubiquitin labeling of the target protein through the interaction between protein and protein, so that the target protein is recognized by a ubiquitin-protease system in a human body and is specifically degraded, and finally the purpose of treating diseases is achieved by regulating the expression level of abnormal proteins. Compared with the traditional small molecule inhibitor, PROTACs has remarkable advantages, including high catalytic activity, low toxicity, small dependence on target affinity, capability of effectively overcoming drug resistance caused by target mutation, capability of eliminating abnormal accumulation of pathogenic proteins and the like. Through more than twenty years of research and development, PROTACs has been widely applied to a plurality of fields such as oncology, neurodegenerative diseases, inflammation, immunology and the like, and has a wide application prospect when a plurality of candidate drugs enter a clinical research stage. Multiple myeloma is a common malignant tumor in the blood system, and is caused by malignant proliferation of plasma cells, and the problem of relapse and difficult treatment is a major challenge facing the current clinic, so that development of a treatment strategy capable of overcoming drug resistance or targeting a new action mechanism is urgently needed. The proteolysis targeting chimera can induce target protein ubiquitination by recruiting E3 ubiquitin ligase, so that the target protein is degraded by a proteasome, and a brand new paradigm is provided for the targeting treatment of traditional 'non-patent medicine' targets. Compared with the continuous occupation of the traditional inhibitor on the target, the proteolytic targeting chimeric has the advantages of good catalytic activity, low dosage requirement, capability of effectively overcoming the drug resistance of the target and the like, however, the proteolytic targeting chimeric for treating the multiple myeloma at present has the problems of small available quantity, large molecular weight, high preparation cost, low activity and the like, and the problems obviously increase the screening difficulty of candidate drugs and restrict the clinical transformation process of the proteolytic targeting chimeric for treating the multiple myeloma. PT-2385 is a selective hypoxia inducible factor-2 (HIF-2) inhibitor, and can effectively inhibit the expression of tumor-derived VEGFA proteins, and after treatment by PT-2385 (10 mg/kg), the expression level of proliferation markers Ki67 and angiogenesis markers CD-31 is obviously reduced. The clinical research compound PT-2799 obtained by further optimizing on the basis of PT-2385 structure has successfully completed clinical research, reaches the main research end point and is marketed in batches, and is used for treating VHL disease-related renal cell carcinoma, central nervous system angioblastoma and pancreatic neuroendocrine tumor. Chinese patent CN107973754a discloses a small molecule inhibitor, a preparation method thereof and application thereof in the treatment of multiple myeloma, and the small molecule inhibitor in the patent can inhibit the activity of bruton's tyrosine protein kinase, thus being applicable to the treatment of multiple myeloma, such as IgE-type multiple myeloma. However, the action mechanism of small molecule inhibitors such as PT-2385 and derivatives thereof depends on the traditional 'occupation driving' mode, and the inhibition effect is exerted by continuously occupying target active sites, so that the problems of target drug resistance and the like are unavoidable after long-term administration of patients. Disclosure of Invention The invention aims to provide a proteolytic targeting chimeric for treating multiple m