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Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides

A technology of bifunctional compounds and solvates, applied in the fields of peptides, drug combinations, organic chemistry, etc.

Pending Publication Date: 2021-07-23
ARVINAS OPERATIONS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Therefore, non-specific effects and the inability to target and modulate RAF remain obstacles to the development of effective therapeutics

Method used

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  • Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
  • Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
  • Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 20-

[1974] Example 20 - Synthesis Scheme F: Compounds 512, 513 and 516

[1975] Method F

[1976]

[1977] 4-(4-(3-(2,6-difluoro-3-(propylsulfonylamino)benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) - tert-butyl piperazine-1-carboxylate (16).

[1978]

[1979] To N-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-1-sulfonamide (5) (70.8 mg, 0.155mmol) in a solution of dioxane (6ml) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)piperazine-1-carboxylate tert-butyl ester (60.0mg, 0.155mmol), K 2 CO 3 (64.2 mg, 0.465 mmol), tricyclohexylphosphine (4.33 mg, 0.0155 mmol) and water (2 mL). The reaction mixture was then degassed under vacuum and flushed with argon (5x), to which Pd(dba) was added 2 (4.44mg, 0.00773mmol), and the reaction mixture was heated at 90°C for 3h. TLC showed a small amount of SM (Hex:AcOEt, 3:7), the reaction mixture was vacuum filtered on a pad of celite, the filtrate was poured into saturated aqu...

Embodiment 473

[3029] Step 1: Preparation of (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester

[3030]

[3031] Put (2S,4R)-2-carbamoyl-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.00g, 4.343mmol, 1 equivalent), imidazole (739.0mg, 10.855 mmol, 2.50 eq) and TBDPSCl (1.43 g, 5.203 mmol, 1.20 eq) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred overnight at room temperature. Then 150 mL of water was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate (250 mL×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was applied to a silica gel column eluting with dichloromethane / methanol (98:2). This gave 1.55 g (76.15%) of tert-butyl (2S,4R)-4-[(tert-butyldiphenylsilyl)oxy]-2-carbamoylpyrrolidine-1-carboxylate as free Color oil. LC / MS(ESI)m / z: 469.25[M+1] + .

[3032] Step 2: Pr...

Embodiment

[4454] Assay and Degradation Data

[4455] Cellular assay protocol for target protein degradation (A375 cells). A375 cells were cultured in ATCC DMEM+10% FBS in 12-well plates, and treated with the compounds shown in Tables 1-41 or 0.1% DMSO vehicle control for 16 hours. Cells were harvested in Cell Signaling Lysis Buffer (Cat. No. 9803) supplemented with Roche Protease Inhibitor Tablets (Cat. No. 11873580001), and the lysate was clarified by microcentrifugation. Proteins were separated by SDS-PAGE and transferred to nitrocellulose membranes using the Invitrogen iBlot system. Immunoblots were performed for BRAF (Santa Cruz Cat. No. 9002), CRAF (BD Cat. No. 610151 ) and pErk (Cell Signaling Cat. No. 9106). GAPDH (catalog no.) was used as a loading control. Quantification was performed using BioRad Image Lab 5 software.

[4456] Intracellular Western Cell Assay Protocol for Target Protein Degradation (A375 Cells). A375 cells were cultured in ATCC DMEM+10% FBS in 96-well pla...

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Abstract

The present disclosure relates to bifunctional compounds, ULM- L-PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and / or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

Description

[0001] Cross References to Related Applications [0002] This disclosure claims the benefit of and priority to U.S. Provisional Application No. 62 / 728,581, filed September 7, 2018, and is a continuation-in-part of U.S. Patent Application No. 15 / 853,166, filed December 22, 2017, which Published on June 28, 2018 as U.S. Patent Application Publication No. 2018 / 0179183A1, which claims U.S. Provisional Application No. 62 / 438,803, filed December 23, 2016, and U.S. Provisional Application No. 62 / 582,698, all of which are hereby incorporated by reference in their entirety. [0003] incorporated by reference [0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016; and U.S. Patent Application 15 / 206,497, filed July 11, 2016; and U.S. Patent Application 15 / 209,648, filed July 13, 2016; and U.S. Patent Application Serial No. 62 / 406,888, filed October 11, 2016; and U.S. Patent Application Serial No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Applicatio...

Claims

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Application Information

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IPC IPC(8): A61P35/00C07D401/14C07D471/04C07D519/00C07K5/083A61K31/437
CPCC07D401/14C07D519/00C07D471/04A61P35/00C07K5/06034C07K5/06191C07K5/06078C07K5/06165A61K31/496A61K31/4545A61K47/55A61K31/506A61K31/4439C07D417/14
Inventor 安德鲁·P·克鲁基思·R·霍恩伯格J·王克雷格·M·克鲁斯绍尔·J-FH·董Y·钱库尔特·齐默尔曼
Owner ARVINAS OPERATIONS INC
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