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N/o-linked degrons and degronimers for protein degradation

A ligand and SO2 technology, applied in medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc.

Pending Publication Date: 2020-02-07
C4 THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This study suggests that thalidomide-cereblon binding in vivo may be responsible for the teratogenicity of thalidomide

Method used

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  • N/o-linked degrons and degronimers for protein degradation
  • N/o-linked degrons and degronimers for protein degradation
  • N/o-linked degrons and degronimers for protein degradation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0902] VII. Synthesis of Representative Compounds Example 1: General Synthesis of N-Linked Compounds of the Invention

[0903] Scenario 1: Common Procedures A and B

[0904]

[0905] General Procedure A

[0906] To a stirred solution of 1-2 (1.0 mmol) in DMF (3 mL) was added the aniline 1-1 (2.5 mmol). The resulting solution was heated at 80°C-100°C for 5-24 hours to yield 1-3. The reaction mixture was then cooled to room temperature and evaporated under reduced pressure. Following the procedure given below, the crude reaction material was purified by reverse phase preparative HPLC to give pure 1-3.

[0907] Non-limiting examples of compounds formed by General Procedure A include

[0908]

[0909] General procedure B

[0910] To a mixture of 1-1 (1 mmol) and 1-2 (2 mmol) in dioxane (3 mL) was added N,N-diisopropylethylamine (2 mmol). The resulting solution was heated at 70-110 °C for 24 hours in a sealed tube to yield 1-3. The reaction mixture was then cooled to r...

Embodiment 2

[1118] Example 2: N-heterocyclic anilino type

[1119] Scheme 7: Synthesis of compound 94:

[1120]

[1121] step 1:

[1122] Following the general procedure shown in Scheme 1, tert-butyl 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylate compound 73 was synthesized using DIPEA / DMF. Yield -71.4%; LC MS: ES+378.3

[1123] Step 2:

[1124] To a pre-cooled solution of 4M dioxane-HCl was added compound 73 (46 mg, 121 μmol) at 0 °C, and the resulting mixture was stirred at ambient temperature for 3 hours to yield crude compound 94. The reaction mixture was concentrated under reduced pressure, and the resulting solid was triturated with ether-pentane to give Compound 94 (35.0 mg, 111 μmol, 92%) as a brown solid. 1 H NMR (400MHz, deuterium oxide) δ7.90(s, 1H), 7.68(s, 1H), 4.61(dt, J=12.0, 7.7Hz, 1H), 4.45(dd, J=13.2, 5.3Hz, 1H ), 3.63(d, J=13.0Hz, 2H), 3.25(t, J=13.1Hz, 2H), 2.86–2.77(m, 2H), 2.43–2.28(m, 2H), 2.31–2.17(m, 2H), 2.11 (dd, J = 12.2, 6.7 Hz, 1H); LC MS: ES+278....

Embodiment 3

[1134] Embodiment 3: the synthesis of N-alkyl compound of the present invention

[1135]

[1136] Following the general procedure shown in Scheme 1, compound 97 was synthesized using DIPEA / dioxane. Yield-19%; 1H NMR (400MHz, DMSO-d6) δ10.61(s, 1H), 4.58-4.52(m, 2H), 4.49-4.41(m, 2H), 4.27-4.19(m, 1H) , 3.54(dd, J=12.48, 4.6Hz, 1H), 2.60-2.55(m, 1H), 2.49-2.44(m, 1H), 2.29(s, 3H), 2.05-1.97(m, 1H), 1.78 -1.74 (m, 1H); LC MS: ES+199.3.

[1137]

[1138] Following the general procedure shown in Scheme 1, compound 98 was synthesized using DIPEA / dioxane. Yield - 22%; 1 H NMR (400MHz, DMSO-d6) δ10.62(s, 1H), 3.89-3.71(m, 5H), 3.62-3.56(m, 1H), 2.59-2.49(m, 2H), 2.21(s, 3H) ), 2.04-1.96 (m, 1H), 1.79-1.74 (m, 1H), 1.37 (s, 9H); LC MS: ES-296.28.

[1139]

[1140] Following the general procedure shown in Scheme 1, compound 99 was synthesized using DIPEA / dioxane. Yield-14%; 1H NMR (400MHz, DMSO-d6) δ10.73(s, 1H), 7.64-7.60(m, 2H), 7.36(t, J=7.76Hz, 2H), 7.12(t, J =7.12H...

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Abstract

The invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, andmethods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Application No. 62 / 522,541, filed June 20, 2017, which is hereby incorporated by reference for all purposes. technical field [0003] The present invention provides a degronimer with an E3 ubiquitin ligase targeting moiety (Degron) that can be linked to The targeting ligand of protein, the invention also provides its use method and composition as well as its preparation method. The present invention also provides degrons useful in the treatment of disorders mediated by cereblon or Ikaros family proteins. Background technique [0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of nearly all cellular processes, including antigen proc...

Claims

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Application Information

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IPC IPC(8): A61K31/426A61K31/427A61K45/06
CPCA61K45/06C07D401/14C07D401/12C07D405/12C07D413/12C07D471/04C07D487/04C07D495/04C07D207/456C07D211/42C07D211/56C07D211/88C07D403/04C07D495/14G07F17/3211G07F17/3225G07F17/3244G07F17/3246G07F17/3272G07F17/3288
Inventor A·J·菲利普斯C·G·纳斯维斯查克J·A·亨德森梁焱科何敏生M·杜普莱西斯陈启礼
Owner C4 THERAPEUTICS INC
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