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Macrocyclic prodrug compounds useful as therapeutic agents

A technology for compounds and drugs, applied in the field of macrocyclic prodrug compounds used as therapeutic agents, can solve the problems of not being able to support all the work and the rationality of drug design.

Active Publication Date: 2014-10-29
ONCOSYNERGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, the portfolio of known kinase inhibitors does not yet support all the work to be done in analyzing the roles of different members of the kinome
This is not just academic research, as until the mechanisms of kinases and their selectivity are understood, the plausibility of drug design will continue to be hampered

Method used

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  • Macrocyclic prodrug compounds useful as therapeutic agents
  • Macrocyclic prodrug compounds useful as therapeutic agents
  • Macrocyclic prodrug compounds useful as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0357] Compound preparation method

[0358] Modular synthetic methods can be used to prepare macrocycles in non-prodrug form (eg, active form or active form with protecting groups). Methods and procedures for the preparation of macrocycles in non-prodrug form are described in detail in International Application PCT / US2007 / 017754 and US Serial No. Serial No. 11 / 891,652, the contents of which are incorporated herein by reference in their entirety. Various prodrugs can be synthesized from active macrocycles by methods known to those skilled in the art for the preparation of prodrugs. For example, a phosphate ester of a hydroxyl group can be prepared by reacting the hydroxyl group with a phosphorylating reagent such as a phosphorus oxychloride analog. The sodium salts of all phosphonates can be obtained by treating the final compound with a basic ionic resin such as Dowex 550a.

[0359] Schemes 1, 2 and 3 below illustrate general synthetic strategies for the synthesis of diphos...

Embodiment 1

[0471] Example 1: Synthesis of para-mono-phosphoamidate compounds 10a and 10b:

[0472]

[0473] To the CH of the corresponding phenolic macrocycle 10a or 10b (1.0 2 Cl 2 To the solution were added DBU (0.9 equiv), bis(dimethylamino)phosphoryl chloride (1.0 equiv) and DMAP (catalytic amount). The reaction mixture was stirred overnight at room temperature. Then with saturated NH 4 The organic phase was washed with aqueous Cl and brine, and then washed with MgSO 4 dry. The desired monophosphates 11a and 11b were purified and isolated by column chromatography (EtOAc to 5% MeOH in EtOAc) in 50-60% yield.

[0474]

[0475] 1 H NMR (CDCl 3 , 400MHz) δ11.53(s, 1H), 11.16(s, 1H), 7.11(s, 1H), 7.06(s, 1H), 6.51(d, J=16.1Hz, 1H), 5.97(dt, J =15.6, 7.5Hz, 1H), 5.42-5.35(m, 1H), 5.32-5.28(m, 2H), 5.13(d, J=15.6Hz, 1H), 5.09-5.05(m, 2H), 4.78( s, 2H), 4.76(s, 2H), 4.37-4.33(m, 4H), 4.12(s, 2H), 4.10(s, 2H), 3.53-3.52(m, 4H), 3.42-3.41(m, 4H), 2.70(s, 6H), 2.70(s, 6H), 2.68(...

Embodiment 2

[0478] Embodiment 2: the synthesis of o-mono-phosphoamidate (ortho-mono-phosphoamidate) compound 13:

[0479]

[0480] CH of bisphenol 10a (300 mg, 0.63 mmol, 1.0 eq) 2 Cl 2 (5mL) solution was added i-Pr 2 Net (104 μL, 0.63 mmol, 1.0 equiv) and EOMCl (58 μL, 0.63 mmol, 1.0 equiv). The reaction was slowly warmed to room temperature and stirring was continued overnight. Then the reaction mixture was washed with saturated NH 4 Aq. Cl (15 mL) was washed and washed with CH 2 Cl 2 (20mL×2) extraction; then the combined organic layers were washed with brine (20mL) and washed with anhydrous Na 2 SO 4 dry. After evaporation, the residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate=3:2) to obtain 165 mg of the desired mono-protected compound 12 (49%). The compound can also be obtained by selective deprotection of the EOM group ortho to the carbonyl by treatment with TFA in MeOH:THF at room temperature.

[0481]

[0482] CH to mono-EOM prot...

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Abstract

The present invention includes macrocyclic prodrug compounds, pharmaceutical compositions comprising them. The present invention also includes the use of these compounds in the treatment of various diseases including autoimmune diseases, inflammatory diseases, neurological diseases or neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, hormone-related diseases and tumors or symptoms caused by neurofibromatosis.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 61 / 030,446, filed February 21, 2008, entitled "Macrocyclic Prodrug Compounds Useful as Therapeutics," the contents of which are incorporated herein by reference in their entirety for all purposes. This application is also related to International Application PCT / US2007 / 017754, filed August 10, 2007, entitled "Macrocyclic Compounds Useful as Inhibitors of Kinase and HSP90" and U.S. Serial No. 11 / 891,652, filed August 10, 2007 International application PCT / US2007 / 075739 entitled "Treatment of Neurofibromatosis with Radicicol and its Derivatives", and international application PCT / US2009 / 031149, the contents of which are incorporated herein by reference in their entirety for all purposes. Field of Invention [0003] The present invention relates to prodrugs of novel derivatives, analogs and intermediates of the natural products radicicol and pochonin, a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/00C07D315/00A61K31/365
CPCC07D313/00A61P5/00A61P9/00A61P11/06A61P17/00A61P21/00A61P25/00A61P25/28A61P29/00A61P35/00A61P37/06A61P37/08A61P43/00C07D315/00C07D405/12
Inventor J·赫克N·温辛格尔J·C·沙巴拉S·巴尔吕埃娜R·陈A·鲁本施泰因J-C·于
Owner ONCOSYNERGY
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