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Britianone base derivatives useful as inhibitors of topoisomerase Ib (TOP1) and/or tyrosyl-DNA phosphodiesterase 1 (TDP1)

A C1-C6, C1-C2 technology for use as an inhibitor of topoisomerase IB (TOP1) and/or tyrosyl-DNA phosphodiesterase 1 (TDP1) derivatization of xanthoxyline realm

Pending Publication Date: 2022-05-27
UNITED STATES OF AMERICA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Among the Tdp1 inhibitors, sodium orthovanadate (7, figure 2 ) is the first reported Tdp1 inhibitor that mimics a transition-state DNA substrate, but only at millimolar concentrations

Method used

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  • Britianone base derivatives useful as inhibitors of topoisomerase Ib (TOP1) and/or tyrosyl-DNA phosphodiesterase 1 (TDP1)
  • Britianone base derivatives useful as inhibitors of topoisomerase Ib (TOP1) and/or tyrosyl-DNA phosphodiesterase 1 (TDP1)
  • Britianone base derivatives useful as inhibitors of topoisomerase Ib (TOP1) and/or tyrosyl-DNA phosphodiesterase 1 (TDP1)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1. General procedure for the synthesis of compounds

[0203] General procedure for the synthesis of Schiff bases 12a, 12b and 33. The reaction solution of 6-bromoveratrol (9.8 g, 40 mmol) and amine (ethanolamine, 3-aminopropanol or 4-methoxybenzylamine, 42 mmol) in methanol (200 mL) was stirred at room temperature for 12 h, then Concentrate under reduced pressure. The residue was washed with petroleum ether (2x10 mL) to give a white solid. 1 H NMR spectroscopy showed that the Schiff base intermediate was pure and was used in the next synthesis without further purification.

[0204]N-(2-hydroxyethyl)-6-bromoveratraldimine (12a). 1 H NMR (CDCl 3 )δ8.58(s, 1H), 7.54(s, 1H), 6.99(s, 1H), 3.95-3.89(m, 8H), 3.79(t, J=4.7Hz, 2H).

[0205] N-(3-hydroxypropyl)-6-bromoveratrol aldimine (12b). 1 H NMR (CDCl 3 )δ8.53(s, 1H), 7.45(s, 1H), 7.00(s, 1H), 3.91-3.86(m, 8H), 3.82(t, J=6.2Hz, 2H), 1.96(quint, J =6.0Hz, 2H).

[0206] N-(4-Methoxybenzyl)-6-bromoveratrol aldi...

Embodiment 2

[0252] Example 2. Synthesis of compounds 39–45

[0253] The 6-alkoxy substituted benzophenanthridone derivatives (39a / b-45a / b) were synthesized as shown in Scheme 2.

[0254]

[0255] The reagents and conditions used in Scheme 2 were as follows: (a) MeOH, room temperature. (b)i)N 2 , Compound 14, Ni(cod) 2 ,P(o-Tol) 3 , MeCN, 80℃; ii) CsOH, K 3 Fe(CN) 6 , MeOH, H 2 O, 80℃. (c)(COCl) 2 ,DMSO,TEA,DCM,-60℃. (d) HCl, AcOH, room temperature. (e) POCl 3 , DMF, 100℃. (f)HOCH 2 CH 2 R, THF, NaH, 70°C. (g)Br(CH 2 ) 3 Br, DMF, NaH, room temperature. (h) Amine (for dimethylamine, in a pressure vessel), DMF, K 2 CO 3 , KI, room temperature.

[0256] Synthesis of 2,3-Dimethoxy-[1,3]dioxolo[4',5':4,5]benzo[1,2-c]phenanthridine-13(12H)- Ketone (36). A reaction solution of 35 (270 mg, 0.5 mmol) and concentrated hydrochloric acid (0.4 mL) in acetic acid (4 mL) was added to a 50 mL round bottom flask. The flask was sealed with a rubber stopper. The reaction solution w...

Embodiment 3

[0288] Example 3: Synthesis of compounds 50-63 and 67

[0289] Scheme 3 outlines the synthesis of 5-aminoethyl substituted benzophenanthridone derivatives 50-63 and 67.

[0290]

[0291] The reagents and conditions used in Scheme 3 are as follows: (a) PBr 3 , TCM, room temperature; (b) Pd / C, H 2 (g), THF, room temperature; (c) Formaldehyde solution, Zn, CH 3 CO 2 H,H 2 O, room temperature; (d) RCl, DIPEA, DCM, room temperature.

[0292] Replacing the hydroxyl group of 17a with bromine afforded bromide 65 in 91% yield. After substituting the bromide with an azide group, a Pd / C catalytic reduction reaction was carried out under a hydrogen atmosphere to afford the target amine 67 in 51% yield from 65 (two steps). The primary amine intermediate 67 was reacted with formaldehyde to form a Schiff base, which was reduced using zinc dust to give intermediate 50 in 59% yield. 67 and 50 in dichloromethane with appropriate reagents (eg RC(O)Cl, RSO 2 Acylation of Cl, dialkyl ch...

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Abstract

Compounds of Formula I and pharmaceutically acceptable salts thereof are disclosed. Certain compounds and salts of Formula I are active and can be used as Top1 and / or Tdp1 inhibitors. The present disclosure provides pharmaceutical compositions containing a compound of Formula I as a sole active agent, or optionally one or more additional active agents. The present disclosure provides methods of treating cancer using compounds of Formula I. The disclosed compounds of Formula I can be used alone to treat cancer, but can also be used in combination with another active agent, such as a Top1 inhibitor, such as camptothecin or a camptothecin analogue.

Description

[0001] Citations for Relevant Applications [0002] This application claims priority to and the benefit of US Provisional Application No. 62 / 732,885, filed with the US Patent and Trademark Office on September 18, 2018, and Chinese Patent Application No. 2018108274671, filed with the China Patent Office on July 25, 2018, and their contents It is hereby incorporated by reference in its entirety. [0003] Statement of Government Interest [0004] The subject of the present disclosure was funded by the National Cancer Institute and the National Institutes of Health (BC 006161). The U.S. government has certain rights in this application. This work was also supported by the National Natural Science Foundation of China (No. 81373257). technical field [0005] Topoisomerase IB (Top1) inhibitors are a well-known class of antineoplastic drugs, including camptothecin and its derivatives. Tdp1 is an enzyme that repairs damage caused by stalled Top1 covalent complexes, a process that o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/00A61P31/00A61P35/00C07D491/056C07D491/153A61K31/4741A61K31/4355A61K31/4418C07D221/18A61K31/496A61K31/5377
CPCC07J73/008C07J73/005C07J73/00C07D491/153A61P35/00A61P35/02A61P25/00A61P31/00C07D221/18C07D491/056C07D491/22C07D471/04
Inventor 安林坤张晓茹王浩文伊夫·乔治·庞米尔叶夫根尼·A·基谢廖夫阿扎尔·阿利·拉夫吉凯利·基塞霍·阿加马
Owner UNITED STATES OF AMERICA
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