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Tricyclic lactones for treatment of cancer

A carbocyclic and heterocyclic technology, applied in the field of new tricyclic compounds, can solve the problems of low activity and no activity

Inactive Publication Date: 2013-05-08
格雷克顿发展制药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the obtained analogues became inactive or less active than (-)-sarcolide

Method used

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  • Tricyclic lactones for treatment of cancer
  • Tricyclic lactones for treatment of cancer
  • Tricyclic lactones for treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0162] The final compound of formula (II) can be prepared via the electron enriched double bond of intermediate (III) using mCPBA, dimethyldioxirane, trifluoromethyldioxirane, peracid or similar obtained by regioselective and stereoselective epoxidation.

[0163] Process for the preparation of final compounds of formula (I) by lactonization (Scheme 2)

[0164] Methods of preparation of final compounds of formula (I) by lactonization (Scheme2)

[0165]

[0166] Scheme 2: Example of a non-limiting method for the preparation of the final compound of formula (I) as disclosed herein by hydrolysis and lactonization of the compound of formula (II) as disclosed herein.

[0167] Ester hydrolysis of (II) under basic or acidic conditions, followed by acid-catalyzed epoxide opening and subsequent lactonization yields the final lactone compound (I).

[0168] Preparation of tetrahydroindene intermediates of formula (III) via intermolecular [4+2]vinyl allene Diels-Alder cyclization ...

Embodiment 1

[0227] 2a1-Hydroxy-4,7,7-trimethyl-4,5,5a,6,7,7a-hexahydroindeno[1,7-bc]furan-2(2a1H)-one

[0228]

[0229] 1 H NMR (CDCl 3 )6.91(1H,d,J=3.8Hz),4.30(1H,s),2.49(1H,m),2.43(1H,m),2.11(1H,m),1.87(1H,ddd,J=14.6 , 6.5 and 2.4Hz), 1.63 (1H, dd, J = 10.0 and 4.2Hz), 1.57 (1H, dd, J = 10.2 and 4.1Hz), 1.45 (1H, dd, J = 13.2 and 6.9Hz), 1.22 (3H,d,J=7.2Hz),1.17(3H,s),0.91(3H,s)

[0230] 13 C NMR (CDCl 3 ) 170.1, 146.8, 128.7, 107.2, 95.3, 80.5, 41.9, 39.9, 39.1, 30.0, 29.3, 28.0, 24.7, 19.8

[0231] HRMS C 13 h 19 o 3 [M+1] Calculated: 223.1334, Measured: 223.1345

Embodiment 2

[0233] 2a 1 -Hydroxy-4-methyl-7-phenyl-4,5,5a,6,7,7a-hexahydroindeno[1,7-bc]furan-2(2a 1 H)-keto

[0234]

[0235] 1 H NMR (CDCl 3 )7.31(2H,m),7.22(1H,m),7.06(2H,d,J=7.3Hz),7.01(1H,d,J=3.9Hz),4.93(1H,d,J=8.5Hz) ,3.53(1H,dt,J=12.5 and 7.9Hz),2.56(1H,m),2.50(1H,m),2.00(2H,m),1.73(1H,ddd,J=14.3,10.0 and 4.3Hz ),1.60(1H,q,J=12.5Hz),1.27(3H,d,J=7.2Hz)

[0236] 13 C NMR (CDCl 3 ) 170.1, 147.2, 137.1, 128.9, 128.8, 128.6, 127.2, 88.9, 82.8, 80.1, 47.4, 41.1, 33.7, 29.6, 27.9, 19.9

[0237] HRMS C 17 h 18 o 3 Na[M+1] Calculated: 293.1154, Measured: 293.1147

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Abstract

The present invention discloses novel compounds useful for the inhibition of IL-6 / STAT signaling and / or PI3K / NF-[kappa]B signaling in the treatment of associated diseases or conditions, e.g. cancer. A pharmaceutical composition comprising such novel compounds, its use and a method thereof, is also disclosed.

Description

technical field [0001] The present invention relates to novel tricyclic compounds, pharmaceutical compositions comprising such compounds and methods of treating or ameliorating conditions, especially cancer, by using such compounds. Background technique [0002] IL-6 is a pleiotropic cytokine with multiple biological activities in the fields of immune regulation, hematopoiesis, inflammation and tumorigenesis. It is produced by a variety of cell types and acts on a large and diverse population of cells and tissues. Binding of IL-6 to the IL-6 receptor results in the recruitment and complex formation of two gp130 molecules located at the cell membrane. Intracellular dimerization of the two gp130 proteins recruits members of the Janus family of tyrosine kinases (JAK) to the complex, enabling transphosphorylation. JAKs will subsequently phosphorylate additional targets including the gp130 receptor, the phosphorylation of which is essential for the phosphorylation and activatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D303/38C07D307/93A61K31/365A61K31/336A61P35/00
CPCA61K31/336C07D303/40C07D303/38C07D307/93A61K31/365A61K45/06A61P1/04A61P3/10A61P9/10A61P9/12A61P11/00A61P11/06A61P17/00A61P17/04A61P19/02A61P25/00A61P25/16A61P25/28A61P29/00A61P31/12A61P31/14A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00
Inventor 立他·伊德勒夫马丁·约翰松奥洛夫·斯特纳爱德华多·穆诺茨
Owner 格雷克顿发展制药公司
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