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BR-112019014127-B1 - Pharmaceutical composition for the treatment of tumors.

BR112019014127B1BR 112019014127 B1BR112019014127 B1BR 112019014127B1BR-112019014127-B1

Abstract

A pharmaceutical composition is provided for the treatment of a tumor used in combination therapy with lenvatinib and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

Inventors

  • Yoichi Ozawa
  • Yusaku Hori
  • Kazuhiko Yamada
  • Hiroshi Kamiyama
  • Masahiro Matsuki

Assignees

  • EISAI R&D MANAGEMENT CO., LTD

Dates

Publication Date
20260310
Application Date
20180206
Priority Date
20170208

Claims (3)

  1. 1. Use of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) and lenvatinib or a pharmaceutically acceptable salt thereof, characterized in that it is for the production of a pharmaceutical composition comprising E7386 and a pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, wherein the two pharmaceutical compositions are a combination for simultaneous use, for the treatment of a tumor.
  2. 2. Use according to claim 1, characterized in that lenvatinib, or the pharmaceutically acceptable salt thereof, is lenvatinib mesylate.
  3. 3. Use, according to claim 1 or 2, characterized by the tumor being breast cancer, thyroid cancer, hepatocellular carcinoma, colorectal cancer, renal cell carcinoma, head and neck cancer, endometrial cancer or melanoma.

Description

Technical Field [0001] The present invention relates to a pharmaceutical composition for the treatment of a tumor, which is used in the combination therapy of lenvatinib and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide. Antecedent Technique [0002] Lenvatinib is an oral tyrosine kinase inhibitor having an inhibitory effect on angiogenesis (Patent Literature 1) and targeting vascular endothelial growth factor receptors (VEGFRs) 1 to 3, fibroblast growth factor receptors (FGFRs) 1 to 4, transfection-rearranged (RET), KIT and platelet-derived growth factor receptor (PDGFR) α (Patent Literatures 2 to 5), and is known as a therapeutic agent for various tumors such as thyroid cancer, lung cancer, melanoma, endometrial cancer, renal cell carcinoma, glioma, hepatocellular carcinoma and ovarian cancer. The compound name of lenvatinib is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. [0003] (6S,9aS)-N-Benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (hereinafter also referred to as E7386) is known as a compound having a modulating effect on the Wnt Pathway (Patent Literature 6). [0004] There are no previous reports regarding the combination therapy of lenvatinib and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide exhibiting any antitumor effect. [0005] In general, a tumor therapy agent, when used alone, is often not effective for all patients. Accordingly, attempts have been made to date to improve the treatment rate by using a plurality of tumor-fighting therapeutic agents in combination and achieving intensification of the antitumor effect or relief of adverse reactions (Patent Literature 7 to 9). List of Citations Patent Literature Patent Literature 1: U.S. Patent No. 7253286 Patent Literature 2: Publication of U.S. Patent Application No. 2004-253205 Patent Literature 3: Publication of U.S. Patent Application No. 2010-105031 Patent Literature 4: Publication of U.S. Patent Application No. 2009-209580 Patent Literature 5: Publication of U.S. Patent Application No. 2009-264464 Patent Literature 6: U.S. Patent No. 9174998 Patent Literature 7: International Publication No. WO 2009/140549 Patent Literature 8: Publication of US Patent Application No. 2004-259834 Patent Literature 9: U.S. Patent No. 6217866 Summary of the Invention Technical Problem [0006] Under such circumstances, further development of a novel combination therapy of therapeutic agents for tumors is anticipated. Solution to the Problem [0007] The present inventors conducted diligent studies and consequently completed the present invention by discovering that the combined administration of lenvatinib and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide exhibits an unexpected antitumor effect. [0008] Specifically, the present invention provides the following [1] to [33]. [1] A pharmaceutical composition comprising(6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1- c][1,2,4]triazine-1(6H)-carboxamide, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7- Dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide is administered in combination with lenvatinib or a pharmaceutically acceptable salt thereof.[2] A pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.[3] A pharmaceutical composition for treating a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2- en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6- (2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide is administered in combination with lenvatinib or a pharmaceutically acceptable salt thereof.[4] A pharmaceutical composition f