Granted Patent
B2
US 12,721,851 · App. 18/293,848 · Granted Sep 1, 2026
Pharmaceutical composition for treating solid tumors
Assignee:
Eisai R&D Management Co., Ltd.
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Abstract
The present invention provides a pharmaceutical composition for treating a solid 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 (Compound A) represented by the formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered to a human subject together with an effective amount of a 5-HT 3 receptor antagonist to suppress gastrointestinal symptoms in such a manner that Compound A or the pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg to about 150 mg per dose of Compound A; and the gastrointestinal symptom is a gastrointestinal symptom associated with administration of Compound A or a pharmaceutically acceptable salt thereof
Claims (26)
1 . A method for treating a solid tumor, the method comprising:
administering, to a human subject with the solid tumor, (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 represented by the formula (I) or a pharmaceutically acceptable salt thereof twice daily at a dose of about 10 mg to about 150 mg per dose 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; and
administering an effective amount of a 5-HT 3 receptor antagonist to suppress a gastrointestinal symptom in combination to the human subject;
wherein the gastrointestinal symptom is a gastrointestinal symptom associated with administration, to the human subject, of the (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 or the pharmaceutically acceptable salt thereof
2 . The method according to claim 1 , wherein the gastrointestinal symptom is at least one selected from nausea and vomiting.
3 . The method according to claim 1 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg per dose 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.
4 . The method according to claim 1 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered in combination with the 5-HT 3 receptor antagonist simultaneously or separately.
5 . The method according to claim 1 , wherein the 5-HT 3 receptor antagonist is at least one selected from the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, and a pharmaceutically acceptable salt thereof.
6 . The method according to claim 1 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered in combination with a dosage of about 0.1 mg to about 100 mg of the 5-HT 3 receptor antagonist as a daily dose.
7 . The method according to claim 1 , wherein the 5-HT 3 receptor antagonist is at least one selected from ramosetron hydrochloride and granisetron hydrochloride.
8 . The method according to claim 1 , wherein the 5-HT 3 receptor antagonist is granisetron hydrochloride and administered in combination once daily at a dose of about 2 mg of granisetron.
9 . The method according to claim 1 , wherein the 5-HT 3 receptor antagonist is ramosetron hydrochloride and administered once daily at a dose of about 0.1 mg of ramosetron.
10 . The method according to claim 1 , wherein the (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 or the pharmaceutically acceptable salt thereof is (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.
11 . A method for treating a solid tumor while suppressing a gastrointestinal symptom, the method comprising:
administering, to a human subject with the solid tumor, (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 represented by the formula (I) or a pharmaceutically acceptable salt thereof twice daily at a dose of about 10 mg to about 150 mg per dose 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; and
administering an effective amount of a 5-HT 3 receptor antagonist to suppress a gastrointestinal symptom in combination to the human subject with a solid tumor;
wherein the gastrointestinal symptom is a gastrointestinal symptom associated with administration, to the human subject, of the (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 or the pharmaceutically acceptable salt thereof
12 . The method according to claim 11 , wherein the gastrointestinal symptom is at least one selected from nausea and vomiting.
13 . The method according to claim 11 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg per dose 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.
14 . The method according to claim 11 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered in combination with the 5-HT 3 receptor antagonist simultaneously or separately.
15 . The method according to claim 11 , wherein the 5-HT 3 receptor antagonist is at least one selected from the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, and a pharmaceutically acceptable salt thereof.
16 . The method according to claim 11 , wherein the (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 or the pharmaceutically acceptable salt thereof is administered in combination with a dosage of about 0.1 mg to about 100 mg of the 5-HT 3 receptor antagonist as a daily dose.
17 . The method according to claim 11 , wherein the 5-HT 3 receptor antagonist is at least one selected from ramosetron hydrochloride and granisetron hydrochloride.
18 . The method according to claim 11 , wherein the 5-HT 3 receptor antagonist is granisetron hydrochloride and administered in combination once daily at a dose of about 2 mg of granisetron.
19 . The method according to claim 11 , wherein the 5-HT 3 receptor antagonist is ramosetron hydrochloride and administered once daily at a dose of about 0.1 mg of ramosetron.
20 . The method according to claim 11 , wherein the (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 or the pharmaceutically acceptable salt thereof is (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.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 6, 2024
From: TAMAI, TOSHIYUKI; NAGAO, SATOSHI
To: EISAI R&D MANAGEMENT CO., LTD.
Reel/Frame 066356/0202 →
Priority Claims (1)
JP 2021-146389
· Sep 8, 2021
· national
Continuity (1)
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