Use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceutical compositions for the treatment of solid tumors.

Abstract

This invention provides a pharmaceutical composition for the treatment of solid tumors, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide (compound A) or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg to about 150 mg, based on compound A. A mg dose, together with an effective amount of a 5-HT3 receptor antagonist for inhibiting digestive symptoms induced by administration of compound A or a pharmaceutically acceptable salt thereof, was administered to human subjects. [Chem. 1]

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition for the treatment of solid tumors. Prior Technology

[0002] The Wnt / β-catenin signaling pathway is a highly conserved signaling pathway in animal evolution, regulating gene expression related to cell proliferation and differentiation, body axis formation, and organogenesis. Abnormal activation of the Wnt / β-catenin signaling pathway is known in various cancers, including colorectal cancer and hepatocellular carcinoma.

[0003] If Wnt, acting as a ligand, binds to receptors such as Frizzled on the cell membrane surface, it inhibits the activity of GSK-3β (Glycogen synthase kinase) via the intracellular molecule Dvl. As a result, β-catenin is released from the complex containing GSK-3β, AXIN, APC, and β-catenin-beta-1. The free and stable β-catenin migrates to the nucleus and forms a complex with the transcription factor TCF / LEF (T-cell factor / lymphoid enhancer factor). This complex requires CREP-binding protein (CBP) or P300 protein as transcriptional co-activators. Activated TCF / LEF induces the expression of various genes, including MYC, cyclin D, and its own TCF / LEF. TCF / LEF is known to be a major downstream factor in the Wnt / β-catenin signaling pathway, responsible for the regulation of gene expression based on this pathway (e.g., Patent Documents 1-2).

[0004] As compounds with Wnt pathway modulating effects, the following formula (X) represents (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-disideoxy-2-(prop-2-en-1-yl)-octahydro-1H-pyrro[2,1-c][1,2,4]triazin-1- Methamide (Patent Document 1), and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide (Patent Document 2). [Chemistry 1] The (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-disideoxy-2-(prop-2-en-1-yl)-octahydro-1H-pyrro[2,1-c][1,2,4]triazin-1-methylamine disclosed in Patent Document 1 is similar to that disclosed in Patent Document 2. In the IUPAC nomenclature, (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methylamine is represented by formula (I). [Chemistry 2] Although the chemical bonds in formulas (X) and (I) are represented differently, they represent the same stereostructure. Therefore, in this description, formula (I) is used as the structural formula, and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide is used as the chemical name. [Existing Technical Documents] [ ] [Patent Literature] [ ]

[0005] Patent Document 1: International Publication No. 2015 / 098853 Patent Document 2: International Publication No. 2016 / 208576 Summary of the Invention

[0006] [The problem the invention aims to solve] [ ] However, there are no data on the actual administration of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide (hereinafter also referred to as compound A, or E7386) or a pharmaceutically acceptable salt thereof to human subjects, and the optimal dose or method of administration is unknown. Furthermore, adverse events resulting from the administration of compound A or a pharmaceutically acceptable salt thereof in human subjects and methods for their control are also unknown.

[0007] Therefore, the object of the present invention is to provide a pharmaceutical composition or preparation containing a dosage of compound A or a pharmaceutically acceptable salt thereof suitable for administration to human subjects. Additionally, the present invention also provides a method for suppressing digestive symptoms accompanying administration of compound A.

[0008] Generally, responses to anticancer drugs vary from person to person, and the discomfort experienced as a side effect requires further individualized management. Chemotherapy-induced nausea and vomiting (CINV) is a representative side effect causing significant discomfort for patients, making its proper management crucial. Guidelines for CINV have been developed in Europe, the United States, and Japan, and CINV is being improved. However, due to the need to consider individual differences and patient background factors, controlling CINV remains challenging. Furthermore, management methods differ depending on the timing of CINV occurrence, requiring patients to provide detailed reports on the timing and frequency of its occurrence. In the field of anticancer therapy using anticancer drugs, there is a need for more effective and less burdensome suppression of nausea and vomiting associated with anticancer treatment. [Technical means to solve the problem]

[0009] The present invention provides the following [1]~

[18] and [P1]~[P14]. [1] A pharmaceutical composition for the treatment of solid tumors, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof, as represented by formula (I). (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof. The dosage was administered twice daily, at a dose of approximately 10 mg to approximately 150 mg (based on the formula (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide), in combination with a 5-HT3 receptor antagonist effective in suppressing gastrointestinal symptoms, to human subjects. The digestive symptoms described are those caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 3] [2] According to the pharmaceutical composition described in [1], the digestive symptoms are selected from at least one of nausea and vomiting. [3] According to the pharmaceutical composition described in [1] or [2], (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methylamine Or a pharmaceutically acceptable salt thereof, administered at a dose of approximately 120 mg per administration, based on (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide. [4] The pharmaceutical composition according to any one of [1] to [3] is administered simultaneously or separately with the 5-HT3 receptor antagonist. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the 5-HT3 receptor antagonist is selected from at least one of the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or a pharmaceutically acceptable salt thereof. [6] The pharmaceutical composition according to any one of [1] to [5] is administered in combination with the 5-HT3 receptor antagonist in an amount of about 0.1 mg to about 100 mg per day. [7] The pharmaceutical composition according to any one of [1] to [6], wherein the 5-HT3 receptor antagonist is selected from at least one of ramosetron hydrochloride and granisetron hydrochloride. [8] The pharmaceutical composition according to any one of [1] to [6], wherein the 5-HT3 receptor antagonist is ondansetron hydrochloride hydrate. [9] The pharmaceutical composition according to any one of [1] to [6], wherein the 5-HT3 receptor antagonist is palonosetron hydrochloride.

[10] The pharmaceutical composition according to any one of [1] to [7], wherein the 5-HT3 receptor antagonist is granisetron hydrochloride, administered in combination at a dose of about 2 mg granisetron once a day.

[11] The pharmaceutical composition according to any one of [1] to [7], wherein the 5-HT3 receptor antagonist is ramusetron hydrochloride, administered once daily at a dose of about 0.1 mg of ramusetron.

[12] The pharmaceutical composition according to any one of [1] to

[11] , wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6 H)-Ceramide or its pharmaceutically acceptable salt (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-Ceramide.

[13] A (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyraclo[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof, represented by formula (I), is used for the treatment of solid tumors. (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof. The dosage was administered twice daily, at a dose of approximately 10 mg to approximately 150 mg (based on the formula (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide), in combination with a 5-HT3 receptor antagonist effective in suppressing gastrointestinal symptoms, to human subjects. The digestive symptoms described are those accompanying administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 4]

[14] Use of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof, as represented by formula (I), for the manufacture of pharmaceutical compositions for the treatment of solid tumors. (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof. The dosage was administered twice daily, at a dose of approximately 10 mg to approximately 150 mg (based on the formula (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide), in combination with a 5-HT3 receptor antagonist effective in suppressing gastrointestinal symptoms, to human subjects. The digestive symptoms described are those caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 5]

[15] A method for treating solid tumors, comprising: The (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or its pharmaceutically applicable form represented by formula (I) The accepted salt was administered twice daily to human subjects with solid tumors at doses of approximately 10 mg to approximately 150 mg, based on (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide; and The human subjects were co-administered with an effective amount of 5-HT3 receptor antagonist that inhibited gastrointestinal symptoms. The digestive symptoms described are those caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 6]

[16] A method of administering (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof to a human subject, comprising: The (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or its pharmaceutically applicable form represented by formula (I) The accepted salt was administered twice daily to human subjects with solid tumors at doses of approximately 10 mg to approximately 150 mg, based on (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide; and The human subjects were co-administered with an effective amount of 5-HT3 receptor antagonist that inhibited gastrointestinal symptoms. The digestive symptoms described are those caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 7]

[17] A method for simultaneously suppressing digestive symptoms and treating solid tumors includes: The (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or its pharmaceutically applicable form represented by formula (I) The accepted salt was administered twice daily to human subjects with solid tumors at doses of approximately 10 mg to approximately 150 mg, based on (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methamide; and The human subjects were co-administered with an effective amount of 5-HT3 receptor antagonist that inhibited gastrointestinal symptoms. The digestive symptoms described are those caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof. [Chemistry 8]

[18] A treatment method for a solid tumor, 5-HT3 receptor antagonists were selected to suppress gastrointestinal symptoms in human subjects. (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-di-sideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tri-1(6H)-methamide or a pharmaceutically acceptable salt thereof, in combination with a 5-HT3 receptor antagonist, was administered to human subjects for the treatment of solid tumors. The gastrointestinal symptoms were caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof. Digestive symptoms in human subjects were suppressed. [P1] A medicine, which is used in the following manner: (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide, i.e., compound A or a pharmaceutically acceptable salt thereof, represented by formula (I), is administered orally to a human subject twice daily at a dose of about 10 mg to about 150 mg based on compound A. [Chemistry 9] [P2] According to the medicine described in [P1], the medicine achieves an average AUC (0-12 h) of compound A per 1 mg of approximately 7.58 h·ng / mL to approximately 31.3 h·ng / mL after a single administration to a human subject. [P3] According to the medicine described in [P1] or [P2], the medicine achieves an average AUC (0-12 h) of approximately 71.4 h·ng / mL to approximately 3040 h·ng / mL after a single administration to a human subject. [P4] According to the pharmaceuticals described in [P1] to [P3], the pharmaceuticals, after a single administration to a human subject, achieve an average Cmax of approximately 2.79 ng / ml to approximately 11.3 ng / ml per 1 mg of compound A. [P5] According to any one of [P1] to [P4], the medicine achieves an average Cmax of about 23.5 ng / ml to about 1100 ng / ml after a single administration to a human subject. [P6] According to any one of [P1] to [P5], the AUC(0-tau), ss is less than about 7700 h·ng / mL after repeated administration to human subjects for 8 days. [P7] The medicine according to any one of [P1] to [P6] is used in the following manner: administered together with a 5-HT3 receptor antagonist that inhibits digestive symptoms accompanying administration of the medicine according to any one of [P1] to [P6]. [P8] According to the medicine described in [P7], the digestive symptoms are selected from at least one of nausea and vomiting. [P9] According to the medicine described in [P7] or [P8], the 5-HT3 receptor antagonist is administered at a dosage of about 0.3 mg to about 8 mg per day. [P10] The medicine according to any one of [P1] to [P9] is used to treat solid cancer. [P11] According to the medicine described in [P10], the solid cancer is a digestive system cancer, a gastrointestinal endocrine tumor, uterine cancer, malignant melanoma, or lung cancer. [P12] According to the medicine described in [P9], the 5-HT3 receptor antagonist is selected from the group consisting of ondansetron hydrochloride hydrate, granisetron hydrochloride, palonosetron hydrochloride, dorastron, ramosetron hydrochloride, and tropisetron hydrochloride. [P13] A treatment for solid cancer comprising orally administering, twice daily, to a human subject (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide, i.e., compound A or a pharmaceutically acceptable salt thereof, at a dose of about 10 mg to about 150 mg based on compound A. [Chemistry 10] [P14] According to the treatment method described in [P13], it includes administering a 5-HT3 receptor antagonist together with compound A or a pharmaceutically acceptable salt thereof when the human subject exhibits digestive symptoms associated with administration of compound A or a pharmaceutically acceptable salt thereof. [Invention Effects] [ ]

[0010] According to the present invention, a medicine or preparation containing a pharmaceutically acceptable salt thereof of compound A, suitable for administration to a human subject, is available. Additionally, a method for suppressing digestive symptoms accompanying administration of compound A or a pharmaceutically acceptable salt thereof is also available. Simple Explanation of the Diagram

[0011] [Figure 1] is a graph showing the relationship between the pharmacokinetics of compound A or its pharmaceutically acceptable salt and the vomiting flag, showing the AUC (AUC (0-tau), ss) of each subject at time point on day 8 of cycle 1 (C1D8). [Figure 2] is a graph showing the relationship between the pharmacokinetics of compound A or its pharmaceutically acceptable salt and the vomiting flag, showing the relationship between Cmax (Cmax, ss) and the vomiting flag for each subject at time point 8 of cycle 1 (C1D8). [Figure 3] is a graph showing the relationship between the pharmacokinetics of compound A or its pharmaceutically acceptable salts and the vomiting flag (including the final vomiting management in the dose escalation phase, including additional cases). It is a graph showing the relationship between the AUC and the vomiting flag for each subject at day 8 of cycle 1 (C1D8). In Figure 3, the vertical axis represents AUC (0-tau) and ss (h*ng / mL), and the horizontal axis represents the vomiting flag value. [Figure 4] is a graph showing the relationship between the pharmacokinetics of compound A or its pharmaceutically acceptable salts and the vomiting flag (including the final vomiting management in the dose escalation phase, including additional cases). It is a graph showing the relationship between Cmax and the vomiting flag for each subject at day 8 of cycle 1 (C1D8). In Figure 4, the vertical axis represents Cmax (Cmax, ss), and the horizontal axis represents the vomiting flag value. [Figure 5] is a diagram showing the final vomiting management in the dose escalation phase, including additional cases. In Figure 5, the vertical axis represents the dosage (mg) of compound A per dose, and the horizontal axis represents the vomiting flag value. Implementation

[0012] The embodiments of the present invention will now be described. These embodiments are merely illustrative examples and are not intended to limit the invention to these specific embodiments. The present invention can be implemented in various forms without departing from its spirit. Furthermore, the documents cited in this specification, as well as published publications, patent gazettes, and other patent documents, are incorporated herein by reference.

[0013] I. Definition In order to better understand the invention described in this specification, the following definitions are provided for use in this invention.

[0014] The term "human subjects" refers to an arbitrary group of subjects that exhibit clinical signs or symptoms of cancer.

[0015] The terms "bioequivalent" or "bioequivalence" are technical terms defined according to the 34th edition of "Approved Drug Products with Therapeutic Equivalence Evaluations," commonly known as the "Orange Book," published by the U.S. Department of Health and Human Services. Bioequivalence of different formulations of the same drug source includes equivalence regarding the rate and extent of drug absorption. To determine whether two formulations are biologically equivalent, the extent and rate of absorption of the test formulation are compared to that of the standard formulation. Standard bioequivalence studies are conducted in a broad, crossover manner, involving the administration of single doses of both the test drug and the standard drug to multiple volunteers, typically 12–24 healthy adults, followed by the measurement of drug levels in blood or plasma over time. Detailed guidelines for establishing bioequivalence of formulations are published by the FDA, the Generic Drugs Division, and the Bioequivalence Division.

[0016] Two formulations are generally considered "biologically equivalent" if their PK parameters, such as Cmax, AUC, or tmax, differ by less than -20% / +25%. Another method for assessing average biological equivalence involves calculating a 90% confidence interval by comparing the mean measurements (population geometric mean) of the test and standard formulations. To establish biological compatibility, the calculated confidence interval for the mean ratio of the formulations must typically be within the range of 80% to 125%. In addition to this common method, other methods, including (1) logarithmic transformation of pharmacokinetic data, (2) methods for evaluating order effects, and (3) methods for evaluating outlier data, can also be used to establish biological equivalence. For example, in (1) above, the confidence interval for the difference in the mean values ​​of the logarithmically transformed PK parameters must typically be within the range of 80% to 125%.

[0017] The term "preparation" refers to the means by which a drug (active ingredient in a pharmaceutical product (API)) is administered to patients and other mammals, or to facilitate the dosing, administration, and delivery of a drug. Preparations are classified, for example, according to the route of administration and site of application, including oral, topical, rectal, vaginal, intravenous, subcutaneous, intramuscular, intraocular, intranasal, intraocular, and inhalation administration. Alternatively, preparations are classified according to their physical form, such as solid, semi-solid, or liquid. Further, preparations are classified according to the General Principles of the Japanese Pharmacopoeia, 18th Revision (JP18) or the United States Pharmacopeia-NF(37)(USP37). <1151> The descriptions in the papers on pharmaceutical formulations are based on the subdivision of forms, functions and characteristics, including but not limited to tablets, capsules or injections.

[0018] The term "excipient" refers to a typical inactive ingredient used as a component of a formulation or pharmaceutical composition.

[0019] The term "mean" refers to the geometric mean. Pharmacokinetic parameters, such as "mean Cmax" or "mean AUC," refer to the geometric mean of Cmax or AUC.

[0020] The following is a list of abbreviations and definitions of terms used in this application. AUC: Area under the plasma concentration-time curve AUC(0-tau): Area under the plasma concentration-time curve from 0 hours to the final quantifiable concentration. AUC(0-inf): Area under the plasma concentration-time curve from 0 hours to infinity. CL / F: Apparent systemic clearance after extravascular (e.g., oral) administration Cmax: Maximum observed concentration t1 / 2: Final excretion half-life tmax: The time to reach the maximum (peak) concentration of the drug after administration. Cmax,ss: The highest plasma concentration under steady-state conditions. tmax,ss: Time to reach the highest plasma concentration under steady-state conditions AUC(0-tau),ss: Area under the plasma concentration-time curve at steady state for each unit dose and interval. Rac(AUC): The cumulative coefficient calculated from the AUC(0-tau) and ss after a single throw. Rac(Cmax): The cumulative coefficient calculated based on Cmax, ss, and Cmax after a single throw. Effective t1 / 2(h): Effective disappearance half-life Vz / F: Apparent distribution volume of the terminal phase %CV: square root(exp[SD**2]-1)*100

[0021] Unless otherwise specified, the term "about" refers to a value that is 5% higher or lower than the value modified by the term. For example, the term "about 10 mg" means a range of 9.5 mg to 10.5 mg.

[0022] A range “about” one specific value to “about” another specific value can be expressed using the symbol “~”. The specific values ​​at the endpoints of each range are included within that range. When used in this specification, the singular forms of words such as "a", "an" and "the" include multiple references unless otherwise specified in the context.

[0023] The amount of compound A or its pharmaceutically acceptable salt contained in the pharmaceuticals, pharmaceutical compositions (also referred to as "pharmaceuticals") or oral preparations of the present invention is expressed in terms of the amount of compound A in its free form. For example, the term "dosage of about 10 mg per dose based on compound A" means that each dose contains an amount of compound A or its pharmaceutically acceptable salt equivalent to about 10 mg of free compound A. When the pharmaceutical composition or oral preparation of the present invention is in the form of a dosage unit containing a specific amount of compound A or its pharmaceutically acceptable salt, such as tablets and capsules, the amount of compound A or its pharmaceutically acceptable salt contained in the pharmaceutical composition or oral preparation can be determined based on one or more dosage units. For example, "oral preparation containing about 10 mg of compound A or its pharmaceutically acceptable salt" means that the amount of compound A or its pharmaceutically acceptable salt contained in one dosage unit is about 10 mg, or the total amount of compound A or its pharmaceutically acceptable salt contained in two or more dosage units is about 10 mg.

[0024] Additionally, when compound A is a pharmaceutically acceptable salt, "average Cmax per 1 mg of compound A" or "average AUC per 1 mg of compound A" means the average Cmax or average AUC relative to 1 mg of compound A in its free form.

[0025] When compound A is in a pharmaceutically acceptable salt form, the amount of pharmaceutically acceptable salt of compound A contained in the pharmaceutical composition or oral formulation of the present invention is described in this application as a value related to the free form of compound A. Furthermore, when compound A is in a pharmaceutically acceptable salt form, the amount of pharmaceutically acceptable salt of compound A contained in the pharmaceutical composition or oral formulation is described in this application as a value related to the free form of compound A.

[0026] The pharmaceutical and pharmaceutical composition of the present invention comprises compound A or a pharmaceutically acceptable salt thereof represented by formula (I), and is capable of being used for the treatment of solid tumors (also known as solid cancers). Furthermore, the pharmaceutical and pharmaceutical composition of the present invention involves administering compound A or a pharmaceutically acceptable salt thereof to human subjects twice daily at an amount of approximately 10 mg to approximately 150 mg of compound A each time, in combination with a 5-HT3 receptor antagonist effective in inhibiting gastrointestinal symptoms induced by administration of compound A or a pharmaceutically acceptable salt thereof. The pharmaceutical and pharmaceutical composition of the present invention may be administered simultaneously with or separately from the 5-HT3 receptor antagonist. For example, the 5-HT3 receptor antagonist may be administered before or after administration of the pharmaceutical and pharmaceutical composition of the present invention. In one embodiment, the pharmaceutical composition of the present invention comprises both compound A or a pharmaceutically acceptable salt thereof and a 5-HT3 receptor antagonist.

[0027] The "5-HT3 receptor antagonist" of this invention refers to any compound or biomolecule that blocks the binding of serotonin (5-HT: 5-hydroxytryptamine) to the 5-HT3 receptor.

[0028] The "suppression of digestive system symptoms" in this invention means to partially or completely relieve, restore, reduce, suppress, or decrease the severity and / or incidence of digestive system symptoms.

[0029] The terms "digestive symptoms accompanying administration of compound A," "digestive symptoms accompanying administration of a medicine," "digestive symptoms accompanying administration of an oral preparation," or "digestive symptoms caused by administration of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazin-1(6H)-methamide or a pharmaceutically acceptable salt thereof" in this invention refer to the appearance of digestive symptoms after administration of the medicine, oral preparation, or compound A of this invention or a pharmaceutically acceptable salt thereof, i.e., digestive symptoms causally related to compound A. Here, digestive symptoms may include, for example, nausea, vomiting, constipation, loss of appetite, and especially at least one of nausea and vomiting.

[0030] The phrase "administered together with a 5-HT3 receptor antagonist" or "administered in combination with a 5-HT3 receptor antagonist" in this invention means that the medicine, pharmaceutical composition, or oral formulation of this invention can be administered simultaneously or separately from a 5-HT3 receptor antagonist. Furthermore, it also means that the 5-HT3 receptor antagonist can be administered after a human subject presents with gastrointestinal symptoms accompanying administration of the medicine, pharmaceutical composition, or oral formulation of this invention, or it can be administered preventively beforehand or simultaneously.

[0031] When used in this specification, the "effective amount" of a drug, compound, or 5-HT3 receptor antagonist means the amount sufficient to produce any one or more beneficial or desired results.

[0032] II. Description of Implementation Methods In one embodiment, the present invention provides a medicine that is used by orally administering compound A or a pharmaceutically acceptable salt thereof to a human subject twice daily at a dose of about 10 mg to about 150 mg of compound A per dose.

[0033] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg of compound A per administration; wherein, the pharmaceutical composition achieves an average AUC (0-12 h) of about 7.58 h·ng / mL to about 31.3 h·ng / mL per 1 mg of compound A after a single administration to a human subject.

[0034] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg based on compound A; wherein, the pharmaceutical composition achieves an average AUC (0-12 h) of about 71.4 h·ng / mL to about 3040 h·ng / mL after a single administration to a human subject.

[0035] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg of compound A per dose; wherein, after a single administration to a human subject, the pharmaceutical composition achieves an average Cmax of about 2.79 ng / ml to about 11.3 ng / ml per 1 mg of compound A.

[0036] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg based on compound A; wherein, the pharmaceutical composition achieves an average Cmax of about 23.5 ng / ml to about 1100 ng / ml after a single administration to a human subject.

[0037] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg based on compound A; wherein, after repeated administration to a human subject for 8 days, the pharmaceutical composition has an AUC(0-tau) and ss of less than about 7700 h·ng / mL.

[0038] In one embodiment, the present invention provides a medicine or pharmaceutical composition used in such a manner as to administer, orally twice daily, to a human subject a dosage of about 10 mg to about 150 mg of compound A or a pharmaceutically acceptable salt thereof, based on compound A; wherein, the medicine or pharmaceutical composition is used in such a manner as to administer, together with a 5-HT3 receptor antagonist, which inhibits gastrointestinal symptoms accompanying the administration of the medicine or compound A or a pharmaceutically acceptable salt thereof. Here, "to be administered together with a 5-HT3 receptor antagonist" means that the medicine comprising compound A or a pharmaceutically acceptable salt thereof may be administered simultaneously or separately with the 5-HT3 receptor antagonist; furthermore, it also means that the 5-HT3 receptor antagonist may be administered after the patient presents with gastrointestinal symptoms, or may be administered prophylactically beforehand or simultaneously.

[0039] In one embodiment, the present invention provides a pharmaceutical composition used in such a way that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 10 mg to about 150 mg of compound A per administration; wherein, the pharmaceutical composition is used in such a way that it is administered together with a 5-HT3 receptor antagonist that inhibits at least one of nausea and vomiting accompanying the administration of the pharmaceutical composition or compound A or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner as follows: Compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of approximately 80 mg per dose, calculated as compound A; wherein, after a single administration to a human subject, the pharmaceutical composition achieves an average Cmax of approximately 2.32 ng / ml to approximately 3.45 ng / ml or approximately 0.663 ng / ml to approximately 17.3 ng / ml per 1 mg of compound A.

[0041] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of approximately 80 mg per dose, calculated as compound A; wherein, the pharmaceutical composition achieves an average AUC (0-12 h) of approximately 6.06 h·ng / mL to 9.48 h·ng / mL, or approximately 2.14 h·ng / mL to approximately 37.2 h·ng / mL after a single administration to a human subject.

[0042] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 100 mg per dose, based on compound A; wherein, after a single administration to a human subject, the pharmaceutical composition achieves an average Cmax of about 3.54 ng / ml to about 5.54 ng / ml, or about 2.63 ng / ml to about 11.8 ng / ml per 1 mg of compound A.

[0043] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of about 100 mg per dose, calculated as compound A; wherein, the pharmaceutical composition achieves an average AUC (0-12 h) of about 11.3 h·ng / mL to about 17.8 h·ng / mL, or about 3.82 h·ng / mL to about 30.4 h·ng / mL after a single administration to a human subject.

[0044] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of approximately 120 mg of compound A per administration; wherein, after a single administration to a human subject, the pharmaceutical composition achieves an average Cmax of approximately 3.71 ng / ml to approximately 5.80 ng / ml or approximately 2.02 ng / ml to approximately 11.5 ng / ml per 1 mg of compound A.

[0045] In one embodiment, the present invention provides a pharmaceutical composition used in such a manner that compound A or a pharmaceutically acceptable salt thereof is orally administered twice daily to a human subject at a dose of approximately 120 mg of compound A per administration; wherein, the pharmaceutical composition achieves an average AUC (0-12 h) of approximately 12.7 h·ng / mL to 19.9 h·ng / mL, or approximately 11.7 h·ng / mL to approximately 21.2 h·ng / mL after a single administration to a human subject.

[0046] In another embodiment, the present invention provides a method for suppressing digestive symptoms accompanying administration of an oral formulation containing compound A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, comprising administering a 5-HT3 receptor antagonist together with the oral formulation containing compound A or a pharmaceutically acceptable salt thereof to a patient exhibiting digestive symptoms accompanying administration of an oral formulation containing compound A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0047] This specification provides a pharmaceutical composition for the treatment of solid tumors and a method for treating solid tumors.

[0048] In one embodiment of the present invention, a pharmaceutical composition for the treatment of solid tumors is provided, comprising compound A represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of approximately 10 mg to approximately 150 mg of compound A each time, in combination with a 5-HT3 receptor antagonist effective in inhibiting digestive symptoms, wherein the digestive symptoms are caused by administration of compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0049] In some implementations, the digestive symptoms are selected from at least one of nausea and vomiting.

[0050] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is administered at a dose of approximately 120 mg of compound A per administration.

[0051] In some embodiments, the pharmaceutical composition of the present invention is administered simultaneously or separately in combination with a 5-HT3 receptor antagonist.

[0052] In some embodiments, the 5-HT3 receptor antagonist is selected from at least one of the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the pharmaceutical composition of the present invention is administered in combination with the 5-HT3 receptor antagonist in an amount of about 0.1 mg to about 16 mg per day.

[0054] In some embodiments, the 5-HT3 receptor antagonist is selected from at least one of ramosetron hydrochloride and granisetron hydrochloride.

[0055] In some embodiments, the 5-HT3 receptor antagonist is granisetron hydrochloride, administered in combination at a dose of approximately 2 mg granisetron once daily.

[0056] In some embodiments, the 5-HT3 receptor antagonist is ramusetron hydrochloride, administered once daily at a dose of approximately 0.1 mg of ramusetron.

[0057] In some embodiments, compound A or its pharmaceutically acceptable salt-based compound A is used.

[0058] In one embodiment of the present invention, a compound A represented by formula (I) or a pharmaceutically acceptable salt thereof is provided for the treatment of solid tumors. The dosage of compound A or a pharmaceutically acceptable salt thereof is approximately 10 mg to approximately 150 mg of compound A twice daily, administered in combination with a 5-HT3 receptor antagonist effective in inhibiting digestive symptoms, wherein the digestive symptoms are associated with the administration of compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0059] In one embodiment of the present invention, the use of compound A represented by formula (I) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a pharmaceutical composition for the treatment of solid tumors. The dosage of compound A or a pharmaceutically acceptable salt thereof is approximately 10 mg to approximately 150 mg of compound A twice daily, administered in combination with a 5-HT3 receptor antagonist effective in inhibiting digestive symptoms caused by administration of compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0060] In one embodiment of the present invention, a method for treating solid tumors is provided, comprising administering to a human subject a compound A represented by formula (I) or a pharmaceutically acceptable salt thereof at a dosage of about 10 mg to about 150 mg of compound A twice a day; and co-administering to the human subject a 5-HT3 receptor antagonist in an effective amount for inhibiting digestive symptoms, wherein the digestive symptoms are caused by administration of compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0061] In one embodiment of the present invention, a method for administering compound A or a pharmaceutically acceptable salt thereof to a human subject is provided, comprising: administering compound A or a pharmaceutically acceptable salt thereof, represented by formula (I), to the human subject twice daily at a dose of approximately 10 mg to approximately 150 mg of compound A each time; and co-administering to the human subject a 5-HT3 receptor antagonist in an effective amount for inhibiting digestive symptoms; wherein the digestive symptoms are digestive symptoms caused by administering compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0062] In one embodiment of the present invention, a method for treating a solid tumor while simultaneously suppressing digestive symptoms is provided, comprising: administering to a human subject a compound A represented by formula (I) or a pharmaceutically acceptable salt thereof at a dosage of about 10 mg to about 150 mg of compound A twice a day; and co-administering to the human subject a 5-HT3 receptor antagonist in an effective amount for suppressing digestive symptoms; wherein the digestive symptoms are caused by administering compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0063] In one embodiment of the present invention, a solid tumor is provided. The treatment method involves selecting a 5-HT3 receptor antagonist to suppress digestive symptoms in human subjects. Compound A or a pharmaceutically acceptable salt thereof is administered in combination with the 5-HT3 receptor antagonist to human subjects to treat solid tumors. The digestive symptoms are caused by the administration of compound A or a pharmaceutically acceptable salt thereof to human subjects, and the digestive symptoms in human subjects are suppressed.

[0064] In this specification, the pharmaceutical composition was administered to human subjects.

[0065] In this specification, oral formulations are those administered orally.

[0066] The pharmaceuticals, pharmaceutical compositions, or oral formulations of the present invention can be manufactured by mixing at least one pharmaceutically acceptable excipient with compound A or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the present invention can, for example, be manufactured in accordance with the General Principles of Formulations of the 18th Revision of the Japanese Pharmacopoeia (JP) and the General Principles of the United States Pharmacopeia-NF(37)(USP37). <1151> Pharmaceutical preparations are manufactured using known methods, such as those described in the pharmaceutical formulation.

[0067] Compound A or its pharmaceutically acceptable salts are known to inhibit the β-catenin-CBP interaction, which is an important downstream step in the Wnt / β-catenin signaling pathway, but do not affect the β-catenin-P300 interaction, modulating the TCF / LEF activity dependent on the Wnt / β-catenin signaling pathway (e.g., International Publication No. 2015 / 098853, International Publication No. 2016 / 208576).

[0068] The APC gene and the CTNNB1 gene are known to be associated with the WNT signaling pathway. The APC gene, located on the long arm of chromosome 5, is considered one of the pathogenic genes for familial adenomatous polyposis (FAP). The CTNNB1 gene encodes β-catenin. In this embodiment, it is envisioned that the pharmaceutical composition or oral formulation is more suitable for administration to human subjects who possess gene variations associated with WNT signaling, represented by abnormalities in the APC or CTNNB1 genes.

[0069] In this specification, compound A or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art, such as International Publication No. 2015 / 098853 and International Publication No. 2016 / 208576.

[0070] The term "pharmaceutically acceptable salt" in this specification is not particularly limited to any salt that forms a salt with a compound represented by general formula (I) and is pharmaceutically acceptable. Examples include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, etc., but are not limited to these.

[0071] In this invention, one embodiment of "compound A or a pharmaceutically acceptable salt thereof" is, for example, compound A, namely (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide.

[0072] Oral formulations typically contain 0.001 to 99.5% by mass, preferably 0.001 to 90% by mass of compound A.

[0073] In this embodiment, the terms "cancer," "tumor," or "cancer" typically refer to a physiological state in mammals characterized by uncontrolled cell growth.

[0074] The pharmaceutical composition or oral preparation of this embodiment is effective in treating solid tumors (also known as solid cancers). Solid tumors (solid cancers) are typically cysts or abnormal growths or tumors of tissue that do not contain fluid. Examples of solid tumors include, for instance, digestive system cancers (e.g., esophageal cancer, gastric cancer, pancreatic cancer, biliary tract cancer, colorectal cancer, small bowel cancer, liver cancer), gastrointestinal endocrine tumors, uterine cancer, malignant melanoma, and lung cancer. The pharmaceutical composition or oral preparation of this embodiment is particularly useful for treating digestive system cancers. The pharmaceutical composition or oral preparation of this embodiment is particularly useful for treating colorectal cancer, small bowel cancer, and gastrointestinal endocrine tumors.

[0075] In this embodiment, the “subject,” “human subject,” or “patient” who is given the pharmaceutical composition or oral preparation is a human subject who needs it, preferably a patient who is determined to have the above-mentioned solid tumor (solid cancer) or has a high probability of having it.

[0076] In this embodiment, the medicine, pharmaceutical composition, or oral preparation, based on the dosage per administration, may include approximately 10 mg to approximately 150 mg, approximately 10 mg to approximately 120 mg, approximately 10 mg to approximately 100 mg, approximately 10 mg to approximately 80 mg, approximately 10 mg to approximately 45 mg, approximately 10 mg to approximately 30 mg, approximately 10 mg to approximately 20 mg, approximately 10 mg to approximately 15 mg, approximately 20 mg to approximately 150 mg, approximately 20 mg to approximately 120 mg, approximately 20 mg to approximately 100 mg, approximately 20 mg to approximately 80 mg, approximately 20 mg to approximately 45 mg, approximately 20 mg to approximately 30 mg, approximately 30 mg to approximately 150 mg, approximately 30 mg to approximately 120 mg, approximately 30 mg to approximately 100 mg, approximately 30 mg to approximately 80 mg, approximately 30 mg to approximately 45 mg, approximately 45 mg to approximately 150 mg, approximately 45 mg to approximately 120 mg, approximately 45 mg to approximately 45 mg, approximately 45 mg to approximately 120 mg, approximately 45 mg to approximately 150 ... Compound A is present in doses of approximately 100 mg, 45 mg to approximately 80 mg, 80 mg to approximately 150 mg, 80 mg to approximately 120 mg, 80 mg to approximately 100 mg, approximately 80 mg, approximately 100 mg, or approximately 120 mg. The dosage of the pharmaceutical, pharmaceutical composition, or oral preparation, per administration, is less than 160 mg based on compound A. Preferably, the dosage per administration is approximately 80 mg, approximately 100 mg, or approximately 120 mg based on compound A; more preferably, it is approximately 100 mg or approximately 120 mg based on compound A. In other embodiments, the dosage of compound A or a salt thereof per administration is approximately 120 mg based on compound A. The daily dose, calculated based on compound A, is approximately 10 mg to approximately 300 mg, preferably approximately 20 mg to approximately 280 mg, approximately 160 mg to approximately 240 mg, or approximately 200 mg to approximately 240 mg, with further preference being approximately 200 mg or approximately 240 mg. The daily dose of the pharmaceutical composition or oral formulation, calculated based on compound A, is less than 320 mg. The pharmaceutical, pharmaceutical composition, or oral formulation is particularly preferably used as follows: twice daily at a dose of approximately 80 mg to approximately 120 mg of compound A per administration. If each administration dose is 160 mg or more based on compound A, there is a tendency to have difficulty suppressing gastrointestinal symptoms (caused by) the administration of compound A or its pharmaceutically acceptable salts. Therefore, each administration dose is less than 160 mg based on compound A. Furthermore, based on results from non-clinical trials, there is a possibility that increased blood concentrations of compound A may lead to cardiotoxicity or drug-drug interactions (DDI). Therefore, it is better to reduce the risk by lowering Cmax, and since the estimated half-life is currently short, it is recommended to administer it twice a day.

[0077] In this specification, the term "about" means including ±10% error of the corresponding value. For example, when stating "about 10 mg", it includes amounts in the range of "9 mg to 11 mg".

[0078] When the pharmaceutical, pharmaceutical composition, or oral formulation of this embodiment is administered to a human subject and blood is collected after a single administration, it is preferable that the average Cmax of compound A reaches the range of about 23.5 ng / mL to about 1100 ng / mL. More preferably, the average Cmax of compound A after a single administration reaches the range of about 29.8 ng / mL to about 870 ng / mL, about 66 ng / mL to about 1100 ng / mL, about 223 ng / mL to about 696 ng / mL, or about 279 ng / mL to about 557 ng / mL.

[0079] In this embodiment, when the medicine, pharmaceutical composition, or oral formulation is administered to a human subject followed by a single blood sample collection, the average AUC (0-12 h) of compound A preferably reaches the range of approximately 71.4 h·ng / mL to approximately 3040 h·ng / mL. More preferably, the average Cmax of compound A after a single administration reaches the range of approximately 89.2 h·ng / mL to approximately 2430 h·ng / mL, approximately 105 h·ng / mL to approximately 2980 h·ng / mL, approximately 214 h·ng / mL to approximately 2430 h·ng / mL, approximately 606 h·ng / mL to approximately 2390 h·ng / mL, or approximately 758 h·ng / mL to approximately 1920 h·ng / mL. AUC (0-12 h) is the area under the curve when plotting the change in plasma concentration over time from administration to 12 hours later.

[0080] When the pharmaceutical, pharmaceutical composition, or oral formulation of this embodiment is repeatedly administered to human subjects for 8 days followed by blood collection, the average Cmax of compound A preferably reaches the range of about 50 ng / mL to about 2000 ng / mL. More preferably, the average Cmax of compound A after continuous administration for 8 days reaches the range of about 12.6 ng / mL to about 2140 ng / mL, about 318 ng / mL to about 2140 ng / mL, about 43.1 ng / mL to about 1150 ng / mL, or about 589 ng / mL to about 1080 ng / mL.

[0081] When the pharmaceutical, pharmaceutical composition, or oral formulation of this embodiment is repeatedly administered to human subjects for 8 days followed by blood collection, the average AUC (0-tau), ss of compound A preferably reaches the range of about 45.4 h·ng / mL to about 9550 h·ng / mL. More preferably, the average AUC (0-tau), ss of compound A after 8 days of repeated administration reaches the range of about 56.7 h·ng / mL to about 7640 h·ng / mL, about 789 h·ng / mL to about 7640 h·ng / mL, about 1680 h·ng / mL to about 3380 h·ng / mL, or about 2100 h·ng / mL to about 3400 h·ng / mL. AUC (0-tau), ss is the area under the plasma concentration-time curve per unit administration interval at steady state.

[0082] Furthermore, when the pharmaceutical or oral formulation of this embodiment is repeatedly administered to human subjects for 8 days followed by blood sampling, the average AUC (0-tau) ss of compound A is preferably less than approximately 9000 h·ng / mL, less than approximately 8000 h·ng / mL, less than approximately 7700 h·ng / mL, or less than approximately 7640 h·ng / mL. In a specific embodiment, when the pharmaceutical or oral formulation of this embodiment is repeatedly administered to human subjects for 8 days followed by blood sampling, the average AUC (0-tau) ss of compound A is less than approximately 7640 h·ng / mL. The tendency to suppress digestive system symptoms accompanying administration of the pharmaceutical composition or oral formulation of this embodiment and reduce the physical / psychological burden on human subjects is increased.

[0083] In this embodiment, the pharmaceutical or pharmaceutical composition preferably has the following 1-day dose: an amount that achieves an average AUC (0-12 h) of approximately 7.58 h·ng / mL to approximately 31.3 h·ng / mL per 1 mg of compound A after a single administration to a human subject, administered orally twice daily. The pharmaceutical composition further preferably has the following 1-day dose: an amount that achieves an average AUC (0-12 h) of approximately 7.58 h·ng / mL to approximately 19.9 h·ng / mL per 1 mg of compound A after a single administration to a human subject, administered orally twice daily.

[0084] In this embodiment, the preferred daily dose of the pharmaceutical product or pharmaceutical composition is the following: twice daily orally, at a dose that achieves an average Cmax of approximately 2.79 ng / ml to approximately 11.3 ng / ml per 1 mg of compound A after a single administration to a human subject. A further preferred daily dose of the pharmaceutical composition is the following: twice daily orally, at a dose that achieves an average Cmax of approximately 2.79 ng / ml to approximately 5.54 ng / ml per 1 mg of compound A after a single administration to a human subject.

[0085] Furthermore, regarding the ranges of the aforementioned mean Cmax, mean AUC (0-12 h), and AUC (0-tau), ss, the significant digits are set to 3, with the fourth digit rounded off. Additionally, pharmacokinetic parameters are generally roughly proportional to the dose, exhibiting linearity. For example, the upper limit can be estimated based on the values ​​of 120 mg BID or 100 mg BID obtained in the examples, or by calculating the value of 1 mg of compound A, thus estimating the value of 150 mg BID. Furthermore, the minimum or maximum value obtained from individual data at the same dose can be considered as the lower or maximum limit of each range, and the range can be set based on this value.

[0086] The pharmaceuticals, pharmaceutical compositions, or oral preparations of this embodiment can also be used in combination with a 5-HT3 receptor antagonist. When the aforementioned pharmaceutical compositions or oral preparations are administered, patients may sometimes experience gastrointestinal symptoms. Here, in this embodiment, nausea and vomiting are preferred gastrointestinal symptoms. The gastrointestinal symptoms accompanying the administration of the pharmaceutical compositions or oral preparations of this embodiment, i.e., nausea or vomiting, can be suppressed by administering a 5-HT3 receptor antagonist, but are difficult to suppress with other antiemetics.

[0087] Furthermore, in cases where patients who have been given a medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof experience gastrointestinal symptoms, administration of a 5-HT3 receptor antagonist is permissible. The medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof may be administered simultaneously or separately from the 5-HT3 receptor antagonist. The medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof may also be a kit containing an additional 5-HT3 receptor antagonist. Here, "administered together with a 5-HT3 receptor antagonist" or "administered in combination with a 5-HT3 receptor antagonist" means that the medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof may be administered simultaneously or separately from the 5-HT3 receptor antagonist. That is, the 5-HT3 receptor antagonist can be administered after a patient who has been given a pharmaceutical composition or oral formulation containing compound A or a pharmaceutically acceptable salt thereof develops gastrointestinal symptoms associated with the administration of the pharmaceutical composition or oral formulation of this embodiment, or it can be administered prophylactically before or at the same time as the administration of the aforementioned pharmaceutical composition or oral formulation.

[0088] More specifically, in this invention, "simultaneous administration" in "simultaneous or separate administration" means that two subjects in a combined administration are administered simultaneously (at the same time), or substantially simultaneously (at the same time), via the same administration pathway, and simultaneously, or substantially simultaneously, via different administration pathways. Here, "simultaneous administration" also includes the case where two subjects are given a single formulation. Additionally, in this invention, "separate administration" in "simultaneous or separate administration" means that two subjects in a combined administration are administered sequentially (at different times), via the same or different administration pathways. More specifically, it refers to a method of administration where one of the two subjects in a combined administration begins administration of the other after administration has concluded. "Separate administration" also includes cases where the administration frequency or duration differs in the administration plans for the two subjects.

[0089] 5-HT3 receptor antagonists are compounds that antagonize 5-HT3 receptors with serotonin (5-HT: 5-hydroxytryptamine) as a ligand. Examples of 5-HT3 receptor antagonists used with the pharmaceuticals, pharmaceutical compositions, or oral formulations of this embodiment include 5-HT3 receptor antagonist antiemetics. Examples of 5-HT3 receptor antagonist antiemetics include azasetron hydrochloride, ondansetron hydrochloride hydrate, granisetron hydrochloride, palonosetron hydrochloride, dorastron, ramosetron hydrochloride, and tropisetron hydrochloride. Examples of 5-HT3 receptor antagonists used with the pharmaceutical compositions or oral formulations of this embodiment include azasetron, ondansetron, indisetron, ramosetron, granosetron, and palonosetron, or pharmaceutically acceptable salts thereof. In another embodiment, the 5-HT3 receptor antagonist is preferably ondansetron hydrochloride hydrate, ramosetron hydrochloride, granisetron hydrochloride, or palonosetron hydrochloride, with ramosetron hydrochloride or granisetron hydrochloride being more preferred. In some embodiments, the 5-HT3 receptor antagonist is, for example, ondansetron hydrochloride hydrate. In other embodiments, the 5-HT3 receptor antagonist is, for example, ramosetron hydrochloride or granisetron hydrochloride. In still other embodiments, the 5-HT3 receptor antagonist is, for example, palonosetron hydrochloride.

[0090] Ondansetron hydrochloride dihydrate (CAS registration number: 103639-04-9) is a non-proprietary name, and is a compound with the following structural formula, chemically named (±)-2,3-dihydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]carbazol-4(1H)-one monohydrochloride dihydrate. [Chemistry 11]

[0091] Granisetron hydrochloride (CAS Registry Number: 107007-99-8) is a non-proprietary name and is a compound with the following structural formula, chemically named 1-methyl-N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide hydrochloride. [Chemistry 12]

[0092] Ramosetron hydrochloride (CAS Registry Number: 132907-72-3) is a non-proprietary name and is a compound with the following structural formula, chemically named (-)-(R)-5-[(1-methyl-3-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride. [Chemistry 13]

[0093] Palonosetron hydrochloride (CAS Registry Number: 135729-62-3) is a non-proprietary name and is a compound with the following structural formula, chemically named (3aS)-2-[(3S)-quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one monohydrochloride. [Chemistry 14]

[0094] This embodiment also has the following form: a solid tumor (solid carcinoma). The treatment methods include administering a medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient to a human subject.

[0095] Another embodiment of the present invention is a method for suppressing digestive symptoms associated with administration of compound A or a pharmaceutically acceptable salt thereof, comprising administering a 5-HT3 receptor antagonist to a patient exhibiting digestive symptoms associated with administration of a medicine, pharmaceutical composition or oral preparation containing compound A or a pharmaceutically acceptable salt thereof.

[0096] Another embodiment of the present invention is a method for treating solid tumors, comprising: administering compound A or a pharmaceutically acceptable salt thereof to a human subject with a solid tumor at a dosage of about 10 mg to about 150 mg of compound A twice daily; and co-administering said human subject a 5-HT3 receptor antagonist in an effective amount for suppressing gastrointestinal symptoms. The gastrointestinal symptoms are caused by the administration of compound A or a pharmaceutically acceptable salt thereof to the human subject.

[0097] When human subjects experience gastrointestinal symptoms such as nausea or vomiting after administration of a medicine, pharmaceutical composition, or oral preparation containing compound A or a pharmaceutically acceptable salt thereof, administration of a 5-HT3 receptor antagonist can suppress these gastrointestinal symptoms. Here, "suppress" means to partially or completely relieve, restore, reduce, inhibit, decrease the severity of, and / or reduce the incidence of gastrointestinal symptoms.

[0098] 5-HT3 receptor antagonists can be administered orally or non-orally. Examples of dosage forms for 5-HT3 receptor antagonists include tablets, powders, granules, syrups, capsules, and oral liquids. Examples of dosage forms for non-oral administration of 5-HT3 receptor antagonists include injections, drops, suspensions, dressings, lotions, nebulizers, and plasters; in one embodiment, it is an injection or drop. The 5-HT3 receptor antagonist of this invention can be formulated using methods described in the 18th revised edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopeia (USP), or the European Pharmacopoeia (EP).

[0099] The dosage of the 5-HT3 receptor antagonist, on a daily basis, is approximately 0.1 mg to approximately 100 mg. In some embodiments, the dosage of the 5-HT3 receptor antagonist, on a daily basis, is approximately 0.1 mg to approximately 16 mg. In some embodiments, the dosage is approximately 0.3 mg to approximately 8 mg. The dosage varies depending on the age and severity of the symptoms of the subject. In the case of commercially available medical pharmaceutical products, by administering them according to the usage / dosage described in their accompanying documentation, it is possible to more reliably suppress gastrointestinal symptoms accompanying the administration of the pharmaceutical composition or oral formulation of the present invention.

[0100] When administering ondansetron hydrochloride hydrate as a 5-HT3 receptor antagonist, it may be administered orally or intravenously, for example, at a dose of approximately 4 mg once daily. Alternatively, when administering ondansetron hydrochloride hydrate, it may be administered orally, for example, at a dose of approximately 24 mg once daily, or approximately 8 mg twice daily. Other embodiments include intravenous administration, for example, at a dose of approximately 8 mg, or approximately 0.15 mg / kg. Furthermore, the dosage may be adjusted appropriately based on the subject's age, symptoms, etc. Additionally, if the effect is insufficient, an additional dose of the same amount may be administered.

[0101] When granisetron hydrochloride is administered as a 5-HT3 receptor antagonist, it may be given as an intravenous injection or intravenous drip of approximately 40 μg / kg of granisetron once daily. In another embodiment, granisetron hydrochloride may be administered intravenously, for example, at a dose of approximately 1 mg or approximately 0.01 mg / kg of granisetron. Furthermore, if symptoms do not improve, an additional dose of approximately 40 μg / kg may be given, but this may be adjusted according to age and symptoms. When granisetron hydrochloride is administered as a 5-HT3 receptor antagonist, it may be given orally, for example, at a dose of approximately 2 mg once daily or approximately 1 mg twice daily. As another embodiment, granisetron hydrochloride may be administered, for example, via a patch (transdermal absorption system) containing approximately 34.3 mg of granisetron in an area of ​​approximately 52 cm². The dosage may be adjusted according to age and symptoms.

[0102] When ramusetron hydrochloride is used as a 5-HT3 receptor antagonist, for example, approximately 0.3 mg (calculated as ramusetron hydrochloride) can be administered intravenously once daily. The dosage may be adjusted according to age and symptoms. If the effect is insufficient, additional doses of the same amount may be administered, but the daily dose should not exceed approximately 0.6 mg. When ramusetron hydrochloride is used as a 5-HT3 receptor antagonist, for example, it can be administered orally once daily at a dose of approximately 0.1 mg (calculated as ramusetron). The dosage may be adjusted according to age and symptoms.

[0103] When palonosetron hydrochloride is administered as a 5-HT3 receptor antagonist, approximately 0.75 mg of palonosetron can be administered intravenously once daily, or approximately 0.5 mg orally. In another embodiment, approximately 0.25 mg of palonosetron hydrochloride can be administered intravenously or orally. The dosage may be adjusted according to age and symptoms.

[0104] When used as a 5-HT3 receptor antagonist, dorastron mesylate can be administered orally once daily at a dose of approximately 1.8 mg / kg or approximately 100 mg. The dosage may be adjusted according to age and symptoms.

[0105] When tropisetron hydrochloride is used as a 5-HT3 receptor antagonist, it can be administered orally or intravenously at a dose of approximately 5 mg (calculated as tropisetron). The dosage may be adjusted according to age and symptoms.

[0106] This embodiment provides a pharmaceutical composition for the treatment of solid tumors, comprising compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered to human subjects in combination with an amount of 5-HT3 receptor antagonist that inhibits gastrointestinal symptoms, wherein the gastrointestinal symptoms are associated with the administration of compound A or a pharmaceutically acceptable salt thereof to the human subjects.

[0107] In one particular embodiment, a pharmaceutical composition for the treatment of solid tumors is provided, comprising compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered to a human subject in combination with an amount of a 5-HT3 receptor antagonist for the suppression of gastrointestinal symptoms, wherein the gastrointestinal symptoms are associated with the administration of compound A or a pharmaceutically acceptable salt thereof to the human subject, selected from at least one of nausea and vomiting. Here, "the amount for suppressing gastrointestinal symptoms" can be, for example, an amount of about 0.1 mg to about 100 mg per day. Furthermore, "the 5-HT3 receptor antagonist" here can be, for example, at least one selected from ondansetron hydrochloride hydrate, ramosetron hydrochloride, and granisetron hydrochloride.

[0108] In a particular implementation, the "amount of 5-HT3 receptor antagonist that inhibits digestive symptoms" may include, for example, (a) a dose of ondansetron hydrochloride of about 4 mg once a day, calculated as ondansetron; (b) a dose of granisetron hydrochloride of about 2 mg once a day, calculated as granisetron; or (c) a dose of ramosetron hydrochloride of about 0.1 mg once a day, calculated as ramosetron.

[0109] As another embodiment, a pharmaceutical composition for the treatment of solid tumors is provided, comprising compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of approximately 120 mg of compound A each time, in combination with ondansetron hydrochloride hydrate administered once daily at a dose of approximately 4 mg of ondansetron, wherein the gastrointestinal symptoms are accompanied by administration of compound A or a pharmaceutically acceptable salt thereof to human subjects at least one selected from nausea and vomiting.

[0110] As another embodiment, a pharmaceutical composition for the treatment of solid tumors is provided, comprising compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered to human subjects in combination with granisetron hydrochloride at a dose of about 120 mg of compound A twice daily, and a dose of about 2 mg of granisetron once daily, wherein the gastrointestinal symptoms are accompanied by administration of compound A or a pharmaceutically acceptable salt thereof to human subjects at least one selected from nausea and vomiting.

[0111] As another embodiment, a pharmaceutical composition for the treatment of solid tumors is provided, comprising compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is administered to human subjects in combination with ramusetron hydrochloride at a dose of about 120 mg of compound A twice daily, and at a dose of about 0.1 mg of ramusetron once daily, wherein the gastrointestinal symptoms are accompanied by administration of compound A or a pharmaceutically acceptable salt thereof to human subjects at least one selected from nausea and vomiting. [Example] [ ]

[0112] This study was conducted as a non-blinded Phase 1 clinical trial of compound A. The study consisted of a dose-escalation portion evaluating the safety and tolerability of compound A, and an extended portion evaluating the safety, tolerability, and pre-efficacy of compound A. The doses in the examples are expressed as doses of compound A in its free form.

[0113] 1. Clinical trial drugs Tablets containing compound A were used as clinical trial drugs. Compound A was synthesized according to the method disclosed in International Publication No. 2016 / 208576.

[0114] 2. Invest in subjects Subjects who meet all of the following selection criteria (1) to (15) and do not meet any of the exclusion criteria (1) to (17) will be administered compound A. [Selection of Criteria] (1) Patients diagnosed with solid carcinoma on histological or cytological basis who meet the following criteria. • Dosage escalation portion: Patients with solid tumors, including colorectal cancer, that have progressed, become unresectable, or recurrent without standard treatment or other effective treatment. • Extended scope: Patients with colorectal cancer who have progressed on third-line therapy or subsequent treatments, or those with unresectable or recurrent colorectal cancer, or patients with small bowel cancer or gastrointestinal neuroendocrine tumors who have received at least one systemic anticancer therapy regimen after discussions and agreement with clinical trial sponsors. (2) Dosage escalation: Colorectal cancer patients must undergo a biopsy and submit a preserved tumor sample (if it has already been preserved). Extended Section: Patients with lesions suitable for biopsy must undergo a biopsy. Patients with lesions unsuitable for biopsy may be enrolled without a biopsy after reaching an agreement with the clinical trial sponsor. Preserved tumor specimens must be submitted (if already preserved). (3) It is expected to survive for more than 12 weeks after administration of compound A. (4) ECOG-PS is 0~1 (5) • Dosage escalation: Consent must be obtained from Japanese individuals aged 20 and above. • Extended section: Consent was obtained for patients aged 20 and older. (6) Patients whose adverse events caused by pre-treatment for cancer (excluding hair loss and grade 2 peripheral neuropathy) have recovered to grade 0-1 (with kidney / bone marrow / liver function meeting the selection criteria). (7) Patients who underwent pretreatment prior to compound A administration and subsequently experienced the following periods a) Patients who have undergone chemotherapy and radiotherapy for more than 3 weeks b) Patients who have received antibody treatment for more than 4 weeks c) Patients who have used clinical trial drugs or clinical trial medical devices for more than 4 weeks. d) Patients who have received blood transfusions, platelet transfusions, or G-CSF preparations for more than 2 weeks. (8) Having adequate renal function (i.e., serum creatinine < 2.0 mg / dL, or creatinine clearance ≥ 40 mL / min based on the Cockcroft-Gault method) (9) Possessing adequate bone marrow function (i.e., neutrophil count ≥ 1500 / mm3, platelet count ≥ 100000 / mm3, and hemoglobin ≥ 9.0 g / dL). (10) Adequate liver function (i.e., as coagulation capacity, International Standard Ratio (INR) ≤ 1.5, total bilirubin ≤ 1.5 × Upper Limit of Reference (ULN), and alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) ≤ 3 × ULN (if liver metastasis is present, ≤ 5 × ULN)). (11) Possessing adequate serum inorganic matter (i.e., calcium (albumin correction): within the baseline range, corrected calcium concentration (mg / dL) = measured calcium concentration (mg / dL) + 4 - serum albumin concentration (g / dL), potassium concentration above the lower limit of the baseline, and magnesium concentration above the lower limit of the baseline). (12) Patients who are able to consent to the clinical trial implementation plan (13) Patients with at least one lesion that can be measured in RECIST 1.1 (14) When 25-hydroxyvitamin D is less than 10 ng / mL, patients who agree to continue taking vitamin D should do so according to the guidelines of each medical institution or the clinical judgment of the attending physician or clinical trial assistant. (15) Dosage escalation portion: Patients who consent to skin tissue biopsy outside the tumor Extended section: Patients with at least 5 patients who consented to skin tissue biopsies other than tumors at each dose.

[0115] [Exclusion Criteria] Participants who meet any of the following criteria will be excluded from this clinical trial. (1) Patients with any of the following heart conditions • Patients with heart failure classified as grade II or higher by the New York Heart Association (NYHA). • Patients with unstable ischemic heart disease (myocardial infarction within 6 months prior to starting compound A administration, or angina requiring nitrates more than twice a week) • Patients with QT interval prolongation (QTcF > 480 msec) are observed. • Patients with a left ventricular ejection ratio (LVEF) < 50% (2) Compound A was administered to patients who had undergone major surgery within the previous 21 days. (3) Patients who have been found to have no tolerance to compound A or the excipient. (4) Patients diagnosed as HIV positive (5) Patients with active infections who are determined to require systemic treatment (6) Patients with meningeal carcinoma (7) Patients who have taken the following medications • Patients who have ingested potent cytochrome P450 (CYP)3A or drugs or supplements that act as CYP3A receptors with a narrow therapeutic area within 4 weeks prior to the start of compound A administration. • Patients who have ingested drugs or foods that strongly inhibit CYP3A within two weeks prior to the administration of compound A. (8) Patients who have received systemic or topical steroid-based immunosuppressive therapy (prednisone more than 10 mg / day or equivalent) within 2 weeks prior to the start of compound A administration, or patients who are scheduled to receive such therapy. (9) Patients with brain or subdural metastases. This excludes patients who discontinued corticosteroids after completing local treatment 4 weeks prior to starting Compound A. Signs (e.g., on radiographic examination) or symptoms must be stable 4 weeks prior to starting Compound A. (10) Patients with pulmonary lymphangiopathy who are in a state of respiratory failure and require active treatment (including oxygen therapy). (11) Patients who are unable to take compound A orally, show signs of malabsorption in the gastrointestinal tract, or have other physical conditions (nausea, diarrhea, vomiting, etc.) that the attending physician or clinical trial assistant determines may affect the absorption of compound A. (12) Patients who meet the following bone diseases or bone conditions • Osteoporosis with a T score less than -2.5 based on DXA scan • Fasting serum β-CTX > 1000 pg / mL · Osteopathy • Determining the need for bisphosphonate treatment for hypercalcemia • A history of fracture within 6 months prior to the administration of compound A. • Condition requiring surgical treatment • Not treated with bisphosphonates or denosumab for bone metastases (except for lesions that have undergone radiation therapy). (13) All states that the attending physician or clinical trial assistant judges to have an impact on the evaluation of the trial. (14) Compound A is administered to patients with active malignant tumors within 24 months prior to the start of treatment (excluding primary disease, fully treated non-invasive melanoma, basal cell carcinoma / squamous cell carcinoma of the skin, non-invasive cervical cancer / bladder cancer and early gastric / colorectal cancer). (15) Female patients who are breastfeeding or pregnant at screening or baseline (patients with a positive urine test for human chorionic gonadotropin [hCG] or human chorionic gonadotropin β subunit [β-hCG]). Eligibility for participation is determined if a breastfeeding patient will discontinue breastfeeding at the time of participation in the clinical trial. Even if the screening result is negative, a repeat test is required if the administration of compound A was not performed within 7 days prior to the start of the trial. (16) Patients who are of reproductive age and who, along with their partners, do not agree to use medically appropriate contraception for up to 90 days for men and up to 30 days for women during the trial and after the administration of compound A (Note) (17) Patients with a history of administration of compound A

[0116] 3. Methods In the dose-reduction phase, a 3+3 design was used to evaluate the safety and tolerability of compound A at multiple doses. The starting dose of compound A was set at 10 mg BID (twice a day).

[0117] The extended section evaluates the further safety, tolerability, and pre-efficacy of compound A. This extended section investigates doses deemed tolerable based on the dose-escalation results or optimal doses based on PK or PD analysis.

[0118] [Definition of DLT] DLT refers to adverse events considered causally related to compound A, occurring during cycle 1 (28 days). Severity was assessed using NCI CTCAE v5.0. (a) Blood toxicity • Grade 4 neutropenia that persists for more than 8 days despite appropriate treatment, including G-CSF administration. • Grade 3-4 febrile neutropenia Grade 4 thrombocytopenia • Grade 3 thrombocytopenia with bleeding lasting more than 8 days or requiring platelet transfusion. Grade 4 anemia • Events requiring red blood cell transfusion in grade 3 anemia (b) Non-hemotoxicity Events of level 4 or higher • Clinically significant grade 3 events (excluding diarrhea, nausea, and vomiting that recover to grade 0-1 within 7 days with appropriate treatment) Grade 3 osteoporosis • Grade 2 or higher fragility fractures, occurring without a history of trauma or caused by falls from a height below the victim's own height. • The increase in fasting serum C-terminal peptide-β isomer (β-CTX) of type I collagen was greater than 2-fold from baseline, with a value exceeding 1000 pg / mL, and despite administration of bisphosphonates or denosumab, no return to baseline was confirmed within 4 weeks. • Clinically significant grade 3-4 abnormal clinical test values • When the attending physician or clinical trial assistant determines that compound A has no tolerability, and administration or withdrawal of compound A is suspended for more than 8 days.

[0119] The background of the subjects administered the medication is shown in Table 1. The majority of subjects (82.1%) had an ECOG (Eastern Cooperative Oncology Group) performance status of 0. This also included subjects with variants in NRAS, KRAS, APC, and CTNNB1. Furthermore, Table 1 does not include the background of subjects who received compound A at a dosage of 120 mg BID. [Table 1] [characteristic] [total] [(] [N = 28] [)] [Median age, years (range)] 59.5(36,77) [gender,] [n] [(] [%] [)] male 17(60.7) female 11(39.3) ECOG-PS,n(%) 0 23(82.1) 1 5 (17.9) [Median weight] [kg] [(scope)] 60.85 (42.2, 89.9) [Tumor type,] [n] [(] [%] [)] Colorectal cancer 16 (57.1) Endometrial cancer 2(7.1) Gastric cancer 1(3.6) Hepatocellular carcinoma 1(3.6) Pancreatic cancer 2(7.1) Small bowel carcinoma 2(7.1) other 4(14.3) [Number of systemic anticancer pretreatment treatments] [n] [(] [%] [)] 0 3(10.7) 1 0 2 1(3.6) 3 2(7.1) >=4 22(78.6) [NRAS] [mutation,] [n] [(] [%] [)] Yes / No / Unknown 1(3.6) / 7(25.0) / 20(71.4) [KRAS] [mutation,] [n] [(] [%] [)] Yes / No / Unknown 7(25.0) / 5(17.9) / 16(57.1) [APC] [mutation,] [n] [(] [%] [)] Yes / No / Unknown 10(35.7) / 1(3.6) / 17(60.7) [CTNNB1] [mutation,] [n] [(] [%] [)] Yes / No / Unknown 2(7.1) / 0 / 26(9.3)

[0120] Based on Table 2, the dosage of compound A was increased or decreased based on the initial results of 10 mg BID. [Table 2] Number of patients exhibiting DLT response 0 people Three participants were enrolled in the 15 mg BID group to continue the trial. 1 person Three additional participants were added to the 10 mg BID group to continue the trial. 2 or more people Reduce the dose to 5 mg BID and continue the trial.

[0121] Based on the results of the additional 10 mg BID in Table 3, the dosage of compound A was further increased or decreased. [Table 3] Number of patients exhibiting DLT response 0 people (Less than 1 of the 6 cases) The patient was deemed to have tolerance to the 10 mg BID dose. Three participants were enrolled in the 15 mg BID group to continue the trial. 1 person (Two out of all six cases) The presence or absence of tolerance to compound A will be determined through consultation among the clinical trial sponsor, the attending physician, medical experts, and efficacy and safety evaluation consultants. 2 or more people (More than 3 of the 6 cases) Reduce the dose to 5 mg BID and continue the trial.

[0122] For doses higher than 20 mg BID, determine the next dose based on Table 4. [Table 4] Adverse events causally related to compound A observed in period 1 Incremental dose of the next dose (%) Level 1 or below 100% One case showed level 2*1*2 40~60% Two or more cases showed grade 2*1*2 or one or more cases showed grade 3*2 or higher. 25~39% *1 Excludes hair loss, nausea or vomiting that can be controlled by antiemetics, and abnormal clinical test values ​​that are not clinically problematic based on the judgment of the attending physician or clinical trial assistant. *2 Grade 2, 3 or higher adverse events (excluding DLT)

[0123] The above procedure was repeated, with the dosage gradually increased. Furthermore, since the results of the test on the 10 mg BID indicated tolerability, no test was conducted on the 5 mg BID.

[0124] 4.Investment method 〔Preliminary investment〕 Prior to administration, consent was obtained from the subjects, and screening to confirm suitability and baseline assessment to confirm disease status were conducted. After screening, patients who met all selection criteria and did not conflict with exclusion criteria were registered as subjects. Baseline assessment was conducted from 3 days before compound A administration until just before administration, proceeding to the administration period after confirming disease status.

[0125] [Investment Period] During the administration period, each cycle is 28 days. Compound A (an oral formulation containing Compound A) is administered to the subjects. Subjects continue to receive Compound A until disease progression occurs, intolerance is observed, the subject wishes to discontinue, consent is withdrawn, or the clinical trial sponsor terminates the clinical trial. Each 28-day cycle is defined as a single period; designations such as "C1D28" indicate the number of cycles and the number of days within that cycle. For example, "C1D28" refers to day 28 of cycle 1. Subjects are hospitalized until C1D28. Examinations and assessments are conducted at C1D15. Based on the results, discharge is permitted if the attending physician or clinical trial assistant determines there are no medical problems. Furthermore, if administration continues after the examinations and assessments at C2D1, written consent for continuation must be obtained before administration at C2D1.

[0126] Use tablets containing compound A as compound A, administered orally twice daily (BID). Fast for 2 hours before and 1 hour after administration. Take the tablets with water, preferably at the prescribed time, but if this is difficult, wait at least 8 hours after the last administration.

[0127] 5. Evaluation (1) Pharmacokinetics In the dose escalation phase, blood samples were collected from the subjects according to the schedule described in Table 5 to evaluate the pharmacokinetics of compound A. In the extension phase, blood samples were collected from the subjects before the first administration in C1D1 and C1D8, 0.5, 1, and 2 hours after oral administration of compound A, and before the first administration in C2D1 to evaluate the pharmacokinetics of compound A. Data for C1D1 (day 1 of cycle 1) correspond to the results of a single administration, and data for C1D8 (day 8 of cycle 1) correspond to the results of repeated administration at twice-daily doses for 8 days. [Table 5] Blood collection day blood collection point Before the first administration of Compound A 0.25 hours after the first administration of compound A 0.5 hours after the first administration of compound A One hour after the first administration of compound A Two hours after the first administration of compound A Four hours after the first administration of compound A Six hours after the first administration of compound A Eight hours after the first administration of compound A 12 hours after the first administration of compound A C1D8 Before the first administration of Compound A 0.25 hours after the first administration of compound A 0.5 hours after the first administration of compound A One hour after the first administration of compound A Two hours after the first administration of compound A Four hours after the first administration of compound A Six hours after the first administration of compound A Eight hours after the first administration of compound A 12 hours after the first administration of compound A C2D1 Before the first administration of Compound A C3D1 Before the first administration of Compound A C4D1 Before the first administration of Compound A C5D1 Before the first administration of Compound A C6D1 Before the first administration of Compound A

[0128] The pharmacokinetic parameters at each dose in the dose escalation section are shown in Tables 6 and 7. [Table 6] [dose,] [mg BID] [(] [n] [)] [C1D1] [C, max , ] [(] [ng / mL] [)] [t, max , ] [(] [h] [)] [AUC] [, ( , ] [, 0-12 h , ] [, ) , ] [(] [h*ng / mL] [)] [10 mg] [(] [n = 3] [)] 37.2 (42.6) 2.00 (0.25-2.00) 131 (39.7) [15 mg] [(] [n = 4] [)] 135 (28.9) 0.75 (0.50-2.00) 310 (42.5) [20 mg] [(] [n = 3] [)] 146 (209) 1.00 (0.50-2.00) 501 (76.8) [30 mg] [(] [n = 3] [)] 105 (17.7) 2.00 (2.00-2.00) 349 (55.5) [45 mg] [(] [n = 4] [)] 209 (201) 1.00 (1.00-2.00) 865 (109) [80 mg] [(] [n = 3] [)] 279 (251) 2.00 758 (1.00-2.00) (182) [100 mg] [(] [n = 6] [)] 443 (93.9) 0.50 (0.25-4.00) 1420 (70.5)

[0120] [mg] [(] [n = 3] [)] 557 (72.2) 2.00 (0.50-12.0) 1910 (7.40) [160 mg] [(] [n = 2] [)] 481,1750 0.50, 1.00 2510,8060 [Table 7] [Dosage] [mg BID] [(] [n] [)] [C1D8] [ ] [C, max,ss , ] [(] [ng / mL] [)] [t, max,ss , ] [(] [h] [)] [AUC] [, ( , ] [, 0-tau , ] [, ) , ] [, ,ss , ] [(] [h*ng / mL] [)] [Rac] [(] [AUC] [)] [Rac] [(] [C, max , ] [)] [efficient] [t] [, ½ , ] [(] [h] [)] [10 mg] [(] [n = 3] [)] 53.9 (272) 2.00 (1.00-2.00) 210 (168) 1.60 (113) 1.45 (178) 9.03-27.9b [15 mg] [(] [n = 4] [)] 159 (38.1) 0.75 (0.50-2.00) 504 (34.3) 1.62 (52.6) 1.17 (67.3) 7.10 (118) [20 mg] [(] [n = 3] [)] 278 (161) 0.50 (0.50-1.00) 866 (96.6) 1.73 (58.6) 1.90 (36.5) 12.2-18.0b [30 mg] [(] [n = 3] [)] 68.3 (31.9) 2.00 (0.50-4.00) 396 (41.2) 1.13 (20.6) 0.653 (14.4) 3.27-6.81b [45 mg] [(] [n = 4] [)] 199 (124) 3.00 (1.00-4.00) 1070 (69.6) 1.24 (37.0) 0.95 (63.3) 6.59 (56.3)c [80 mg] [(] [n = 3] [)] 737 (59.1) 1.00 (0.50-1.00) 2100 (51.8) 2.79 (85.6) 2.64 (106) 17.4 (120)

[0100] [mg] [(] [n = 6] [)] 862 (115) 1.00 (0.50-1.00) 2700a (127) 2.18a (41.3) 2.13a (50.6) 13.0 (61.1) [120 mg] [(] [n = 3] [)] 737 (9.04) 1.00 (1.00-2.00) 2460 (10.7) 1.28 (3.33) 1.32 (61.1) 5.49 (7.98) [160 mg] [(] [n = 2] [)] 2980,3850 1.00, 1.00 9060,21300 2.64, 3.60 2.20, 6.20 17.5, 25.6 a is based on 5 patients, b is based on 2 patients, and c is based on 3 patients. tmax is reported as the median (range). All other values ​​are reported as the geometric mean (%CV). Parameters for two patients are reported for both patients.

[0129] It can be generally observed that the exposure level tends to increase with the increase of the dosage of compound A, but the values ​​are not perfect.

[0130] (2) Tolerance Tolerability analyses were performed using a dose-escalation analysis (DLT) group of subjects (the group of subjects who received the investigational drug as pre-determined in period 1 of the dose escalation phase, and the group whose adherence to the DLT was confirmed regardless of whether compound A was administered) and other safety analyses were performed using a safety analysis group of subjects (the group of subjects who received the investigational drug more than once; this is the group of subjects analyzed for all safety assessments (excluding DLT assessments)).

[0131] Based on the actual treatment administered, general statistics regarding safety data were calculated (number, mean, standard deviation, median, minimum, and maximum for continuous variables; number and ratio for categorical variables). Safety evaluation included adverse events, clinical examination values, vital signs (dilatational blood pressure, systolic blood pressure, pulse rate, respiratory rate, and change in body temperature from baseline), the ratio of subjects with at least one confirmed QTcF abnormality after compound A administration based on 12-lead electrocardiogram, echocardiography or MUGA scan, T-score based on DXA scan bone mineral density, and ECOG-PS assessment. As clinical examination values, the following tests are performed: hematological tests (red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, white blood cell components (neutrophils, lymphocytes, monocytes, eosinophils, basophils), coagulation tests (INR), blood biochemistry tests (liver function tests (AST, ALT, ALP, GGT, total bilirubin, direct bilirubin), kidney function tests (BUN, creatinine), other tests (blood glucose, albumin, cholesterol, LDH, total protein, uric acid, amylase, lipase, Na, K, Cl, Ca, phosphorus, Mg), viral tests (HBs antigen a, HBs antibody a, HBc antibody a, HCV antibody a, HIV antibody a, HBV DNA b, β-CTX c, 25-hydroxyvitamin D d), and urine tests (pH, protein, glucose, ketones, occult blood, specific gravity)).

[0132] The side effects observed after administration of compound A, i.e., treatment-emergent adverse events (TEAEs) causally related to compound A, are shown in Tables 8 and 9. In the tables, the values ​​in parentheses represent the percentage of subjects who observed adverse events relative to all 28 subjects recorded in Table 1. It is evident that nausea and vomiting were observed at high rates at all dosages ranging from 10 mg BID to 160 mg BID. Furthermore, Tables 8 and 9 do not include data from subjects administered at the 120 mg BID dosage. [Table 8] [Table 9]

[0133] 6. Inhibit adverse events (nausea or vomiting) causally related to compound A. In the tolerability evaluation, methods for suppressing nausea or vomiting, which were repeatedly observed as adverse events during cycle 1 and accompanied by administration of compound A, were investigated. The study examined the effects of administering various antiemetics to subjects who observed gastrointestinal symptoms such as nausea or vomiting, investigating whether these medications could suppress the occurrence of nausea or vomiting. Domperidone (a 5-HT1A receptor antagonist, Nauzelin tablets), metoclopramide (a peripheral D2 receptor antagonist, metoclopramide tablets), ramosetron hydrochloride (a 5-HT3 receptor antagonist, Nessia tablets), and granisetron (a 5-HT3 receptor antagonist, Ketterex tablets) were used as antiemetics.

[0134] Twenty participants who complained of vomiting during period 1 were given antiemetics as needed. Two participants experienced improvement with propranolol or metoclopramide (antiemetics other than 5-HT3 receptor antagonists). However, four participants did not experience improvement even with domperidone, metoclopramide, or propranolol (antiemetics other than 5-HT3 receptor antagonists); improvement was subsequently achieved by switching the antiemetic to ramosetron or granisetron (5-HT3 receptor antagonists). Twelve participants experienced suppression of vomiting with ramosetron or granisetron (5-HT3 receptor antagonists). Of these twelve, two were given granisetron at the onset of nausea to prevent vomiting, and vomiting was successfully prevented. However, two subjects who received compound A at a dose of 160 mg BID failed to suppress vomiting even when given ramosetron or granisetron (5-HT3 receptor antagonists).

[0135] The highest AUC (0-tau), ss at time C1D8 for subjects whose vomiting was successfully suppressed by administration of a 5-HT3 receptor antagonist was 7640 h·ng / mL. The lowest AUC (0-tau), ss at time C1D8 for subjects whose vomiting was not suppressed even by administration of a 5-HT3 receptor antagonist was 9060 h·ng / mL.

[0136] When the AUC (0-tau) and ss at C1D8 are below 7640 h·ng / mL, it is predicted that administration of a 5-HT3 receptor antagonist can suppress gastrointestinal symptoms associated with the administration of compound A or its pharmaceutically acceptable salts. If the AUC (0-tau) and ss at C1D8 are above 9060 h·ng / mL, it is predicted that even administration of a 5-HT3 receptor antagonist will not suppress gastrointestinal symptoms, i.e., nausea or vomiting, associated with the administration of compound A or its pharmaceutically acceptable salts. That is, it is known that even with a 160 mg BID, it is very likely that administration of a 5-HT3 receptor antagonist will not suppress gastrointestinal symptoms associated with the administration of compound A or its pharmaceutically acceptable salts. Therefore, the recommended dose is determined to be less than 160 mg BID. The recommended dose is considered to be from about 80 mg to about 120 mg, especially preferably 100 mg BID or 120 mg BID.

[0137] Figures 1 and 2 are graphs showing the relationship between Cmax (Cmax, ss) or AUC (AUC(0-tau), ss) and vomiting flags for each subject at time point C1D8. Vomiting flags are listed in Table 10. For example, vomiting flag 3 refers to an example where vomiting was initially suppressed by an antiemetic other than a 5-HT3 receptor antagonist, but was successfully suppressed when the 5-HT3 receptor antagonist was switched to. [Table 10] Vomiting flag N state 0 10 No nausea or vomiting, or no need to administer antiemetics. 1 2 Vomiting can be suppressed with antiemetics other than 5-HT3 receptor antagonists. 2 12 Vomiting can be suppressed with 5-HT3 receptor antagonists 3 4 Vomiting cannot be suppressed with antiemetics other than 5-HT3 receptor antagonists, but vomiting can be suppressed with 5-HT3 receptor antagonists. 4 2 Vomiting cannot be suppressed with 5-HT3 receptor antagonists

[0138] 7. Pharmacokinetics of additional cases in the dose escalation phase Five additional subjects were given 120 mg BID. Pharmacokinetic parameters for the 120 mg BID, including the three patients previously shown in Table 7, are presented in Tables 11 and 12. [Table 11] Dosage, mg bid, (Subject #) C1D1 Cmax (ng / mL) tmax (h) AUC(0-12 h) (h*ng / mL) 120 mg (n = 8) 557 (72.2) 2.00 (0.50-12.0) 1910 (7.40) [Table 12] Dosage, mg BID (n) C1D8 Cmax,ss (ng / mL) tmax,ss (h) AUC(0-tau), ss (h*ng / mL) Rac(AUC) Rac(Cmax) Effective t½(h) 120 mg (n = 8) 751a (150) 1.00a (0.50-2.00) 2460a (119) 1.31a (34.4) 1.55a (84.7) 751a (150) The geometric mean (%CV) value is displayed rounded to three significant figures, except for tmax, which is reported as the median (range). a is based on n = 7 subjects.

[0139] In the 8 cases of 120 mg BID, the occurrence of nausea or vomiting as adverse events causally related to compound A is shown in Table 13. [Table 13] Better option 120 mg (N = 8) n(%) any level level ≥ 3 Subjects with any treatment-related TEAEs 8 (100.0) 0 nausea 7 (87.5) 0 Vomit 2 (25.0) 0

[0140] Five additional patients were also discussed to determine whether the occurrence of adverse events causally related to compound A, namely nausea or vomiting, could be suppressed. Four patients who complained of vomiting during cycle 1 were administered ramosetron hydrochloride or granisetron hydrochloride (5-HT3 receptor antagonists). Additionally, three of the four patients who complained of vomiting were administered granisetron hydrochloride to prevent gastrointestinal symptoms (nausea, vomiting) associated with compound A administration.

[0141] Patients who were given granisetron hydrochloride prophylactically did not subsequently vomit, and nausea or vomiting, which are associated with the administration of compound A, were successfully prevented by the 5-HT3 receptor antagonist (vomiting flag 2). One subject who was given granisetron hydrochloride after nausea or vomiting was observed also experienced suppression of vomiting (vomiting flag 2).

[0142] The overall results of vomiting management, including additional cases, are shown in Figure 5 and Table 14. [Table 14] Vomiting flag N state 0 11 No nausea or vomiting, or no need to administer antiemetics. 1 2 Vomiting can be suppressed with antiemetics other than 5-HT3 receptor antagonists. 2 16 Vomiting can be suppressed with 5-HT3 receptor antagonists 3 4 Vomiting cannot be suppressed with antiemetics other than 5-HT3 receptor antagonists, but vomiting can be suppressed with 5-HT3 receptor antagonists. 4 2 Vomiting cannot be suppressed with 5-HT3 receptor antagonists exclude 1 total 36

[0143] Furthermore, regarding the patient who was initially identified as vomiting flag 3 in the previous analysis, subsequent analysis revealed that vomiting or nausea was not associated with the digestive symptoms of compound A, and therefore the patient was excluded from the data.

[0144] In addition, C1D8 hemodynamic data could not be obtained for two cases: one with 100 mg BID and one with 120 mg BID. Therefore, C1D1 hemodynamic values ​​were used to plot the data for the case with 100 mg BID in Figures 1-4 and the case with 120 mg BID in Figures 3 and 4.

[0145] Regarding the five additional cases, it was also predicted that when the AUC (0-tau) at C1D8 was below 7640 h·ng / mL, administration of a 5-HT3 receptor antagonist could suppress gastrointestinal symptoms associated with the administration of compound A or its pharmaceutically acceptable salts. Therefore, the clinically recommended dose is considered to be approximately 80 mg to approximately 120 mg, with 100 mg BID or 120 mg BID being particularly preferred, and 120 mg BID being the most preferred.

Claims

1. The use of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tri-1(6H)-methamide or a pharmaceutically acceptable salt thereof, as represented by formula (I), in the manufacture of a pharmaceutical composition for the treatment of solid tumors, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazinyl)tetrahydroacryl-1-yl]pyridinyl-2H-pyrro[2,1-c][1,2,4]triazinyl-1(6H)-methamide or a pharmaceutically acceptable salt thereof, twice daily, based on approximately 10 mg of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazinyl)tetrahydroacryl-1-yl]pyridinyl-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-disideoxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]triazinyl-1(6H)-methamide. A dose of approximately 150 mg, administered in combination with a 5-HT3 receptor antagonist effective in inhibiting gastrointestinal symptoms, wherein the gastrointestinal symptoms are caused by administration to human subjects of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a pharmaceutically acceptable salt thereof, wherein the solid tumor is uterine cancer, and the gastrointestinal symptoms are selected from at least one of nausea and vomiting.

2. The use as claimed in claim 1, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide or a drug thereof The pharmaceutically acceptable salt is administered at a dose of approximately 120 mg per administration, based on (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methamide.

3. The use as claimed in claim 1, wherein the pharmaceutical composition for treating solid tumors is administered simultaneously or separately in combination with the 5-HT3 receptor antagonist.

4. The use as claimed in claim 1, wherein the 5-HT3 receptor antagonist is selected from at least one of the group consisting of azasetron, ondansetron, indisetron, ramosetron, granisetron and palonosetron, or a pharmaceutically acceptable salt thereof.

5. The use as claimed in claim 1, wherein the pharmaceutical composition for treating solid tumors is administered in combination with the 5-HT3 receptor antagonist in an amount of about 0.1 mg to about 100 mg per day.

6. The use as claimed in claim 1, wherein the 5-HT3 receptor antagonist is selected from at least one of ramosetron hydrochloride and granisetron hydrochloride.

7. The use as claimed in claim 1, wherein the 5-HT3 receptor antagonist is granisetron hydrochloride, administered in combination at a dose of about 2 mg granisetron once a day.

8. The use as claimed in claim 1, wherein the 5-HT3 receptor antagonist is ramosetron hydrochloride, administered once daily at a dose of approximately 0.1 mg of ramosetron.

9. The use as claimed in claim 1, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroazin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyro[2,1-c][1,2,4]triazin-1(6H)-methyl Amines or their pharmaceutically acceptable salts (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)tetrahydroacryl-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxy-2-(prop-2-en-1-yl)hexahydro-2H-pyrro[2,1-c][1,2,4]tris(6H)-methylamine.

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