Preparation containing cyclic peptide compound and method for producing the same

Abstract

Formulations of cyclic compounds containing unnatural amino acids are provided. [Solution] The following formula (1): TIFF2023015334000037.tif73170 or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component.

Description

[Technical Field]

[0001] The present invention relates to a formulation containing a cyclic peptide compound having KRAS inhibitory activity and a method for producing the same. [Background technology]

[0002] Compounds conventionally used as oral drugs have been considered desirable to have a molecular weight of 500 g / mol or less, as is known from Lipinski's law (Non-Patent Literature 1). In recent years, it has become known that compounds with a molecular weight exceeding 500 g / mol are difficult for conventional small-molecule compounds to interact with, and can contribute to interactions at the surface of target proteins called tough targets, i.e., inhibition of protein-protein interactions. These molecules are neither small molecules with a molecular weight of 500 g / mol or less that have been used as oral drugs, nor large molecules with a molecular weight exceeding 100,000 g / mol like antibody drugs. They are called medium-molecule compounds (molecular weight 500-2000 g / mol) and are attracting attention as a new modality that can realize drug discovery targeting tough targets (Non-Patent Literature 2).

[0003] Peptides composed of natural amino acids, such as insulin used to treat hyperglycemia, have poor metabolic stability, and it has traditionally been difficult to develop them as oral drugs. However, it has been found that the metabolic stability and membrane permeability of peptides can be improved by cyclizing peptides or by using non-natural amino acids, such as N-methyl amino acids, in the peptide (Non-Patent Documents 3, 4).

[0004] It has become known that among cyclic peptides containing non-natural amino acids, cyclic peptides containing N-substituted amino acids in particular may possess metabolic stability and membrane permeability, i.e., may exhibit drug-like properties (Patent Document 1).

[0005] Library compounds of cyclic peptides containing non-natural amino acids have been suggested to be useful in creating inhibitors of protein-protein interactions (Non-Patent Literature 5).

[0006] The conditions for cyclic peptides containing non-natural amino acids to be drug-like molecules with sufficient membrane permeability and metabolic stability for use as pharmaceuticals have also been clarified, further increasing the attention given to cyclic peptides as a pharmaceutical modality (Patent Documents 2 and 3).

[0007] Patent document 6 discloses a cyclic peptide that exhibits pharmacological activity. Patent document 6 also discloses formulation technology for cyclosporine. Research is also being conducted on the oral formulation of somatostatin (Non-patent document 6). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2013 / 100132 [Patent Document 2] International Publication No. 2018 / 225864 [Patent Document 3] International Publication No. 2020 / 122182 [Patent Document 4] International Publication No. 2012 / 122059 [Patent Document 5] International Publication No. 2017 / 181061 [Patent Document 6] International Publication No. 2018 / 031730 [Patent Document 7] International Publication No. 2016 / 071515 [Non-patent literature]

[0009] [Non-Patent Document 1] Adv. Drug Del. Rev. 1997, 23, 3-25. [Non-Patent Document 2] Future Med. Chem., 2009, 1,1289-1310. [Non-Patent Document 3] Acc. Chem. Res., 2008, 41, 1331 - 1342. Non - Patent Document 4 Angew. Chem. Int. Ed., 2013, 52, 254 - 269. Non - Patent Document 5 Chem. Rev., 2019, 119, 10360 - 10391. Non - Patent Document 6 Ther. Deliv. (2017) 8(10), 867 - 878. Summary of the Invention Non - Patent Document 5 Chem. Rev., 2019, 119, 10360 - 10391. Non - Patent Document 6 Ther. Deliv. (2017) 8(10), 867 - 878. Summary of the Invention Problems to be Solved by the Invention

[0010] The present invention aims to provide a formulation of a cyclic compound containing non - natural amino acids. The present invention aims to provide a method for producing a formulation of a cyclic compound having an efficient RAS inhibitory effect.

[0011] In Patent Document 4, the inhibition of the binding between RAS and SOS is described, and in Patent Document 5, a peptide that competes with a compound that binds to RAS is described. However, these documents do not show pharmacological effects, especially the effects on tumor cells. Also, these documents do not describe drug - like peptides.

[0012] In Patent Documents 6 and 7, there are descriptions regarding the formulation of cyclic peptides, but all of them only describe the formulation of specific compounds.

[0013] Non - Patent Document 2 describes peptides used as pharmaceuticals, but does not describe drug - like peptides or peptides useful for RAS - mutant cancers.

[0014] Non - Patent Documents 3 and 4 describe that peptides containing N - methyl amino acids can be applied as pharmaceuticals, but do not describe peptides useful for RAS - mutant cancers.

[0015] Non-patent document 5 describes that cyclic peptides may be applicable as pharmaceuticals, but it does not describe any peptides that are useful for RAS-mutated cancers.

[0016] Non-patent document 6 provides somatostatin as an example and describes the elements necessary for oral formulation, but it only describes somatostatin in general.

[0017] Therefore, it is necessary to provide pharmaceutical formulations that are superior to cyclic compounds containing unnatural amino acids. [Means for solving the problem]

[0018] The present inventors, through diligent research to solve the above problems, have found that by adding specific additives to the active ingredient, it is possible to formulate a drug that can be used as a pharmaceutical. They found that surfactants are effective as specific additives, and preferably, a combination of hydrophobic and hydrophilic surfactants is effective. Furthermore, they found that adding an oily component can make the formulation even more effective. They also found that a mixture of the active ingredient and these additives can be formulated and used in a drug with a specific dosage form.

[0019] The formulation according to the present invention has been found to have excellent stability of the active ingredient within the formulation and excellent dissolution from the formulation.

[0020] In other words, the present invention relates to the following: [1] The following formula (1): [ka] A composition comprising a compound represented by , or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component. [2] The composition according to [1], wherein the liquid additive is a surfactant. [3] The composition according to [2], wherein the surfactant is a combination of a hydrophobic surfactant and a hydrophilic surfactant. [4] The composition according to [3], wherein the HLB value of the hydrophobic surfactant is 0 or more and less than 10, and the HLB value of the hydrophilic surfactant is 10 or more and 30 or less. [5] The composition according to [3] or [4], wherein the hydrophobic surfactant is at least one selected from the group consisting of propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, and hydrophobic polyoxyethylene hydrogenated castor oil. [6] The composition according to any one of [3] to [5], wherein the hydrophobic surfactant is at least one selected from the group consisting of propylene glycol fatty acid esters and sorbitan fatty acid esters. [7] The composition according to any one of [3] to [6], wherein the hydrophobic surfactant comprises a propylene glycol fatty acid ester. [8] The composition according to [5], wherein the propylene glycol fatty acid ester is at least one selected from the group consisting of propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate. [9] The composition according to [5], wherein the glycerin fatty acid ester is at least one selected from the group consisting of glyceryl monocaproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, and glyceryl monolinoleate.

[10] The composition according to [5], wherein the polyglycerin fatty acid ester is diglyceryl monooleate.

[11] The composition according to [5], wherein the sorbitan fatty acid ester is at least one selected from the group consisting of sorbitan monocaprylate, sorbitan monocaprate, sorbitan monolaurate, sorbitan monomyristate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

[12] The composition according to [5], wherein the hydrophobic polyoxyethylene hydrogenated castor oil is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 5 and polyoxyethylene hydrogenated castor oil 10.

[13] The composition according to any one of [3] to [7], wherein the hydrophobic surfactant is propylene glycol monocaprylate.

[14] The composition according to any one of [3] to

[13] , wherein the hydrophilic surfactant is at least one selected from the group consisting of polyethylene glycol fatty acid ester, polyoxyethylene castor oil, hydrophilic polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, and any combination thereof.

[15] The composition according to any one of [3] to

[14] , wherein the hydrophilic surfactant is at least one selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid ester, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, and any combination thereof.

[16] The composition according to any one of [3] to

[15] , wherein the hydrophilic surfactant comprises polyoxyethylene castor oil.

[17] The composition according to

[14] , wherein the polyethylene glycol fatty acid ester is at least one selected from the group consisting of polyoxyethylene hydroxystearate, polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyoxyl stearate 40.

[18] The composition according to

[14] , wherein the polyoxyethylene castor oil is at least one selected from the group consisting of polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.

[19] The composition according to

[14] , wherein the polyoxyethylene castor oil is polyoxyl 35 castor oil.

[20] The composition according to

[14] , wherein the hydrophilic polyoxyethylene hydrogenated castor oil is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60.

[21] The composition according to

[14] , wherein the polyoxyethylene sorbitan fatty acid ester is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[22] The composition according to any one of [3] to

[15] , wherein the hydrophilic surfactant is at least one selected from the group consisting of polyoxyl 35 castor oil, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, and combinations thereof.

[23] The composition according to any one of [3] to

[15] , wherein the hydrophilic surfactant comprises polyoxyl 35 castor oil.

[24] The composition according to [3], wherein the hydrophobic surfactant is a propylene glycol fatty acid ester and the hydrophilic surfactant contains polyoxyethylene castor oil.

[25] The composition according to [3], wherein the hydrophobic surfactant is propylene glycol monocaprylate, and the hydrophilic surfactant is at least one selected from the group consisting of polyoxyl 35 castor oil, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, and combinations thereof.

[26] The composition according to [3], wherein the hydrophobic surfactant is propylene glycol monocaprylate and the hydrophilic surfactant contains polyoxyl 35 castor oil.

[27] A composition according to any one of [1] to

[26] , wherein the composition contains an oily component.

[28] The composition according to any one of [1] to

[27] , wherein the oily component is at least one selected from the group consisting of fatty acids, acylglycerols, vegetable oils and combinations thereof.

[29] The composition according to any one of [1] to

[28] , wherein the oily component is at least one selected from the group consisting of fatty acids, acylglycerols, and combinations thereof.

[30] The composition according to any one of [1] to

[29] , wherein the oily component comprises a fatty acid.

[31] The composition according to

[28] , wherein the fatty acid is at least one selected from the group consisting of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid.

[32] The composition according to

[28] , wherein the fatty acid is at least one selected from the group consisting of oleic acid, linoleic acid, and linolenic acid.

[33] The composition according to

[28] , wherein the acylglycerol is at least one selected from the group consisting of triacetin, triptyline, tricaproin, tricapryline, tricaprine, tripalmitin, tripalmitorein, glyceryl tristearate, triolein, trilinolein, trilinolenin, and medium-chain fatty acid triglycerides.

[34] The composition according to

[28] , wherein the acylglycerol is triacetin.

[35] The composition according to

[28] , wherein the vegetable oil is at least one selected from the group consisting of olive oil, almond oil, coconut oil, cocoa butter, macadamia nut oil, avocado oil, safflower oil, soybean oil, linseed oil, rapeseed oil, castor oil, corn oil, and palm oil.

[36] The composition according to any one of [1] to

[35] , wherein the oily component is oleic acid or triacetin.

[37] The composition according to any one of [1] to

[36] , wherein the oily component is oleic acid.

[38] The composition according to [3], comprising a propylene glycol fatty acid ester as a hydrophobic surfactant, polyoxyethylene castor oil as a hydrophilic surfactant, and a fatty acid as an oily component.

[39] The composition according to [3], comprising propylene glycol monocaprylate as a hydrophobic surfactant, polyoxyl 35 castor oil as a hydrophilic surfactant, and oleic acid as an oily component.

[40] A composition according to any one of [1] to

[39] , further comprising an antioxidant.

[41] The composition according to

[40] , wherein the antioxidant is at least one selected from the group consisting of dl-α-tocopherol, butyrated hydroxytoluene, butyrated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinone, astaxanthin, and D-α-tocopheryl polyethylene glycol 1000 succinate.

[42] The composition according to any one of [1] to

[41] , further comprising a solubilizing agent.

[43] The composition according to

[42] , wherein the solubilizer is at least one selected from the group consisting of ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and combinations thereof.

[44] The composition according to any one of [1] to

[43] , wherein the compound represented by formula (1), a salt thereof, or a solvate thereof is the compound represented by formula (1) or a hydrate thereof.

[45] The composition according to

[44] , wherein the hydrate is a hydrate of a compound represented by formula (1).

[46] The composition according to

[44] , wherein the compound represented by formula (1), or a salt thereof, or a solvate thereof is the compound represented by formula (1).

[47] The composition according to any one of [1] to

[46] , wherein the content of the compound represented by formula (1), or a salt thereof, or a solvate thereof in the whole composition is 10% by weight or less.

[48] ​​The composition according to any one of [1] to

[47] , wherein the content of the compound represented by formula (1), or a salt thereof, or a solvate thereof in the whole composition is 8% by weight or less.

[49] The composition according to any one of [1] to

[48] , wherein the content of the compound represented by formula (1), or a salt thereof, or a solvate thereof, in the whole composition is 7% by weight or less.

[50] The composition according to any one of [1] to

[49] , wherein the content of the liquid additive in the whole composition is 50% by weight or more and 97% by weight or less.

[51] The composition according to any one of [1] to

[50] , wherein the content of the liquid additive in the whole composition is 55% by weight or more and 96% by weight or less.

[52] The composition according to any one of [1] to

[51] , wherein the content of the liquid additive in the whole composition is 70% by weight or more and 90% by weight or less.

[53] The composition according to any one of [3] to

[52] , wherein the content of the hydrophobic surfactant in the whole composition is 20% by weight or more and 70% by weight or less.

[54] The composition according to any one of [3] to

[53] , wherein the content of the hydrophobic surfactant in the whole composition is 25% by weight or more and 65% by weight or less.

[55] The composition according to any one of [3] to

[54] , wherein the content of the hydrophobic surfactant in the whole composition is 30% by weight or more and 55% by weight or less.

[56] The composition according to any one of [3] to

[55] , wherein the content of the hydrophilic surfactant in the whole composition is 20% by weight or more and 40% by weight or less.

[57] The composition according to any one of [3] to

[56] , wherein the content of the hydrophilic surfactant in the whole composition is 25% by weight or more and 35% by weight or less.

[58] The composition according to any one of [3] to

[57] , wherein the content of the hydrophilic surfactant in the whole composition is 28% by weight or more and 33% by weight or less.

[59] The composition according to any one of [1] to

[58] , wherein the content of the oily component in the whole composition is 0% by weight or more and 50% by weight or less.

[60] The composition according to any one of [1] to

[59] , wherein the content of the oily component in the whole composition is 1% by weight or more and 40% by weight or less.

[61] The composition according to any one of [1] to

[60] , wherein the content of the oily component in the whole composition is 10% by weight or more and 20% by weight or less.

[62] The composition according to any one of [1] to

[61] , wherein the oily component comprises a fatty acid.

[63] The composition according to any one of [3] to

[62] , wherein the weight ratio of the hydrophobic surfactant to the hydrophilic surfactant is 0.5 to 3.0.

[64] The composition according to any one of [3] to

[63] , wherein the weight ratio of the hydrophobic surfactant to the hydrophilic surfactant is 1.0 to 2.5.

[65] The composition according to any one of [3] to

[64] , wherein the weight ratio of the hydrophobic surfactant to the hydrophilic surfactant is 1.5 to 2.0.

[66] The composition according to any one of [1] to

[65] , wherein the weight ratio of the liquid additive to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 5 or more.

[67] The composition according to any one of [1] to

[66] , wherein the weight ratio of the liquid additive to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 10 or more.

[68] The composition according to any one of [1] to

[66] , wherein the weight ratio of the liquid additive to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 5 to 2000.

[69] The composition according to any one of [1] to

[68] , wherein the weight ratio of the total of the liquid additive and the oily component to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 10 or more.

[70] The composition according to any one of [1] to

[69] , wherein the weight ratio of the total of the liquid additive and the oily component to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 10 to 2000.

[71] The composition according to any one of [1] to

[70] , wherein the weight ratio of the total of the liquid additive and the oily component to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 10 to 1000.

[72] The composition according to any one of [1] to

[71] , wherein the composition is a liquid.

[73] The composition according to any one of [1] to

[72] , wherein the average particle size of the droplets formed when the composition is dispersed in water is less than 200 nm.

[74] The composition according to

[73] , wherein the average particle size of the droplets is 10 nm or more and less than 200 nm.

[75] The composition according to

[74] , wherein the average particle size of the droplets is 50 nm or more and 200 nm or less. A pharmaceutical preparation containing the composition described in any one of items

[76] , [1], to

[75] .

[77] The pharmaceutical preparation according to

[76] , wherein the dosage form of the preparation is a capsule.

[78] A method for producing the composition according to any one of [1] to

[75] , comprising the following steps; (1) The following formula (1): [ka] A process of providing a compound represented by, or a salt thereof, or solvates thereof, a liquid additive, and optionally an oily component; (2) A step of mixing a compound represented by formula (1), or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component; and, (3) A step of obtaining a composition in which a compound represented by formula (1), a salt thereof, or a solvate thereof is dissolved.

[79] The method according to

[78] , wherein the compound represented by formula (1), or a salt thereof, or a solvate thereof provided in step (1) is a hydrate of the compound represented by formula (1).

[80] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least one peak is selected as the diffraction angle 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-1] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least two peaks are included as diffraction angles 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-2] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least three peaks are included as diffraction angles 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-3] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least four peaks are included in the diffraction angle 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-4] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least five peaks are included as diffraction angles 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-5] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least six peaks are included in the diffraction angle 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-6] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least seven peaks are included as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-7] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least eight peaks are included as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-8] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least nine peaks are included as diffraction angles 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-9] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least 10 peaks are included as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-10] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least 11 peaks are selected as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-11] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least 12 peaks are selected as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). [80-12] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which the diffraction angle 2θ includes peaks at 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°).

[81] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least one peak is selected as the diffraction angle 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-1] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least two peaks are included in the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-2] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least three peaks are included in the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-3] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least four peaks are included in the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-4] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least five peaks are included in the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-5] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least six peaks are included in the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-6] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which the diffraction angles 2θ include peaks at 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°). [81-7] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which, as diffraction angle 2θ, at least seven peaks are selected from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°). [81-8] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which, as diffraction angle 2θ, at least 10 peaks are selected from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°). [81-9] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least 13 peaks are selected as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°). [81-10] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which at least 15 peaks are selected as diffraction angles 2θ from among 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°). [81-10] The method according to

[79] , wherein the hydrate of the compound represented by formula (1) is a crystal, and the crystal has a powder X-ray diffraction pattern in which the diffraction angle 2θ includes peaks at 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°). A method for producing a pharmaceutical product, comprising the steps of providing a composition described in any one of items

[82] [1] to

[75] , and formulating the composition to provide a pharmaceutical product. A method for producing a capsule formulation, comprising the steps of providing a composition described in any one of items

[83] [1] to

[75] , and filling a capsule with the composition to provide a capsule formulation. [Effects of the Invention]

[0021] The composition according to the present invention is excellent in various properties necessary for a pharmaceutical formulation. For example, the composition according to the present invention has desirable particle properties when the liquid composition is emulsified to form droplets, and is extremely stable and dispersible, as well as excellent absorbability into the body. [Brief explanation of the drawing]

[0022] [Figure 1] Figure 1 is a graph showing the results of powder X-ray diffraction measurements of the hydrate crystal (Form C) of compound 1 obtained in preparation example 3. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 2] Figure 2 shows the results of thermogravimetric and differential thermal analysis of the hydrate crystal of compound 1 (Form C). The horizontal axis represents temperature (°C) and measurement time (minutes), and the right vertical axis represents the weight change of the sample in thermogravimetric analysis (mg). The left vertical axis represents the heat flow (mW) observed in differential thermal analysis. [Figure 3] Figure 3 shows the crystal structure of the hydrate crystal of compound 1 (Form C) obtained by single-crystal X-ray structure analysis. [Figure 4] Figure 4 shows the results of dynamic water vapor adsorption measurements of the hydrate crystal of compound 1 (Form C). The vertical axis represents weight change (%), and the horizontal axis represents relative humidity (%). In Figure 4, "Cycle1 Sorp" (black diamond mark) indicates adsorption in cycle 1, "Cycle1 Desorp" (black square mark) indicates desorption in cycle 1, "Cycle2 Sorp" (black triangle mark) indicates adsorption in cycle 2, and "Cycle2 Desorp" (black square mark) indicates desorption in cycle 2. [Figure 5] Figure 5 is a graph showing the temporal change in the degree of dispersion of the formulations according to the present invention (formulation C, formulation F) and comparative example (formulation AJ) into fasting artificial intestinal fluid (FaSSIF). [Modes for carrying out the invention]

[0023] The composition of the present invention is of the following formula (1): [ka] The compound represented by ("(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28, It contains "31,34,37-Undekaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undekaazacyclotetratriacontin-21,1'-cyclopentane]-15-carboxamide" (hereinafter sometimes referred to as "Compound 1"), or a salt thereof, or a solvate thereof, and a liquid additive.

[0024] Furthermore, the composition according to the present invention optionally contains an oily component, and preferably contains an oily component.

[0025] Compounds (active ingredients) The compounds that can be used in the present invention are compounds represented by formula (1) above, salts thereof, or solvates thereof. The salt of compound 1 may preferably be a chemically or pharmaceutically acceptable salt thereof. The compounds that can be used in the present invention, or salts thereof, may also be solvates thereof, preferably chemically or pharmaceutically acceptable solvates thereof. The compounds used in the present invention may preferably be exclusively in the form of a free compound in a composition, but depending on the form of the composition, they may also be in the form of a salt or a solvate.

[0026] In the present invention, salts of compound 1 include, for example, hydrochloride salts; hydrobromide salts; hydroiodide salts; phosphate salts; phosphonate salts; sulfate salts; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylate salts such as acetate salts, citrate salts, malate salts, tartrate salts, succinate salts, and salicylate salts; or alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts are produced, for example, by contacting compound 1 with an acid or base that can be used in the manufacture of pharmaceuticals.

[0027] In the present invention, a solvate refers to a compound that, together with a solvent, forms a single molecular group, and is not particularly limited as long as it is a solvate formed with a solvent that is permissible to ingest in conjunction with the administration of a drug. Examples include not only solvates with a single solvent such as hydrates, alcohol hydrates (ethanol hydrate, methanol hydrate, 1-propanol hydrate, 2-prol hydrate, etc.), and dimethyl sulfoxide, but also solvates formed with multiple solvents for one compound molecule, or solvates formed with multiple types of solvents for one compound molecule. If the solvent is water, it is called a hydrate. Hydrates are preferred as solvates of the compounds of the present invention, and specifically, examples of such hydrates include 1-10 hydrates, preferably 1-5 hydrates, and more preferably 1-3 hydrates. In the hydrate of compound 1 used in the present invention, the number of water molecules can change due to the desorption of water molecules bound to compound 1 depending on the surrounding environment such as temperature and humidity.

[0028] Compound 1, its salts, or solvates thereof that can be used in the present invention may be provided in crystalline, amorphous, or mixture thereof form, preferably in crystalline form. A preferred example of a crystalline compound 1, its salts, or solvates thereof that can be used in the present invention is a crystalline form of the hydrate of compound 1 (also known as Form C).

[0029] Crystals of compound 1 or its salts, or their solvates, can be characterized by techniques known in the art, such as powder X-ray diffraction (XRPD), moisture content measurement methods (e.g., Karl Fischer method), scanning electron microscopy (SEM) analysis, solid-state NMR, or thermal techniques such as differential scanning calorimetry (DSC), or any other standard quantitative measurement method.

[0030] In powder X-ray diffraction, the diffraction angle 2θ is preferably the diffraction peak measured using CuKα radiation.

[0031] For example, the crystals of the hydrate of Compound 1 that can be used in the present invention have a powder X-ray diffraction pattern containing at least one of the following peaks as diffraction angle 2θ in powder X-ray diffraction. 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, 17.813° (±0.2°)

[0032] In the notation of diffraction angle 2θ, when "(±0.2°)" is described at the end of the listed diffraction angle 2θ, it means that a range of ±0.2° is allowed for each of the listed values of diffraction angle 2θ.

[0033] Compound 1 used in the present invention includes all isotopes of Compound 1. Isotopes of Compound 1 are those in which at least one atom is replaced by an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons) at an abundance ratio different from the natural abundance ratio. Examples of isotopes contained in Compound 1 include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, and fluorine atoms, which are respectively 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, etc. are included. In particular, 3 H and 14 radioactive isotopes such as C that emit radioactivity and decay are useful in in vivo tissue distribution tests of pharmaceuticals or compounds. Stable isotopes do not decay, have little change in abundance over time, and have no radioactivity, so they can be used safely. Isotopes of Compound 1 can be converted according to conventional methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes. The acids or bases used for the formation of salts of Compound 1, as well as the solvents used for the formation of solvates of Compound 1, can also contain all isotopes.

[0034] Liquid additives The "liquid additive" that can be used in the composition according to the present invention is a pharmaceutically acceptable additive that can dissolve the compound used in the present invention. In the present invention, "liquid additive" means an additive that is dissolved in the composition. Additives that are not dissolved at the stage of being provided as raw materials for the manufacture of the composition can be dissolved during the manufacturing process by mixing with other components or heating, etc., and become a component of the composition according to the present invention. As the liquid additive, an additive that is liquid at room temperature can be preferably used. In this specification, "room temperature" is used in the ordinary sense in the art and is not particularly limited, but unless otherwise specified, it is preferably 1 to 30°C, more preferably 15 to 28°C.

[0035] Liquid additives that can be used in the present invention are preferably surfactants, and among surfactants, hydrophobic surfactants and hydrophilic surfactants are preferred. In the present invention, it is desirable to use a combination of hydrophobic surfactants and hydrophilic surfactants.

[0036] In the hydrophobic and hydrophilic surfactants that can be used in the present invention, it is preferable to use those in which the HLB value (Hydrophilic-Lipophilic Balance value) of the hydrophobic surfactant is preferably less than 10, more preferably 0 or more and less than 10, and the HLB value of the hydrophilic surfactant is preferably 10 or more, more preferably 10 or more and 30 or less, and even more preferably 10 or more and 20 or less. The HLB value is a value that represents the degree of affinity of the surfactant to water and oil (organic compounds insoluble in water), and is well known to those skilled in the art. For example, values ​​based on methods known as the Griffin method, Atlas method, Davis method, etc., can be adopted.

[0037] Preferably, hydrophobic surfactants include propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, and hydrophobic polyoxyethylene hydrogenated castor oil, and these can also be used in combination. More preferably, propylene glycol fatty acid esters or sorbitan fatty acid esters can be used as hydrophobic surfactants, and even more preferably, propylene glycol fatty acid esters can be used.

[0038] Preferred propylene glycol fatty acid esters include propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate. Of these, propylene glycol monocaprylate is more preferably used.

[0039] Preferred glycerin fatty acid esters include glyceryl monocaproate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, and glyceryl monolinoleate.

[0040] Preferably, the polyglycerol fatty acid ester is diglyceryl monooleate.

[0041] Preferred sorbitan fatty acid esters include sorbitan monocaprylate, sorbitan monocaprate, sorbitan monolaurate, sorbitan monomyristate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

[0042] In this specification, hydrophobic polyoxyethylene hydrogenated castor oil refers to hydrophobic polyoxyethylene hydrogenated castor oil, for example, polyoxyethylene hydrogenated castor oil with an HLB value of preferably less than 10, more preferably 0 or more and less than 10. Examples of hydrophobic polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 5 and polyoxyethylene hydrogenated castor oil 10.

[0043] Preferred hydrophilic surfactants include polyethylene glycol fatty acid esters, polyoxyethylene castor oil, hydrophilic polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, D-α-tocopheryl polyethylene glycol 1000 succinate, and caprylocaproyl polyoxyl-8 glyceride, and these can also be used in combination. More preferably, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid esters, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, or combinations thereof can be used as hydrophilic surfactants, and even more preferably, polyoxyethylene castor oil can be used.

[0044] Preferred polyethylene glycol fatty acid esters include polyoxyethylene hydroxystearate, polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyoxyl 40 stearate.

[0045] Examples of polyoxyethylene castor oil include polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil, with polyoxyl 35 castor oil being more preferred.

[0046] In this specification, hydrophilic polyoxyethylene hydrogenated castor oil refers to hydrophilic polyoxyethylene hydrogenated castor oil, for example, polyoxyethylene hydrogenated castor oil with an HLB value of preferably 10 or more, more preferably 10 to 30, and even more preferably 10 to 20. Examples of hydrophilic polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60.

[0047] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

[0048] More preferably, the hydrophilic surfactants available are polyoxyl 35 castor oil, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, or a combination thereof.

[0049] As a surfactant, propylene glycol monocaprylate is preferably used as a hydrophobic surfactant, and polyoxyl 35 castor oil, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, polysorbate 80, or a combination thereof can be used as a hydrophilic surfactant.

[0050] Preferably, the surfactant is a propylene glycol fatty acid ester as the hydrophobic surfactant and preferably contains at least polyoxyethylene castor oil as the hydrophilic surfactant. Particularly preferably, the surfactant is a propylene glycol monocaprylate as the hydrophobic surfactant and preferably contains at least polyoxyl 35 castor oil as the hydrophilic surfactant.

[0051] Oily components The composition according to the present invention may contain an oily component. Preferred oily components include fatty acids, acylglycerols, vegetable oils, and combinations thereof. More preferably, fatty acids or acylglycerols can be used as the oily component, and more preferably, fatty acids can be used.

[0052] Preferred fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. Of these, oleic acid, linoleic acid, and linolenic acid are more preferred, and oleic acid is even more preferred.

[0053] Examples of acylglycerols include triacetin, triptyline, tricaproin, tricapryline, tricaprin, tripalmitin, tripalmitorein, glyceryl tristearate, triolein, trilinolein, trilinolenin, and medium-chain triglyceride fatty acids. Of these, triacetin is preferred.

[0054] Examples of vegetable oils include olive oil, almond oil, coconut oil, cocoa butter, macadamia nut oil, avocado oil, safflower oil, soybean oil, linseed oil, rapeseed oil, castor oil, corn oil, and palm oil.

[0055] Such oily components can preferably be oleic acid, triacetin, or a combination thereof, and more preferably oleic acid.

[0056] In the composition of the present invention, it is preferable to use a propylene glycol fatty acid ester as the hydrophobic surfactant, to include at least polyoxyethylene castor oil as the hydrophilic surfactant, and to use a fatty acid as the oily component. Particularly preferable is to use propylene glycol monocaprylate as the hydrophobic surfactant, to include at least polyoxyl 35 castor oil as the hydrophilic surfactant, and to use oleic acid as the oily component.

[0057] The compositions according to the present invention may further contain antioxidants. Preferred antioxidants include dl-α-tocopherol, butyrated hydroxytoluene, butyrated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable quinones, astaxanthin, and D-α-tocopheryl polyethylene glycol 1000 succinate, as well as combinations thereof. More preferably, dl-α-tocopherol is used as an antioxidant.

[0058] The composition according to the present invention may further contain a solubilizer. Preferred solubilizers include ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, diethylene glycol monoethyl ether, and combinations thereof. More preferably, the solubilizer is ethanol or propylene glycol, and even more preferably propylene glycol.

[0059] In the composition according to the present invention, the content of compound 1, its salt, or its solvates may be any concentration that allows it to dissolve in the liquid additive and optionally used oily components and exhibit a certain effectiveness, and the content is not particularly limited. However, the upper limit of the content of compound 1, its salt, or its solvates in the overall composition is preferably 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, or 2% by weight or less, more preferably 10% by weight or less, 8% by weight or less, or 7% by weight or less. The lower limit of the content is not particularly limited, but is preferably an amount greater than 0%, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, 0.5% by weight or more, 0.6% by weight or more, 0.7% by weight or more, 0.8% by weight or more, 0.9% by weight or more, or 1% by weight or more, and is more preferably 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, or 0.5% by weight or more. Furthermore, the content can be within any combination of the above lower and upper limits. For example, the range of the content can preferably be 0.1% by weight or more and 10% by weight or less, 0.2% by weight or more and 10% by weight or less, 0.3% by weight or more and 10% by weight or less, 0.4% by weight or more and 10% by weight or less, 0.5% by weight or more and 10% by weight or less, etc.

[0060] In the composition according to the present invention, a liquid additive, preferably a surfactant, is included in such a manner that compound 1 or a salt thereof, or a solvate thereof, can be dissolved. The content is not particularly limited, but the content of the liquid additive relative to the whole composition can preferably be 50% by weight or more and 97% by weight or less, more preferably 55% by weight or more and 96% by weight or less, and even more preferably 70% by weight or more and 90% by weight or less.

[0061] In the composition according to the present invention, the content of the hydrophobic surfactant in the total composition can preferably be 20% by weight or more and 70% by weight or less, more preferably 25% by weight or more and 65% by weight or less, and even more preferably 30% by weight or more and 55% by weight or less.

[0062] In the composition according to the present invention, the content of the hydrophilic surfactant in the total composition can preferably be 20% by weight or more and 40% by weight or less, more preferably 25% by weight or more and 35% by weight or less, and even more preferably 28% by weight or more and 33% by weight or less.

[0063] In the composition according to the present invention, the weight ratio of the hydrophobic surfactant to the hydrophilic surfactant (hydrophobic surfactant / hydrophilic surfactant) is preferably 0.5 to 3.0, more preferably 1.0 to 2.5, and even more preferably 1.5 to 2.0.

[0064] In the composition according to the present invention, the content of the oily component in the total composition is preferably 0% by weight or more and 50% by weight or less, more preferably 1% by weight or more and 40% by weight or less, and even more preferably 10% by weight or more and 20% by weight or less.

[0065] When an antioxidant is included in the composition according to the present invention, the content of the antioxidant in the total composition is not particularly limited as long as it does not adversely affect the pharmaceutical properties of the formulation, but is preferably 0.01% by weight or more, more preferably 0.01% by weight or more and 5% by weight or less, even more preferably 0.1% by weight or more and 5% by weight or less, and even more preferably 0.1% by weight or more and 2% by weight or less.

[0066] When a solubilizing agent is included in the composition according to the present invention, the content of the solubilizing agent relative to the whole composition is not particularly limited as long as it does not adversely affect the pharmaceutical properties of the formulation, but is preferably 1% by weight or more and 20% by weight or less, and more preferably 2% by weight or more and 15% by weight or less.

[0067] In the composition according to the present invention, the weight ratio of the liquid additive to the compound represented by formula (1), or its salt, or its solvate (liquid additive / compound 1 or its salt, or its solvate) is not particularly limited, as long as compound 1 or its salt, or its solvate, can be dissolved, but is preferably 5 or more, more preferably 10 or more. The upper limit of the weight ratio is not particularly limited, but for example, it can be preferably 2000 or less, and more preferably 1000 or less. The weight ratio can be within any combination of the lower and upper limits, for example, the weight ratio can be preferably 5 to 2000, more preferably 10 to 2000, and even more preferably 10 to 1000. The liquid additive is preferably a surfactant.

[0068] In the composition according to the present invention, the weight ratio of the total liquid additive and the oily component to the compound represented by formula (1), or its salt, or its solvate (total liquid additive and oily component / compound 1 or its salt, or its solvate) is not particularly limited, but preferably 10 or more, as long as compound 1 or its salt, or its solvate, can be dissolved. The upper limit of the weight ratio is not particularly limited, but for example, it can be preferably 2000 or less, and more preferably 1000 or less. The weight ratio can be within any combination of the lower and upper limits, for example, the weight ratio can be preferably 10 to 2000, more preferably 10 to 2000. The liquid additive is preferably a surfactant.

[0069] The composition of the present invention may be in the form of a liquid, a gel, or a semi-solid, and is preferably a liquid.

[0070] The composition according to the present invention is characterized by having a small average particle size and a narrow particle size distribution when the composition is dispersed in a liquid such as water.

[0071] For example, with respect to a mixed solution of the composition of the present invention and water, when the mixed solution is stirred at a temperature suitable for handling such as stirring and mixing of the composition, and / or a temperature that does not affect the stability of the substances contained in the composition, such as around room temperature (about 25°C), under a certain dilution ratio (e.g., the composition is 0.01 to 1 volume%) of the total mixed solution, and the composition of the present invention is dispersed in the solution, the average particle size of the droplets formed is preferably less than 200 nm, more preferably 10 nm or more and less than 200 nm, and even more preferably 50 nm or more and less than 200 nm. Furthermore, the composition of the present invention has a polydispersity index (PDI), which is an index representing the particle size distribution, preferably less than 0.5, more preferably 0.4 or less, and even more preferably 0.3 or less. The average particle size and polydispersity index of the compounds in the composition can be determined using known methods such as dynamic light scattering (DLS).

[0072] Furthermore, even with regard to mixed solutions using a solution that simulates the internal environment of the body (for example, the Japanese Pharmacopoeia Dissolution Test Solution No. 1, pH 1.2, used in disintegration tests of enteric-coated preparations, and simulated internal body temperature (e.g., 36-37°C)), when the composition of the present invention is dispersed in the solution by stirring at a certain dilution ratio (e.g., the composition is 0.01-1 volume percent of the total mixed solution), the particle size distribution of the droplets formed can similarly exhibit the characteristics of a small average particle size and a narrow particle size distribution. In other words, droplets with a small average particle size and a narrow particle size distribution can be formed even in the digestive tract.

[0073] Such compositions of the present invention may have excellent dispersibility in liquids and excellent absorption in the body.

[0074] <Pharmaceutical preparations> The pharmaceutical formulation according to the present invention is a pharmaceutical formulation comprising a composition containing compound 1 of the present invention or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component.

[0075] The pharmaceutical formulation according to the present invention can be manufactured by introducing a pharmaceutically acceptable carrier in addition to compound 1 of the present invention or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component, and optionally an antioxidant, a solubilizer, etc. For formulation, commonly used excipients, binders, lubricants, colorants, flavoring agents, and odor-correcting agents, as well as stabilizers, emulsifiers, absorption enhancers, pH adjusters, and preservatives as needed, can be used, and the formulation can be manufactured by conventional methods using components generally used as raw materials for pharmaceutical formulations.

[0076] The formulation according to the present invention may be administered orally or parenterally. Oral administration is preferred, but the method of administration is not limited to oral administration.

[0077] For example, to manufacture an oral formulation, compound 1 of the present invention or its salt, or solvates thereof, liquid additives, any oily components, etc., are further, if necessary, combined with binders, disintegrants, lubricants, colorants, flavoring agents, odor-correcting agents, etc., and then prepared as a liquid, capsule, etc. by a conventional method. Since the composition of the present invention is preferably a liquid, liquid formulations can be made as injections or capsules.

[0078] When the composition of the present invention is made into a capsule, the capsule can be one that is commonly used in capsule formulations.

[0079] The type of capsule is not particularly limited, and those commonly used in this art can be used. For example, capsules include hard capsules and soft capsules. Hard capsules usually consist of a cap and a body, and can be manufactured by placing a cap over a body filled with a pharmaceutical product. Preferred raw materials for hard capsules include, for example, gelatin, hydroxypropyl methylcellulose, pullulan, or mixtures thereof, and their size can be defined by standards such as No. 9, No. 5, No. 4, No. 3, No. 2, No. 1, No. 0, No. 00, and No. 000. Soft capsules can be manufactured, for example, by encasing a pharmaceutical product in a base such as gelatin. Preferred raw materials for soft capsules include, for example, gelatin, starch, carrageenan, agar, glycerin, sorbitol, or mixtures thereof.

[0080] Examples of excipients include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide.

[0081] Examples of binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol / polyoxyethylene block polymer, and meglumine.

[0082] Examples of disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.

[0083] Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

[0084] As coloring agents, those permitted for addition to pharmaceuticals are used, while as flavoring and deodorizing agents, cocoa powder, peppermint, aromatic powders, peppermint oil, borneol, cinnamon powder, etc., are used.

[0085] When manufacturing liquid preparations such as syrups or injectable preparations, compound 1 used in the present invention, its salt, or a solvate thereof is compounded by conventional methods by adding a pH adjuster, a solvent, an isotonic agent, and, if necessary, a solubilizer and stabilizer.

[0086] For example, parenteral administration can be specifically described as injectable, nasal, pulmonary, or transdermal formulations. Examples of injectable formulations include intravenous, intramuscular, intraperitoneal, or subcutaneous injections, which can be administered systemically or locally. Examples of nasal formulations include absorption of the active ingredient in the formulation through the nasal mucosa or administration of the formulation through the nasal cavity, which can be administered systemically or locally. Examples of pulmonary formulations include administration of the formulation to the lungs through the trachea, which can be administered systemically or locally. Examples of transdermal formulations include application of the formulation to the skin, which can be administered systemically or locally.

[0087] Furthermore, the administration method can be appropriately selected depending on the patient's age and symptoms. The dosage of the pharmaceutical preparation containing compound 1 or its salt, or its solvates, used in this invention can be selected, for example, in the range of 0.001 mg to 100 mg per kg of body weight per dose. Alternatively, the dosage can be selected in the range of 0.1 to 1000 mg / body per patient, but is not necessarily limited to these values. The dosage and administration method will vary depending on the patient's weight, age, symptoms, etc., but a person skilled in the art can select them appropriately.

[0088] <Method for producing the composition and pharmaceutical formulation> The method for producing the composition according to the present invention is: (1) The following formula (1): [ka] Step 1: Providing a compound represented by, or a salt thereof, or solvates thereof, a liquid additive, and optionally an oily component; (2) A step of mixing the compound represented by formula (1), or a salt thereof, or a solvate thereof, a liquid additive, and optionally an oily component (step 2); and, (3) The process includes the step of obtaining a composition in which a compound represented by formula (1), a salt thereof, or a solvate thereof is dissolved (step 3).

[0089] In the method for producing the composition of the present invention, compound 1 or a salt thereof supplied in step (1), or a solvate thereof, is preferably a hydrate of the compound represented by formula (1), and more preferably contains one or more water molecules of the compound represented by formula (1). The number of water molecules contained in the hydrate of the compound represented by formula (1) can be desorbed depending on the surrounding environment such as temperature and humidity.

[0090] Furthermore, in the method for producing the composition of the present invention, the compound 1 or its salt, or its solvate supplied in step (1), is preferably a crystal of compound 1 or its salt, or its solvate 1, and more preferably a crystal of the hydrate of the compound represented by formula (1). It is desirable that the crystal of the hydrate of the compound represented by formula (1) contains one or more water molecules, but as mentioned above, the number of water molecules can be desorbed depending on the surrounding environment such as temperature and humidity.

[0091] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least one peak is included as the diffraction angle 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°).

[0092] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least one peak is included as the diffraction angle 2θ of 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°).

[0093] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least one peak is included as the diffraction angle 2θ of 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0094] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least two peaks are included as diffraction angles 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0095] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least three peaks are included as diffraction angles 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0096] Crystals of the hydrate of the compound represented by formula (1) can have a powder X-ray diffraction pattern in which at least four peaks are included as diffraction angles 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0097] Crystals of the hydrate of the compound represented by formula (1) may have a powder X-ray diffraction pattern in which at least five peaks are included as diffraction angles 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0098] Crystals of the hydrate of the compound represented by formula (1) can have a powder X-ray diffraction pattern in which at least six peaks are included as diffraction angles 2θ from among 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0099] The hydrate crystals of the compound represented by formula (1) preferably have a powder X-ray diffraction pattern in which the diffraction angle 2θ includes peaks at 7.921°, 9.956°, 10.435°, 11.729°, 12.704°, 15.895°, and 16.643° (±0.2°).

[0100] It is more preferable that the hydrate crystals of the compound represented by formula (1) have a powder X-ray diffraction pattern in which the diffraction angle 2θ includes peaks at 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°).

[0101] It is even more preferable that the hydrate crystals of the compound represented by formula (1) have a powder X-ray diffraction pattern in which the diffraction angle 2θ includes peaks at 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 14.752°, 14.968°, 15.895°, 16.190°, 16.643°, 17.813°, and 19.424° (±0.2°).

[0102] The analysis by powder X-ray diffraction according to the present invention can be performed according to conventional methods, such as the "Powder X-ray Diffraction Measurement Method" described in the Japanese Pharmacopoeia (15th Edition). Furthermore, according to the Japanese Pharmacopoeia, the diffraction angles 2θ typically coincide within a range of ±0.2° for the same crystal form. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction perfectly coincide, but also crystals in which the diffraction angles of the peaks coincide with an error of approximately ±0.2°.

[0103] The proportions of each component used, such as Compound 1 or its salts, or their solvates, liquid additives, and oily components, are as described above.

[0104] In the step of mixing each component, the compound represented by formula (1), or its salt, or its solvates, liquid additives, and optionally each component of the oily component, as well as components commonly used as excipients for pharmaceuticals as needed, are put into a known stirring and mixing device and mixed.

[0105] The mixing temperature and mixing time for each component are not particularly limited, as long as they do not adversely affect the components. For example, the mixing temperature is preferably 0 to 50°C, more preferably 10 to 30°C, and the mixing time is preferably about 5 to 60 minutes.

[0106] A method for producing a pharmaceutical formulation according to the present invention may include the steps of providing a composition of the present invention and formulating the composition to provide a pharmaceutical formulation.

[0107] A method for producing a pharmaceutical formulation according to the present invention may include the steps of providing the composition of the present invention and filling capsules with the composition to produce a capsule formulation.

[0108] The method for producing a pharmaceutical formulation according to the present invention may include a step of filling capsules with the composition obtained from the method for producing the composition, thereby providing a capsule formulation. That is, the method may include a step of filling capsules with the composition obtained from steps (1) to (3) in the method for producing the composition, thereby providing a capsule formulation.

[0109] In this invention, the meaning of the terms "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0110] In this specification, the term "approximately" when used in combination with a number means a range of values ​​within +10% and -10% of that number.

[0111] In this specification, the range symbol "~" includes the values ​​at both ends of the range; for example, "A~B" means a range where A is greater than or equal to B and B is less than or equal to B.

[0112] In this specification, the unit of molecular weight is "g / mol". In this specification, the unit of molecular weight may be omitted.

[0113] The use of the articles “a,” “an,” and “the” in both this specification and the claims shall be interpreted as encompassing both singular and plural forms unless otherwise specifically indicated herein or explicitly refuted by the context.

[0114] All prior art documents cited herein are incorporated herein by reference. [Examples]

[0115] The present invention will be further illustrated by the following examples and reference examples, but the present invention is not limited thereto. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. The LC / MS analytical conditions are shown in Table 1.

[0116] [Table 1]

[0117] Unless otherwise indicated herein, the meanings of English terms and abbreviations used herein are as follows: Triacetin Oleic acid: Oleic acid Propylene glycol (PG) monocaprylate: Propylene glycol monocaprylate Glycerol monooleate: Glycerol monooleate Sorbitan trioleate: Sorbitan trioleate Polyoxyl 35 castor oil: Polyoxyethylene (15) hydroxystearate PEG-8 Caprylic / Capric Glycerides: Caprylocaproyl polyoxyl-8 glycerides Polysorbate 80: Polysorbate 80 Propylene glycol (PG): Propylene glycol EtOH: Ethanol PEG400: Polyethylene glycol 400 D-α-Tocopherol polyethylene glycol 1000 succinate: D-α-Tocopherol polyethylene glycol 1000 succinate dl-α-tocopherol:dl-α-tocopherol

[0118] Boc:tert-butoxycarbonyl t-Butyl CSA: (+)-10-Camphor sulfonic acid DBU:1,8-Diazabicyclo[5.4.0]-7-Undecene DCM: Dichloromethane DCE: 1,2-Dichloroethane DMA: Dimethylacetamide DMF: N,N-dimethylformamide DIC: N,N'-Diisopropylcarbodiimide DIPEA: N,N-diisopropylethylamine DMAP: N,N-dimethyl-4-aminopyridine DMSO: Dimethyl sulfoxide EDTA: Ethylenediaminetetraacetic acid Fmoc:9-Fluorenylmethyloxycarbonyl Fmoc-OSu: N-succinimidyl 9-fluorenylmethyl carbonate HOAt: 1-Hydroxy-7-Azabenzotriazole HOBt: 1-hydroxybenzotriazole HOOBt:3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine MTBE: Methyl tert-butyl ether NMP: N-methyl-2-pyrrolidone oxyma: ethyl cyano(hydroxyimino)ethyl acetate TES: Triethylsilane TFA: Trifluoroacetic acid TFE: 2,2,2-trifluoroethanol THF: Tetrahydrofuran TfOH: Trifluoromethanesulfonic acid TsOH: p-toluenesulfonic acid WSCI·HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0119] Unless otherwise specified, the reagents used in the implementation of this invention, such as liquid additives, surfactants, oily components, solubilizers, antioxidants, or solvents, were supplied by commercial suppliers without purification.

[0120] The mixing of additives, compounds represented by formula (1), salts thereof, or solvates thereof with additives or formulations was carried out using conventional laboratory equipment and by methods well known to those skilled in the art, such as shaking or stirring, to ensure that the mixture was homogeneous.

[0121] The solubility of the compound represented by formula (1), its salt, or its solvate was measured by adding an additive or formulation to the compound, then performing operations such as shaking or stirring, visually confirming dissolution, and calculating the solubility from the volume of liquid added. Measurement is also possible using instruments such as high-performance liquid chromatography.

[0122] Test Method 1: Measurement of particle size distribution by dynamic scattering (DLS) The particle size distribution is determined by dynamic scattering (DLS) using the ZETASIZER Nano-ZS (Malvern). The sample is placed in a disposable cell (small volume cuvette) and set in the ZETASIZER Nano-ZS (Malvern) to determine the particle size distribution by dynamic scattering (DLS). The average particle size (Z-average size) and the polydispersity index (PDI) are used as indicators to represent the particle size distribution. Z-average is the average particle size based on scattering intensity using the cumulant method. PDI is an indicator that represents the width of the particle size distribution and is shown in the range of 0 to 1. PDI=0 represents a suspension with no particle size distribution, dispersions with a PDI of 0.1 or less are considered monodisperse, and dispersions with a PDI value between 0.1 and 0.5 are considered to have a narrow distribution. On the other hand, dispersions with a PDI greater than 0.5 are considered polydisperse.

[0123] Test Method 2: Assessment of Variance To estimate the dispersion performance of the formulations in fasting intestinal fluid (FaSSIF), the dispersion profile was analyzed using a μDISS Profiler (Pion Inc.). 100 μL of each formulation was added to a 10 mL FaSSIF surface kept warm at 37°C and stirred at a speed of 200 rpm. At 5, 10, 15, 20, 25, 30, and 60 minutes, 50 μL of the solution was dispensed from the center of the container through a guide plastic tube, and the concentration of the target compound was determined by UPLC. The degree of dispersion (%) was calculated using the following formula. Degree of dispersion (%) = (Concentration of compound in the sampled solution / Concentration of compound when the entire formulation is uniformly dispersed) x 100

[0124] Test Method 3: Calculation of Pharmacokinetic Parameters The collected blood is separated into plasma by centrifugation, deproteinized with acetonitrile, and then the plasma concentration is measured using an LC-MS / MS instrument. From the obtained plasma concentration profiles, the area under the plasma drug concentration-time curve (AUC) and peak plasma concentration (Cmax) are calculated using non-compartmental analysis with the pharmacokinetic analysis software Phoenix WinNonlin 8.2 (Certara LP).

[0125] Preparation Example 1: Manufacturing of Compound 1 Compound 1 having the following structure ("(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4, 7,10,13,17,20,23,28,31,34,37-Undekaoxotetratriacontahydro-2H,4H-Spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]Undekaazacyclotetratriacontin-21,1'-cyclopentane]-15-Carboxamide) was synthesized according to Scheme 1 below.

[0126] compound 1 [ka]

[0127] Scheme 1 [ka]

[0128] Synthesis of compound aa033-b ((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid)

[0129] [ka]

[0130] Fmoc-Asp(OAl)-OH((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (200 g, 506 mmol), p-toluenesulfonic acid (5.7 g, 0.05 equivalents), and paraformaldehyde (45.6 g, 3 equivalents) were mixed with toluene and stirred at 110°C for 16 hours. The reaction mixture was drained under reduced pressure, the residue was dissolved in ethyl acetate, and washed twice with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then drained under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0 / 100~30 / 70) to obtain compound aa033-a (9H-fluoren-9-ylmethyl (4S)-5-oxo-4-(2-oxo-2-prop-2-enoxyethyl)-1,3-oxazolidine-3-carboxylate) (175g, 85%). Another batch synthesized in the same manner was mixed and used in the next reaction. LCMS(ESI)m / z=408(M+H) + Retention time: 1.407 minutes (Analysis conditions SMDmethod_20)

[0131] A mixed solution of compound aa033-a (100g, 245mmol), zinc bromide (ZnBr2) (110g, 496mmol), and triethylsilane (TES) (56g, 481.6mmol) in dichloromethane (DCM) (1L) was stirred at room temperature under a nitrogen atmosphere for 48 hours. Four batches of the same scale reaction mixture were mixed and the solvent was removed under reduced pressure. The residue was dissolved in MTBE and extracted 10 times with 0.5M phosphate buffer (pH=approximately 7.5). The aqueous layers were mixed, the pH was adjusted to 2 with 5M hydrochloric acid solution, and extracted twice with isopropyl acetate (IPAC). The organic layers were mixed, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To remove IPAC, MTBE was added to the resulting residue and the solvent was removed under reduced pressure, a process that was repeated six times to obtain compound aa033-b((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid). (270g, 54%) LCMS(ESI)m / z=410(M+H) + Retention time: 1.956 minutes (Analysis conditions SMDmethod_05)

[0132] Synthesis of compound aa011-a Under a nitrogen atmosphere and ice cooling, HOBt (17.72g, 131mmol) was added to a solution of WSCI·HCl (27.4g, 143mmol) in DMF (217mL), and then compound aa033b (48.8g, 119mmol) was added as a mixed solution of DCM (90mL) and DMF (90mL), and the mixture was stirred at 0°C for 30 minutes. Dimethylamine THF solution (2mol / l, 65.6mL, 131mmol) was added dropwise, and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with ethyl acetate (488 mL), the organic phase was washed twice with hydrochloric acid (1 mol / L, 390 mL), then with water, and further washed twice with a mixture of saturated sodium bicarbonate aqueous solution and water (1:1, 488 mL). Finally, it was washed once with a mixture of saturated brine and water (1:1, 488 mL). The resulting organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound aa011-a (51.16 g, yield 98%). LCMS(ESI)m / z=437.0(M+H) + Retention time: 1.262 minutes (Analysis conditions SMDFA05)

[0133] Synthesis of compound aa079, (2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid (Fmoc-MeGly(cPent)-OH) [ka]

[0134] Compound aa079-a ((2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonylamino]acetic acid, Fmoc-Gly(cPent)-OH) (CAS No.: 220497-61-0) (30.0 g, 82 mmol), paraformaldehyde (7.39 g, 246 mmol), and CSA (0.954 g, 4.10 mmol) were mixed in toluene (160 mL). Trifluoroacetic acid (TFA) (9.0 mL) was added, and the mixture was stirred at 60 °C for 4 hours. After the reaction mixture was cooled to room temperature, the solid was removed by filtration. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate (220 mL), and then washed sequentially with saturated sodium bicarbonate aqueous solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound aa079-b as the crude product. No further purification was performed, and the next reaction was carried out. LCMS(ESI)m / z=378(M+H) + Retention time: 1.01 minutes (Analysis conditions SQDFA05)

[0135] Using the entire amount of compound aa079-b obtained above, trifluoroacetic acid (TFA) (76 mL, 984 mmol) was added to a mixture of triethylsilane (TES) (65.5 mL, 410 mmol) and dichloroethane (DCE) (90 mL) of aa079-b, and the mixture was stirred at 60°C for 16 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the resulting solid was washed with n-hexane / ethyl acetate (95 / 5) and dried under reduced pressure to obtain compound 2279 ((2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid, Fmoc-MeGly(cPent)-OH) (29.1 g, 2 steps, 93%). LCMS(ESI)m / z=380(M+H) + Retention time: 0.92 minutes (Analysis conditions SQDFA05)

[0136] Synthesis of compound 1217-a Solution A was obtained by adding WSCI·HCl (31.5 g, 164 mmol) at room temperature to a solution of compound aa079 (42.2 g, 111 mmol) and Oxyma (19.99 g, 141 mmol) in DMF (391 mL) and stirring for 30 minutes.

[0137] Under a nitrogen atmosphere, DBU (17.49 mL, 117 mmol) was added dropwise to a solution of compound aa011-a (51.16 g, 117 mmol) in DMF (391 mL) at room temperature, and the mixture was stirred for 5 minutes. Pyridine hydrochloride (14.9 g, 129 mmol) was then added, and the mixture was stirred for 10 minutes. Solution A and DIPEA (22.46 mL, 129 mmol) were added to the resulting reaction mixture, and the mixture was stirred under a nitrogen atmosphere at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (422 mL), washed twice with hydrochloric acid (1 mol / L, 422 mL), and the resulting aqueous phase was extracted twice with ethyl acetate (422 mL). All organic phases were mixed and washed sequentially with water (422 mL), a 1:1 mixture of saturated sodium bicarbonate aqueous solution and water (422 mL), and a 1:1 mixture of saturated brine and water (422 mL). The resulting organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. DCM (512 mL) was added to the resulting residue and stirred for 0.5 hours. Magnesium sulfate (30 g) was then added and stirred for 30 minutes, after which the solids were removed by filtration. The resulting solution was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 1217-a (55.55 g, yield 87%). LCMS(ESI)m / z=598.2(M+Na) + Retention time: 1.320 minutes (Analysis conditions SMDAM05)

[0138] Synthesis of compound 1217-b Under a nitrogen atmosphere at room temperature, a solution of compound 1217-a (55.55 g, 96 mmol) in DCM (193 mL) was mixed with tetrakis(triphenylphosphine)palladium(0) (1.115 g, 0.965 mmol), and then phenylsilane (8.31 mL, 67.5 mmol) was added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with MTBE (556 ml) and extracted with a mixture of saturated sodium bicarbonate aqueous solution and water (1:1,556 ml). The resulting organic phase was extracted with water (278 ml). The aqueous phase was mixed, and DCM (556 ml) was added. Phosphoric acid (56.7 g, 579 mmol) was added dropwise to adjust the pH to 2-3, and after separating the organic phase, the aqueous phase was extracted with DCM (556 ml). The obtained organic phases were mixed, washed with a saturated brine and water mixture (1:1, 556 ml), dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 1217-b. (48.87 g, yield 95%) LCMS(ESI)m / z=536(M+H) + Retention time: 1.138 minutes (Analysis conditions SMDAM05)

[0139] Synthesis of compound 1217-b-resin 2-chlorotrityl chloride resin (purchased from SUNRESIN, 1.36 mmol / g, 114 g, 155 mmol) was placed in a reaction vessel with a filter, DCM (1140 mL) was added, and the mixture was stirred at 25°C for 45 minutes, after which the solvent was drained through the filter. Compound 1217-b (48.87 g, 91 mmol), methanol (29.6 mL, 730 mmol), and DIPEA (76 mL, 438 mmol) in a DCM (798 mL) solution were added to the reaction vessel, and the mixture was stirred at 25°C for 60 minutes, after which the solution was drained through the filter. Subsequently, methanol (111 mL, 2737 mmol) and DIPEA (76 mL, 438 mmol) in a DCM (684 mL) solution were added to the reaction vessel, and the mixture was stirred at 25°C for 90 minutes, after which the solution was drained through the filter. DCM (570 mL) was added to the reaction vessel, and the mixture was stirred for 5 minutes, after which the solution was drained through the filter. The washing operation of this resin was repeated four more times, and the resulting resin was dried under reduced pressure to obtain compound 1217-b-resin (140.5 g). The supported amount was calculated to be 0.482 mmol / g using the resin quantification method described in this example.

[0140] Synthesis of compound 1217-c-resin The resin obtained above (0.482 mmol / g, 60 g, 28.92 mmol) was placed in a plastic solid-phase reaction vessel. At room temperature, DCM (600 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solvent was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solvent was drained from the frit. This resin washing step was repeated once more. A DMF solution of diazabicycloundecene (DBU) (2 v / v%, 420 mL) was added to this solid-phase reaction vessel to deprotect the Fmoc group. After shaking for 10 minutes, the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was drained from the frit. A solution of triethylamine hydrochloride (7.96 g, 57.8 mmol) in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was drained from the frit. A solution of DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was drained from the frit. A solution of DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes, the solution was drained from the frit. This resin washing process with DMF was repeated one more time.

[0141] A solution of Fmoc-cLeu-OH (40.7 g, 116 mmol) (CAS No.: 117322-30-2) and Oxyma (10.3 g, 72.3 mmol) in DMF (180 mL) was mixed with a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10%, 216 mL). After 2 minutes, this mixture was added to the solid-phase reaction vessel prepared above. This solid-phase reaction vessel was shaken at 50°C for 24 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was drained from the frit. This resin washing step with DMF was repeated four more times. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was drained from the frit. This resin washing step with DCM was repeated five more times. The resulting resin was dried under reduced pressure to obtain compound 1217-c-resin (62.5 g).

[0142] Synthesis of compound aa134

[0143] Synthesis of compound aa134, (2S)-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-Hph(4-CF3-35-F2)-OH [ka]

[0144] Synthesis of compound aa132-a, (1-O-benzyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate) [ka]

[0145] (4S)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid (Boc-Glu-OBn, CAS No. 30924-93-7) (200 g, 592.82 mmol), N-hydroxyphthalimide (106 g, 649.78 mmol, 1.10 equivalents), and DMAP (3.6 g, 29.47 mmol, 0.05 equivalents) were dissolved in THF (2 L) and DIC (138 mL, 1.54 equivalents) dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 16 hours, solids were removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was diluted with toluene, the resulting solid was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by recrystallization (acetone / heptane) to obtain compound aa132-a(1-O-benzyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate). (230g, 80%) LCMS(ESI)m / z=505.2(M+Na) + Retention time: 0.992 minutes (Analysis conditions SMDmethod_16)

[0146] Nickel bromide trihydrate (NiBr2·3H2O) (13.5g, 49.7 mmol, 0.3 equivalents) and 4,4'-di-tert-butyl-2,2'-bipyridyl (dtbbpy, CAS number 72914-19-3) (13.3g, 49.7 mmol, 0.3 equivalents) were added to DMA (400 mL), and the mixture was stirred at 50°C for 3 hours under a nitrogen atmosphere to prepare a Ni solution.

[0147] Compound aa132-a(1-O-benzyl 5-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate) (80 g, 166 mmol), zinc powder (54.2 g, 829 mmol, 5 equivalents), and 4-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (CAS No. 156243-64-0, 86.6 g, 332 mmol, 2 equivalents) were mixed in DMA (400 mL) under a nitrogen atmosphere at room temperature for 1 hour. The previously prepared Ni solution was added, and the mixture was stirred at room temperature for 16 hours. An aqueous solution of EDTA·2Na (800 mL, 10%) was added to the reaction mixture, and the solid was removed by filtration. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain compound aa134-a (57.2 g, 69%). LCMS(ESI)m / z=496(M+Na) + Retention time: 1.544 minutes (Analysis conditions SMDmethod_15)

[0148] A toluene mixture (690 mL) of compound aa134-a (57.2 g, 121 mmol) was cooled to 0°C, and trifluoromethanesulfonic acid (TfOH) (54.4 g, 362 mmol, 3 equivalents) was added dropwise. After stirring at room temperature for 1 hour, water (58 mL) was added. This mixture was extracted with water, and the combined aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a 60 g residue. Acetonitrile / water (400 / 400 mL) was added to the residue, and the pH was adjusted to 7 with aqueous sodium hydroxide solution (48%). Fmoc-OSu (36.6 g, 108.6 mmol, 0.9 equivalents) was added to this solution, and the pH was adjusted to 8.0 with aqueous sodium hydroxide solution (48%), after which the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered while washing with acetonitrile / water (1 / 1) to remove solid components. The filtrate was diluted with acetonitrile and adjusted to acidity with 6 mol / L hydrochloric acid solution. The precipitated solid was collected by filtration to obtain compound aa134 ((2S)-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)butanoic acid, Fmoc-Hph(4-CF3-35-F2)-OH). (52g, 83%)

[0149] LCMS(ESI)m / z=528.45(M+Na) + Retention time: 3.538 minutes (Analysis conditions SMDmethod_14) 1H-NMR(300MHz,DMSO-d6)δ12.69(s,1H),7.90(d,J=7.5Hz,2H),7.78-7.54(m,3H),7.48-7.20(m,6H),4.33(d, J=6.3Hz,2H),4.24(t,J=6.9Hz,1H),3.97-3.84(m,1H),2.79-2.65(m,2H),2.15-2.00(m,1H),2.00-1.83(m,1H)

[0150] Synthesis of compound aa113, (2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid (Fmoc-EtPhe(4-Me)-OH) [ka]

[0151] Under a nitrogen atmosphere, compound aa113-a ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-methylphenyl)propanoic acid, Fmoc-Phe(4-Me)-OH) (5.62 g, 14.0 mmol, CAS number 199006-54-7) was suspended in dichloroethane (DCE) (17.5 mL), and paraaldehyde (5.61 mL, 42.0 mmol) and trifluoroacetic acid (TFA) (9.65 mL, 126 mmol) were added. The mixture was stirred at 60°C for 6 hours. The resulting reaction solution containing compound aa113-b was used directly in the next step. LCMS(ESI)m / z=428(M+H) + Retention time: 1.03 minutes (Analysis conditions SQDFA05)

[0152] To the reaction solution of the obtained compound aa113-b, dichloroethane (DCE) (17.5 mL), trifluoroacetic acid (TFA) (19.3 mL, 252 mmol), and triethylsilane (TES) (20.1 mL, 126 mmol) were added, and the mixture was stirred at 60°C for 17 hours. After cooling to room temperature and concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate (40 mL). The organic layer was washed with saturated sodium bicarbonate aqueous solution (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL), washed twice with hexane (15 mL), and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid-containing acetonitrile / 0.1% formic acid-containing distilled water) to obtain compound aa113((2S)-2-[ethyl(9H-fluoren-9-ylmethoxycarbonyl)amino]-3-(4-methylphenyl)propanoic acid, Fmoc-EtPhe(4-Me)-OH). (4.4g, 2 steps, 73%) LCMS(ESI)m / z=430(M+H) + Retention time: 0.95 minutes (Analysis conditions SQDFA05)

[0153] The subsequent extensions of Fmoc-Pro-OH (CAS No.: 71989-31-6), Fmoc-Hph(4-CF3-35-F2)-OH (compound aa134), Fmoc-MeGly-OH (CAS No.: 77128-70-2), Fmoc-EtPhe(4-Me)-OH (compound aa113), Fmoc-Aze(2)-OH (CAS No.: 136552-06-2), Fmoc-MeAla-OH (CAS No.: 84000-07-7), and Fmoc-Ile-OH (CAS No.: 71989-23-6) were synthesized using the Fmoc solid-phase synthesis method with an Intavis peptide synthesizer (Multipep RSi). Detailed procedures were followed according to the manual provided with the synthesizer.

[0154] The compound 1217-c-resin obtained as described above (200 mg per solid-phase reaction vessel) was added to 30 solid-phase reaction vessels and set up in a peptide synthesizer. Dichloromethane (DCM) was added to all 30 solid-phase reaction vessels and allowed to stand for 1 hour to swell the resin. After that, the solvent was drained from the frit.

[0155] Elongation of Fmoc-Pro-OH A DMF solution of diazabicycloundecene (DBU) (2v / v%, 1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and after heating to 30°C for 10 minutes, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was then added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process with DMF was repeated three more times. Next, an NMP solution of Fmoc-Pro-OH (CAS number 71989-31-6) (0.6 mol / L) and HOAt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed using the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels. The mixture was then allowed to stand at 40°C for 4 hours. After that, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0156] Elongation of Fmoc-Hph(4-CF3-35-F2)-OH (compound aa134) A DMF solution of diazabicycloundecene (DBU) (2v / v%, 1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels containing the resin obtained above, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process with DMF was repeated three more times. Next, an NMP solution of Fmoc-Hph(4-CF3-35-F2)-OH (compound aa134) (0.45 mol / L) and HOAt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels. The mixture was then allowed to stand at 40°C for 2.5 hours. After that, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0157] Elongation of Fmoc-MeGly-OH To all 30 solid-phase reaction vessels containing the resin obtained above, a DMF solution of diazabicycloundecene (DBU) (2 v / v%, 1.4 mL per solid-phase reaction vessel) was added, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing step with DMF was repeated three more times. Subsequently, an NMP solution of Fmoc-MeGly-OH (0.6 mol / L) and HOAt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed using the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels, and allowed to stand at 40°C for 2.5 hours. Subsequently, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0158] Extension of Fmoc-EtPhe(4-Me)-OH (compound aa113) A DMF solution of diazabicycloundecene (DBU) (2v / v%, 1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels containing the resin obtained above, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process with DMF was repeated three more times. Next, the NMP solution of Fmoc-EtPhe(4-Me)-OH (0.6 mol / L) and HOAt (0.375 mol / L) prepared as described above (0.6 mL per solid-phase reaction vessel) and the DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels. The mixture was then allowed to stand at 40°C for 2.5 hours. After that, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0159] Elongation of Fmoc-Aze(2)-OH A DMF solution of diazabicycloundecene (DBU) (2v / v%, 1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels containing the resin obtained above, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process with DMF was repeated three more times. Next, a mixed solution of NMP and DMSO (7:3) of Fmoc-Aze(2)-OH (0.6 mol / L) and HOOBt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed in the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels, and allowed to stand at 60°C for 5 hours. Subsequently, a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and allowed to stand at 60°C for 5 hours. After that, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0160] Elongation of Fmoc-MeAla-OH To all 30 solid-phase reaction vessels containing the resin obtained above, a DMF solution of diazabicycloundecene (DBU) (2 v / v%, 1.4 mL per solid-phase reaction vessel) was added, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing step with DMF was repeated three more times. Subsequently, an NMP solution of Fmoc-MeAla-OH (0.6 mol / L) and HOAt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed using the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels, and allowed to stand at 40°C for 2.5 hours. Subsequently, the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times.

[0161] Elongation of Fmoc-Ile-OH To all 30 solid-phase reaction vessels containing the resin obtained above, a DMF solution of diazabicycloundecene (DBU) (2 v / v%, 1.4 mL per solid-phase reaction vessel) was added, and the mixture was heated to 35°C for 10 minutes before the solution was drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing step with DMF was repeated three more times. Subsequently, an NMP solution of Fmoc-Ile-OH (0.6 mol / L) and HOAt (0.375 mol / L) (0.6 mL per solid-phase reaction vessel) and a DMF solution of N,N'-diisopropylcarbodiimide (DIC) (10 v / v%, 0.72 mL per solid-phase reaction vessel) were mixed using the mixing vial of the synthesizer and added to all 30 solid-phase reaction vessels, and allowed to stand at 40°C for 10 hours. The solution was then drained from the frit. DMF (1.4 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated two more times. Subsequently, DCM (1.6 mL per solid-phase reaction vessel) was added to all 30 solid-phase reaction vessels, and the solvent was drained from the frit. This resin washing process was repeated five more times. The resin was collected from all 30 solid-phase reaction vessels, mixed, and the subsequent operations were carried out.

[0162] Elongation of Fmoc-MeLeu-OH (CAS number: 103478-62-2) The resin obtained above was added to a 200 mL plastic solid-phase reaction vessel, and 60 mL of DCM was added. After shaking at 30°C for 5 minutes, the solvent was drained from the frit. 50 mL of toluene was added to this solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This toluene washing step for the resin was repeated once more. A toluene solution of diazabicycloundecene (DBU) (2 v / v%, 45 mL) was added to this solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solution was drained from the frit.

[0163] To this solid-phase reaction vessel, 50 mL of toluene was added and shaken at 30°C for 5 minutes, after which the solvent was drained from the frit. This toluene washing step for the resin was repeated once more. To this solid-phase reaction vessel, 50 mL of DCM was added and shaken at 30°C for 5 minutes, after which the solvent was drained from the frit. This DCM washing step for the resin was repeated once more. To this solid-phase reaction vessel, a solution of Fmoc-MeLeu-OH (4.25 g, 11.57 mmol), [ethylcyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxym) (6.10 g, 11.57 mmol), and DIPEA (3.03 mL, 17.35 mmol) in 45 mL of DCM was added and shaken at 30°C for 3 hours. After that, the solution was drained from the frit. 50 mL of DMF was added to the solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times. 50 mL of DCM was added to the solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This resin washing step with DCM was repeated three more times. The resulting resin was then dried under reduced pressure.

[0164] 60 mL of DCM was added to the solid-phase reaction vessel described above, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. 50 mL of DMF was added to this solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This DMF washing step was repeated one more time. 45 mL of a DMF solution of diazabicycloundecene (DBU) (2 v / v%) was added to this solid-phase reaction vessel, and after shaking at 30°C for 15 minutes, the solution was drained from the frit. 50 mL of DMF was added to this solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This DMF washing step was repeated four more times. 50 mL of DCM was added to this solid-phase reaction vessel, and after shaking at 30°C for 5 minutes, the solvent was drained from the frit. This DCM washing step was repeated four more times to obtain a resin supported with compound 1217-d.

[0165] Synthesis of compound 1217-d (excision of peptide from resin) A mixed solution of 2,2,2-trifluoroethanol (TFE) (60 mL), DCM (60 mL), and DIPEA (0.909 mL) was added to the solid-phase reaction vessel containing the resin obtained above, and the mixture was shaken at room temperature for 2 hours. The solution was then collected from the frit. A mixed solution of 2,2,2-trifluoroethanol (TFE) (30 mL) and DCM (30 mL) was added to this solid-phase reaction vessel, and the mixture was shaken at room temperature for 5 minutes, after which the solution was collected from the frit. Furthermore, a mixed solution of 2,2,2-trifluoroethanol (TFE) (30 mL) and DCM (30 mL) was added to this solid-phase reaction vessel, and the mixture was shaken at room temperature for 5 minutes, after which the solution was collected from the frit. All the collected solutions were mixed, and the solvent was removed under reduced pressure to obtain compound 1217-d as the crude product (3.85 g). LCMS(ESI)m / z=1453.9(MH)- Retention time: 0.67 minutes (Analysis conditions SQDAA50)

[0166] Synthesis of Compound 1 (Peptide cyclization and purification) Compound 1217-d (3.85 g) obtained as described above was dissolved in a mixture of isopropyl acetate (529 mL) and DIPEA (0.915 mL, 5.24 mmol), and HCTU (O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, CAS number 330645-87-9) (1.805 g, 4.36 mmol) was added, and the mixture was stirred at room temperature for 21 hours. After that, the solvent was removed under reduced pressure until the volume of the solution was reduced to about half. A mixture of saturated ammonium chloride aqueous solution (40 mL) and water (40 mL) was added to the obtained solution, and the mixture was extracted with isopropyl acetate (350 mL). The obtained organic phase was sequentially washed with a mixture of saturated sodium bicarbonate aqueous solution (40 mL) and water (40 mL), and then with a mixture of saturated saline solution (40 mL) and water (40 mL). After drying with sodium sulfate, the solvent was removed under reduced pressure to obtain 3.36 g of residue. The obtained residue was purified by reverse-phase silica gel column chromatography (Daisogel SP-120-40 / 60-ODS-RPS, using acetonitrile (containing 0.1% formic acid) / water (containing 0.1% formic acid) as the eluate), and the eluate containing the target product was freeze-dried to obtain amorphous compound 1 (1.36 g, yield 34%). The mass spectral values ​​and liquid chromatography retention times of the obtained compound 1 are as follows. LCMS(ESI)m / z=1437.7(M+H) + Retention time: 7.496 minutes (Analysis conditions SSC-A-AF-01)

[0167] Preparation Example 2: Preparation of seed crystals used in Preparation Example 3 The amorphous compound 1 (122.3 mg) obtained in Preparation Example 1 was dissolved in DMSO (0.612 mL), and this solution (0.015 mL) was freeze-dried at -20°C for 2 days. A water-acetonitrile mixture (3:1, 0.015 mL) was added to the freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain hydrate crystals of compound 1 (Form C).

[0168] Preparation Example 3: Crystallization of compound 1: ((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl) Synthesis of Form C of hydrate crystals of )-4,7,10,13,17,20,23,28,31,34,37-undekaoxotetratriacontahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undekaazacyclotetratriacontin-21,1'-cyclopentane]-15-carboxamide) The reaction kettle containing the solution of Compound 1 substituted with nitrogen was charged, the external temperature of the reaction kettle was set to 40 °C, and purified water (10.9 kg) filtered using a filter (CCF-G100-D1N) was added. A suspension obtained by adding pulverized crystals of Compound 1 (10.2 g) obtained by the same operation as in Preparation Example 2 to a mixed solution of acetone (59.2 g) / water (61.2 g) was added to the reaction kettle. The container containing the suspension was added to the reaction kettle while washing it with a mixed solution of acetone (59.2 g) / water (61.2 g), and then stirred for 2 hours and 1 minute. Purified water (2.7 kg) filtered using a filter (CCF-G100-D1N) was added, and the mixture was stirred for 7 hours and 10 minutes. Further, a suspension obtained by adding pulverized crystals of Compound 1 (10.2 g) obtained by the same operation as in Preparation Example 2 to a mixed solution of acetone (59.2 g) / water (61.2 g) was added to the reaction kettle. The container containing the suspension was added to the reaction kettle while washing it with a mixed solution of acetone (59.2 g) / water (61.2 g), and then stirred for 12 hours and 40 minutes. Purified water (2.7 kg) filtered using a filter (CCF-G100-D1N) was added, and the mixture was stirred for 2 hours. After the external temperature of the reaction kettle was decreased from 40 °C to 25 °C over 1 hour, the reaction mixture was stirred for 18 hours and 44 minutes. The reaction mixture was pressure-filtered using a filter cloth (PF-020), and the crystals obtained while washing the inside of the reaction kettle and the filter with a mixed solution of acetone (7.5 kg) and purified water (7.5 kg) filtered using a filter (CCF-G100-E1N) were washed. The obtained crystals were washed with purified water (17.0 kg x 2) filtered using a filter (CCF-G100-E1N), the filtration device for recovering the crystals was depressurized, the external temperature of the filtration device was set to 70 °C, and the crystals were dried for 17 hours. Further, the crystals were dried at an external temperature of room temperature to 30 °C for 27 hours. The dried product was recovered from the filter, and 2.6 kg of white powder was obtained.

[0169] It was confirmed that the obtained white powder had the same structure as the compound obtained in "Synthesis of Compound 1 (Cyclization and Purification of Peptide)" of Preparation Example 1.

[0170] The retention time was confirmed by the HPLC analysis method shown below. HPLC analysis conditions Equipment: Waters ACQUITY UPLC H-Class Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 150 mm, 1.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B) Elution method: B) 20% (0 min) → 100% (24 min) → 100% (29 min) → 20% (29.1 min) → 20% (34 min) Flow rate: 0.3 mL / min Column temperature: 50°C Detection wavelength: 220 nm (PDA) Retention time determined by HPLC analysis: 18.199 minutes

[0171] Powder X-ray analysis was performed using the XRPD apparatus shown below. XRPD measurement conditions Measurement device: X'pert-pro MPD (manufactured by PANalytical) Source: CuKα Tube voltage: 45 kV Tube current: 40 mA Scanning range: 3~40° Scanning speed: 4.2° / min Sampling width: 0.017°

[0172] The measurement results showed that the 2θ values ​​were observed to have major peaks at 4.964°, 7.921°, 8.296°, 8.855°, 9.956°, 10.435°, 11.729°, 12.704°, 13.552°, 13.901°, 15.895°, 16.643°, and 17.813° (±0.2°). The analysis results are shown in Figure 1.

[0173] Thermogravimetric and differential thermal analysis was performed on the hydrate crystals (Form C) of compound 1 obtained by the same method as in Preparation Example 3 under the following conditions. The results are shown in Figure 2. Measurement device: TGA / DSC 3+ (manufactured by Mettler Toledo) Measurement range: 25~350℃ Heating rate: 10°C / min Atmosphere: Dry nitrogen

[0174] The water content of the hydrate crystal of compound 1 (Form C), obtained by the same method as in Preparation Example 3, was measured by Karl Fischer titration. The measurement was performed using CA-310 (manufactured by Nitto Seikou Analytech) after the sample had been acclimatized in the laboratory environment. The measurement results showed that the water content of the hydrate crystal of compound 1 (Form C) was 6.50 wt%.

[0175] The single-crystal X-ray structure analysis of the hydrate crystal (Form C) of compound 1, obtained by the same method as in Preparation Example 3, was performed under the following conditions. Measurement device: Rigaku R-AXIS RAPID-II with a VariMaxCu diffractometer (manufactured by Rigaku Corporation) Cathode: Cu Tube voltage: 40 kV Tube current: 30 mA Temperature: -180℃ Measurement: Measurements were performed using a strategy and exposure time that was expected to yield sufficient diffraction spots for structural analysis. Structural analysis: Initial structure determination was performed using direct methods (SIR2004, CrystalStructure, Rigaku), and structural refinement was performed using the full-matrix least-squares method (SHELXL-2017 / 1, APEX3, Bruker). All non-hydrogen atoms were refined using an anisotropic temperature factor. Hydrogen atoms in water molecules were placed in appropriate positions using restraining and refined using an isotropic temperature factor 1.5 times larger than that of the bonded oxygen atoms. Other hydrogen atoms were placed in appropriate positions using a riding model and were given an isotropic temperature factor 1.2 times larger than that of the bonded non-hydrogen atoms. The results are shown in Figure 3.

[0176] Based on the results of thermogravimetric and differential thermal analysis, Karl Fischer titration, and single-crystal X-ray structural analysis, it was confirmed that the hydrate crystal of compound 1 (Form C) is indeed a hydrate crystal containing water molecules in its crystal structure.

[0177] The dynamic vapor sorption measurement of the hydrate crystal (Form C) of Compound 1 obtained in the same manner as in Preparation Example 3 was carried out. The results are shown in Figure 4. Measuring device: DVS Intrinsic (manufactured by Surface Measurement Systems) Temperature: 25 °C Relative humidity (%) measurement points: Cycle 1: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, 0 (%); Cycle 2: 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 90, 80, 70, 60, 50, 40, 30, 20, 10, 0 (%) Threshold value: 0.001 dm / dt (% / min) Minimum sorption time: 10 minutes Maximum sorption time: 1440 minutes

[0178] As a result of the measurement, it was confirmed that the hydrate crystal (Form C) of Compound 1 is a hydrate crystal that changes in weight by 3.3% with the change in the hydration number in the range of relative humidity of 0 to 95%.

[0179] The hydrate crystal (Form C) of Compound 1 obtained in Preparation Example 3 (hereinafter sometimes referred to as "Compound I") was used for the preparation and evaluation of the following compositions or preparations. Hereinafter, the compound serving as the active ingredient used in the examples is described as "Compound I", but Compound I dissolved in a liquid additive or the like means the free Compound 1.

[0180] Search for compositions containing compound I Test Example 1 (Evaluation of solubility of compound I in various additives) The solubility of compound I in various additives was determined. Liquid additives were added to compound I and stirred. If compound I did not dissolve, further additives were added and stirred again. This process was repeated until compound I dissolved, and the approximate solubility was determined from the amount of additive required to dissolve compound I. Polyoxyethylene (15) hydroxystearate (Solutol HS15) is a solid at room temperature (RT), so it was heated to 37°C to become liquid before determining its solubility. The solubility of other additives was determined at room temperature. The results are shown in Table 2. The results showed that PG monocaprylate exhibited high solubility in compound I.

[0181] [Table 2]

[0182] Test Example 2 (Evaluation of the solubility of compound I in each formulation) Additive mixtures using PG monocaprylate, which exhibited high solubility, were prepared based on the formulations in Table 3. Next, the solubility of compound I in each additive mixture 1 to 4 was measured. Assuming water transfer from the capsule shell when formulated as capsules, the solubility of additive mixtures with 3% water added was also measured. As shown in Table 4, it was found that additive mixtures 1 to 4 could dissolve compound I at a high concentration of 100 mg / mL or more. Furthermore, when water was added to each additive mixture, the solubility of compound I decreased to 60-70 mg / mL, so it was decided that the solubility of compound I in each additive mixture would be evaluated with water added from then on.

[0183] [Table 3]

[0184] [Table 4]

[0185] Furthermore, in order to find the optimal formulation, additive mixtures 5 to 45 were prepared based on the formulations in Tables 5 to 10.

[0186] [Table 5]

[0187] [Table 6]

[0188] [Table 7]

[0189] [Table 8]

[0190] [Table 9]

[0191] [Table 10]

[0192] Next, the solubility of compound I in each formulation 5-45 to which water was added was measured. The results are shown in Table 11.

[0193] [Table 11]

[0194] Examples 1-22 Based on the formulations in Table 12, formulations A to V, which are compositions of the present invention, were prepared by the following method.

[0195] [Table 12]

[0196] Example 1 (Preparation of Formulation A) Compound I was weighed into a vial, and 1 mL of additive mixture 1 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation A was obtained.

[0197] Example 2 (Preparation of Formulation B) Compound I was weighed into a vial, and 1 mL of additive mixture 2 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation B was obtained.

[0198] Example 3 (Preparation of Formulation C) Compound I was weighed into a vial, and 1 mL of additive mixture 3 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation C was obtained.

[0199] Example 4 (Preparation of Formulation D) Compound I was weighed into a vial, and 1 mL of additive mixture 4 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation D was obtained.

[0200] Example 5 (Preparation of Formulation E) Compound I was weighed into a vial, and 1 mL of additive mixture 7 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation E was obtained.

[0201] Example 6 (Preparation of Formulation F) Compound I was weighed into a vial, and 1 mL of additive mixture 19 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation F was obtained.

[0202] Example 7 (Preparation of Formulation G) Compound I was weighed into a vial, and 1 mL of additive mixture 20 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation G was obtained.

[0203] Example 8 (Preparation of Formulation H) Compound I was weighed into a vial, and 1 mL of additive mixture 21 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation H was obtained.

[0204] Example 9 (Preparation of Formulation I) Compound I was weighed into a vial, and 1 mL of additive mixture 25 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation I was obtained.

[0205] Example 10 (Preparation of Formulation J) Compound I was weighed into a vial, and 1 mL of additive mixture 26 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation J was obtained.

[0206] Example 11 (Preparation of Formulation K) Compound I was weighed into a vial, and 1 mL of additive mixture 28 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation K was obtained.

[0207] Example 12 (Preparation of Formulation L) Compound I was weighed into a vial, and 1 mL of additive mixture 29 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation L was obtained.

[0208] Example 13 (Preparation of Formulation M) Compound I was weighed into a vial, and 1 mL of additive mixture 30 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation M was obtained.

[0209] Example 14 (Preparation of Formulation N) Compound I was weighed into a vial, and 1 mL of additive mixture 32 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation N was obtained.

[0210] Example 15 (Preparation of Formulation O) Compound I was weighed into a vial, and 1 mL of additive mixture 33 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation O was obtained.

[0211] Example 16 (Preparation of Formulation P) Compound I was weighed into a vial, and 1 mL of additive mixture 34 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation P was obtained.

[0212] Example 17 (Preparation of Formulation Q) Compound I was weighed into a vial, and 1 mL of additive mixture 35 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation Q was obtained.

[0213] Example 18 (Preparation of Formulation R) Compound I was weighed into a vial, and 1 mL of additive mixture 40 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation R was obtained.

[0214] Example 19 (Preparation of Formulation S) Compound I was weighed into a vial, and 1 mL of additive mixture 41 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation S was obtained.

[0215] Example 20 (Preparation of Formulation T) Compound I was weighed into a vial, and 1 mL of additive mixture 42 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation T was obtained.

[0216] Example 21 (Preparation of Formulation U) Compound I was weighed into a vial, and 1 mL of additive mixture 44 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation U was obtained.

[0217] Example 22 (Preparation of Formulation V) Compound I was weighed into a vial, and 1 mL of additive mixture 45 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation V was obtained.

[0218] The table below summarizes the weight percentage of each component contained in the formulations of Examples 1 to 22 relative to the total formulation. [Table 13]

[0219] Comparative Examples 1-19 Based on the formulations in Table 14, formulations W to AO, which are the compositions of the present invention, were prepared by the following method.

[0220] [Table 14]

[0221] Comparative Example 1 (Preparation of Formulation W) Compound I was weighed into a vial, and 1 mL of additive mixture 8 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation W was obtained.

[0222] Comparative Example 2 (Preparation of Formulation X) Compound I was weighed into a vial, and 1 mL of additive mixture 9 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation X was obtained.

[0223] Comparative Example 3 (Preparation of Formulation Y) Compound I was weighed into a vial, and 1 mL of additive mixture 10 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation Y was obtained.

[0224] Comparative Example 4 (Preparation of Formulation Z) Compound I was weighed into a vial, and 1 mL of additive mixture 13 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation Z was obtained.

[0225] Comparative Example 5 (Preparation of Formulation AA) Compound I was weighed into a vial, and 1 mL of additive mixture 14 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AA was obtained.

[0226] Comparative Example 6 (Preparation of Formulations A and B) Compound I was weighed into a vial, and 1 mL of additive mixture 15 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AB was obtained.

[0227] Comparative Example 7 (Preparation of Formulation AC) Compound I was weighed into a vial, and 1 mL of additive mixture 16 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AC was obtained.

[0228] Comparative Example 8 (Preparation of Formulation AD) Compound I was weighed into a vial, and 1 mL of additive mixture 17 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AD was obtained.

[0229] Comparative Example 9 (Preparation of Pharmaceutical AE) Compound I was weighed into a vial, and 1 mL of additive mixture 18 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AE was obtained.

[0230] Comparative Example 10 (Preparation of Formulation AF) Compound I was weighed into a vial, and 1 mL of additive mixture 22 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AF was obtained.

[0231] Comparative Example 11 (Preparation of Pharmaceutical Aggregate) Compound I was weighed into a vial, and 1 mL of additive mixture 23 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AG was obtained.

[0232] Comparative Example 12 (Preparation of Formulation AH) Compound I was weighed into a vial, and 1 mL of additive mixture 24 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AH was obtained.

[0233] Comparative Example 13 (Preparation of Formulation AI) Compound I was weighed into a vial, and 1 mL of additive mixture 27 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AI was obtained.

[0234] Comparative Example 14 (Preparation of Formulation AJ) Compound I was weighed into a vial, and 1 mL of additive mixture 31 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AJ was obtained.

[0235] Comparative Example 15 (Preparation of Formulation AK) Compound I was weighed into a vial, and 1 mL of additive mixture 36 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AK was obtained.

[0236] Comparative Example 16 (Preparation of Formulation AL) Compound I was weighed into a vial, and 1 mL of additive mixture 37 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AL was obtained.

[0237] Comparative Example 17 (Preparation of Formulation AM) Compound I was weighed into a vial, and 1 mL of additive mixture 38 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AM was obtained.

[0238] Comparative Example 18 (Preparation of Formulation AN) Compound I was weighed into a vial, and 1 mL of additive mixture 39 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AN was obtained.

[0239] Comparative Example 19 (Preparation of Formulation AO) Compound I was weighed into a vial, and 1 mL of additive mixture 43 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved, and formulation AO was obtained.

[0240] The table below summarizes the weight percentage of each component contained in the formulations of Comparative Examples 1 to 19 relative to the total formulation. [Table 15]

[0241] Test Example 3 (Particle Size Distribution Measurement by DLS) Next, water was added to formulations A through V prepared in Examples 1 through 22 and formulations W through AO prepared in Comparative Examples 1 through 19 to generate dispersions. The particle size of droplets formed in the dispersion was measured, and the particle size distribution at room temperature (approximately 25°C) was evaluated. 4 μL of each formulation was placed in a vial, followed by the addition of 396 μL of water. The particle size distribution of the stirred samples was then determined by dynamic scattering (DLS) using the method described in Test Method 1. The average particle size (Z-average size) and polydispersity index (PDI) were used as indices to represent the particle size distribution. In DLS, PDI is an index representing the width of the particle size distribution and is expressed in the range of 0 to 1. PDI=0 represents a suspension with no particle size distribution, dispersions with a PDI of 0.1 or less are considered monodisperse, and dispersions with a PDI between 0.1 and 0.5 are considered to have a narrow distribution. On the other hand, dispersions with a PDI greater than 0.5 are considered polydisperse. As shown in Table 16, formulations A through V all exhibited good dispersion characteristics, with small average particle sizes (less than 200 nm) and a narrow distribution with a PDI of less than 0.5. On the other hand, formulations W through AO had larger average particle sizes (greater than 200 nm) and polydisperse characteristics with a PDI exceeding 0.5.

[0242] [Table 16]

[0243] Test Example 4 (80°C Stability Test) Stability tests were conducted to estimate the long-term stability of the pharmaceuticals. First, 10 mg each of formulations A, C, F, H, and J prepared in Examples 1, 3, 6, 8, and 10 were placed in glass vials and sealed in brown bottles containing silica gel and oxygen absorber. Each brown bottle was placed in an 80°C constant temperature bath and stored for two weeks. The concentration of compound I before and after storage was quantified by UPLC, and the remaining percentage was calculated using the following formula. Remaining percentage (%) = (Concentration of compound I after storage / Concentration of compound I before storage) x 100

[0244] As shown in Table 17, compound I showed a high retention rate of over 95% in all formulations, indicating that these formulations are suitable for development as pharmaceuticals.

[0245] [Table 17]

[0246] Test Example 5 (40°C Stability Test) Since self-emulsifying formulations are liquids, they are primarily filled into capsules for development as pharmaceuticals. Therefore, 10 mg each of formulations A, C, and F prepared in Examples 1, 3, and 6 were placed in hard capsules and sealed in brown bottles containing silica gel and an oxygen absorber. Each brown bottle was placed in a 40°C constant temperature bath and stored for 6 months. The concentration of compound I before and after storage was quantified by UPLC, and the remaining percentage was calculated using the following formula. Remaining percentage (%) = (Concentration of compound I after storage / Concentration of compound I before storage) x 100

[0247] As shown in Table 18, compound I showed a high retention rate of over 95% in all formulations, indicating that these formulations are suitable for development as pharmaceuticals.

[0248] [Table 18]

[0249] Test Example 6 (Evaluation of Dispersion) According to the dispersibility evaluation method described in Test Method 2, the dispersion profiles of formulations C, F, and formulation AJ (as a comparison) in fasting artificial intestinal fluid (FaSSIF) were analyzed using a μDISS instrument providing controlled temperature and stirring speed (37°C, 200 rpm) to estimate their dispersion performance. 100 μL of each formulation was added to a 10 mL FaSSIF surface kept at 37°C and stirred at a speed of 200 rpm. At 5, 10, 15, 20, 25, 30, and 60 minutes, 50 μL of the solution was dispensed from the center of the container through a guide plastic tube, and the concentration of compound I was determined by UPLC. The degree of dispersion (%) was calculated using the following formula. Dispersion degree (%) = (Concentration of compound I in the sampled solution / Concentration of compound I when the entire formulation is uniformly dispersed) x 100

[0250] As shown in Figure 5, formulation C was found to be completely dispersed immediately after the start of the test. Furthermore, formulation F also showed a dispersion rate of over 80% after 60 minutes, and was found to be a better formulation compared to formulation AJ.

[0251] Next, formulations AP to AS were prepared to evaluate their absorption in rats. Example 23 (Preparation of AP capsule formulation for rat administration) Compound I was weighed into a vial, and 1 mL of additive mixture 3 was added per 60 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved. The solution containing the dissolved compound was filled into No. 9 gelatin capsules to prepare formulation AP.

[0252] Example 24 (Preparation of capsule formulation AQ for rat administration) Compound I was weighed into a vial, and 1 mL of additive mixture 19 was added per 60 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved. The solution containing the dissolved compound was filled into No. 9 gelatin capsules to prepare formulation AQ.

[0253] Comparative Example 20 (Preparation of AR capsule formulation for rat administration) Compound I was weighed into a vial, and 1 mL of additive mixture 31 was added per 60 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved. The solution containing the dissolved compound was filled into No. 9 gelatin capsules to prepare formulation AR.

[0254] Comparative Example 21 (Preparation of rat-administered solution formulation AS) Compound I was weighed into a vial and dissolved in 1 mL of dimethyl sulfoxide (DMSO) per 10 mg of compound I. Then, 0.5 mL of polyoxyl 35 castor oil and 8.5 mL of water were added and the mixture was thoroughly stirred to prepare solution formulation AS.

[0255] The table below summarizes the weight percentage of each component contained in the formulations of Examples 23 and 24 and Comparative Example 20 relative to the total formulation. [Table 19]

[0256] Test Example 7 (Rat Absorption Evaluation) The capsule formulations AP and AQ from Examples 23 and 24, and the capsule formulation AR and solution formulation AS from Comparative Examples 20 and 21 were orally administered to four rats (Wister Hannover, male) at a dose of 10 mg / kg for each formulation. Formulations AP, AQ, and AR were administered orally as capsules, followed by forced oral administration of 5 mL / kg of water. The solution formulation AS was administered orally as is. Blood samples were collected approximately 0.5, 1, 2, 4, 7, 24, and 48 hours after administration, and the concentration of compound I in the plasma was quantified by LC-MS / MS using the method described in Test Method 3. The area under the plasma drug concentration-time curve (AUC) and the maximum plasma concentration (Cmax) were calculated.

[0257] Table 20 shows the AUC and Cmax after administration of each formulation. Capsule formulations AP and AQ from Examples 23 and 24 were found to exhibit higher AUC and Cmax than capsule formulation AR from Comparative Example 20. Furthermore, capsule formulation AP from Example 23 was found to exhibit similar AUC and Cmax to solution formulation AS from Comparative Example 21.

[0258] [Table 20]

[0259] Next, capsule formulation AT and solution formulation AU were prepared to evaluate absorption in monkeys. Example 25 (Preparation of capsule formulation AT for administration to monkeys) Compound I was weighed into a vial, and 1 mL of additive mixture 3 was added per 50 mg of compound I. The mixture was stirred using a stirring bar to confirm that compound I was completely dissolved. The solution containing the dissolved compound was filled into No. 1 gelatin capsules to prepare formulation AT.

[0260] Comparative Example 22 (Preparation of Solution Formulation AU for Administration to Monkeys) Compound I was weighed into a vial and dissolved in 1 mL of dimethyl sulfoxide (DMSO) per 15 mg of compound I. Then, 0.25 mL of polyoxyl 35 castor oil and 8.75 mL of water were added and the mixture was thoroughly stirred to prepare solution formulation AU.

[0261] Test Example 8 (Monkey Absorption Evaluation) The capsule formulation AT from Example 25 and the solution formulation AU from Comparative Example 22 were orally administered to cynomolgus monkeys at a dose of 3 mg / kg, with four samples of each formulation administered orally. The capsule formulation AT was administered orally as is, followed by forced oral administration of 4 mL / kg of water. The solution formulation AU was administered orally as is. Blood samples were collected approximately 0.5, 1, 2, 4, 7, 24, and 48 hours after administration, and the concentration of compound I in the plasma was quantified by LC-MS / MS using the method described in Test Method 3. The area under the plasma drug concentration-time curve (AUC) and the maximum plasma concentration (Cmax) were calculated.

[0262] Table 21 shows the AUC and Cmax after administration of each formulation. It was found that the capsule formulation AT of Example 25 showed similar AUC and Cmax to the solution formulation AU of Comparative Example 22.

[0263] [Table 21]

[0264] Example 26 (Manufacturing of Capsules (Hard Capsules) 1) Compound I was weighed into a stainless steel container, and 51.5 mg of Propylene glycol monocaprylate, 13.3 mg of Oleic acid, 31.1 mg of Polyoxyl 35 castor oil, and 0.2 mg of dl-α-tocopherol were added per 0.5 mg of Compound I. The mixture was then stirred and mixed using a homogenizer. The solution containing the dissolved compounds was filled into No. 3 gelatin capsules and band-sealed to prepare formulation AV.

[0265] Example 27 (Manufacturing of Capsules (Hard Capsules) 2) Compound I was weighed into a stainless steel container, and 123.6 mg of Propylene glycol monocaprylate, 31.9 mg of Oleicacid, 74.6 mg of Polyoxyl 35 castor oil, and 0.5 mg of dl-α-tocopherol were added per 12 mg of Compound I. The mixture was then stirred and mixed using a homogenizer. The solution containing the dissolved compounds was filled into No. 3 gelatin capsules and band-sealed to prepare formulation AW.

[0266] Example 28 (Manufacturing of Capsules (Soft Capsules) 3) Compound I was weighed into a stainless steel container, and 206.4 mg of Propyleneglycol monocaprylate, 53.3 mg of Oleic acid, 124.6 mg of Polyoxyl 35 castor oil, and 0.8 mg of dl-α-tocopherol were added per 19.1 mg of Compound I. The mixture was then stirred and mixed using a stirring blade. The solution containing the dissolved compounds was filled into soft gelatin capsules to prepare formulation AX.

[0267] Example 29 (Manufacturing of Capsules (Soft Capsules) 4) Compound I was weighed into a stainless steel container, and 46.4 mg of Propylene glycol monocaprylate, 12.0 mg of Oleicacid, and 28.0 mg of Polyoxyl 35 castor oil were added per 4.5 mg of Compound I. The mixture was then stirred and mixed using a stirring blade. The solution containing the dissolved compounds was filled into soft gelatin capsules to prepare formulation AY.

[0268] Example 30 (Manufacturing of Capsules (Soft Capsules) 5) Compound I was weighed into a stainless steel container, and 61.8 mg of Propyleneglycol monocaprylate, 16.0 mg of Oleic acid, and 37.3 mg of Polyoxyl 35 castor oil were added per 6.0 mg of Compound I. The mixture was then stirred and mixed using a stirring blade. The solution containing the dissolved compounds was filled into soft gelatin capsules to prepare formulation AZ.

[0269] The table below summarizes the weight percentage of each component contained in the formulations of Examples 25-30 relative to the total formulation. [Table 22]

[0270] Test Example 9 (Particle Size Distribution Measurement by DLS) Next, the particle size distribution of formulations AV, AW, AX, AY, and AZ, prepared in Examples 26-30, was evaluated when dispersed in water. 9.9 mL of Japanese Pharmacopoeia Dissolution Test Solution 1, pH 1.2 was placed in a vial, followed by the addition of 100 μL of each formulation. 100 μL of this mixed sample was then taken and added to a vial containing 0.9 mL of Japanese Pharmacopoeia Dissolution Test Solution 1, pH 1.2, and mixed. For these samples, the particle size distribution by dynamic scattering (DLS) was determined using the method described in Test Method 1. As in Test Example 3, the average particle size (Z-average size) and polydispersity index (PDI) were used as indicators of the particle size distribution. As shown in Table 23, formulations AV, AW, AX, AY, and AZ all exhibited good dispersions with small average particle sizes (less than 200 nm) and narrow distributions with PDIs of less than 0.5.

[0271] [Table 23]

[0272] Test Example 10 (Pharmacological Test Example) Protein-protein interaction inhibitory activity between Kras and SOS1 using AlphaScreen (KrasG12D-SOS PPI) The protein-protein interaction inhibitory activity (PPI) of Kras and SOS1 can be measured by methods known to those skilled in the art, using equipment and reagents available from commercial suppliers. Specifically, biotin-tagged human Kras and His-tagged human SOS1 enzymes expressed in E. coli, purified, and loaded with GDP were used. The PPI was measured by energy transfer from nickel-conjugated donor beads to streptavidin-conjugated acceptor beads. This measurement utilizes the fact that irradiating the donor beads with 680 nm light causes energy transfer to the acceptor beads via singlet oxygen, and light of 520-620 nm is detected from the acceptor beads. The 50% inhibitory concentration (IC) was measured from the inhibition rate compared to a control group without compound 1. 50 The value was calculated.

[0273] IC of Compound 1 50 The value was 0.0010 μM. Compound 1 was shown to inhibit the protein-protein interaction between Kras and SOS1. It is known that inhibiting the binding of K-ras to SOS1 inhibits downstream signaling of Kras. Therefore, it was suggested that compound 1 also possesses cell proliferation inhibitory activity.

[0274] Measurement of AsPC-1 cell growth inhibitory activity (AsPC-1 CGI) The AsPC-1 cell growth inhibitory activity can be measured by methods known to those skilled in the art, using equipment, reagents, and cell lines available from commercial suppliers. Specifically, compound 1 was serially diluted with dimethyl sulfoxide, and 200 nL was dispensed into a U-bottom 96-well plate using Labcyte Echo. Human pancreatic cancer strain AsPC-1 was prepared as a cell suspension at a concentration of 1000 cells / 100 μL in RPMI-1640 medium supplemented with 15% fetal bovine serum. This cell suspension was dispensed at a rate of 100 μL per well into plates containing compound 1, and cultured at 37°C in a 5% carbon dioxide incubator. After 96 hours, 80 μL of CellTiter-Glo (Promega) was added to each well, and fluorescence was measured. The cell growth inhibitory activity (CGI) of the test compound was determined from the growth inhibition rate with compound 1 added compared to the control without compound 1 added. 50 The IC of compound 1 was calculated as the value. 50 The value (μM) was 0.02 μM or less, indicating that it has an antitumor effect. [Industrial applicability]

[0275] The compositions according to the present invention, by containing specific components with respect to specific compounds, can be made to exhibit various properties necessary for pharmaceutical formulations. For example, compositions containing such specific components have desirable particle characteristics, excellent stability and dispersibility of the active ingredient, and excellent absorption into the body. Therefore, the compositions according to the present invention are suitable for use as pharmaceutical formulations.

Claims

1. The following formula (1): 【Chemistry 1】 or a salt thereof, or a solvate thereof, and a liquid additive, A composition, which when dispersed in water forms droplets having an average particle size of less than 200 nm.

2. The composition of claim 1 , wherein the liquid additive is a surfactant.

3. The composition described in claim 2, wherein the surfactant is at least one selected from the group consisting of hydrophobic surfactants and hydrophilic surfactants.

4. The composition of claim 3 , wherein the surfactant is a combination of the hydrophobic surfactant and the hydrophilic surfactant.

5. The composition according to claim 4, wherein the HLB value of the hydrophobic surfactant is 0 or more and less than 10, and the HLB value of the hydrophilic surfactant is 10 or more and 30 or less.

6. The composition of claim 1 , wherein the composition further comprises an oil component.

7. The composition according to claim 1, wherein the content of the liquid additive in the entire composition is 50% by weight or more and 97% by weight or less.

8. The composition according to claim 1 , wherein a weight ratio of the liquid additive to the compound represented by formula (1), or a salt thereof, or a solvate thereof is 5 or more.

9. The composition described in claim 3, wherein the content of the hydrophobic surfactant in the entire composition is 20% by weight or more and 70% by weight or less.

10. The composition described in claim 3, wherein the content of the hydrophilic surfactant in the entire composition is 20% by weight or more and 40% by weight or less.

11. The composition described in claim 6, wherein the content of the oily component in the entire composition is 1% by weight or more and 40% by weight or less.

12. The composition described in claim 6, wherein the weight ratio of the sum of the liquid additive and the oily component to the compound represented by formula (1), or its salt, or a solvate thereof is 10 or more.

13. 2. The composition according to claim 1, wherein the content of the compound represented by formula (1), or a salt thereof, or a solvate thereof in the entire composition is 10% by weight or less.

14. The composition described in claim 1, wherein the average particle diameter of the droplets is 10 nm or more and less than 200 nm.

15. The composition according to claim 3, wherein the hydrophobic surfactant is at least one selected from the group consisting of propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, and hydrophobic polyoxyethylene hydrogenated castor oil.

16. The composition of claim 3, wherein the hydrophobic surfactant is a propylene glycol fatty acid ester.

17. The composition described in claim 16, wherein the propylene glycol fatty acid ester is at least one selected from the group consisting of propylene glycol monocaproate, propylene glycol monocaprylate, propylene glycol monocaprate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate.

18. The composition of claim 16, wherein the propylene glycol fatty acid ester is propylene glycol monocaprylate.

19. The composition according to claim 3, wherein the hydrophilic surfactant is at least one selected from the group consisting of polyethylene glycol fatty acid esters, polyoxyethylene castor oil, hydrophilic polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, D-α-tocopheryl polyethylene glycol 1000 succinate, caprylocaproyl polyoxyl-8 glyceride, and any combination thereof.

20. The composition of claim 3, wherein the hydrophilic surfactant is polyoxyethylene castor oil.

21. The composition described in claim 20, wherein the polyoxyethylene castor oil is at least one selected from the group consisting of polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.

22. The composition of claim 20, wherein the polyoxyethylene castor oil is polyoxyl 35 castor oil.

23. The composition described in claim 6, wherein the oily component is at least one selected from the group consisting of fatty acids, acylglycerols, vegetable oils, and combinations thereof.

24. The composition described in claim 23, wherein the oily component is a fatty acid.

25. The composition described in claim 24, wherein the fatty acid is at least one selected from the group consisting of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid.

26. The composition described in claim 25, wherein the fatty acid is at least one selected from the group consisting of oleic acid, linoleic acid, and linolenic acid.

27. The composition of claim 26, wherein the fatty acid is oleic acid.

28. The composition of claim 1, wherein the composition further comprises an antioxidant.

29. The composition of claim 28, wherein the antioxidant is at least one selected from the group consisting of dl-α-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, pharma- ceutical acceptable quinones, astaxanthin, and D-α-tocopheryl polyethylene glycol 1000 succinate.

30. The composition of claim 28, wherein the antioxidant is dl-α-tocopherol.

31. A pharmaceutical formulation comprising the composition according to any one of claims 1 to 30.

32. The pharmaceutical formulation according to claim 31, wherein the compound represented by formula (1), or a salt thereof, or a solvate thereof is a hydrate of the compound represented by formula (1).

33. The pharmaceutical formulation according to claim 31, wherein the compound represented by formula (1), or a salt thereof, or a solvate thereof, is a compound represented by formula (1).

34. The pharmaceutical formulation of claim 31, wherein the formulation is in the form of a capsule.

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