Method for producing cyclic peptide crystals

Abstract

Disclosed is a method for producing a cyclic peptide crystal, the method comprising contacting a cyclic peptide with a specific solvent.

Description

Technical Field

[0001] The present invention relates to a method for producing crystals of cyclic peptides containing N-substituted amino acid residues and a method for screening those crystals. Background Art

[0002] To date, it has been considered desirable for compounds used as oral drugs to have a molecular weight of 500 g / mol or less, as known from Lipinski's rules (Non-Patent Document 1). In recent years, it has been gradually learned that compounds with a molecular weight exceeding 500 g / mol may contribute to inhibiting protein-protein interactions in proteins (referred to as "difficult targets") that have been considered difficult to target with conventional small molecule compounds. These molecules are called medium-sized molecules (molecular weight 500 g / mol to 2000 g / mol), which are neither small molecules with a molecular weight of 500 g / mol or less that have been mainly used as oral drugs nor polymer molecules with a molecular weight exceeding 100,000 g / mol, such as antibody drugs, and have come to occupy a prominent position as a new mode of drug discovery that can achieve targeting of difficult targets (Non-Patent Document 2).

[0003] Peptides composed of natural amino acids (such as insulin for treating hyperglycemia) have poor metabolic stability and are conventionally difficult to develop as oral drugs. However, it has been found that by cyclizing peptides and using unnatural amino acids such as N-methyl amino acids in the peptides, the metabolic stability and membrane permeability of the peptides are improved (Non-Patent Documents 3 and 4).

[0004] Among cyclic peptides containing unnatural amino acids, it has been gradually learned that cyclic peptides containing N-substituted amino acids in particular can have metabolic stability or membrane permeability, that is, can have drug-likeness (Patent Document 1). It has also been proposed that cyclic peptides containing unnatural amino acids can be used to produce inhibitors of protein-protein interactions (Non-Patent Document 5).

[0005] Although cyclic peptides are attracting attention in drug discovery as medium-sized molecules, there have been no reports on the crystals of many cyclic peptides containing N-substituted amino acids. On the other hand, regarding cyclosporin A, which has long been considered a cyclic peptide, it has been reported that it has multiple crystal forms (Patent Documents 2 and 3, Non-Patent Documents 6, 7, and 8).

[0006] [Citation List]

[0007] [Patent Documents]

[0008] [Patent Document 1] International Publication No. WO 2013 / 100132

[0009] [Patent Document 2] International Publication No. WO 2012 / 166610

[0010] [Patent Document 3] Japanese Patent Publication No. 2017-210488

[0011] [Non-Patent Document]

[0012] [Non-Patent Document 1] Adv. Drug Del. Rev. 1997, 23, 3-25.

[0013] [Non-Patent Document 2] Future Med. Chem., 2009, 1, 1289-1310.

[0014] [Non-Patent Document 3] Acc. Chem. Res., 2008, 41, 1331-1342.

[0015] [Non-Patent Document 4] Angew. Chem. Int. Ed., 2013, 52, 254-269.

[0016] [Non-Patent Document 5] Chem. Rev., 2019, 119, 10360-10391.

[0017] [Non-Patent Document 6] J. Pharm. Sci., 2018, 107, 3070-3079.

[0018] [Non-Patent Document 7] J. Inclusion Phenomena & Macrocyclic Chem., 2000, 37, 137-153.

[0019] [Non-Patent Document 8] Zeitschrift fuer Kristallographie, 1996, 211, 313-318. Summary of the Invention

[0020] [Technical Problem]

[0021] For the crystallization of cyclic peptides in drug development, it is necessary to find and determine the optimal crystallization conditions for each individual cyclic peptide through trial and error. A general and simple technique is needed to obtain these cyclic peptides in crystalline form. In view of such circumstances, the present invention has been made. In one aspect, an object of the present invention is to provide a method for producing crystals of cyclic peptides containing N-substituted amino acid residues. In one aspect, an object of the present invention is to provide a method for screening crystals of cyclic peptides containing N-substituted amino acid residues. In one aspect, an object of the present invention is to provide a method for screening crystallization methods. Furthermore, in one aspect, an object of the present invention is to provide a method for separating and purifying a target cyclic peptide or its salt, or its solvate in crystalline form without using column chromatography.

[0022] [Solution to the problem]

[0023] To solve the above problems, the present inventors conducted in-depth research and found a method for effectively screening crystals to obtain cyclic peptides in crystal form by contacting cyclic peptides with a specific solvent. In addition, the present invention was completed as a method for producing crystals applicable to a variety of cyclic peptides.

[0024] That is, the present invention provides the following.

[0025] [A1] A method for producing cyclic peptide crystals, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I), (II), and (III):

[0026] (I) Characterized by containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues;

[0027] (II) Characterized by containing at least 2 N-substituted amino acid residues; and

[0028] (III) Characterized by having a molecular weight (g / mol) of 1204 or greater and 3000 or less.

[0029] [A1-1] The method according to [A1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

[0030] [A1-2] The method according to [A1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0031] [A2] The method according to any one of [A1] to [A1-2], wherein the solvent is any solvent selected from the group consisting of the following (1), (2), and (3):

[0032] (1) (i) A solvent having a molecular weight of 18 or greater and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or greater and 170 or less;

[0033] (2) Water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent; and

[0034] (3) (i) A PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent, and water, and a PEG-based solvent.

[0035] [A3]According to the method according to any one of [A1] to [A1-2], wherein the solvent is (i) a solvent having a molecular weight of 18 or more and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or more and 170 or less.

[0036] [A4]According to the method according to [A3], wherein the solvent is a solvent selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, ketone solvents, aliphatic hydrocarbon solvents, and water.

[0037] [A5]According to the method according to [A3], wherein the solvent is a solvent selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents.

[0038] [A6]According to the method according to [A3], wherein the solvent is a solvent selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents.

[0039] [A7]According to the method according to [A3], wherein the solvent is a solvent selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogen solvents.

[0040] [A8]According to the method according to [A3], wherein the solvent is a solvent selected from the group consisting of: amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents.

[0041] [A9]According to the method according to any one of [A1] to [A1-2], wherein the solvent is a solvent (A) having a molecular weight of 18 or more and 170 or less, or a mixed solvent of a solvent (A) having a molecular weight of 18 or more and 170 or less and a solvent (B) having a molecular weight of 18 or more and 170 or less, the solvent (A) being one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the solvent (B) being one or more selected from the group consisting of: aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0042] [A10]The method according to any one of [A1] to [A1-2], wherein the solvent is a solvent (A) having a molecular weight of 18 or greater and 170 or less, or a mixed solvent of a solvent (A) having a molecular weight of 18 or greater and 170 or less and a solvent (B) having a molecular weight of 18 or greater and 170 or less. The solvent (A) is selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents. And the solvent (B) is selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0043] [A11]The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents.

[0044] [A12]The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogen solvents.

[0045] [A13]The method according to [A9], wherein the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents.

[0046] [A14]The method according to [A9] or [A10], wherein the solvent (A) is an amide solvent.

[0047] [A15]The method according to [A14], wherein the amide solvent is one or more selected from the group consisting of formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone.

[0048] [A16]The method according to [A14], wherein the amide solvent is formamide.

[0049] [A17]The method according to [A9] or [A10], wherein the solvent (A) is a sulfoxide solvent.

[0050] [A18]The method according to [A17], wherein the sulfoxide solvent is one or more selected from the group consisting of dimethyl sulfoxide, phenyl methyl sulfoxide, and diethyl sulfoxide.

[0051] [A19]The method according to [A17], wherein the sulfoxide solvent is dimethyl sulfoxide.

[0052] [A20]The method according to [A9] or [A10], wherein the solvent (A) is an aromatic hydrocarbon solvent.

[0053] [A21]The method according to [A20], wherein the aromatic hydrocarbon solvent is one or more selected from the group consisting of benzene, toluene, xylene, ethylbenzene, tetralin, and cumene.

[0054] [A22]The method according to [A20], wherein the aromatic hydrocarbon solvent is toluene, tetralin, or cumene.

[0055] [A23]The method according to [A9] or [A10], wherein the solvent (A) is a halogenated solvent.

[0056] [A24]The method according to [A23], wherein the halogenated solvent is one or more selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride.

[0057] [A25]The method according to [A23], wherein the halogenated solvent is dichloromethane or chlorobenzene.

[0058] [A26]The method according to [A9] or [A10], wherein the solvent (A) is an alcohol solvent.

[0059] [A27]The method according to [A26], wherein the alcohol solvent is one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol.

[0060] [A28]The method according to [A26], wherein the alcohol solvent is methanol, ethanol, 1-propanol, isopropanol, or n-butanol.

[0061] [A29]The method according to [A9] or [A10], wherein the solvent (A) is an ether solvent.

[0062] [A30]The method according to [A29], wherein the ether solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and tert-butyl methyl ether.

[0063] [A31]The method according to [A29], wherein the ether solvent is tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole or tert-butyl methyl ether.

[0064] [A32]The method according to [A9] or [A10], wherein the solvent (A) is an ester solvent.

[0065] [A33]The method according to [A32], wherein the ester solvent is one or more selected from the group consisting of ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate and γ-valerolactone.

[0066] [A34]The method according to [A32], wherein the ester solvent is ethyl acetate, isopropyl acetate or n-butyl acetate.

[0067] [A35]The method according to [A9] or [A10], wherein the solvent (A) is a nitrile solvent.

[0068] [A36]The method according to [A35], wherein the nitrile solvent is one or more selected from the group consisting of acetonitrile, benzonitrile and propionitrile.

[0069] [A37]The method according to [A35], wherein the nitrile solvent is acetonitrile.

[0070] [A38]The method according to [A9] or [A10], wherein the solvent (A) is a ketone solvent.

[0071] [A39]The method according to [A38], wherein the ketone solvent is one or more selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone and 3-acetylpyridine.

[0072] [A40]The method according to [A38], wherein the ketone solvent is acetone, methyl ethyl ketone or methyl isobutyl ketone.

[0073] [A41]The method according to any one of [A9] to [A40], wherein the solvent (B) is one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol and water.

[0074] [A42]The method according to any one of [A9] to [A40], wherein the solvent (B) is an aliphatic hydrocarbon solvent, ethylene glycol or water.

[0075] [A43]The method according to any one of [A9] to [A40], wherein the solvent (B) is an aliphatic hydrocarbon solvent.

[0076] [A44]The method according to [A43], wherein the aliphatic hydrocarbon solvent is one or more selected from the group consisting of: n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane.

[0077] [A45]The method according to [A43], wherein the aliphatic hydrocarbon solvent is n-heptane, cyclohexane, or methylcyclohexane.

[0078] [A46]The method according to any one of [A9] to [A40], wherein the solvent (B) is water.

[0079] [A46-1]The method according to any one of [A9] to [A40], wherein the solvent (B) is ethylene glycol.

[0080] [A47]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:40.

[0081] [A48]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5.

[0082] [A49]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:4.

[0083] [A50]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 10:1 to 1:40.

[0084] [A51]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7, or 1:2 to 1:5.

[0085] [A52]The method according to any one of [A9] to [A46], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:2 to 1:4.

[0086] [A52-1]According to the method according to any one of [A9] to [A52], wherein the solvent (A) is a solvent having a molecular weight of 18 or more and 160 or less, a molecular weight of 18 or more and 150 or less, a molecular weight of 18 or more and 140 or less, or a molecular weight of 32 or more and 135 or less.

[0087] [A52-2]According to the method according to any one of [A9] to [A52], wherein the solvent (A) is a solvent having a molecular weight of 32 or more and 135 or less.

[0088] [A52-3]According to the method according to any one of [A9] to [A52-2], wherein the solvent (B) is a solvent having a molecular weight of 18 or more and 160 or less, a molecular weight of 18 or more and 135 or less, a molecular weight of 18 or more and 120 or less, or a molecular weight of 18 or more and 105 or less.

[0089] [A52-4]According to the method according to any one of [A9] to [A52-2], wherein the solvent (B) is a solvent having a molecular weight of 18 or more and 105 or less.

[0090] [A53]According to the method according to any one of [A9] to [A52-4], wherein the solvent (A) and the solvent (B) have a melting point of 25 °C or lower.

[0091] [A54]According to the method according to any one of [A1] to [A1-2], wherein the solvent is a solvent containing 0.01 wt / v% to 30 wt / v% surfactant and 5 v / v% to 50 v / v% water-soluble organic solvent based on the total amount of the solvent.

[0092] [A55]According to the method according to [A54], wherein the surfactant is one or more selected from the group consisting of: cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.

[0093] [A56]The method according to [A54], wherein the surfactant is one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0094] [A57]The method according to [A54], wherein the surfactant is one or more selected from the group consisting of: alkyl sulfates, alkylarylpolyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0095] [A58]The method according to [A54], wherein the surfactant is an alkyl sulfate, an alkylarylpolyoxyethylene ether, a polyoxyethylene glycerol fatty acid ester, or a polyoxyethylene sorbitan fatty acid ester.

[0096] [A59]The method according to [A54], wherein the surfactant is sodium dodecyl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 hydrogenated castor oil, or polyoxyethylene sorbitan monolaurate.

[0097] [A59-1]The method according to [A54], wherein the surfactant is Polyoxyl 35 hydrogenated castor oil.

[0098] [A60]The method according to [A54], wherein the surfactant is an ionic surfactant or a non-ionic surfactant.

[0099] [A61]The method according to [A54], wherein the surfactant is an ionic surfactant.

[0100] [A62]The method according to [A61], wherein the ionic surfactant is one or more selected from the group consisting of: cationic surfactants, anionic surfactants, and amphoteric surfactants.

[0101] [A63]The method according to [A61], wherein the ionic surfactant is one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithin.

[0102] [A64]The method according to [A61], wherein the ionic surfactant is an alkyl sulfate.

[0103] [A65]The method according to [A61], wherein the ionic surfactant is dodecyl sulfate.

[0104] [A66]The method according to [A61], wherein the ionic surfactant is sodium dodecyl sulfate.

[0105] [A67]The method according to [A54], wherein the surfactant is a non-ionic surfactant.

[0106] [A68]The method according to [A67], wherein the non-ionic surfactant is one or more selected from the group consisting of: alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0107] [A69]The method according to [A67], wherein the non-ionic surfactant is one or more selected from the group consisting of: alkylaryl polyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0108] [A70]The method according to [A67], wherein the non-ionic surfactant is one or more selected from the group consisting of: 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate.

[0109] [A71]The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent.

[0110] [A72]The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is an alcohol solvent or a sulfoxide solvent.

[0111] [A73]The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is methanol, ethanol, 1-propanol, 2-propanol or dimethyl sulfoxide.

[0112] [A74]The method according to any one of [A54] to [A70], wherein the water-soluble organic solvent is ethanol or dimethyl sulfoxide.

[0113] [A75]The method according to any one of [A54] to [A74], wherein the content of the surfactant is 0.02 wt / v% to 20 wt / v%, 0.05 wt / v% to 15 wt / v%, 0.1 wt / v% to 10 wt / v%, 0.12 wt / v% to 8 wt / v%, 0.15 wt / v% to 5 wt / v% or 0.18 wt / v% to 3 wt / v% based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 v / v% to 40 v / v%, 5 v / v% to 30 v / v%, 5 v / v% to 25 v / v%, 8 v / v% to 20 v / v% or 10 v / v% to 15 v / v% based on the total amount of the solvent.

[0114] [A76]The method according to any one of [A54] to [A74], wherein the content of the surfactant is 0.1 wt / v% to 10 wt / v% based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 v / v% to 25 v / v% based on the total amount of the solvent.

[0115] [A77]The method according to any one of [A1] to [A1-2], wherein the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent and water, and a PEG-based solvent.

[0116] [A78]The method according to any one of [A1] to [A1-2], wherein the solvent is a PEG-based solvent.

[0117] [A79]The method according to any one of [A1] to [A1-2], wherein the solvent is a mixed solvent of one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent and water, and a PEG-based solvent.

[0118] [A80]The method according to [A78] or [A79], wherein the PEG-based solvent is (i) represented by R 1 (OCHR 3 CH 2 )nOR 2The solvent represented, n is a natural number of 1 or greater and 10 or less, or (ii) by R 1 (OCHR 3 CH 2 )nOR 2 The mixture of solvents represented, the average value of n is 3 to 100, where R 1 And R 2 Are each independently hydrogen, C 1 To C 4 Alkyl or -C(=O)R 4 , R 3 Is hydrogen or C 1 To C 4 Alkyl, and R 4 Is C 1 To C 18 Alkyl optionally substituted by a hydroxyl group or C 1 To C 18 Alkenyl.

[0119] [A81] The method according to [A78] or [A79], wherein the PEG-based solvent is (i) the solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 The solvent represented, n is a natural number of 1, 2, 3 or 4, or (ii) the mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 The average value of n is 3 to 100, where R 1 Is hydrogen or C 1 To C 4 Alkyl, R 2 Is hydrogen, C 1 To C 4 Alkyl, or -C(=O)R 4 , R 3 Is hydrogen or C 1 To C 4 Alkyl, and R 4 Is C 10 To C 18 Alkyl.

[0120] [A82] The method according to [A78] or [A79], wherein the PEG-based solvent is (i) the solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 The solvent represented, n is a natural number of 1, 2, 3 or 4, or (ii) by R 1 (OCHR3 CH 2 )nOR 2 A mixture of solvents represented, where the average value of n is from 3 to 100, wherein R 1 is hydrogen or methyl, and R 2 is hydrogen, methyl or -C(=O)R 4 , R 3 is hydrogen or methyl, and R 4 is C 11 to C 17 alkyl.

[0121] [A83] The method according to [A78] or [A79], wherein the PEG-based solvent is diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol or polyethylene glycol mono-fatty acid ester.

[0122] [A84] The method according to [A78] or [A79], wherein the PEG-based solvent is polyethylene glycol.

[0123] [A84-2] The method according to [A84], wherein the polyethylene glycol has a number average molecular weight of 150 to 5000.

[0124] [A84-3] The method according to [A84], wherein the polyethylene glycol has a number average molecular weight of 360 to 440, 540 to 660, 900 to 1100 or 1800 to 2200.

[0125] [A85] The method according to [A84], wherein the polyethylene glycol is PEG400, PEG600, PEG1000 or PEG2000.

[0126] [A86] The method according to [A78] or [A79], wherein the PEG-based solvent is polyethylene glycol mono-fatty acid ester.

[0127] [A87] The method according to [A86], wherein the polyethylene glycol mono-fatty acid ester is polyethylene glycol monostearate or polyethylene glycol monolaurate.

[0128] [A88]The method according to any one of [A77] or [A79] to [A87], wherein one or more selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water.

[0129] [A89]The method according to any one of [A77] or [A79] to [A87], wherein one or more selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more selected from the group consisting of 2-propanol, n-heptane, and water.

[0130] [B1]A method for producing a cyclic peptide crystal, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I) and (II):

[0131] (I) Characterized by containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues; and (II) Characterized by containing at least 2 N-substituted amino acid residues.

[0132] The solvent is solvent (A) or a mixed solvent containing solvent (A) and solvent (B), wherein solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents, and solvent (B) is one or more selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0133] [B1-1]The method according to [B1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarizing microscope.

[0134] [B1-2]The method according to [B1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0135] [B2]The method according to any one of [B1] to [B1-2], wherein solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents.

[0136] [B3]The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an amide solvent.

[0137] [B4]The method according to [B3], wherein the amide solvent is one or more selected from the group consisting of: formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone.

[0138] [B5]The method according to [B3], wherein the amide solvent is formamide.

[0139] [B6]The method according to any one of [B1] to [B1-2], wherein the solvent (A) is a sulfoxide solvent.

[0140] [B7]The method according to [B6], wherein the sulfoxide solvent is one or more selected from the group consisting of: dimethyl sulfoxide, phenylmethyl sulfoxide, and diethyl sulfoxide.

[0141] [B8]The method according to [B6], wherein the sulfoxide solvent is dimethyl sulfoxide.

[0142] [B9]The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an aromatic hydrocarbon solvent.

[0143] [B10]The method according to [B9], wherein the aromatic hydrocarbon solvent is one or more selected from the group consisting of: benzene, toluene, xylene, ethylbenzene, tetrahydronaphthalene, and cumene.

[0144] [B11]The method according to [B9], wherein the aromatic hydrocarbon solvent is toluene, tetrahydronaphthalene, or cumene.

[0145] [B12]The method according to any one of [B1] to [B1-2], wherein the solvent (A) is a halogenated solvent.

[0146] [B13]The method according to [B12], wherein the halogenated solvent is one or more selected from the group consisting of: dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride.

[0147] [B14]The method according to [B12], wherein the halogenated solvent is dichloromethane or chlorobenzene.

[0148] [B15]The method according to any one of [B1] to [B1-2], wherein the solvent (A) is an ester solvent.

[0149] [B16]The method according to [B15], wherein the ester solvent is one or more selected from the group consisting of ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerolactone.

[0150] [B17]The method according to [B15], wherein the ester solvent is ethyl acetate, isopropyl acetate, or n-butyl acetate.

[0151] [B18]The method according to any one of [B1] to [B17], wherein the solvent (B) is an aliphatic hydrocarbon solvent.

[0152] [B19]The method according to [B18], wherein the aliphatic hydrocarbon solvent is one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane.

[0153] [B20]The method according to [B18], wherein the aliphatic hydrocarbon solvent is n-heptane, cyclohexane, or methylcyclohexane.

[0154] [B21]The method according to any one of [B1] to [B17], wherein the solvent (B) is water.

[0155] [B21-1]The method according to any one of [B1] to [B17], wherein the solvent (B) is ethylene glycol.

[0156] [B22]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:40.

[0157] [B23]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5.

[0158] [B24]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:0 to 1:4.

[0159] [B25]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 10:1 to 1:40.

[0160] [B26]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7, or 1:2 to 1:5.

[0161] [B27]The method according to any one of [B1] to [B21], wherein the volume ratio (v / v) of the solvent (A) to the solvent (B) in the solvent is 1:2 to 1:4.

[0162] [B28]The method according to any one of [B1] to [B27], wherein the solvent (A) and the solvent (B) have a melting point of 25°C or lower.

[0163] [B29]A method for producing a cyclic peptide crystal, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I) and (II):

[0164] (I) It has the characteristic of containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues; and

[0165] (II) It has the characteristic of containing at least 2 N-substituted amino acid residues, and

[0166] the solvent is water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent.

[0167] [B29-1]The method according to [B29], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

[0168] [B29-2]The method according to [B29], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0169] [B30]The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.

[0170] [B31]The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0171] [B32]The method according to any one of [B29] to [B29-2], wherein the surfactant is one or more selected from the group consisting of: alkyl sulfates, alkylarylpolyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0172] [B33]The method according to any one of [B29] to [B29-2], wherein the surfactant is alkyl sulfate, alkylarylpolyoxyethylene ether, polyoxyethylene glycerol fatty acid ester, or polyoxyethylene sorbitan fatty acid ester.

[0173] [B34]The method according to any one of [B29] to [B29-2], wherein the surfactant is sodium dodecyl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 hydrogenated castor oil, or polyoxyethylene sorbitan monolaurate.

[0174] [B35]The method according to any one of [B29] to [B29-2], wherein the surfactant is an ionic surfactant or a non-ionic surfactant.

[0175] [B36]The method according to any one of [B29] to [B29-2], wherein the surfactant is an ionic surfactant.

[0176] [B37]The method according to [B36], wherein the ionic surfactant is one or more selected from the group consisting of: cationic surfactants, anionic surfactants, and amphoteric surfactants.

[0177] [B38]The method according to [B36], wherein the ionic surfactant is one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithin.

[0178] [B39]The method according to [B36], wherein the ionic surfactant is an alkyl sulfate.

[0179] [B40]The method according to [B36], wherein the ionic surfactant is dodecyl sulfate.

[0180] [B41]The method according to [B36], wherein the ionic surfactant is sodium dodecyl sulfate.

[0181] [B42]The method according to any one of [B29] to [B29-2], wherein the surfactant is a non-ionic surfactant.

[0182] [B43]The method according to [B42], wherein the non-ionic surfactant is one or more selected from the group consisting of: alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0183] [B44]The method according to [B42], wherein the non-ionic surfactant is one or more selected from the group consisting of: alkylaryl polyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0184] [B45]The method according to [B42], wherein the non-ionic surfactant is one or more selected from the group consisting of: 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, Polyoxyl 35 hydrogenated castor oil, and polyoxyethylene sorbitan monolaurate.

[0185] [B46]The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent.

[0186] [B47]The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is an alcohol solvent or a sulfoxide solvent.

[0187] [B48]The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is methanol, ethanol, 1-propanol, 2-propanol or dimethyl sulfoxide.

[0188] [B49]The method according to any one of [B29] to [B45], wherein the water-soluble organic solvent is ethanol or dimethyl sulfoxide.

[0189] [B50]The method according to any one of [B29] to [B49], wherein the content of the surfactant is 0.02 wt / v% to 20 wt / v%, 0.05 wt / v% to 15 wt / v%, 0.1 wt / v% to 10 wt / v%, 0.12 wt / v% to 8 wt / v%, 0.15 wt / v% to 5 wt / v% or 0.18 wt / v% to 3 wt / v% based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 v / v% to 40 v / v%, 5 v / v% to 30 v / v%, 5 v / v% to 25 v / v%, 8 v / v% to 20 v / v% or 10 v / v% to 15 v / v% based on the total amount of the solvent.

[0190] [B51]The method according to any one of [B29] to [B49], wherein the content of the surfactant is 0.1 wt / v% to 10 wt / v% based on the total amount of the solvent, and the content of the water-soluble organic solvent is 5 v / v% to 25 v / v% based on the total amount of the solvent.

[0191] [B52]A method for producing a cyclic peptide crystal, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I) and (II):

[0192] (I) It has the characteristic of containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues; and

[0193] (II) It has the characteristic of containing at least 2 N-substituted amino acid residues, and

[0194] the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent and water, and a PEG-based solvent.

[0195] [B52-1]The method according to [B52], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

[0196] [B52-2]The method according to [B52], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0197] [B53]The method according to any one of [B52] to [B52-2], wherein the solvent is a PEG-based solvent.

[0198] [B54]The method according to any one of [B52] to [B52-2], wherein the solvent is a mixed solvent selected from one or more of the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, water, and PEG-based solvents.

[0199] [B55]The method according to [B53] or [B54], wherein the PEG-based solvent is (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number of 1 or greater and 10 or less, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , where the average value of n is from 3 to 100, wherein R 1 and R 2 are each independently hydrogen, C 1 to C 4 alkyl or -C(=O)R 4 , R 3 is hydrogen or C 1 to C 4 alkyl, and R 4 is C 1 to C 18 alkyl optionally substituted with a hydroxyl group or C 1 to C 1 8-alkenyl optionally substituted with a hydroxyl group.

[0200] [B56]The method according to [B53] or [B54], wherein the PEG-based solvent is (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number of 1, 2, 3, or 4, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , where the average value of n is from 3 to 100, wherein R 1 is hydrogen or C 1 to C4 Alkyl, R 2 is hydrogen, C 1 to C 4 alkyl, or -C(=O)R 4 , R 3 is hydrogen or C 1 to C 4 alkyl, and R 4 is C 10 to C 18 alkyl.

[0201] [B57] According to the method described in [B53] or [B54], wherein the PEG-based solvent is (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , n is a natural number of 1, 2, 3 or 4, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , the average value of n is 3 to 100, wherein R 1 is hydrogen or methyl, R 2 is hydrogen, methyl or -C(=O)R 4 , R 3 is hydrogen or methyl, and R 4 is C 11 to C 17 alkyl.

[0202] [B58] According to the method described in [B53] or [B54], wherein the PEG-based solvent is diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol or polyethylene glycol mono-fatty acid ester.

[0203] [B59] According to the method described in [B53] or [B54], wherein the PEG-based solvent is polyethylene glycol.

[0204] [B59-2] According to the method described in [B59], wherein the polyethylene glycol has a number average molecular weight of 150 to 5000.

[0205] [B59-3] According to the method described in [B59], wherein the polyethylene glycol has a number average molecular weight of 360 to 440, 540 to 660, 900 to 1100 or 1800 to 2200.

[0206] [B60] According to the method described in [B59], wherein the polyethylene glycol is PEG400, PEG600, PEG1000 or PEG2000.

[0207] [B61]The method according to [B53] or [B54], wherein the PEG-based solvent is polyethylene glycol mono-fatty acid ester.

[0208] [B62]The method according to [B61], wherein the polyethylene glycol mono-fatty acid ester is polyethylene glycol monostearate or polyethylene glycol monolaurate.

[0209] [B63]The method according to any one of [B52] to [B52-2] or [B54] to [B62], wherein one or more selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water.

[0210] [B64]The method according to any one of [B52] to [B52-2] or [B54] to [B62], wherein one or more selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water are one or more selected from the group consisting of 2-propanol, n-heptane, and water.

[0211] [C1]The method according to any one of [A1] to [A89] or [B1] to [B64], wherein, in the step of bringing the cyclic peptide into contact with the solvent, the concentration of the cyclic peptide is 1 mg / mL to 2000 mg / mL.

[0212] [C2]The method according to any one of [A1] to [A89] or [B1] to [B64], wherein in the step of bringing the cyclic peptide into contact with the solvent, the concentration of the cyclic peptide is 5 mg to 1500 mg / mL, 10 mg to 1000 mg / mL, 10 mg to 500 mg / mL, 10 mg to 100 mg / mL, 10 mg to 50 mg / mL, 100 mg to 400 mg / mL, 100 mg to 200 mg / mL, or 500 mg to 1000 mg / mL.

[0213] [C3]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C2], wherein the cyclic peptide used in the step of bringing the cyclic peptide into contact with the solvent is a lyophilized product.

[0214] [C4]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C2], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is a lyophilized product of a dimethyl sulfoxide solution.

[0215] [C5]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C4], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is from 0.5 mg to 200 kg.

[0216] [C6]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C4], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is from 1 mg to 1 g.

[0217] [C7]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C4], wherein the cyclic peptide used in the step of contacting the cyclic peptide with a solvent is from 0 g to 200 kg, from 100 g to 100 kg, from 0.5 mg to 10 g, from 1 mg to 1 g, from 1 mg to 100 mg, from 1 mg to 10 mg or from 1 mg to 5 mg.

[0218] [C8]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C7], wherein the step of contacting the cyclic peptide with a solvent does not include adding a seed crystal.

[0219] [C9]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C7], wherein the step of contacting the cyclic peptide with a solvent includes adding a seed crystal.

[0220] [C10]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C9], further comprising a filtration step after the step of contacting the cyclic peptide with a solvent.

[0221] [C11]The method according to any one of [A1] to [A89], [B1] to [B64] or [C1] to [C10], wherein the step of contacting the cyclic peptide with a solvent is carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks.

[0222] [C12]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C10], wherein the step of contacting the cyclic peptide with the solvent is carried out at a constant temperature of 0 °C to 110 °C, 10 °C to 100 °C, 15 °C to 90 °C, or 20 °C to 80 °C, or heating and cooling are repeated 10 times or more, 20 times or more, or 30 times or more and 1000 times or less, 500 times or less, or 100 times or less between a lower temperature of 10 °C, 20 °C, 30 °C, 40 °C, 45 °C, 50 °C or 55 °C and an upper temperature of 100 °C, 90 °C, 85 °C, 80 °C, 75 °C, 70 °C or 60 °C, and carried out for 1 hour to 6 weeks, 2 hours to 4 weeks, 4 hours to 2 weeks, or 6 hours to 7 days.

[0223] [C13]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C10], wherein the step of contacting the cyclic peptide with the solvent is carried out at a constant temperature of 20 °C to 90 °C for 12 hours to 7 days.

[0224] [C14]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C10], wherein the step of contacting the cyclic peptide with the solvent is heated and cooled repeatedly 30 times or more and 100 times or less between a lower temperature of 50 °C and an upper temperature of 90 °C, and carried out for 12 hours to 7 days.

[0225] [D1]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide contains a cyclic moiety composed of a total of 7 to 15 amino acid residues, 8 to 14 amino acid residues, 9 to 13 amino acid residues, 10 to 13 amino acid residues, 11 to 13 amino acid residues, 11 to 12 amino acid residues, or 11 amino acid residues, and the total number of amino acids is 9 to 18 residues, 10 to 16 residues, 10 to 14 residues, 11 to 14 residues, 11 to 13 residues, 11 to 12 residues, or 11 residues.

[0226] [D2]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide contains a cyclic moiety composed of a total of 11 to 13 amino acid residues, and the total number of amino acids is 11 to 14 residues.

[0227] [D2-1]The method according to any one of [A1] to [A89], [B1] to [B64], or [C1] to [C14], wherein the cyclic peptide contains a cyclic moiety composed of a total of 11 amino acid residues, and the total number of amino acids is 11 residues.

[0228] [D3]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D2], wherein the cyclic peptide contains at least 3 N-substituted amino acid residues, 4 N-substituted amino acid residues, or 5 N-substituted amino acid residues.

[0229] [D3-1]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D3], wherein the cyclic peptide contains at least 1 N-unsubstituted amino acid residue, 2 N-unsubstituted amino acid residues, or 3 N-unsubstituted amino acid residues.

[0230] [D4]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D2], wherein the cyclic peptide contains at least 5 N-substituted amino acid residues.

[0231] [D4-1]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4], wherein the cyclic peptide contains at least 3 N-unsubstituted amino acid residues.

[0232] [D4-2]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-alkyl amino acid.

[0233] [D4-3]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-methyl amino acid or an N-ethyl amino acid.

[0234] [D4-4]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D4-1], wherein the N-substituted amino acid is an N-methyl amino acid.

[0235] [D5] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D4-4], wherein the cyclic peptide contains at least one β-amino acid backbone.

[0236] [D6] A method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D4-4], wherein the cyclic peptide contains at least one β-amino acid backbone in the cyclic portion.

[0237] [D7] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D6], wherein the cyclic peptide contains a cyclic portion consisting of a 28- to 55-membered ring, a 28- to 49-membered ring, a 31- to 46-membered ring, a 34- to 43-membered ring, a 34- to 40-membered ring, a 34- to 37-membered ring or a 34-membered ring.

[0238] [D8] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D6], wherein the cyclic peptide contains a cyclic portion consisting of a 34- to 40-membered ring.

[0239] [D8-1] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D6], wherein the cyclic peptide contains a cyclic portion consisting of a 34-membered ring.

[0240] [D8-2] The method according to [D8-1], wherein the cyclic portion composed of a 34-membered ring has the following cyclic structure, which is a cyclic peptide composed of 10 α-amino acid residues and 1 amino acid residue having a β-amino acid skeleton, with a total of 11 amino acid residues.

[0241] [D8-3] The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D6], wherein the cyclic peptide is the following structure:

[0242] [Formula 1]

[0243]

[0244] Where P 1 , P 3 , P 5 , P 6 , P 10 and P 11 Each is C 1 To C6 alkyl; P 4 is C 1 to C 6 alkyl or P 4 bonded to P 4 the nitrogen atom, R 4 and R 4 the carbon atom to which they are bonded together form a 4- to 7-membered saturated heterocycle; P 8 is C 1 to C 6 alkyl or P 8 bonded to P 8 the nitrogen atom, R 8 and R 8 the carbon atom to which they are bonded together form a 4- to 7-membered saturated heterocycle; the 4- to 7-membered saturated heterocycle is optionally substituted by C 1 to C 6 alkoxy; R 1 , R 2 , R 3 , R 5 , R 7 and R 10 each is a hydrogen atom, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl or aralkyl optionally having substituents; R 4 is a hydrogen atom or C 1 to C 6 alkyl, except when R 4 and P 4 form a 4- to 7-membered saturated heterocycle; R 8 is a hydrogen atom or C 1 to C 6 alkyl, except when R 8 and P 8 form a 4- to 7-membered saturated heterocycle; R 9 bonded to Q 9 and R 9 and Q 9 the carbon atoms to which they are bonded together form a 3- to 7-membered saturated carbocycle; and R 11 is a hydrogen atom, C 1 to C 6 alkyl, di-C 1 to C 6 alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl.

[0245] [D8-4] According to the method of [D8-3], wherein P 1 , P 3 , P 5 , P 6 , P 10and P 11 Each is methyl or ethyl respectively.

[0246] [D8-5] The method according to [D8-3] or [D8-4], wherein P 4 is methyl or forms a 4-membered saturated heterocycle together with the nitrogen atom bonded to P 4 , the carbon atoms bonded to R 4 and R 4 .

[0247] [D8-6] The method according to any one of [D8-3] to [D8-5], wherein P 8 forms a 5-membered saturated heterocycle together with the nitrogen atom bonded to P 8 , the carbon atoms bonded to R 8 and R 8 , and the 5-membered saturated heterocycle is optionally substituted with C 1 to C 6 alkoxy.

[0248] [D8-7] The method according to any one of [D8-3] to [D8-6], wherein R 1 and R 2 are each C 1 to C 6 alkyl; R 3 is a hydrogen atom or C 1 to C 6 alkyl; R 4 is a hydrogen atom, except when R 4 forms a 4- to 7-membered saturated heterocycle with P 4 ; R 5 is optionally substituted C 3 to C 6 cycloalkyl or benzyl; R 7 is optionally substituted phenethyl; R 9 forms a 5-membered saturated carbocycle together with Q 9 and the carbon atoms bonded to R 9 and Q 9 ; R 10 is C 1 to C 6 alkyl or C 3 to C 6 cycloalkyl; and R 11 is methyl, di-C 1 to C 6 alkylaminocarbonyl or 6-membered cyclic aminocarbonyl.

[0249] [D9]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D8-7], wherein the cyclic peptide has a molecular weight (g / mol) of 1205 or greater, 1206 or greater, 1207 or greater, 1208 or greater, 1210 or greater, 1220 or greater, 1230 or greater, 1250 or greater, or 1300 or greater and 2800 or less, 2500 or less, 2000 or less, 1900 or less, 1800 or less, 1700 or less, or 1600 or less.

[0250] [D10]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D8-7], wherein the cyclic peptide has a molecular weight (g / mol) of 1300 or greater and 1600 or less.

[0251] [D11]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D10], wherein the cyclic peptide has a ClogP of 4 or greater and 25 or less.

[0252] [D12]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D10], wherein the cyclic peptide has a ClogP of 5 or greater, 6 or greater, 7 or greater, 8 or greater or 9 or greater and 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less or 18 or less.

[0253] [D13]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D10], wherein the cyclic peptide has a ClogP of 9 or greater and 18 or less.

[0254] [D14]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D10], wherein the ClogP of the cyclic peptide is greater than the ClogP of cyclosporin A.

[0255] [D14-1]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14], wherein the cyclic peptide has a ClogP / amino acid residue number of 0.3 or greater and 2.3 or less, 0.5 or greater and 1.9 or less, 0.7 or greater and 1.8 or less or 0.8 or greater and 1.6 or less.

[0256] [D14-2]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14], wherein the cyclic peptide has a ClogP / amino acid residue number of 0.8 or greater and 1.6 or less.

[0257] [D14-3]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 1200 mg / mL or less, 800 mg / mL or less, 600 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 25 mg / mL or less, 10 mg / mL or less, 5.0 mg / mL or less, or 2.6 mg / mL or less.

[0258] [D14-4]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 0.8 mg / mL or greater.

[0259] [D14-5]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 0.9 mg / mL or greater, 1.0 mg / mL or greater, or 1.1 mg / mL or greater.

[0260] [D14-6]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2], wherein the solubility of the cyclic peptide in 50 mM phosphate buffer (pH 6.5) is 1.1 mg / mL or greater.

[0261] [D14-7]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2], which has two or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0262] [D14-8]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-2] has three or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0263] [D15]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D14-4], wherein the cyclic peptide is a cyclic peptide excluding cyclosporin A.

[0264] [D16]The method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D15], wherein the cyclic peptide is a cyclic peptide excluding (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxa-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 nonatriacontane-33,1′-cyclopentane]-27-carboxamide cyclic peptide.

[0265] [E1]A method for screening cyclic peptide crystals, the method comprising the following steps (a) and (b):

[0266] (a) a step of producing cyclic peptide crystals by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D16]; and

[0267] (b) a step of analyzing the crystals by powder X-ray crystal diffraction.

[0268] [E2]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing formamide.

[0269] [E3]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing formamide and a solvent containing dimethyl sulfoxide.

[0270] [E4]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane.

[0271] [E5]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil.

[0272] [E6]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester.

[0273] [E7]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing polyethylene glycol.

[0274] [E8]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol.

[0275] [E9]The method according to [E1], wherein the crystals to be screened include crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil, crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, and crystals produced using a solvent containing formamide.

[0276] [F1]A method for screening a method for crystallizing a cyclic peptide, the method comprising the following steps (a) and (b):

[0277] (a) A step of producing cyclic peptide crystals by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16]; and

[0278] (b) A step of analyzing the crystals by powder X-ray crystallography.

[0279] [F2]The method according to [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing formamide.

[0280] [F3]The method according to [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing formamide and a solvent containing dimethyl sulfoxide.

[0281] [F4]The method according to [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane.

[0282] [F5]According to the method described in [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil.

[0283] [F6]According to the method described in [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing polyethylene glycol mono-fatty acid ester.

[0284] [F7]According to the method described in [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing polyethylene glycol.

[0285] [F8]According to the method described in [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol.

[0286] [F9]According to the method described in [F1], wherein the crystallization method to be screened includes a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil, a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing formamide.

[0287] [F10]According to the method described in any one of [E1] to [E9] or [F1] to [F9], wherein in the step of contacting the cyclic peptide with the solvent, the cyclic peptide used for each condition is 0.5 mg to 10 mg.

[0288] [F11]According to the method described in any one of [E1] to [E9] or [F1] to [F10], wherein the crystals or crystallization methods to be screened are 2 or more types, 5 or more types, 10 or more types, 15 or more types, or 20 or more types.

[0289] [F12]According to the method described in any one of [E1] to [E9] or [F1] to [F11], wherein the step of contacting the cyclic peptide with the solvent does not include adding crystal seeds.

[0290] [G1]A method for increasing the probability of producing cyclic peptide crystals, the method comprising the step of producing cyclic peptide crystals by the method described in any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], or [D1] to [D16].

[0291] [H1]Use of any solvent selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, polyoxyethylene glycerol fatty acid esters, and polyethylene glycol mono-fatty acid esters in the production of cyclic peptide crystals.

[0292] [H2]Use of amide solvents in the production of cyclic peptide crystals.

[0293] [H3]Use of formamide in the production of cyclic peptide crystals.

[0294] [H4]Use of sulfoxide solvents in the production of cyclic peptide crystals.

[0295] [H5]Use of dimethyl sulfoxide in the production of cyclic peptide crystals.

[0296] [H6]Use of aromatic hydrocarbon solvents in the production of cyclic peptide crystals.

[0297] [H7]Use of toluene, tetrahydronaphthalene or cumene in the production of cyclic peptide crystals.

[0298] [H8]Use of Polyoxyl 35 hydrogenated castor oil in the production of cyclic peptide crystals.

[0299] [H9]Use of polyethylene glycol mono-fatty acid ester in the production of cyclic peptide crystals.

[0300] [H10]Use of polyethylene glycol in the production of cyclic peptide crystals.

[0301] [H11]The use according to any one of [H1] to [H10], wherein the cyclic peptide crystals are produced by the method according to any one of [D1] to [D16].

[0302] [I1]A method for purifying cyclic peptides, the method comprising the steps of producing cyclic peptide crystals by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D16] and collecting the crystals by solid-liquid separation.

[0303] [J1]A screening kit for producing cyclic peptide crystals, wherein the cyclic peptide crystals are produced by the use according to any one of [H1] to [H11].

[0304] [K1]A method for producing cyclic peptides, the method comprising the step of producing cyclic peptide crystals containing formamide.

[0305] [K2]A method for producing cyclic peptides, the method comprising the step of producing cyclic peptide crystals containing dimethyl sulfoxide.

[0306] [K3]A method for producing cyclic peptides, the method comprising the step of producing cyclic peptide crystals containing aromatic hydrocarbon solvents.

[0307] [K4]A method for producing cyclic peptides, the method comprising the step of producing cyclic peptide crystals containing toluene, tetrahydronaphthalene or cumene.

[0308] [K5]A method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing Polyoxyl 35 hydrogenated castor oil.

[0309] [K6]A method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing polyethylene glycol mono-fatty acid ester.

[0310] [K7]A method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing polyethylene glycol.

[0311] [K8]The method according to any one of [K1] to [K7], wherein the cyclic peptide crystals are produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14] or [D1] to [D16].

[0312] [L1]A method for producing crystals of (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 hentriacontane-33,1′-cyclopentane]-27-carboxamide, the method comprising subjecting (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15Step of contacting nonacosane-33,1′-cyclopentane]-27-carboxamide with a solvent, wherein the solvent is solvent (A) or a mixed solvent containing solvent (A) and solvent (B), and the solvent (A) is one or more selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents, and the solvent (B) is one or more selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0313] [L2] The method according to [L1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

[0314] [L3] The method according to [L1], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0315] [L4] The method according to any one of [L1] to [L3], wherein the solvent is toluene.

[0316] [L5] The method according to any one of [L1] to [L3], wherein the solvent is dimethyl sulfoxide.

[0317] [L6] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of ethanol and water.

[0318] [L7] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of acetonitrile and water.

[0319] [L8] The method according to any one of [L1] to [L3], wherein the solvent is cumene.

[0320] [L9] The method according to any one of [L1] to [L3], wherein the solvent is tetralin.

[0321] [L10] The method according to any one of [L1] to [L3], wherein the solvent is formamide.

[0322] [L11] The method according to any one of [L1] to [L3], wherein the solvent is diisopropyl ether.

[0323] [L12] The method according to any one of [L1] to [L3], wherein the solvent is a mixed solvent of 3-acetylpyridine and ethylene glycol.

[0324] [L13]A method for producing crystals of (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 tritriacontane-33,1′-cyclopentane]-27-carboxamide, the method comprising the step of contacting (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 tritriacontane-33,1′-cyclopentane]-27-carboxamide with a solvent, wherein the solvent is water containing 0.01 wt / v% to 30 wt / v% surfactant and 5 v / v% to 50 v / v% water-soluble organic solvent based on the total amount of the solvent.

[0325] [L14]The method according to [L13], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarizing microscope.

[0326] [L15]The method according to [L13], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0327] [L16]The method according to any one of [L13] to [L15], wherein the surfactant is one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.

[0328] [L17]The method according to any one of [L13] to [L15], wherein the surfactant is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol and the water-soluble organic solvent is ethanol.

[0329] [L18]The method according to any one of [L13] to [L15], wherein the surfactant is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol and the water-soluble organic solvent is dimethyl sulfoxide.

[0330] [L19]The method according to any one of [L13] to [L15], wherein the surfactant is Polyoxyl 35 hydrogenated castor oil and the water-soluble organic solvent is ethanol.

[0331] [L20]The method according to any one of [L13] to [L15], wherein the surfactant is Polyoxyl 35 hydrogenated castor oil and the water-soluble organic solvent is dimethyl sulfoxide.

[0332] [L21]The method according to any one of [L13] to [L15], wherein the surfactant is polyoxyethylene sorbitan monolaurate (Tween 80) and the water-soluble organic solvent is ethanol.

[0333] [L22]The method according to any one of [L13] to [L15], wherein the surfactant is polyoxyethylene sorbitan monolaurate and the water-soluble organic solvent is dimethyl sulfoxide.

[0334] [L23]The method according to any one of [L13] to [L15], wherein the surfactant is sodium dodecyl sulfate and the water-soluble organic solvent is ethanol.

[0335] [L24]The method according to any one of [L13] to [L15], wherein the surfactant is sodium dodecyl sulfate and the water-soluble organic solvent is dimethyl sulfoxide.

[0336] [L25]A method for producing crystals of (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 39-ane-33,1′-cyclopentane]-27-carboxamide, the method comprising the steps of: contacting (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 39-ane-33,1′-cyclopentane]-27-carboxamide with a solvent, wherein the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol-based solvent, an aliphatic hydrocarbon-based solvent, and water, and a PEG-based solvent.

[0337] [L26]The method according to [L25], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

[0338] [L27]The method according to [L25], wherein the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0339] [L28]The method according to any one of [L13] to [L15], wherein the solvent is tetraethylene glycol.

[0340] [L29]The method according to any one of [L13] to [L15], wherein the solvent is polyethylene glycol.

[0341] [L30]The method according to any one of [L13] to [L15], wherein the solvent is triethylene glycol dimethyl ether.

[0342] [L31]According to the method according to any one of [L13] to [L15], wherein the solvent is ethylene glycol.

[0343] [L32]According to the method according to any one of [L13] to [L15], wherein the solvent is PEG400.

[0344] [M1]Crystals produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], [D1] to [D16], [K1] to [K7] or [L32] to [L32].

[0345] [M2]A pharmaceutical composition comprising crystals produced by the method according to any one of [A1] to [A89], [B1] to [B64], [C1] to [C14], [D1] to [D16], [K1] to [K7] or [L32] to [L32].

[0346] [Advantages of the Invention]

[0347] According to the present invention, a method for producing crystals of a cyclic peptide containing an N-substituted amino acid residue is provided. According to the present invention, a method for screening crystals of a cyclic peptide containing an N-substituted amino acid residue is also provided. According to the present invention, a method for screening a crystallization method is also provided. According to the present invention, a method for separating and purifying a target cyclic peptide or a salt thereof, or a solvate thereof in crystal form without using column chromatography is also provided. Description of the Drawings

[0348] Figure 1 Figure 1 (A) shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-1-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 1 (B) shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 1 (C) shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 1 (D) shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 1 (E) shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-3-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).​​

[0349] Figure 2 Figure 2 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-4-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 2 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-4-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 2 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 2 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 2 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0350] Figure 3 Figure 3 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-4. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 3 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-5. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 3 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-6. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 3 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-7. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 3 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-8. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0351] Figure 4 Figure 4 shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-9. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0352] Figure 5 Figure 5 ​​​​​​​​(A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-6-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 5 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 5 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 5 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 5 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-4. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0353] Figure 6 Figure 6 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-8. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 6 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-9. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 6 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-10. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 6 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-12. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 6 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-14. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0354] Figure 7 Figure 7 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-15. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 7 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-16. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 20 (°). Figure 7 ​​​​(C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-17. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 7 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-18. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 7 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-19. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0355] Figure 8 Figure 8 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-20. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 8 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-21. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 8 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-22. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 8 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-23. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 8 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-24. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0356] Figure 9 Figure 9 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-25. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 9 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-26. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 9 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-29. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 9 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-31. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 9 ​​​​(E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-32. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0357] Figure 10 Figure 10 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-33. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 10 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-7-34. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 10 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-1. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 10 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-3. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 10 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-5. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0358] Figure 11 Figure 11 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-6. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 11 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-10. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 11 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-13. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 11 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-14. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 11 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-15. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0359] Figure 12 Figure 12 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-16. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 12 ​​​​​​(B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-17. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 12 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-19. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 12 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-20. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 12 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-21. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0360] Figure 13 Figure 13 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-22. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 13 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-23. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 13 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-24. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 13 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-25. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 13 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-26. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0361] Figure 14 Figure 14 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-28. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 14 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-30. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 14 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-31. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 14 ​​​​(D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-32. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 14 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-33. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0362] Figure 15 Figure 15 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-34. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 15 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-35. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 15 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-36. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 15 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-37. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 15 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-38. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0363] Figure 16 Figure 16 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-39. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 16 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-40. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 16 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-41. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 16 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-42. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 16 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-43. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0364] Figure 17 Figure 17 ​​​​​​(A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-44. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 17 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 2-8-45. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0365] Figure 18 Figure 18 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-1-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 18 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-4-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 18 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 18 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 18 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0366] Figure 19 Figure 19 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-4. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 19 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-5. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 19 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-6. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 19 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-7. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 19 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-8. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0367] Figure 20 Figure 20 ​​​​​​(A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-9. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 20 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-10. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 20 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-11. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 20 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-12. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 20 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-13. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0368] Figure 21 Figure 21 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-14. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 21 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-15. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 21 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-16. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 21 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-17. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 21 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-18. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0369] Figure 22 Figure 22 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-19. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 22 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-20. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 22 ​​​​(C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-21. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 22 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-22. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 22 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-23. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0370] Figure 23 Figure 23 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-24. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 23 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-25. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 23 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-26. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 23 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-27. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 23 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-28. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0371] Figure 24 Figure 24 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-29. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 24 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-5-30. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 20 (°). Figure 24 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-7-1. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 24 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-1. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 24 ​​​​(E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0372] Figure 25 Figure 25 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 25 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-4. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 25 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-5. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 25 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-8-6. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0373] Figure 26 Figure 26 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-1-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 26 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-3-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 20 (°). Figure 26 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-4-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 26 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-4-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 26 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-4-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0374] Figure 27 Figure 27 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-4-4. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 27 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-4-5. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 27 ​​​​​​(C) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-4-6. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). In addition to 19.2° and 24.4° derived from PEG2000, multiple diffraction peaks were also observed. These are the diffraction peaks of the CP04 crystal. Figure 27 (D) shows the results of powder X-ray diffraction measurement of PEG2000. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). It has characteristic peaks at 19.2° and 24.4°.

[0375] Figure 28 Figure 28 (A) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-4-7. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). In addition to 21.7° and 24.1° derived from polyethylene glycol monostearate (n = about 4) (palmitate, stearate mixture), multiple diffraction peaks were also observed. These are the diffraction peaks of the CP04 crystal. Figure 28 (B) shows the results of powder X-ray diffraction measurement of polyethylene glycol monostearate (n = about 4) (palmitate, stearate mixture). The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). It has characteristic peaks at 21.7° and 24.1°. Figure 28 (C) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-4-8. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 28 (D) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-4-9. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 28 (E) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-4-10. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°).

[0376] Figure 29 Figure 29 (A) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-5-1. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 29 (B) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-5-2. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 20 (°). Figure 29 (C) shows the results of powder X-ray diffraction measurement of the crystal obtained in Example 4-5-3. The ordinate represents the diffraction intensity, and the abscissa represents the diffraction angle 2θ (°). Figure 29 ​​​​(D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-5-4. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 29 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-5-5. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0377] Figure 30 Figure 30 Shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-5-6. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0378] Figure 31 Figure 31 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-7-1. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 31 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-7-2. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 31 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-7-3. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 31 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-7-4. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 31 (E) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-8-1. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0379] Figure 32 Figure 32 (A) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-8-2. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 32 (B) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-8-3. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 32 (C) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-8-4. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 32 (D) shows the results of powder X-ray diffraction measurements of the crystals obtained in Example 4-8-5. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0380] ​​​​​​​Figure 33 Figure 33 (A) shows the crystal structure obtained by single crystal X-ray structural analysis of the crystal of compound CP01 obtained in Example 2-1-1. Detailed Description

[0381] As used herein, the term "room temperature" means a temperature of about 20 °C to about 25 °C.

[0382] As used herein, the term "one or more" means a number of 1 or 2 or more. When the term "one or more" is used in the context of substituents of a group, the term means a number from 1 to the maximum number of acceptable substituents of the group. Specific examples of the term "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and / or greater numbers.

[0383] As used herein, the term "to" indicates that the range includes the values at both ends thereof. For example, "A to B" means a range of A or greater and B or less.

[0384] As used herein, the term "about" when used in combination with a numerical value means a value range of +10% and -10% of the numerical value.

[0385] In the present invention, the term "and / or" is intended to include each combination of the terms "and" and "or" in appropriate combination. Specifically, for example, the term "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, and (vii) A, B and C.

[0386] As used herein, the term "v / v%" means % by volume (volume %) and the term "wt / v%" means % by weight / volume (weight / volume %).

[0387] As used herein, the term "peptide" means a peptide in which two or more amino acids are linked by an amide bond. Peptides having an ester bond in a part of the main chain (such as depsipeptides) are also included in the term "peptide" herein.

[0388] ​As used herein, the term "cyclic peptide" refers to a peptide having a cyclic structure composed of 4 or more amino acid residues. As an aspect of cyclization of cyclic peptides, cyclization can take any form, such as cyclization through a carbon-nitrogen bond (such as an amide bond), cyclization through a carbon-oxygen bond (such as an ester bond or an ether bond), cyclization through a carbon-sulfur bond (such as a thioether bond), cyclization through a carbon-carbon bond, or cyclization through a heterocyclic structure. Among them, cyclization via covalent bonds such as amide bonds, carbon-sulfur bonds or carbon-carbon bonds is preferred. More preferably, cyclization is carried out through an amide bond, and the position of the carboxyl group or amino group used for cyclization can be on the main chain or on the side chain. Most preferably, cyclization is carried out via an amide bond between the carboxyl group on the side chain and the main chain amino group at the N-terminus.

[0389] As used herein, the term "heterocycle" means a non-aromatic heterocycle preferably containing 1 to 5, more preferably 1 to 3 heteroatoms among the atoms constituting the ring. The heterocycle can have double bonds and / or triple bonds in the ring. The carbon atoms in the ring can be oxidized to form carbonyl groups, and the ring can be a monocyclic, fused ring or spiro ring. The number of atoms in the ring constituting the heterocycle is preferably 3 to 12 (3-membered to 12-membered heterocycle), and more preferably 4 to 10 (4-membered to 10-membered heterocycle). Specific examples of heterocycles include azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidinone ring, dioxolane, dioxane ring, thietane ring, octahydroindole ring, 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, azocane ring, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, azepane ring, dioxepane ring, 5,9-dioxaspiro[3,5]nonane ring or a ring in which one or more single bonds in any of these saturated heterocycles are replaced by double bonds or triple bonds.

[0390] The "cyclization" of the term peptide means forming a cyclic moiety containing 4 or more amino acid residues. There is no particular limitation on the number of amino acids contained in the cyclic moiety of the cyclic peptide herein, as long as it is 4 or greater, and examples thereof include 4 to 20 residues, 5 to 15 residues, 6 to 13 residues, 9 to 13 residues, and 11 residues. Preferably, it is 5 to 15 residues, more preferably 9 to 13 residues, and most preferably 11 residues. The method for converting a linear peptide into a cyclic peptide can be carried out by an intramolecular bond formation reaction by the methods described in the following documents: Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, (by R.C. Larock); March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (M.B. Smith and J. March) or the like. Further functional group transformation reactions can also be carried out after the bond formation reaction. Examples of the bonds at the cyclization site of the cyclic peptide include C(O)-N bonds formed by carboxylic acids and amines; C-O-C bonds, C(O)-O bonds, and C(S)-O bonds via oxygen atoms; C(O)-S bonds, C(S)-S bonds, C-S-S-C bonds, C-S-C bonds, C-S(O)-C bonds, and C-S(0 2 )-C via sulfur atoms; and C-N-C bonds, C=N-C bonds, N-C(O)-N bonds, N-C(S)N bonds, and C(S)-N bonds via nitrogen atoms. Further examples thereof include C-C bonds formed by coupling reactions catalyzed by transition metals (such as Suzuki reaction, Heck reaction, and Sonogashira reaction). Examples of the functional group transformation reactions further carried out after the bond formation reaction include oxidation reactions and reduction reactions. Specific examples thereof include reactions in which sulfur atoms are oxidized and converted into sulfoxide groups or sulfone groups. Other examples thereof include reduction reactions in which triple bonds or double bonds in carbon-carbon bonds are reduced and converted into double bonds or single bonds. A closed-loop structure can be formed by bonding two amino acids at the main chain of the amino acids through a peptide bond, or a covalent bond can be formed between two amino acids via a bond, for example, between the side chains of the two amino acids or between one side chain of the two amino acids and the main chain.

[0391] As used herein, the term "cyclic moiety" of a cyclic peptide means a cyclic moiety formed by linking 4 or more amino acid residues.

[0392] As used herein, the term "cyclic peptide crystal" should be understood to have the meaning including (i) crystals of the free form of the cyclic peptide, (ii) crystals of the cyclic peptide solvate, and (iii) mixtures thereof, and can be any one of them.

[0393] As used herein, the solvate is a solvate in which the compound and the solvent form a molecular aggregate together, and there is no particular limitation as long as it is a solvate formed by a solvent acceptable for uptake when administered with the drug. Examples of solvates include hydrates, alcohol solvates (such as ethanol solvate, methanol solvate, 1-propanol solvate or 2-propanol solvate), including not only solvates formed with a single solvent (such as formamide or dimethyl sulfoxide), but also solvates formed by each compound molecule with multiple solvents, or solvates formed by each compound molecule with multiple types of solvents. Note that, as described in Crystal Growth & Design 2012, 12, 2147 - 2152, solvates are different from co-crystals. As used herein, co-crystals are defined as crystals composed of a compound and a component that is solid at 25°C. Although the term "cyclic peptide crystal" as used herein includes (i) crystals of the free form of the cyclic peptide, (ii) crystals of the cyclic peptide solvate, and (iii) mixtures thereof, it does not include co-crystals containing the cyclic peptide, nor mixtures of co-crystals containing the cyclic peptide and any of the crystals of (i) to (iii) above.

[0394] As used herein, the term "amino acid" includes natural amino acids and unnatural amino acids. As used herein, the term "amino acid" may mean an amino acid residue. As used herein, the term "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Examples of unnatural amino acids include, but are not specifically limited to, β-amino acids, D-amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids having side chains different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, an amino acid assumes any conformation. The selection of the side chain of the amino acid is not particularly limited, and in addition to a hydrogen atom, the side chain may be freely selected from, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroarylalkyl group, a cycloalkyl group, and a cycloalkyl group bonded in a spiro manner. Substituents may be added to each side chain. Such substituents are not limited and may be one or two or more substituents each independently freely selected from any substituent (including, for example, a halogen atom, an O atom, an S atom, an N atom, a B atom, a Si atom, or a P atom). That is, examples of the side chain include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, or an optionally substituted cycloalkyl group, or oxo, aminocarbonyl, and a halogen atom. In one non-limiting aspect, an amino acid as used herein may be a compound having a carboxyl group and an amino group in the same molecule. Even in such a case, compounds in which the nitrogen atom of the amino group and any atom of the side chain together form a ring (such as proline, hydroxyproline, and azetidine-2-carboxylic acid) are included in the amino acids as used herein.

[0395] As used herein, the term "optionally substituted" means that the group is optionally substituted with any substituent. In addition, substituents may be added to each substituent. Such substituents are also not limited and may be one or two or more substituents each independently freely selected from any substituent (including, for example, a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom). Examples of the substituent include an alkyl group, an alkoxy group, a fluoroalkyl group, a fluoroalkoxy group, oxo, aminocarbonyl, an alkylsulfonyl group, an alkylsulfonylamino group, a cycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an arylalkyl group, a heteroarylalkyl group, a halogen, a nitro group, an amino group, a monoalkylamino group, a dialkylamino group, a cyano group, a carboxyl group, an alkoxycarbonyl group, and a formyl group.

[0396] As used herein, the term "halogen" refers to, for example, F, Cl, Br, or I.

[0397] As used herein, "alkyl" is a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon and having a subset of the hydrocarbon radical or hydrocarbon group structure that contains no heteroatoms (which means atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds and contains hydrogen and carbon atoms in the main chain. Alkyl includes not only straight-chain forms but also branched-chain forms. Preferred examples of alkyl include those having 1 to 20 carbon atoms (C 1 -C 20 ; hereinafter, "C p -C q " means an alkyl group having p to q carbon atoms), preferably C 1 -C 10 alkyl, and more preferably C 1 -C 6 alkyl. Specific examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0398] As used herein, the term "alkynyl" is a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alkynyl includes not only straight-chain forms but also branched-chain forms. Preferred examples of alkynyl include C 2 -C 10 alkynyl, and more preferably C 2 -C 6 alkynyl. Specific examples thereof include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0399] As used herein, the term "alkenyl" is a monovalent group having at least one double bond (two adjacent sp2 carbon atoms). Depending on the conformation of the double bond and substituents (if any), the geometric configuration of the double bond can exhibit entgegen (E) or zusammen (Z) as well as cis or trans conformations. Alkenyl includes not only straight-chain forms but also branched-chain forms. Preferred examples of alkenyl include C 2 -C 10Alkenyl, and more preferred examples thereof include C 2 -C 6 alkenyl. Specific examples thereof include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0400] As used herein, the term "aryl" means a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon ring group. Preferred examples of aryl include C 6 -C 10 aryl. Specific examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl).

[0401] As used herein, the term "heteroaryl" means an aromatic cyclic monovalent group and an aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring or a fused ring with other rings, and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5-membered to 10-membered heteroaryl), and more preferably 5 to 7 (5-membered to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, and fluoropyridyl.

[0402] As used herein, the term "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom in "alkyl" as defined above is replaced by "aryl" as defined above. As aralkyl, C 7 -C 14 aralkyl is preferred, and C 7 -C 10 aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0403] As used herein, the term "heteroarylalkyl (arylalkyl)" means a group in which at least one hydrogen atom in "alkyl" as defined above is replaced by "heteroaryl" as defined above. As heteroarylalkyl, 5-membered to 10-membered heteroaryl-C 1 -C 6 alkyl is preferred, and 5-membered to 10-membered heteroaryl-C 1 -C2 Alkyl. Specific examples of heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0404] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic, and spiro rings. Preferred examples of cycloalkyl include C 3 -C 8 Cycloalkyl. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0405] As used herein, the term "alkoxy" means an oxy group bonded to "alkyl" as defined above. Preferred examples of alkoxy include C 1 -C 6 Alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and 3-methylbutoxy.

[0406] As used herein, the term "alkoxyalkyl" means a group in which one or more hydrogens in "alkyl" as defined above are replaced by "alkoxy" as defined above. As alkoxyalkyl, preferably C 1 -C 6 Alkoxy-C 1 -C 6 Alkyl, more preferably C 1 -C 6 Alkoxy-C 1 -C 2 Alkyl. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0407] As used herein, the term "amino" means -NH 2 in the narrow sense, and means -NRR' in the broad sense. Herein, R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, and heteroaryl, or R and R' and the nitrogen atom to which they are bonded together form a ring. Preferred examples of amino include -NH 2 、mono-C1 -C 6 alkylamino, di-C 1 -C 6 alkylamino and 4- to 8-membered ring amino groups.

[0408] As used herein, the term "monoalkylamino" means an "amino" group as defined above, where R is hydrogen and R' is an "alkyl" as defined above. Preferred examples of monoalkylamino include mono-C1-C6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0409] As used herein, the term "dialkylamino" means an "amino" group as defined above, where R and R' are each independently an "alkyl" as defined above. Preferred examples of dialkylamino include C 1 -C 6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0410] As used herein, the term "alkylsulfonylamino" means a group in which a sulfonyl group is bonded to an "amino" as defined above. Preferred examples thereof include C 1 -C 6 alkylsulfonyl-NH- and (C 1 -C 6 alkylsulfonyl-) 2 -N-. Specific examples of aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, and bis(ethylsulfonyl)amino.

[0411] As used herein, the term "aminocarbonyl" means a carbonyl group bonded to an "amino" as defined above. Preferred examples of aminocarbonyl include -CONH 2 , mono-C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, and 4- to 8-membered ring aminocarbonyl. Specific examples of aminocarbonyl include -CONH 2 , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxothiomorpholin-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl.

[0412] As used herein, the "amino acid residue" constituting a peptide is sometimes simply referred to as an "amino acid".

[0413] As used herein, the term "side chain of an amino acid" in the case of an α-amino acid means an atomic group bonded to the carbon (α-carbon) to which the amino group and the carboxyl group are bonded, other than the amino group and the carboxyl group. For example, the methyl group of Ala is the side chain of an amino acid. In the case of a β-amino acid, an atomic group bonded to the α-carbon and / or β-carbon, other than the amino group bonded to the β-carbon and the carboxyl group bonded to the α-carbon, may be the side chain of an amino acid. Further, in the case of a γ-amino acid, an atomic group bonded to the α-carbon, β-carbon, and / or γ-carbon, other than the amino group bonded to the γ-carbon and the carboxyl group bonded to the α-carbon, may be the side chain of an amino acid.

[0414] As used herein, the term "main chain of an amino acid" in the case of an α-amino acid means the chain portion composed of an amino group, an α-carbon, and a carboxyl group; in the case of a β-amino acid, it means the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group. In the case of a γ-amino acid, it means the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group. Further, the term "α-amino acid backbone" means the chain portion composed of an amino group, an α-carbon, and a carboxyl group; the term "β-amino acid backbone" means the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group; and the term "γ-amino acid backbone" means the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group. As used herein, an amino acid having a "β-amino acid backbone" as a whole or as a substructure may be referred to as an "amino acid having a β-amino acid backbone". For example, aspartic acid has a chain portion (β-amino acid backbone) composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group, and thus belongs to the category of "amino acids having a β-amino acid backbone".

[0415] As used herein, the term "main chain of a peptide" means a structure in which a plurality of amino acids are linked by an amide bond. As used herein, the terms "main chain of a cyclic peptide" and "main chain of a cyclic moiety" mean a structure in which a plurality of amino acids are linked by an amide bond in the cyclic moiety of the cyclic peptide. The "main chain of a peptide", "main chain of a cyclic peptide", and "main chain of a cyclic moiety" may partially contain another bond, such as an ester bond, instead of an amide bond. Further, the "main chain of a cyclic peptide" and "main chain of a cyclic moiety" may include the bonds exemplified herein as follows: a bond at the cyclization site of a cyclic peptide or a bond formed by a peptide cyclization formation reaction.

[0416] As used herein, the term "N-substituted amino acid" means an amino acid in which the amino group contained in the amino acid is replaced by -NHR (R represents an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, or cycloalkyl group optionally having a substituent, and one or two non-adjacent methylene groups in any of these groups are optionally replaced by an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2 -), substituted; and the carbon chain bonded to the N atom and the carbon atom at the α-position can form a ring, as in proline.). As used herein, an "N-substituted amino acid" can be an N-alkyl amino acid, and preferred examples thereof include N-C 1 -C 6 alkyl amino acids, and more preferred examples thereof include N-C 1 -C 4 alkyl amino acids, and most preferred examples thereof include N-ethyl amino acid or N-methyl amino acid, but are not limited to these. As used herein, preferred examples of an "N-substituted amino acid" include N-substituted amino acids in which the amino group contained in the "main chain of the amino acid" is substituted.

[0417] As used herein, the term "N-unsubstituted amino acid" means an amino acid in which the amino group contained in the amino acid is not substituted, i.e., an amino acid represented by -NH 2 As used herein, preferred examples of an "N-unsubstituted amino acid" include N-unsubstituted amino acids in which the amino group contained in the "main chain of the amino acid" is not substituted.

[0418] When the amino acid constituting the cyclic peptide as used herein is aspartic acid, or an amino acid in which one or more of the hydrogen atoms on the α-carbon and β-carbon of aspartic acid are substituted, or an amino acid in which the amino group contained in the "main chain of the amino acid" is substituted, the carboxyl group bonded to the α-carbon contained in the "main chain of the amino acid" may be included in the "main chain of the cyclic peptide". In another aspect, the carboxyl group bonded to the β-carbon contained in the "amino acid side chain" may be included in the "main chain of the cyclic peptide", in which case the "β-amino acid backbone" is included in the "main chain of the cyclic peptide".

[0419] As used herein, the term "number of amino acids" or "number of amino acid residues" refers to the number of amino acid residues (amino acid units) constituting a peptide, and means the number of amino acid units produced after cleavage of the amide bond, ester bond, and cyclized moiety that connect amino acids. For example, the number of amino acids or amino acid residues of a cyclic peptide in which the cyclic moiety is composed of 10 amino acid residues and the linear moiety is composed of 1 amino acid residue is 11.

[0420] As used herein, the term "the cyclic moiety of a cyclic peptide contains an amino acid" means that the main chain of the cyclic moiety of the cyclic peptide contains an amino acid as a substructure.

[0421] As used herein, the term "saturated heterocycle" means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and having no double bonds and / or triple bonds in the ring. The saturated heterocycle can be a monocyclic ring or can form a fused ring with another ring (e.g., an aromatic ring such as a benzene ring). Preferred examples of the saturated heterocycle include 4- to 10-membered saturated heterocycles. Specific examples of the saturated heterocycle include azetidine ring, oxoazetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 2-oxopyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidinone ring, dioxolane ring, dioxane ring, thietane ring, octahydroindole ring, dihydroindole ring, azepane ring, dioxepane ring, and 5,9-dioxaspiro[3.5]nonane ring.

[0422] As used herein, the molecular weight of a cyclic peptide or a solvent is in g / mol unless otherwise specified. Additionally, in the case where the cyclic peptide crystal is a crystal of the free form of the cyclic peptide, a crystal of the cyclic peptide solvate, or a mixture thereof, the "molecular weight of the cyclic peptide" is based on the molecular weight of the free form of the cyclic peptide.

[0423] The cyclic peptide according to an embodiment of the present invention may have a molecular weight (g / mol) of 1205 or greater, 1206 or greater, 1207 or greater, 1208 or greater, 1210 or greater, 1220 or greater, 1230 or greater, 1250 or greater, or 1300 or greater and may be 2800 or less, 2500 or less, 2000 or less, 1900 or less, 1800 or less, 1700 or less, or 1600 or less. The molecular weight (g / mol) of the cyclic peptide of the present invention is preferably 1204 or greater and 3000 or less, more preferably 1300 or greater and 1600 or less, and most preferably 1400 or greater and 1500 or less.

[0424] The cyclic peptide according to an embodiment of the present invention may contain a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues. Additionally, the cyclic peptide according to an embodiment of the present invention may contain a cyclic moiety composed of a total of 7 to 15 residues, 8 to 14 residues, 9 to 13 residues, 10 to 13 residues, 11 to 13 residues, 11 to 12 residues, or 11 amino acid residues, wherein the total number of amino acids is 9 to 18 residues, 10 to 16 residues, 10 to 14 residues, 11 to 14 residues, 11 to 13 residues, 11 to 12 residues, or 11 residues. The cyclic peptide of the present invention preferably contains a cyclic moiety composed of 8 to 16 residues, wherein the total number of amino acids is 8 to 20 residues, more preferably contains a cyclic moiety composed of 11 to 13 residues, wherein the total number of amino acids is 11 to 14 residues, and most preferably contains a cyclic moiety composed of a total of 11 amino acid residues, wherein the total number of amino acids is 11 residues.

[0425] The cyclic peptide according to an embodiment of the present invention may contain at least 3 N-substituted amino acid residues, 4 N-substituted amino acid residues, or 5 N-substituted amino acid residues, and in another embodiment, may contain at least 5 N-substituted amino acid residues. Additionally, the cyclic peptide according to an embodiment of the present invention may contain at least 1 N-unsubstituted amino acid residue, 2 N-unsubstituted amino acid residues, or 3 N-unsubstituted amino acid residues, and in another embodiment, may contain at least 3 N-unsubstituted amino acid residues. The cyclic peptide of the present invention preferably contains at least 3 N-substituted amino acid residues, more preferably contains at least 5 N-substituted amino acid residues, and most preferably contains at least 7 N-substituted amino acid residues.

[0426] The N-substituted amino acid contained in the cyclic peptide according to an embodiment of the present invention may be an N-alkyl amino acid, may be an N-methyl amino acid or an N-ethyl amino acid in another embodiment, and may be an N-methyl amino acid in another embodiment. The N-substituted amino acid contained in the cyclic peptide of the present invention is preferably an N-alkyl amino acid, more preferably an N-methyl amino acid or an N-ethyl amino acid, and most preferably an N-methyl amino acid.

[0427] The cyclic peptide according to an embodiment of the present invention may be a cyclic peptide having the following characteristics (I), (II), and (III):

[0428] (I) Characterized by containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, wherein the total number of amino acids is 8 to 20 residues;

[0429] (II) Characterized by containing at least 2 N-substituted amino acid residues; and

[0430] (III) Characterized by having a molecular weight (g / mol) of 1204 or greater and 3000 or less.

[0431] The cyclic peptide according to an embodiment of the present invention may be a cyclic peptide having the following characteristics (I) and (II):

[0432] (I) Characterized by containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, where the total number of amino acids is 8 to 20 residues; and

[0433] (II) Characterized by containing at least 2 N - substituted amino acid residues.

[0434] The cyclic peptide according to an embodiment of the present invention may contain at least one β - amino acid backbone. Additionally, the cyclic peptide according to an embodiment of the present invention may contain at least one β - amino acid backbone in the cyclic moiety.

[0435] The cyclic peptide according to an embodiment of the present invention may contain a cyclic moiety composed of a 28 - to 55 - membered ring, a 28 - to 49 - membered ring, a 31 - to 46 - membered ring, a 34 - to 43 - membered ring, a 34 - to 40 - membered ring, a 34 - to 37 - membered ring, or a 34 - membered ring. The cyclic peptide according to an embodiment of the present invention may contain a cyclic moiety composed of a 34 - to 40 - membered ring, and the cyclic peptide according to another embodiment may contain a cyclic moiety composed of a 34 - membered ring.

[0436] When the cyclic peptide according to an embodiment of the present invention contains a cyclic moiety composed of a 34 - membered ring, the cyclic moiety composed of a 34 - membered ring above may be a cyclic peptide composed of 10 α - amino acid residues and 1 amino acid residue having a β - amino acid backbone, where there are a total of 11 amino acid residues.

[0437] The cyclic peptide according to an embodiment of the present invention may have the following structure.

[0438] [Formula 2]

[0439]

[0440] [Here, P 1 , P 3 , P 5 , P 6 , P 10 and P 11 are each C 1 to C 6 alkyl; P 4 is C 1 to C 6 alkyl or P 4 bonded to the nitrogen atom to which P 4 is bonded, R 4 and R4 The carbon atoms that are bonded together form a 4- to 7-membered saturated heterocycle; P 8 is C 1 to C 6 alkyl or P 8 and P 8 the nitrogen atom to which it is bonded, R 8 and R 8 the carbon atoms that are bonded together form a 4- to 7-membered saturated heterocycle; the 4- to 7-membered saturated heterocycle is optionally substituted by C 1 to C 6 alkoxy; R 1 、R 2 、R 3 、R 5 、R 7 and R 10 are each a hydrogen atom, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl or aralkyl optionally having substituents; R 4 is a hydrogen atom or C 1 to C 6 alkyl, except when R 4 and P 4 form a 4- to 7-membered saturated heterocycle; R 8 is a hydrogen atom or C 1 to C 6 alkyl, except when R 8 and P 8 form a 4- to 7-membered saturated heterocycle; R 9 and Q 9 and R 9 and Q 9 the carbon atoms that are bonded together form a 3- to 7-membered saturated carbocycle; and R 11 is a hydrogen atom, C 1 to C 6 alkyl, di-C 1 to C 6 alkylaminocarbonyl or 4- to 8-membered cyclic aminocarbonyl.]

[0441] In one embodiment, P 1 、P 3 、P 5 、P 6 、P 10 and P 11 can each be methyl or ethyl. Additionally, in one embodiment, P 4 can be methyl, or the nitrogen atom to which it is bonded, R 4 and R 4 and R 4The bonded carbon atoms together form a 4-membered saturated heterocycle. Additionally, in one embodiment, P 8 can be combined with the nitrogen atom bonded to P 8 , the carbon atoms bonded to R 8 and R 8 to form a 5-membered saturated heterocycle, which 5-membered saturated heterocycle is optionally substituted with a C 1 to C 6 alkoxy group.

[0442] In one embodiment, R 1 and R 2 can each be a C 1 to C 6 alkyl group; R 3 can be a hydrogen atom or a C 1 to C 6 alkyl group; R 4 can be a hydrogen atom, except when R 4 and P 4 form a 4- to 7-membered saturated heterocycle; R 5 can be a C 3 to C 6 cycloalkyl group or benzyl group optionally having substituents; R 7 can be a phenethyl group optionally having substituents; R 9 can be combined with Q 9 and the carbon atoms bonded to R 9 and Q 9 to form a 5-membered saturated carbocycle; R 10 can be a C 1 to C 6 alkyl group or a C 3 to C 6 cycloalkyl group; R 11 can be a methyl group, a di-C 1 to C 6 alkylaminocarbonyl group or a 6-membered ring aminocarbonyl group.

[0443] The ClogP of a cyclic peptide according to an embodiment of the present invention can be determined according to the principle described in the following document: "CLOGP Reference Manual Daylight version 4.9 (Release date: August 1, 2011, https: / / www.daylight.com / dayhtml / doc / clogp / ). Examples of methods for calculating ClogP include using Daylight version 4.95 (Release date: August 1, 2011, ClogP algorithm version 5.4 of Daylight Chemical Information Systems, Inc., database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html) for calculation.

[0444] The ClogP of a cyclic peptide according to an embodiment of the present invention can be 5 or greater, 6 or greater, 7 or greater, 8 or greater, or 9 or greater, and can be 24 or less, 23 or less, 22 or less, 21 or less, 20 or less, 19 or less, or 18 or less. Examples of the range of ClogP of a cyclic peptide according to an embodiment of the present invention include 5 or greater and 23 or less, 6 or greater and 21 or less, 7 or greater and 20 or less, 8 or greater and 19 or less, 9 or greater and 18 or less, 10 or greater and 17 or less, 11 or greater and 16.5 or less, and 11.2 or greater and 16.1 or less. Additionally, the ClogP of a cyclic peptide according to an embodiment of the present invention can be 4 or greater and 25 or less, and the ClogP of a cyclic peptide according to another embodiment can be 9 or greater and 18 or less. Additionally, the ClogP of a cyclic peptide according to an embodiment of the present invention can be greater than the ClogP of cyclosporin A (ClogP: 14.36). The ClogP of the cyclic peptide of the present invention is preferably 5 or greater and 23 or less, more preferably 9 or greater and 18 or less, and most preferably 11.2 or greater and 16.1 or less.

[0445] Preferably, a cyclic peptide according to an embodiment of the present invention has a ClogP / amino acid residue number of 1.0 or greater. The ClogP / amino acid residue number is a value calculated by dividing the ClogP of the cyclic peptide by the number of amino acid residues contained in the cyclic peptide. For example, when the ClogP of the cyclic peptide is 14.0 and the number of amino acid residues contained in the cyclic peptide is 7, the ClogP / amino acid residue number of the cyclic peptide is calculated to be 2.0.

[0446] The ClogP / amino acid residue number of the cyclic peptide according to an embodiment of the present invention is preferably 0.3 or greater, more preferably 0.5 or greater, and most preferably 0.8 or greater. The upper limit of the ClogP / amino acid residue number of the cyclic peptide according to an embodiment of the present invention is preferably 2.3 or less, more preferably 1.9 or less, and most preferably 1.6 or less. Examples of the range of the ClogP / amino acid residue number of the cyclic peptide according to an embodiment of the present invention include 0.3 or more and 2.3 or less, 0.4 or more and 2.3 or less, 0.5 or more and 1.9 or less, 0.7 or more and 1.8 or less, and 0.8 or more and 1.6 or less. The ClogP / amino acid residue number in the cyclic peptide according to an embodiment can be 0.8 or greater and 1.6 or less.

[0447] The solubility of the cyclic peptide according to an embodiment of the present invention in 50 mM phosphate buffer (pH 6.5) can be measured by a general method. For example, for the lyophilized powder of the compound, 50 mM phosphate buffer solution (PPB: phosphate buffer, pH 6.5) is added, and after shaking (1800 rpm, for 22 to 24 hours), the mixed solution is filtered through a filter, and the compound concentration of the filtrate is measured by LC / MS / MS. Based on the measured compound concentration, the solubility (μg / mL) can be calculated. It should be noted that "solubility" means the solubility under the conditions of 25 °C and 1 atm. The solubility of the cyclic peptide according to an embodiment of the present invention in 50 mM phosphate buffer (pH 6.5) can be 1200 mg / mL or less, 800 mg / mL or less, 600 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 25 mg / mL or less, 10 mg / mL or less, 5.0 mg / mL or less, or 2.6 mg / mL or less, and can be 0.8 mg / mL or greater, 0.9 mg / mL or greater, 1.0 mg / mL or greater, or 1.1 mg / mL or greater. The solubility of the cyclic peptide according to an embodiment in 50 mM phosphate buffer (pH 6.5) can be 0.8 mg / mL or greater, and in another embodiment can be 1.1 mg / mL or greater.

[0448] According to an embodiment of the present invention, specific examples of the cyclic peptide having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) may include cyclosporin A.

[0449] The cyclic peptide crystal according to one embodiment of the present invention may have one or more diffraction peaks in powder X-ray diffraction using CuKα radiation. The cyclic peptide crystal according to another embodiment of the present invention may have two or more diffraction peaks in powder X-ray diffraction using CuKα radiation. The cyclic peptide crystal according to another embodiment of the present invention may have three or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

[0450] Note that powder X-ray diffraction using CuKα radiation can be measured, for example, under the following conditions. Specifically, a powder X-ray diffractometer such as D8 Discover, 2D -500 solid detector (manufactured by Bruker) can be used, with CuKα as the radiation source, under conditions such as a tube voltage / tube current of 40 kV / 40 mA or 50 kV / 1000 μA, and in a measurement range of 5 to 31° and an exposure time of 40 to 600 seconds for measurement.

[0451] The cyclic peptide crystal according to one embodiment of the present invention may be a crystal that has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation or has polarization when observed with a polarized light microscope.

[0452] The cyclic peptide according to one embodiment of the present invention may be a cyclic peptide that does not include cyclosporin A. The cyclic peptide according to another embodiment may be a peptide that does not include (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15Cyclic peptides of [[33,1′-cyclopentyl]]nonatriacontan-27-carboxamide, and the cyclic peptides according to another embodiment may exclude cyclosporin A and (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 Cyclic peptides of [[33,1′-cyclopentyl]]nonatriacontan-27-carboxamide. The cyclic peptides according to another embodiment of the present invention may be (3s,9s,12s,17s,20s,23s,27s,30s,36s)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1s)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaooxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.0 12，15 [[33,1′-cyclopentyl]]nonatriacontan-27-carboxamide.

[0453] As used herein, the term "amide solvent" means a solvent containing an amide bond in the molecule. Examples of "amide solvent" or "amide solvent having a molecular weight of 18 or greater and 170 or less" as used herein may include formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone. The "amide solvent" or "amide solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of formamide, N-methylformamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 2-pyrrolidone, and N-methylpyrrolidone, and is preferably formamide, N-methylformamide, N,N-dimethylformamide, 2-pyrrolidone, or N-methylpyrrolidone, more preferably formamide or N,N-dimethylformamide, and most preferably formamide.

[0454] As used herein, the term "sulfoxide solvent" means a solvent belonging to the sulfoxide class. As used herein, examples of "sulfoxide solvent" or "sulfoxide solvent having a molecular weight of 18 or greater and 170 or less" may include dimethyl sulfoxide, phenyl methyl sulfoxide, and diethyl sulfoxide. The "sulfoxide solvent" or "sulfoxide solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of: dimethyl sulfoxide and diethyl sulfoxide, and preferably dimethyl sulfoxide, phenyl methyl sulfoxide, or diethyl sulfoxide, more preferably dimethyl sulfoxide or diethyl sulfoxide, and most preferably dimethyl sulfoxide.

[0455] As used herein, the term "hydrocarbon solvent" means a solvent composed only of carbon atoms and hydrogen atoms.

[0456] As used herein, the term "aromatic hydrocarbon solvent" means a hydrocarbon solvent having one or more aromatic rings in the molecule. As used herein, the "aromatic hydrocarbon solvent" is preferably a solvent having one or more benzene rings in the molecule, and more preferably a solvent having one benzene ring in the molecule. As used herein, examples of "aromatic hydrocarbon solvent" or "aromatic hydrocarbon solvent having a molecular weight of 18 or greater and 170 or less" may include benzene, toluene, xylene, ethylbenzene, tetrahydronaphthalene, and cumene. The "aromatic hydrocarbon solvent" or "aromatic hydrocarbon solvent having a molecular weight of 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of: benzene, toluene, xylene, ethylbenzene, tetrahydronaphthalene, and cumene, and preferably one or more selected from the group consisting of: toluene, xylene, ethylbenzene, tetrahydronaphthalene, and cumene, more preferably toluene, xylene, tetrahydronaphthalene, or cumene, and most preferably toluene, tetrahydronaphthalene, or cumene.

[0457] As used herein, the term "halogen solvent" means a solvent having one or more halogen atoms in the molecule. As used herein, the "halogen solvent" is preferably a solvent having one or more chlorine atoms and / or bromine atoms in the molecule, and more preferably a solvent having one or more chlorine atoms in the molecule. As used herein, examples of "halogen solvent" or "halogen solvent having a molecular weight of 18 or greater and 170 or less" may include dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride. The "halogen solvent" or "halogen solvent having a molecular weight of 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of: dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, bromobenzene, and carbon tetrachloride, and preferably one or more selected from the group consisting of: dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, more preferably dichloromethane, chloroform, 1,2-dichloroethane, or chlorobenzene, and most preferably dichloromethane or chlorobenzene.

[0458] As used herein, the term "alcohol solvent" means a solvent having one or more hydroxyl groups bonded to a carbon atom in the molecule. As used herein, examples of "alcohol solvent" or "alcohol solvent having a molecular weight of 18 or greater and 170 or less" may include methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol. The "alcohol solvent" or "alcohol solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and benzyl alcohol, and is preferably one or more selected from the group consisting of methanol, ethanol, 1-propanol, isopropanol, and n-butanol, more preferably methanol, ethanol, 1-propanol, isopropanol, or n-butanol, and most preferably ethanol.

[0459] As used herein, the term "ether solvent" means a solvent having one or more ether bonds in the molecule. As used herein, examples of "ether solvent" or "ether solvent having a molecular weight of 18 or greater and 170 or less" may include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and tert-butyl methyl ether. The "ether solvent" or "ether solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, anisole, and tert-butyl methyl ether, and is preferably one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole, and tert-butyl methyl ether, more preferably tetrahydrofuran, 1,4-dioxane, diisopropyl ether, anisole, or tert-butyl methyl ether, and most preferably 1,4-dioxane, anisole, or tert-butyl methyl ether.

[0460] As used herein, the term "ester solvent" means a solvent having one or more ester bonds in the molecule. As used herein, examples of "ester solvent" or "ester solvent having a molecular weight of 18 or greater and 170 or less" may include ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerolactone. The "ester solvent" or "ester solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of: ethyl formate, methyl acetate, ethyl acetate, methyl propionate, n-butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerolactone, and is preferably one or more selected from the group consisting of: ethyl acetate, isopropyl acetate, and n-butyl acetate, more preferably ethyl acetate, isopropyl acetate, or n-butyl acetate, and most preferably ethyl acetate or n-butyl acetate.

[0461] As used herein, the term "nitrile solvent" means a solvent having one or more cyano groups bonded to a carbon atom in the molecule. As used herein, examples of "nitrile solvent" or "nitrile solvent having a molecular weight of 18 or greater and 170 or less" may include acetonitrile, benzonitrile, and propionitrile. The "nitrile solvent" or "nitrile solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of: acetonitrile and propionitrile, and is preferably one or more selected from the group consisting of: acetonitrile, benzonitrile, and propionitrile, more preferably acetonitrile, benzonitrile, or propionitrile, and most preferably acetonitrile.

[0462] As used herein, the term "ketone solvent" means a solvent represented by R 1 -C(=O)-R 2 wherein R 1 and R 2 are each independently an alkyl group, an aryl group, or a heteroaryl group, or R 1 and R 2Together form an alkylene group. As used herein, examples of "ketone solvents" or "ketone solvents having a molecular weight of 18 or greater and 170 or less" may include acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone, and 3-acetylpyridine. The "ketone solvent" or "ketone solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, cyclohexanone, diethyl ketone, cyclopentanone, and 3-acetylpyridine, and is preferably one or more selected from the group consisting of acetone, methyl ethyl ketone, cyclohexanone, methyl isobutyl ketone, and 3-acetylpyridine, more preferably acetone, methyl ethyl ketone, cyclohexanone, or methyl isobutyl ketone, and most preferably acetone or methyl ethyl ketone.

[0463] As used herein, the term "aliphatic hydrocarbon solvent" means a hydrocarbon solvent that does not have an aromatic ring in its molecule. As used herein, examples of "aliphatic hydrocarbon solvents" or "aliphatic hydrocarbon solvents having a molecular weight of 18 or greater and 170 or less" may include n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane. The "aliphatic hydrocarbon solvent" or "aliphatic hydrocarbon solvent having a molecular weight of 18 or greater and 170 or less" in one embodiment of the present invention may be one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and methylcyclohexane, and is preferably one or more selected from the group consisting of n-heptane, cyclohexane, and methylcyclohexane, more preferably n-heptane, cyclohexane, or methylcyclohexane, and most preferably n-heptane or cyclohexane.

[0464] As used herein, "water-soluble organic solvents" means organic solvents that are miscible with water in any proportion. As used herein, examples of "water-soluble organic solvents" may include alcohol solvents, amide solvents, nitrile solvents, and sulfoxide solvents. The "water-soluble organic solvent" in one embodiment of the present invention may be an alcohol solvent, an amide solvent, a nitrile solvent, or a sulfoxide solvent, and is preferably an alcohol solvent or a sulfoxide solvent, more preferably methanol, ethanol, 1-propanol, 2-propanol, or dimethyl sulfoxide, and most preferably ethanol or dimethyl sulfoxide.

[0465] As used herein, "PEG solvents" means solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 or mixtures thereof, where n is a natural number of 1 or greater, and R 1 and R 2 are each independently hydrogen, C 1 to C4 alkyl or -C(=O)R 4 , R 3 is hydrogen or C 1 to C 4 alkyl, and R 4 is C 1 to C 18 alkyl optionally substituted with a hydroxyl group or C 1 to C 18 alkenyl. The "PEG-like solvent" in one embodiment of the present invention may be (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number from 1 or greater and 10 or less, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , where the average value of n is from 3 to 100, wherein R 1 and R 2 are each independently hydrogen, C 1 to C 4 alkyl or -C(=O)R 4 , R 3 is hydrogen or C 1 to C 4 alkyl, and R 4 is C 1 to C 18 alkyl optionally substituted with a hydroxyl group or C 1 to C 18 alkenyl. The "PEG-like solvent" in a preferred embodiment of the present invention may be (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number of 1, 2, 3, or 4, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , where the average value of n is from 3 to 100, wherein R 1 is hydrogen or C 1 to C 4 alkyl, R 2 is hydrogen, C 1 to C 4 alkyl, or -C(=O)R 4 , R 3 is hydrogen or C 1 to C4 alkyl, and R 4 is C 10 to C 18 alkyl. The "PEG-based solvent" in a more preferred embodiment of the present invention may be (i) a solvent represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number of 1, 2, 3, or 4, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , where the average value of n is from 3 to 100, where R 1 is hydrogen or methyl, R 2 is hydrogen, methyl, or -C(=O)R 4 , R 3 is hydrogen or methyl, and R 4 is C 11 to C 17 alkyl. The "PEG-based solvent" in an even more preferred embodiment of the present invention may be diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or polyethylene glycol mono-fatty acid ester. The "PEG-based solvent" in an even more preferred embodiment of the present invention may be polyethylene glycol, and in this case, the number-average molecular weight of the polyethylene glycol may be from 150 to 5000, and may preferably be from 360 to 440, 540 to 660, 900 to 1100, or 1800 to 2200. Additionally, the polyethylene glycol may be PEG400, PEG600, PEG1000, or PEG2000. The "PEG-based solvent" in another even more preferred embodiment of the present invention may be polyethylene glycol mono-fatty acid ester, and in this case, the polyethylene glycol mono-fatty acid ester may be polyethylene glycol monostearate or polyethylene glycol monolaurate. The "PEG-based solvent" in the present invention is preferably diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or polyethylene glycol mono-fatty acid ester, more preferably polypropylene glycol or polyethylene glycol mono-fatty acid ester, and most preferably polyethylene glycol mono-fatty acid ester.

[0466] One aspect of the present disclosure is a method for producing a cyclic peptide crystal, the method comprising the step of contacting the cyclic peptide with a solvent.

[0467] The solvent in the production method according to one aspect of the present disclosure may be any solvent selected from the group consisting of the following (1), (2), and (3):

[0468] (1) A solvent having a molecular weight of 18 or greater and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or greater and 170 or less;

[0469] (2) Water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent; and

[0470] (3) (i) A PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent, and water, and a PEG-based solvent.

[0471] The solvent in the production method according to one aspect of the present disclosure may be (i) a solvent having a molecular weight of 18 or greater and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or greater and 170 or less.

[0472] When the solvent in the production method according to one aspect of the present disclosure is (i) a solvent having a molecular weight of 18 or greater and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or greater and 170 or less, the solvent may be a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogenated solvent, an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, a ketone solvent, an aliphatic hydrocarbon solvent, ethylene glycol, and water, or it may be a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogenated solvent, an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, and a ketone solvent. It is preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogenated solvent, and an ester solvent, more preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, and a halogenated solvent, and most preferably a solvent selected from the group consisting of an amide solvent, a sulfoxide solvent, and an aromatic hydrocarbon solvent.

[0473] In one embodiment, the solvent in the production method according to an aspect of the present disclosure may be a solvent (A) having a molecular weight of 18 or greater and 170 or less, or a mixed solvent of a solvent (A) having a molecular weight of 18 or greater and 170 or less and a solvent (B) having a molecular weight of 18 or greater and 170 or less, and in another embodiment may be a solvent (A) or a mixed solvent containing a solvent (A) and a solvent (B). In these cases, the above solvent (A) may be one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the above solvent (B) may be one or more selected from the group consisting of: aliphatic hydrocarbon solvents, ethylene glycol, and water. Additionally, in these cases, the above solvent (A) may be selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, alcohol solvents, ether solvents, ester solvents, nitrile solvents, and ketone solvents, and the above solvent (B) may be selected from the group consisting of: aliphatic hydrocarbon solvents, ethylene glycol, and water.

[0474] For example, the above solvent (A) may be one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents, may be one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, and halogen solvents, may be one or more selected from the group consisting of: amide solvents, sulfoxide solvents, and aromatic hydrocarbon solvents, may be an amide solvent, may be a sulfoxide solvent, may be an aromatic hydrocarbon solvent, may be a halogen solvent, may be an alcohol solvent, may be an ether solvent, may be an ester solvent, may be a nitrile solvent, or may be a ketone solvent. The above solvent (A) is preferably one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents, more preferably an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, or a halogen solvent, and most preferably an amide solvent, a sulfoxide solvent, or an aromatic hydrocarbon solvent.

[0475] For example, the above solvent (B) may be one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water, may be an aliphatic hydrocarbon solvent, ethylene glycol, or water, may be an aliphatic hydrocarbon solvent, or may be water. The above solvent (B) is preferably one or more solvents selected from the group consisting of aliphatic hydrocarbon solvents, ethylene glycol, and water, more preferably an aliphatic hydrocarbon solvent, ethylene glycol, or water, and most preferably n - heptane, cyclohexane, or water.

[0476] In the solvent in the production method according to one aspect of the present disclosure, the volume ratio (v / v) between the above-mentioned solvent (A) and the above-mentioned solvent (B) can be from 1:0 to 1:40, can be from 1:0 to 1:30, 1:0 to 1:20, 1:0 to 1:10, 1:0 to 1:7, or 1:0 to 1:5, can be from 1:0 to 1:4, can be from 10:1 to 1:40, can be from 5:1 to 1:30, 3:1 to 1:20, 2:1 to 1:10, 1:1 to 1:7 or 1:2 to 1:5, or can be from 1:2 to 1:4. The volume ratio (v / v) between the above-mentioned solvent (A) and the above-mentioned solvent (B) in the solvent is preferably from 1:0 to 1:4, more preferably from 1:1 to 1:4, and most preferably from 1:2 to 1:4.

[0477] In the solvent in the production method according to one aspect of the present disclosure, the above-mentioned solvent (A) can be any solvent having a molecular weight of 18 or more and 170 or less, and can be a solvent having a molecular weight of 18 or more and 160 or less, a molecular weight of 18 or more and 150 or less, a molecular weight of 18 or more and 140 or less, or a molecular weight of 32 or more and 135 or less. The above-mentioned solvent (A) preferably has a molecular weight of 18 or more and 150 or less, more preferably a molecular weight of 18 or more and 140 or less, and most preferably a molecular weight of 32 or more and 135 or less.

[0478] In the solvent in the production method according to one aspect of the present disclosure, the above-mentioned solvent (B) can be any solvent having a molecular weight of 18 or more and 170 or less, and can be a solvent having a molecular weight of 18 or more and 160 or less, a molecular weight of 18 or more and 135 or less, a molecular weight of 18 or more and 120 or less, or a molecular weight of 18 or more and 105 or less. The above-mentioned solvent (B) is preferably a solvent having a molecular weight of 18 or more and 135 or less, more preferably a solvent having a molecular weight of 18 or more and 120 or less, and most preferably a solvent having a molecular weight of 18 or more and 105 or less.

[0479] In the solvent in the production method according to one aspect of the present disclosure, the above-mentioned solvent (A) and the above-mentioned solvent (B) can have a melting point of 25°C or lower.

[0480] The solvent in the production method according to one aspect of the present disclosure can be water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent.

[0481] In the case where the solvent in the production method according to one aspect of the present disclosure is water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, in one embodiment, the above surfactant may be one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants. In another embodiment, the above surfactant may be one or more selected from the group consisting of primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters, and in yet another embodiment may be one or more selected from the group consisting of alkyl sulfates, alkylarylpolyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. It is preferably an alkyl sulfate, an alkylarylpolyoxyethylene ether, a polyoxyethylene glycerol fatty acid ester, or a polyoxyethylene sorbitan fatty acid ester, more preferably sodium dodecyl sulfate, 4-(1,1,3,3-tetramethylbutyl)phenyl polyethylene glycol (Triton X-100(R)), Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), or polyoxyethylene sorbitan monolaurate (Tween(R)), and most preferably Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)).

[0482] In the case where the solvent in the production method according to one aspect of the present disclosure is water containing 0.01 wt / v% to 30 wt / v% surfactant and 5 v / v% to 50 v / v% water-soluble organic solvent, the above surfactant may be an ionic surfactant or a nonionic surfactant in one embodiment, an ionic surfactant in another embodiment, and a nonionic surfactant in yet another embodiment.

[0483] The surfactant in one embodiment of the present invention may be one or more selected from the group consisting of: cationic surfactants, anionic surfactants, and amphoteric surfactants. And in another embodiment, the surfactant may be one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, and lecithin. It is preferably an alkyl sulfate, more preferably a dodecyl sulfate, and most preferably sodium dodecyl sulfate.

[0484] The nonionic surfactant in one embodiment of the present invention may be one or more selected from the group consisting of: alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. The nonionic surfactant may preferably be one or more selected from the group consisting of: alkylaryl polyoxyethylene ethers, polyoxyethylene glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, more preferably one or more selected from the group consisting of: 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol (Triton X-100(R)), Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), and polyoxyethylene sorbitan monolaurate (Tween(R)), and most preferably Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)).

[0485] In the case where the solvent in the production method according to one aspect of the present disclosure is water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, in one embodiment, the content of the above surfactant may be 0.02 wt / v% to 20 wt / v%, 0.05 wt / v% to 15 wt / v%, 0.1 wt / v% to 10 wt / v%, 0.12 wt / v% to 8 wt / v%, 0.15 wt / v% to 5 wt / v% or 0.18 wt / v% to 3 wt / v% based on the total amount of the solvent, and the content of the above water-soluble organic solvent may be 5 v / v% to 40 v / v%, 5 v / v% to 30 v / v%, 5 v / v% to 25 v / v%, 8 v / v% to 20 v / v% or 10 v / v% to 15 v / v% based on the total amount of the solvent. Preferably, the content of the above surfactant is 0.01 wt / v% to 30 wt / v% based on the total amount of the solvent, and the content of the above water-soluble organic solvent is 5 v / v% to 40 v / v% based on the total amount of the solvent. More preferably, the content of the above surfactant is 0.05 wt / v% to 15 wt / v% based on the total amount of the solvent, and the content of the above water-soluble organic solvent is 5 v / v% to 30 v / v% based on the total amount of the solvent. Most preferably, the content of the above surfactant is 0.1 wt / v% to 10 wt / v% based on the total amount of the solvent, and the content of the above water-soluble organic solvent is 5 v / v% to 25 v / v% based on the total amount of the solvent.

[0486] The solvent in the production method according to one aspect of the present disclosure may be (i) a PEG-based solvent, or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol-based solvent, an aliphatic hydrocarbon-based solvent, and water, and a PEG-based solvent.

[0487] The solvent in the production method according to one aspect of the present disclosure may be a PEG-based solvent.

[0488] The solvent in the production method according to one aspect of the present disclosure may be a mixed solvent of one or more selected from the group consisting of an alcohol-based solvent, an aliphatic hydrocarbon-based solvent, and water, and a PEG-based solvent.

[0489] "One or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent, and water" in one embodiment of the present invention may be, for example, one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water. They are preferably one or more selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 1-pentanol, 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, benzyl alcohol, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcycloheptane, and water, more preferably one or more selected from the group consisting of 2-propanol, n-heptane, and water, and most preferably 2-propanol, n-heptane, or water.

[0490] The production method according to one aspect of the present disclosure can be carried out, for example, by the following method. The cyclic peptide can be dissolved in a solvent and oscillated for a predetermined time under predetermined temperature conditions to bring it into contact with the solvent, thereby producing cyclic peptide crystals.

[0491] In the step of bringing the cyclic peptide into contact with the solvent included in the production method according to one aspect of the present disclosure, the concentration of the cyclic peptide can be 1 mg to 2000 mg / mL, and can be 5 mg to 1500 mg / mL, 10 mg to 1000 mg / mL, 10 mg to 500 mg / mL, 10 mg to 100 mg / mL, 10 mg to 50 mg / mL, 100 mg to 400 mg / mL, 100 mg to 200 mg / mL, or 500 mg to 1000 mg / mL.

[0492] The cyclic peptide used in the step of bringing the cyclic peptide into contact with the solvent included in the production method according to one aspect of the present disclosure can be a lyophilized product, and can be, for example, a lyophilized product of a dimethyl sulfoxide solution.

[0493] The cyclic peptide used in the step of bringing the cyclic peptide into contact with the solvent included in the production method according to one aspect of the present disclosure can be 0.5 mg to 200 kg in one embodiment, can be 1 mg to 1 g in another embodiment, and can be 0 g to 200 kg, 100 g to 100 kg, 0.5 mg to 10 g, 1 mg to 1 g, 1 mg to 100 mg, 1 mg to 10 mg, or 1 mg to 5 mg in yet another embodiment.

[0494] In one embodiment of the production method according to one aspect of the present disclosure, the step of contacting the cyclic peptide with the solvent does not include seeding. In another embodiment, the step of contacting the cyclic peptide with the solvent includes seeding. The seed crystal can be a cyclic peptide crystal produced by the production method according to one aspect of the present disclosure, or can be a cyclic peptide crystal produced by other methods.

[0495] In one embodiment of the production method according to one aspect of the present disclosure, the method further includes a filtration step after the step of contacting the cyclic peptide with the solvent. The filtration step is a step of filtering the solvent containing the cyclic peptide crystal to collect the crystal by solid-liquid separation. The filtration step can be carried out by filtering the solvent containing the cyclic peptide crystal through, for example, filter paper, and collecting the cyclic peptide crystal by filtration.

[0496] In the production method according to one aspect of the present disclosure, the step of contacting the cyclic peptide with the solvent can be carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks in one embodiment, and can be carried out at a constant temperature of 20°C to 90°C for 12 hours to 7 days in a preferred embodiment. Additionally, in the production method according to one aspect of the present disclosure, the step of contacting the cyclic peptide with the solvent is carried out at a constant temperature of 0°C to 110°C, 10°C to 100°C, 15°C to 90°C, or 20°C to 80°C in one embodiment, or heating and cooling are repeated 10 times or more, 20 times or more, or 30 times or more and 1000 times or less, 500 times or less, or 100 times or less between a lower limit temperature of 10°C, 20°C, 30°C, 40°C, 45°C, 50°C or 55°C and an upper limit temperature of 100°C, 90°C, 85°C, 80°C, 75°C, 70°C or 60°C, and can be carried out for 1 hour to 6 weeks, 2 hours to 4 weeks, 4 hours to 2 weeks, or 6 hours to 7 days. In a preferred embodiment, this step can be repeated heating and cooling 30 times or more and 100 times or less between a lower limit temperature of 50°C and an upper limit temperature of 90°C, and can be carried out for 12 hours to 7 days.

[0497] It can be confirmed that cyclic peptide crystals have been produced by the production method according to one aspect of the present disclosure, for example, by observing the presence of diffraction peaks in powder X-ray diffraction using CuKα radiation and observing polarization and appearance using a polarized light microscope.

[0498] Another aspect of the present disclosure is a method for screening cyclic peptide crystals, the method including the following steps (a) and (b):

[0499] (a) A step of producing cyclic peptide crystals by the method for producing cyclic peptide crystals according to one aspect of the present disclosure; and

[0500] (b) Steps for analyzing the crystal by powder X-ray crystallography. In this case, the crystals to be screened may include, in one embodiment, crystals produced using a solvent containing formamide, may include, in a preferred embodiment, crystals produced using a solvent containing formamide and a solvent containing dimethyl sulfoxide, and may include, in a more preferred embodiment, crystals produced using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. Additionally, in this case, the crystals to be screened may include, in one embodiment, crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), may include, in another embodiment, crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, may include, in yet another embodiment, crystals produced using a solvent containing polyethylene glycol, may include, in a preferred embodiment, crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol, and may include, in another preferred embodiment, crystals produced using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), crystals produced using a solvent containing polyethylene glycol mono-fatty acid ester, and crystals produced using a solvent containing formamide.

[0501] Another aspect of the present disclosure is a method for screening a method for crystallizing a cyclic peptide, the method comprising the following steps (a) and (b):

[0502] (a) Steps of producing cyclic peptide crystals by a method for producing cyclic peptide crystals according to one aspect of the present disclosure; and (b) steps of analyzing the crystals by powder X-ray crystallography. In this case, the crystallization method to be screened may include, in one embodiment, a crystallization method using a solvent containing formamide, may include, in a preferred embodiment, a crystallization method using a solvent containing formamide and a solvent containing dimethyl sulfoxide, and may include, in a more preferred embodiment, a crystallization method using a solvent containing formamide, a solvent containing dimethyl sulfoxide, a solvent containing toluene, and a solvent containing dichloromethane. Additionally, in this case, the crystallization method to be screened may include, in one embodiment, a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL®), may include, in another embodiment, a crystallization method using a solvent containing polyethylene glycol mono-fatty acid ester, may include, in yet another embodiment, a crystallization method using a solvent containing polyethylene glycol, may include, in a preferred embodiment, a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL®), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing polyethylene glycol, and may include, in another preferred embodiment, a crystallization method using a solvent containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL®), a solvent containing polyethylene glycol mono-fatty acid ester, and a solvent containing formamide.

[0503] In the step of contacting the cyclic peptide with the solvent included in the above method for screening a method for crystallizing a cyclic peptide, the cyclic peptide used for each condition may be 0.5 mg to 10 mg.

[0504] In the above method for screening a method for crystallizing a cyclic peptide, the crystals or crystallization methods to be screened may be 2 or more types, 5 or more types, 10 or more, 15 or more types, or 20 or more types.

[0505] In one embodiment, the step of contacting the cyclic peptide with the solvent included in the above method for screening a method for crystallizing a cyclic peptide may not include adding a seed crystal.

[0506] Another aspect of the present disclosure is a method for increasing the probability of producing cyclic peptide crystals, the method including steps of producing cyclic peptide crystals by a method for producing cyclic peptide crystals according to one aspect of the present disclosure.

[0507] Another aspect of the present disclosure is the use of a solvent in the production of cyclic peptide crystals. In one embodiment, the solvent can be a solvent selected from the group consisting of amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, polyoxyethylene glycerol fatty acid esters, and polyethylene glycol mono-fatty acid esters. In another embodiment, the solvent can be an amide solvent, and in a preferred embodiment, the solvent can be formamide. In another embodiment, the solvent can be a sulfoxide solvent, and in a preferred embodiment, the solvent can be dimethyl sulfoxide. In another embodiment, the solvent can be an aromatic hydrocarbon solvent, and in a preferred embodiment, the solvent can be toluene, tetrahydronaphthalene, or cumene. In another preferred embodiment, the solvent can be Polyoxyl 35 hydrogenated castor oil (Cremophor EL(R)), in yet another preferred embodiment, the solvent can be a mono-fatty acid ester, and in yet another preferred embodiment, the solvent can be polyethylene glycol.

[0508] Another aspect of the present disclosure is a screening kit for producing cyclic peptide crystals, wherein the cyclic peptide crystals are produced by using a solvent in the production of cyclic peptide crystals according to one aspect of the present disclosure.

[0509] Another aspect of the present disclosure is a method for purifying a cyclic peptide, the method comprising the steps of producing cyclic peptide crystals by a method for producing cyclic peptide crystals according to one aspect of the present disclosure, and collecting the crystals by solid-liquid separation. The step of collecting the crystals by solid-liquid separation can be, for example, a filtration step.

[0510] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing formamide. In one embodiment, the production method can be a method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure can be crystals of a cyclic peptide formamide solvate.

[0511] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing dimethyl sulfoxide. In one embodiment, the production method can be a method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure can be crystals of a cyclic peptide dimethyl sulfoxide solvate.

[0512] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing an aromatic hydrocarbon solvent. In one embodiment, the production method may be the method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure may be crystals of a cyclic peptide aromatic hydrocarbon solvate.

[0513] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing toluene, tetrahydronaphthalene or cumene. In one embodiment, the production method may be the method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure may be crystals of a cyclic peptide toluene solvate, a cyclic peptide tetrahydronaphthalene solvate or a cyclic peptide cumene solvate.

[0514] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing Polyoxyl 35 hydrogenated castor oil (Cremophor EL®). In one embodiment, the production method may be the method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure may be a cyclic peptide hydrate or may be crystals of a cyclic peptide Polyoxyl 35 hydrogenated castor oil (Cremophor EL®) solvate.

[0515] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing a polyethylene glycol mono-fatty acid ester. In one embodiment, the production method may be the method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure may be a cyclic peptide hydrate or may be crystals of a cyclic peptide polyethylene glycol mono-fatty acid ester solvate.

[0516] Another aspect of the present disclosure is a method for producing a cyclic peptide, the method comprising the step of producing cyclic peptide crystals containing polyethylene glycol. In one embodiment, the production method may be the method for producing cyclic peptide crystals according to one aspect of the present disclosure. That is, the crystals produced by the method for producing cyclic peptide crystals according to one aspect of the present disclosure may be a cyclic peptide hydrate or may be crystals of a cyclic peptide polyethylene glycol solvate.

[0517] [Examples]

[0518] The content of the present invention will be further illustrated by the following examples, but the present invention is not limited to the content of the examples. Except for those specifically described, starting materials, starting reagents, solvents and reagents are obtained from commercial suppliers or synthesized using known methods.

[0519] [Example 1] Synthesis of Cyclic Peptides

[0520] The cyclic peptides CP01 to CP08 (also simply referred to as Compounds CP01 to CP08) shown in Table 1 were synthesized by the same method as described in International Publication No. WO2013 / 100132, International Publication No. WO 2018 / 225864, or International Publication No. WO 2021 / 90855, and the final product was obtained as a dry product. Specifically, Compound 2118 in International Publication No. WO 2021 / 90855 corresponds to Compound CP01, Compound 1787 corresponds to Compound CP02, Compound 926 corresponds to Compound CP03, Compound 1147 corresponds to Compound CP04, Compound 1217 corresponds to Compound CP05, Compound 1201 corresponds to Compound CP06, Compound 301 corresponds to Compound CP07, and Compound 640 corresponds to Compound CP08. Table 1 shows the structural formulas of Compounds CP01 to CP08.

[0521] [Table 1]

[0522]

[0523]

[0524]

[0525] Note that the molecular weights of Compounds CP01 to CP08 are as follows.

[0526] Compound CP01: 1443.8

[0527] Compound CP02: 1454.2

[0528] Compound CP03: 1456.2

[0529] Compound CP04: 1478.2

[0530] Compound CP05: 1437.7

[0531] Compound CP06: 1459.7

[0532] Compound CP07: 1451.1

[0533] Compound CP08: 1463.1

[0534] In addition, the IUPAC names of compounds CP01 to CP08 are as follows.

[0535] Compound CP01: (3S,9S,18S,21S,25S,28S,34S,36R)-9-(Cyclohexylmethyl)-36-ethoxy-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21,28-diisobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecaazabicyclo[32.3.0]heptatriacontane-31,1′-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecanone

[0536] Compound CP02: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-23-isobutyl-7,10,17,18,24,28,31-heptamethyl-20-[(1S)-1-methylpropyl]-27-(piperidine-1-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecanone

[0537] Compound CP03: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-23-isobutyl-7,10,17,18,24,28,31-heptamethyl-20-[(1S)-1-methylpropyl]-27-(morpholine-4-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1′-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecanone

[0538] Compound CP04: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-10-ethyl-23-isobutyl-7,17,18,24,28,31-hexamethyl-20-[(1S)-1-methylpropyl]-27-(morpholine-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecanone Compound CP05: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide

[0539] Compound CP06: (3S,9S,12S,17S,20S,23S,27S,30S,36S,38R)-9-(cyclohexylmethyl)-30-cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-38-ethoxy-23-isobutyl-N,N,7,10,17,18,24,28,31-nonamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide

[0540] Compound CP07: (3S,9S,12S,17S,20S,23S,27R,30S,36S,38R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-38-ethoxy-23-isobutyl-7,10,17,18,24,27,28,31-octamethyl-20,30-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecanone

[0541] Compound CP08: (3S,9S,12S,17S,20S,23S,27R,30S,36S,38R)-3-[2-[3-chloro-4-(trichloromethyl)phenyl]ethyl]-30-cyclopentyl-38-ethoxy-23-isobutyl-7,10,17,18,24,27,28,31-octamethyl-20-[(1S)-1-methylpropyl]-9-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,15,18,21,24,28,31,34-undecaazatricyclo[34.3.0.012,15]undecaazatricyclo-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecanone

[0542] [Example 2] Use a solvent having a molecular weight of 18 or more and 170 or less, or a mixed solvent of two or more thereof to produce cyclic peptide crystals

[0543] Produce cyclic peptide crystals by a method including a step of contacting with (i) a solvent having a molecular weight of 18 or more and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or more and 170 or less. Note that no seed crystal is used in the step of contacting with the solvent in the following production. In addition, in the following examples, %(percentage) represents volume %(v / v%).

[0544] (Example 2-1-1) Dissolve compound CP01 (136.7 mg) in dimethyl sulfoxide (0.684 mL), and lyophilize the dissolved solution (0.015 mL) at -20 °C for 2 days. Add a water / isopropanol mixed solution (water ratio 75%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 5 days to obtain crystals of compound CP01.

[0545] (Example 2-1-2) Dissolve compound CP01 (72.5 mg) in dimethyl sulfoxide (0.363 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 3 days. Add a dichloromethane / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP01.

[0546] (Example 2-2-1) Dissolve compound CP02 (149.2 mg) in dimethyl sulfoxide (0.746 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 3 days. Add formamide (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP02.

[0547] (Example 2-2-2) Dissolve compound CP02 (72.4 mg) in dimethyl sulfoxide (0.362 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 3 days. Add a formamide / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP02.

[0548] (Example 2-2-3) Dissolve compound CP02 (72.4 mg) in dimethyl sulfoxide (0.362 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 3 days. Add a dimethyl sulfoxide / tert-butyl methyl ether mixed solution (tert-butyl methyl ether ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP02.

[0549] (Example 2-3-1) Dissolve compound CP03 (147.4 mg) in dimethyl sulfoxide (0.737 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 3 days. Add formamide (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP03.

[0550] (Example 2-4-1) Dissolve compound CP04 (120.2 mg) in dimethyl sulfoxide (0.601 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add tert-butyl methyl ether (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP04.

[0551] (Example 2-4-2) Dissolve compound CP04 (120.2 mg) in dimethyl sulfoxide (0.601 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add toluene (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain a solid of compound CP04. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0552] (Example 2-4-3) Dissolve compound CP04 (120.2 mg) in dimethyl sulfoxide (0.601 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add n-butyl acetate (0.015 mL) to the resulting lyophilized product, and after shaking the mixture at room temperature for 3 days, further add n-heptane (0.015 mL). A solid of compound CP04 was obtained by shaking at room temperature for 4 days. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0553] (Example 2-4-4) Dissolve compound CP04 (120.2 mg) in dimethyl sulfoxide (0.601 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add cumene (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain a solid of compound CP04. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0554] (Example 2-4-5) Dissolve compound CP04 (50.3 mg) in dimethyl sulfoxide (0.252 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add an ethyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain a solid of compound CP04. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0555] (Example 2-4-6) Dissolve compound CP04 (50.3 mg) in dimethyl sulfoxide (0.252 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add an n-butyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain a solid of compound CP04. It was confirmed by polarized light microscopy that the resulting solid was microcrystals with polarization.

[0556] (Example 2-5-1) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add toluene (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0557] (Example 2-5-2) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add dimethyl sulfoxide (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0558] (Example 2-5-3) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add an ethanol / water mixed solution (water ratio 75%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0559] (Example 2-5-4) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add an acetonitrile / water mixed solution (water ratio 75%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0560] (Example 2-5-5) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add cumene (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0561] (Example 2-5-6) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add tetralin (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0562] (Example 2-5-7) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add formamide (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP05.

[0563] (Example 2-5-8) Dissolve compound CP05 (122.3 mg) in dimethyl sulfoxide (0.612 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add diisopropyl ether (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP05.

[0564] (Example 2-5-9) Dissolve compound CP05 (148.8 mg) in dimethyl sulfoxide (0.744 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 3 days. Add a 3-acetylpyridine / ethylene glycol mixed solution (3-acetylpyridine ratio 50 vol%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 11 days. In addition, add about 10 zirconia beads with a diameter of 1 mm, and shake the mixture for 2 days. Crystals of compound CP05 are obtained by allowing to stand for 5 days and further shaking for 3 days.

[0565] (Example 2-6-1) Dissolve compound CP06 (122.1 mg) in dimethyl sulfoxide (0.611 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add formamide (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 3 days to obtain crystals of compound CP06.

[0566] (Example 2-7-1) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add acetonitrile (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0567] (Example 2-7-2) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add ethyl acetate (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP07. The obtained solid is confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0568] (Example 2-7-3) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add acetone (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0569] (Example 2-7-4) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add propyl acetate (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0570] (Example 2-7-5) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add n-butyl acetate (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP07. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0571] (Example 2-7-6) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add methyl ethyl ketone (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP07. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0572] (Example 2-7-7) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add methyl isobutyl ketone (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP07. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0573] (Example 2-7-8) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add tert-butyl methyl ether (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0574] (Example 2-7-9) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add dimethyl sulfoxide (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0575] (Example 2-7-10) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add a water / acetonitrile mixed solution (water ratio 75%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP07.

[0576] (Example 2-7-11) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add tetrahydrofuran (0.015 mL) to the resulting lyophilized product, and after shaking the mixture at room temperature for 6 days, further add n-heptane (0.015 mL). Crystals of compound CP07 are obtained by shaking at room temperature for 14 days. The resulting solid is confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0577] (Example 2-7-12) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add 1,4-dioxane (0.015 mL) to the resulting lyophilized product, and after shaking the mixture at room temperature for 6 days, further add n-heptane (0.015 mL). Crystals of compound CP07 are obtained by shaking at room temperature for 14 days.

[0578] (Example 2-7-13) Dissolve compound CP07 (75.3 mg) in 1,4-dioxane (0.377 mL), and lyophilize this dissolved solution (0.015 mL) at -20 °C for 2 days. Add toluene (0.015 mL) to the resulting lyophilized product, and after shaking the mixture at room temperature for 6 days, further add n-heptane (0.015 mL). A solid of compound CP07 is obtained by shaking at room temperature for 14 days. The resulting solid is confirmed by polarized light microscopy to be microcrystals with polarization.

[0579] (Example 2-7-14) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was freeze-dried at -20 °C for 3 days. An ethanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0580] (Example 2-7-15) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was freeze-dried at -20 °C for 3 days. A 2-propanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0581] (Example 2-7-16) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was freeze-dried at -20 °C for 3 days. An acetonitrile / tert-butyl methyl ether mixed solution (tert-butyl methyl ether ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0582] (Example 2-7-17) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was freeze-dried at -20 °C for 3 days. A n-butanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0583] (Example 2-7-18) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was freeze-dried at -20 °C for 3 days. An anisole / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the obtained freeze-dried product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0584] (Example 2-7-19) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was lyophilized at -20 °C for 3 days. A dimethyl sulfoxide / tert-butyl methyl ether mixed solution (tert-butyl methyl ether ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0585] (Example 2-7-20) Compound CP07 (72.6 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 1.452 mL) at 70 °C, and the resulting solution (0.06 mL) was lyophilized at -20 °C for 3 days. An acetonitrile / water mixed solution (water ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP07.

[0586] (Example 2-7-21) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. An isopropanol / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP07.

[0587] (Example 2-7-22) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. A 1,4-dioxane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0588] (Example 2-7-23) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. An ethyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP07.

[0589] (Example 2-7-24) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add an acetone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP07.

[0590] (Example 2-7-25) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add a tetrahydrofuran / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP07.

[0591] (Example 2-7-26) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add a dichloromethane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP07.

[0592] (Example 2-7-27) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add an anisole / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain a solid of compound CP07. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0593] (Example 2-7-28) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add a n-butanol / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 7 days to obtain a solid of compound CP07. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0594] (Example 2-7-29) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was freeze-dried at -20 °C for 2 days. A toluene / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0595] (Example 2-7-30) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was freeze-dried at -20 °C for 2 days. An ethyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed by polarized light microscopy to be microcrystals with polarization.

[0596] (Example 2-7-31) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was freeze-dried at -20 °C for 2 days. A n-butyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP07.

[0597] (Example 2-7-32) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was freeze-dried at -20 °C for 2 days. A methyl ethyl ketone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP07.

[0598] (Example 2-7-33) Compound CP07 (50.3 mg) was dissolved in 1,4-dioxane (0.252 mL), and the resulting solution (0.015 mL) was freeze-dried at -20 °C for 2 days. A methyl isobutyl ketone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken at room temperature for 7 days to obtain a solid of compound CP07. The resulting solid was confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0599] (Example 2-7-34) Dissolve compound CP07 (50.3 mg) in 1,4-dioxane (0.252 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add a mixed solution of chlorobenzene / cyclohexane (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP07.

[0600] (Example 2-8-1) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add acetonitrile (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP08.

[0601] (Example 2-8-2) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add ethyl acetate (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0602] (Example 2-8-3) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add acetone (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP08.

[0603] (Example 2-8-4) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add propyl acetate (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the resulting solid was needle-shaped crystals with polarization.

[0604] (Example 2-8-5) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add n-butyl acetate (0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the resulting solid was microcrystals with polarization.

[0605] (Example 2-8-6) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add methyl ethyl ketone (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP08.

[0606] (Example 2-8-7) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add methyl isobutyl ketone (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0607] (Example 2-8-8) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add tert-butyl methyl ether (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the obtained solid was needle-shaped crystals with polarization.

[0608] (Example 2-8-9) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add toluene (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the obtained solid was plate-shaped crystals with polarization.

[0609] (Example 2-8-10) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add dimethyl sulfoxide (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days to obtain crystals of compound CP08.

[0610] (Example 2-8-11) Dissolve compound CP08 (75.3 mg) in 1,4-dioxane (0.376 mL), and lyophilize the resulting solution (0.015 mL) at -20°C for 2 days. Add 1,4-dioxane (0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 6 days. Then, add n-heptane (0.015 mL). The solid of compound CP08 is obtained by shaking at room temperature for 14 days. The obtained solid is confirmed by polarized light microscopy to be needle-shaped crystals with polarization.

[0611] (Example 2-8-12) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize the resulting solution (0.03 mL) at -20°C for 3 days. Add an ethanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 8 days to obtain the solid of compound CP08. The obtained solid is confirmed by polarized light microscopy to be plate-shaped crystals with polarization.

[0612] (Example 2-8-13) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize the resulting solution (0.03 mL) at -20°C for 3 days. Add an isopropanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 8 days to obtain the crystals of compound CP08.

[0613] (Example 2-8-14) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize the resulting solution (0.03 mL) at -20°C for 3 days. Add an ethyl acetate / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 8 days to obtain the crystals of compound CP08.

[0614] (Example 2-8-15) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize the resulting solution (0.03 mL) at -20°C for 3 days. Add an acetone / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the obtained lyophilized product, and shake the mixture at room temperature for 8 days to obtain the crystals of compound CP08.

[0615] (Example 2-8-16) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a tetrahydrofuran / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0616] (Example 2-8-17) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a dichloromethane / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0617] (Example 2-8-18) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a formamide / water mixed solution (water ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain a solid of compound CP08. It is confirmed by polarized light microscopy that the resulting solid is microcrystals with polarization.

[0618] (Example 2-8-19) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a n-butanol / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0619] (Example 2-8-20) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add an ethyl acetate / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0620] (Example 2-8-21) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a n-butyl acetate / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0621] (Example 2-8-22) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a methyl ethyl ketone / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0622] (Example 2-8-23) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a methyl isobutyl ketone / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0623] (Example 2-8-24) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20°C for 3 days. Add a formamide / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0624] (Example 2-8-25) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20 °C for 3 days. Add an anisole / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0625] (Example 2-8-26) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20 °C for 3 days. Add a 1,4-dioxane / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0626] (Example 2-8-27) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20 °C for 3 days. Add a dimethyl sulfoxide / tert-butyl methyl ether mixed solution (tert-butyl methyl ether ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain a solid of compound CP08. It was confirmed by polarized light microscopy that the resulting solid was microcrystals with polarization.

[0627] (Example 2-8-28) Dissolve compound CP08 (72.5 mg) in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and lyophilize this dissolved solution (0.03 mL) at -20 °C for 3 days. Add an ethanol / water mixed solution (water ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 8 days to obtain crystals of compound CP08.

[0628] (Example 2-8-29) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and the resulting solution (0.03 mL) was lyophilized at -20 °C for 3 days. An acetonitrile / water mixed solution (water ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 8 days to obtain a solid of compound CP08. The resulting solid was confirmed by polarized light microscopy to be microcrystals with polarization.

[0629] (Example 2-8-30) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and the resulting solution (0.03 mL) was lyophilized at -20 °C for 3 days. A chlorobenzene / n-heptane mixed solution (n-heptane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP08.

[0630] (Example 2-8-31) Compound CP08 (72.5 mg) was dissolved in a dimethyl sulfoxide / 1,4-dioxane mixed solution (1,4-dioxane ratio 50%, 0.726 mL), and the resulting solution (0.03 mL) was lyophilized at -20 °C for 3 days. An acetone / water mixed solution (water ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 8 days to obtain crystals of compound CP08.

[0631] (Example 2-8-32) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. An isopropanol / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP08.

[0632] (Example 2-8-33) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. A 1,4-dioxane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP08.

[0633] (Example 2-8-34) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add an ethyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0634] (Example 2-8-35) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add an acetone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0635] (Example 2-8-36) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add a tetrahydrofuran / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0636] (Example 2-8-37) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add a dichloromethane / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0637] (Example 2-8-38) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add an anisole / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0638] (Example 2-8-39) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize the resulting solution (0.015 mL) at -20 °C for 2 days. Add a butanol / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0639] (Example 2-8-40) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add a toluene / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0640] (Example 2-8-41) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add an ethyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0641] (Example 2-8-42) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add a n-butyl acetate / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0642] (Example 2-8-43) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add a methyl ethyl ketone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0643] (Example 2-8-44) Dissolve compound CP08 (50.6 mg) in 1,4-dioxane (0.253 mL), and lyophilize this dissolved solution (0.015 mL) at -20°C for 2 days. Add a methyl isobutyl ketone / cyclohexane mixed solution (cyclohexane ratio 80%, 0.015 mL) to the resulting lyophilized product, and shake the mixture at room temperature for 7 days to obtain crystals of compound CP08.

[0644] (Example 2-8-45) Compound CP08 (50.6 mg) was dissolved in 1,4-dioxane (0.253 mL), and the resulting solution (0.015 mL) was lyophilized at -20 °C for 2 days. A mixed solution of chlorobenzene / cyclohexane (cyclohexane ratio 80%, 0.015 mL) was added to the resulting lyophilized product, and the mixture was shaken at room temperature for 7 days to obtain crystals of compound CP08.

[0645] As can be seen from the above results, crystals of all eight cyclic peptides were obtained under any condition of using a solvent having a molecular weight of 18 or more and 170 or less, or a mixed solvent of two or more thereof. Specifically, crystals of five of the eight cyclic peptides were obtained under the condition of using a solvent containing formamide as the solvent (Example). Crystals of four of the eight cyclic peptides were obtained under the condition of using a solvent containing dimethyl sulfoxide as the solvent (Example). Crystals of four of the eight cyclic peptides were obtained under the condition of using a solvent containing toluene, cumene, or tetralin (which is an aromatic hydrocarbon solvent) as the solvent (Example). Crystals of three of the eight cyclic peptides were obtained under the condition of using a solvent containing dichloromethane or chlorobenzene (which is a halogenated solvent) as the solvent (Example). Crystals of four of the eight cyclic peptides were obtained under the condition of using a solvent containing an alcohol solvent as the solvent (Example). Crystals of four of the eight cyclic peptides were obtained under the condition of using a solvent containing an ether solvent as the solvent (Example). Crystals of three of the eight cyclic peptides were obtained under the condition of using a solvent containing an ester solvent as the solvent (Example). Crystals of three of the eight cyclic peptides were obtained under the condition of using a solvent containing a nitrile solvent as the solvent (Example). Crystals of two of the eight cyclic peptides were obtained under the condition of using a solvent containing a ketone solvent as the solvent (Example).

[0646] The solvent for crystallizing various cyclic peptides is preferably one or more selected from the group consisting of formamide, dimethyl sulfoxide, aromatic hydrocarbon solvents, and halogenated solvents, and by using at least one of these solvents, all eight cyclic peptides were successfully crystallized. The results show that a solvent containing formamide or dimethyl sulfoxide is more preferred, and a solvent containing formamide is most preferred.

[0647] [Example 3] Production of cyclic peptide crystals using an aqueous solution containing a surfactant and a water-soluble organic solvent

[0648] Cyclic peptide crystals are produced by a method including a step of contacting with water containing 0.01 wt / v% to 30 wt / v% of a surfactant (for a liquid surfactant) and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent. Note that no seed crystal is used in the step of contacting with the solvent in the following production.

[0649] (Example 3-1-1) Dissolve compound CP01 (19.7 mg) in ethanol (0.197 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours. Heat and cool the mixture 36 times within the range of 50°C to 90°C to obtain crystals of compound CP01.

[0650] (Example 3-4-1) Dissolve compound CP04 (19.5 mg) in ethanol (0.195 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours. Heat and cool the mixture 36 times within the range of 50°C to 90°C to obtain crystals of compound CP04.

[0651] (Example 3-5-1) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours. Heat and cool the mixture 36 times within the range of 50°C to 90°C to obtain crystals of compound CP05.

[0652] (Example 3-5-2) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours. Heat and cool the mixture 36 times within the range of 50°C to 90°C to obtain crystals of compound CP05.

[0653] (Example 3-5-3) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours. Heat and cool the mixture 36 times within the range of 50°C to 90°C to obtain crystals of compound CP05.

[0654] (Example 3-5-4) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0655] (Example 3-5-5) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0656] (Example 3-5-6) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0657] (Example 3-5-7) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0658] (Example 3-5-8) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0659] (Example 3-5-9) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times to obtain crystals of compound CP05.

[0660] (Example 3-5-10) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times to obtain crystals of compound CP05.

[0661] (Example 3-5-11) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times to obtain crystals of compound CP05.

[0662] (Example 3-5-12) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times to obtain crystals of compound CP05.

[0663] (Example 3-5-13) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 1 wt / v%, 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, heating and cooling within the range of 50°C to 90°C 36 times to obtain crystals of compound CP05.

[0664] (Example 3-5-14) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this dissolved solution (0.010 mL) was added a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 0.2 wt / v%, 0.090 mL), and the mixture was stirred for 10 hours, heated and cooled within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0665] (Example 3-5-15) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this dissolved solution (0.010 mL) was added a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 1 wt / v%, 0.090 mL), and the mixture was stirred for 10 hours, heated and cooled within the range of 50°C to 90°C 36 times, thereby obtaining crystals of compound CP05.

[0666] (Example 3-5-16) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this dissolved solution (0.010 mL) was added a Cremophor EL / water mixed solution (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours, thereby obtaining crystals of compound CP05.

[0667] (Example 3-5-17) Compound CP05 (19.1 mg) was dissolved in ethanol (0.191 mL). To this dissolved solution (0.010 mL) was added a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours, thereby obtaining crystals of compound CP05.

[0668] (Example 3-5-18) Compound CP05 (19.2 mg) was dissolved in dimethyl sulfoxide (0.192 mL). To this dissolved solution (0.010 mL) was added a Cremophor EL / water mixed solution (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL), and the mixture was stirred at 25°C for 10 hours, thereby obtaining crystals of compound CP05.

[0669] (Example 3-5-19) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0670] (Example 3-5-20) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0671] (Example 3-5-21) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0672] (Example 3-5-22) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0673] (Example 3-5-23) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0674] (Example 3-5-24) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0675] (Example 3-5-25) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0676] (Example 3-5-26) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0677] (Example 3-5-27) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0678] (Example 3-5-28) Dissolve compound CP05 (19.1 mg) in ethanol (0.191 mL). Add a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 1 wt / v%, 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0679] (Example 3-5-29) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 0.2 wt / v%, 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0680] (Example 3-5-30) Dissolve compound CP05 (19.2 mg) in dimethyl sulfoxide (0.192 mL). Add a sodium dodecyl sulfate / water mixed solution (sodium dodecyl sulfate ratio 1 wt / v%, 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP05.

[0681] (Example 3-7-1) Dissolve compound CP07 (19.3 mg) in dimethyl sulfoxide (0.193 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, and heat and cool within the range of 50 °C to 90 °C 36 times to obtain crystals of compound CP07.

[0682] (Example 3-8-1) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 5 v / v% (5.25 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, and heat and cool within the range of 50 °C to 90 °C 36 times to obtain crystals of compound CP08.

[0683] (Example 3-8-2) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to this dissolved solution (0.010 mL), and stir the mixture for 10 hours, and heat and cool within the range of 50 °C to 90 °C 36 times to obtain crystals of compound CP08.

[0684] (Example 3-8-3) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Cremophor EL / water mixed solution (Cremophor EL ratio 1 v / v% (1.05 wt / v%), 0.090 mL) to the dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP08.

[0685] (Example 3-8-4) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 0.5 v / v% (0.54 wt / v%), 0.090 mL) to the dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP08.

[0686] (Example 3-8-5) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Tween 80 / water mixed solution (Tween 80 ratio 3 v / v% (3.24 wt / v%), 0.090 mL) to the dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP08.

[0687] (Example 3-8-6) Dissolve compound CP08 (19.5 mg) in ethanol (0.195 mL). Add a Triton X-100 / water mixed solution (Triton X-100 ratio 3 v / v% (3.21 wt / v%), 0.090 mL) to the dissolved solution (0.010 mL), and stir the mixture at 25 °C for 10 hours to obtain crystals of compound CP08.

[0688] From the above results, it can be seen that under the condition of using an aqueous solution containing a surfactant and a water-soluble organic solvent, crystals of five out of eight cyclic peptides are obtained. When using Cremophor EL as the surfactant, crystals of four out of eight cyclic peptides are obtained (Example). When using Triton X-100 as the surfactant, crystals of three out of eight cyclic peptides are obtained (Example).

[0689] As conditions for crystallizing various cyclic peptides, conditions using Cremophor EL, Tween 80, or Triton X-100 as surfactants are preferred, and as for the temperature, heating and cooling are preferred. As for water-soluble organic solvents, conditions using ethanol are preferred conditions. Conditions using Cremophor EL as a surfactant are more preferred. Furthermore, the most preferred result is conditions using Cremophor EL as a surfactant, heating and cooling in the range of 50°C to 90°C, and using ethanol as a water-soluble organic solvent.

[0690] [Example 4] Production of cyclic peptide crystals using PEG-based solvents or mixed solvents containing PEG-based solvents

[0691] A method for producing cyclic peptide crystals by a method including a step of contacting with (i) a PEG-based solvent or (ii) a mixed solvent containing one or more selected from the group consisting of an alcohol solvent, an aliphatic solvent, a hydrocarbon solvent, and water and a PEG-based solvent. Note that no seed crystal is used in the step of contacting with the solvent in the following production. In addition, in the following examples, %(percentage) represents volume %(v / v%).

[0692] (Example 4-1-1) To compound CP01 (4.8 mg), PEG400 (0.015 mL) was added, isopropanol (0.005 mL) was added, and further water (0.005 mL) was added, and the mixture was stirred at 80°C to dissolve. The next day, the temperature was lowered to room temperature, and the mixture was further stirred for 3 days, after which crystals of compound CP01 precipitated.

[0693] (Example 4-3-1) To compound CP03 (5.8 mg), polyethylene glycol monolaurate (n = about 10) (0.015 mL) was added, and the mixture was stirred at 80°C to dissolve. The solution was further stirred at 80°C for 1 day, after which crystals of compound CP03 precipitated.

[0694] (Example 4-4-1) To compound CP04 (6.3 mg), tetraethylene glycol (0.030 mL) was added, and the mixture was stirred at 80°C for 1 hour. After cooling to room temperature and further stirring for 1 day, crystals of compound CP04 were obtained.

[0695] (Example 4-4-2) To compound CP04 (5.5 mg), PEG400 (0.030 mL) was added, and the mixture was stirred at 80°C for 40 minutes to obtain crystals of compound CP04.

[0696] (Example 4-4-3) PEG400 (0.020 mL) was added to compound CP04 (5.6 mg), and the mixture was stirred at 80 °C for 30 minutes to obtain crystals of compound CP04.

[0697] (Example 4-4-4) Polyethylene glycol monolaurate (n = about 10) (0.020 mL) was added to compound CP04 (5.4 mg), and the mixture was stirred at 80 °C for 40 minutes to obtain crystals of compound CP04.

[0698] (Example 4-4-5) PEG600 (0.020 mL) heated to 60 °C and melted was added to compound CP04 (5.6 mg), and the mixture was stirred at 60 °C for 10 minutes. The mixture was further stirred at 80 °C for 16 hours. After further stirring at room temperature for 3 hours, crystals of compound CP04 were obtained.

[0699] (Example 4-4-6) PEG2000 heated to 60 °C and melted (0.020 mL) was added to compound CP04 (5.7 mg), and the mixture was stirred at 60 °C for 30 minutes. The temperature was raised to 80 °C, PEG2000 (0.080 mL) was added, and the mixture was stirred for 15 hours. After cooling to room temperature, a mixture of crystals of compound CP04 and crystals of PEG2000 was obtained. Figure 26 (D) shows the X-ray diffraction peaks of PEG2000, which have characteristic peaks at 19.2° and 24.4°. Figure 26 (C) shows the X-ray diffraction peaks of the obtained mixture, and multiple diffraction peaks other than 19.2° and 24.4° were observed. These are the diffraction peaks of CP04 crystals.

[0700] (Example 4-4-7) Polyethylene glycol monostearate (n = about 4) (a mixture of palmitate and stearate) heated to 60 °C and melted (0.030 mL) was added to compound CP04 (6.1 mg), and then the mixture was stirred at 80 °C for 16 hours. After further stirring at room temperature for 3 hours, a mixture of crystals of compound CP04 and crystals of polyethylene glycol monostearate (n = about 4) (a mixture of palmitate and stearate) was obtained. Figure 27 (B) shows the X-ray diffraction peaks of polyethylene glycol monostearate (n = about 4) (a mixture of palmitate and stearate), which have characteristic peaks at 21.7° and 24.1°. Figure 27 (A) shows the X-ray diffraction peaks of the obtained mixture, and multiple diffraction peaks other than 21.7° and 24.1° were observed. These are the diffraction peaks of CP04 crystals.

[0701] (Example 4-4-8) Polyethylene glycol monostearate (n = about 10) (palmitate, stearate mixture) (0.020 mL) heated to 60 °C and melted was added to compound CP04 (5.0 mg), and the mixture was stirred at 80 °C for 16 hours. After further stirring at room temperature for 3 hours, crystals of compound CP04 were obtained.

[0702] (Example 4-4-9) Diethylene glycol dimethyl ether (0.015 mL) was added to compound CP04 (6.1 mg), and further n-heptane (0.015 mL) was added, and the mixture was stirred at room temperature for 5 days to obtain crystals of compound CP04.

[0703] (Example 4-4-10) Triethylene glycol dimethyl ether (0.005 mL) was added to compound CP04 (5.0 mg), and the mixture was stirred at 80 °C to dissolve. The solution was further stirred at 80 °C for 18 hours, after which crystals of compound CP04 precipitated.

[0704] (Example 4-5-1) Tetraethylene glycol (0.020 mL) was added to compound CP05 (about 5 mg), and the mixture was stirred to dissolve. The solution was heated to 80 °C and stirred for 1 hour, after which crystals of compound CP05 precipitated.

[0705] (Example 4-5-2) PEG400 (0.020 mL) was added to compound CP05 (about 5 mg), and the mixture was stirred to dissolve. The solution was heated to 80 °C and stirred for 1 hour, after which crystals of compound CP05 precipitated.

[0706] (Example 4-5-3) Polypropylene glycol (average molecular weight about 425) (0.020 mL) was added to compound CP05 (about 5 mg), and the mixture was stirred to dissolve. The solution was heated to 80 °C and stirred for 1 hour, after which crystals of compound CP05 precipitated.

[0707] (Example 4-5-4) Polyethylene glycol monolaurate (n = about 10) (0.020 mL) was added to compound CP05 (about 5 mg), and the mixture was stirred to dissolve. The solution was heated to 80 °C and stirred for 1 hour, after which crystals of compound CP05 precipitated.

[0708] (Example 4-5-5) Triethylene glycol dimethyl ether (0.020 mL) was added to compound CP05 (about 5 mg), and the mixture was stirred to dissolve. The solution was heated to 80 °C and stirred for 1 hour, after which crystals of compound CP05 precipitated.

[0709] (Examples 4-5-6) Water / ethylene glycol mixed solution (ethylene glycol ratio 80% by volume, 0.015 mL) was added to compound CP05 (5.3 mg), and the mixture was stirred at 100 °C to dissolve. The solution was cooled to room temperature and stirred for 3 days, after which crystals of compound CP05 precipitated.

[0710] (Examples 4-7-1) Triethylene glycol dimethyl ether (0.010 mL) was added to compound CP07 (4.8 mg), and the mixture was stirred at room temperature to dissolve. The solution was further stirred at room temperature for 35 minutes, after which crystals of compound CP07 precipitated.

[0711] (Examples 4-7-2) Polyethylene glycol monolaurate (n = about 10) (0.015 mL) was added to compound CP07 (4.6 mg), and the mixture was stirred at 80 °C to dissolve. The solution was further stirred at 80 °C for 18 hours, after which crystals of compound CP07 precipitated.

[0712] (Examples 4-7-3) Triethylene glycol dimethyl ether (0.010 mL) was added to compound CP07 (4.8 mg), and the mixture was stirred at room temperature for 15 hours, after which crystals of compound CP07 precipitated.

[0713] (Examples 4-7-4) PEG400 (0.020 mL) was added to compound CP07 (10.0 mg), and the mixture was stirred at 80 °C to dissolve. The solution was further stirred at 80 °C for 18 hours, after which crystals of compound CP07 precipitated.

[0714] (Examples 4-8-1) Triethylene glycol dimethyl ether (0.010 mL) was added to compound CP08 (5.0 mg), and the mixture was stirred at room temperature for 20 minutes, after which crystals of compound CP08 precipitated.

[0715] (Examples 4-8-2) PEG400 (0.015 mL) was added to compound CP08 (5.1 mg) to dissolve it at 80 °C. After stirring at 80 °C for 18 hours, the solution was returned to room temperature and further stirred for 1 day, after which crystals of compound CP08 precipitated.

[0716] (Examples 4-8-3) Polyethylene glycol monolaurate (n = about 10) (0.015 mL) was added to compound CP08 (5.3 mg), and the mixture was stirred at 80 °C to dissolve. The solution was further stirred at 80 °C for 10 minutes, and then crystals of compound CP08 precipitated.

[0717] (Example 4-8-4) Triethylene glycol dimethyl ether (0.010 mL) was added to compound CP08 (5.1 mg), and the mixture was stirred at room temperature to dissolve. The solution was further stirred at room temperature for 15 hours, after which crystals of compound CP08 precipitated.

[0718] (Example 4-8-5) PEG400 (0.020 mL) was added to compound CP08 (10.1 mg), and the mixture was stirred at 80 °C to dissolve. The solution was further stirred at 80 °C for 5 hours, after which crystals of compound CP08 precipitated.

[0719] From the above results, it can be seen that crystals of six out of the eight cyclic peptides were obtained under the conditions of using PEG solvents or mixed solvents containing PEG solvents. When using polyethylene glycol mono-fatty acid ester as the PEG solvent, crystals of five out of the eight cyclic peptides were obtained (Examples). When using solvents containing polyethylene glycol (PEG400, PEG600, PEG2000) as the PEG solvent, crystals of five out of the eight cyclic peptides were obtained (Examples).

[0720] As the conditions for crystallizing various cyclic peptides, the conditions of using polyethylene glycol mono-fatty acid ester or polyethylene glycol as the PEG solvent are preferred conditions. More preferably, polyethylene glycol monolaurate or PEG400 is used as the PEG solvent, and the temperature is in the range of room temperature to 80 °C. The most preferred result is the condition of using polyethylene glycol monolaurate as the PEG solvent and the temperature being 80 °C.

[0721] [Example 5] X-ray diffraction measurement of cyclic peptide crystals

[0722] (Example 5-1)

[0723] Powder X-ray diffraction measurements were performed on the crystals obtained in Examples 2, 3, and 4 by the following measurement method. The results are shown in Figure 1 A to Figure 30 D.

[0724] Measurement device: D8 Discover, 2D -500 solid-state detector (manufactured by Bruker)

[0725] Radiation source: CuKα

[0726] Tube voltage and tube current: 40 kV and 40 mA or 50 kV and 1000 μA

[0727] Measurement range: 5 to 31°

[0728] Exposure time: 40 to 600 seconds

[0729] (Example 5-2)

[0730] The single crystal X-ray structure analysis was carried out on the crystal obtained in Example 2-1-1 by the following measuring method.

[0731] Measuring device: Rigaku R-AXIS RAPID-II with VariMax Cu diffractometer (manufactured by Rigaku Corporation)

[0732] Radiation source: CuKα

[0733] Tube voltage and tube current: 40 kV and 30 mA

[0734] Temperature: -180 °C

[0735] Measurement: Measurement was carried out using a strategy and exposure time believed to produce sufficient diffraction points for structure analysis.

[0736] Structure analysis: The initial structure determination was carried out by the direct method (SHELXD97, CrystalStructure 4.2.2, Rigaku Corporation), and the structure refinement was carried out by the full-matrix least-squares method (SHELXL97, CrystalStructure 4.2.2, Rigaku Corporation). Refinement was carried out assuming that all temperature factors were isotropic. The results are shown in Figure 31 A.

Claims

1. A method for producing a cyclic peptide crystal, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I), (II), and (III): Characteristic (I): containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, and the total number of amino acids being 8 to 20 residues; Characteristic (II): containing at least 2 N-substituted amino acid residues; and Characteristic (III): having a molecular weight of 1204 or greater and 3000 or less, with the unit of molecular weight being g / mol.

2. The method according to claim 1, wherein, the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation, or has polarization when observed using a polarized light microscope.

3. The method according to claim 1, wherein, the crystal has one or more diffraction peaks in powder X-ray diffraction using CuKα radiation.

4. The method according to any one of claims 1 to 3, wherein, the solvent is any solvent selected from the group consisting of the following (1), (2), and (3): (1) (i) a solvent having a molecular weight of 18 or greater and 170 or less, or (ii) a mixed solvent containing two or more solvents having a molecular weight of 18 or greater and 170 or less; (2) water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent; and (3) (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more selected from the group consisting of an alcohol solvent, an aliphatic hydrocarbon solvent, and water.

5. The method according to any one of claims 1 to 3, wherein, the solvent is a solvent (A) having a molecular weight of 18 or greater and 170 or less, or a mixed solvent of a solvent (A) having a molecular weight of 18 or greater and 170 or less and a solvent (B) having a molecular weight of 18 or greater and 170 or less, the solvent (A) being one or more selected from the group consisting of an amide solvent, a sulfoxide solvent, an aromatic hydrocarbon solvent, a halogenated solvent, an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, and a ketone solvent, and the solvent (B) being one or more selected from the group consisting of an aliphatic hydrocarbon solvent, ethylene glycol, and water.

6. The method according to claim 5, wherein, the solvent (A) is formamide.

7. The method according to claim 5 or 6, wherein, the solvent (B) is one or more solvents selected from the group consisting of an aliphatic hydrocarbon solvent, ethylene glycol, and water.

8. The method according to any one of claims 5 to 7, wherein, the volume ratio (v / v) between the solvent (A) and the solvent (B) in the solvent is 1:0 to 1:

40.

9. The method according to any one of claims 5 to 8, wherein, the solvent (A) and the solvent (B) have a melting point of 25°C or lower.

10. The method according to any one of claims 1 to 3, wherein, the solvent is water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, and the surfactant is one or more selected from the group consisting of: cationic surfactants, anionic surfactants, amphoteric surfactants, and nonionic surfactants.

11. The method according to any one of claims 1 to 3, wherein, the solvent is water containing 0.01 wt / v% to 30 wt / v% of a surfactant and 5 v / v% to 50 v / v% of a water-soluble organic solvent based on the total amount of the solvent, and the surfactant is one or more selected from the group consisting of: primary amine salts, alkyltrimethylammonium salts, alkylpyridinium salts, alkylpolyoxyethyleneamines, fatty acid salts, rosin acid salts, alkyl sulfates, alkylpolyoxyethylene sulfates, alkylnaphthalene sulfates, lignin sulfates, alkyl phosphates, N-alkyl-β-alanine, N-alkylsulfobetaines, N-alkylhydroxysulfobetaines, lecithin, alkylpolyoxyethylene ethers, alkylarylpolyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

12. The method according to any one of claims 1 to 3, wherein, The solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more selected from the group consisting of alcohol solvents, aliphatic hydrocarbon solvents, and water, and the PEG-based solvent is (i) represented by R 1 (OCHR 3 CH 2 )nOR 2 , where n is a natural number from 1 or greater and 10 or less, or (ii) a mixture of solvents represented by R 1 (OCHR 3 CH 2 )nOR 2 , with an average value of n from 3 to 100, where R 1 and R 2 are each independently hydrogen, C 1 to C 4 alkyl or -C(=O)R 4 , R 3 is hydrogen or C 1 to C 4 alkyl, and R 4 is C 1 to C 18 alkyl optionally substituted with a hydroxyl group or C 1 to C 18 alkenyl optionally substituted with a hydroxyl group.

13. The method according to any one of claims 1 to 3, wherein, the solvent is (i) a PEG-based solvent, or (ii) a mixed solvent containing a PEG-based solvent and one or more selected from the group consisting of: alcohol solvents, aliphatic hydrocarbon solvents, and water, and the PEG-based solvent is diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, polypropylene glycol, or polyethylene glycol mono-fatty acid ester.

14. A method for producing a cyclic peptide crystal, the method comprising the step of contacting a cyclic peptide with a solvent, wherein the cyclic peptide is a cyclic peptide having the following characteristics (I) and (II), Characteristic (I): containing a cyclic moiety composed of a total of 8 to 16 amino acid residues, and the total number of amino acids is 8 to 20 residues; and Characteristic (II): containing at least 2 N-substituted amino acid residues, the solvent is solvent (A) or a mixed solvent containing solvent (A) and solvent (B), the solvent (A) is one or more selected from the group consisting of: amide solvents, sulfoxide solvents, aromatic hydrocarbon solvents, halogen solvents, and ester solvents, and the solvent (B) is one or more selected from the group consisting of: aliphatic hydrocarbon solvents, ethylene glycol, and water.

15. The method according to any one of claims 1 to 14, wherein, in the step of contacting the cyclic peptide with the solvent, the concentration of the cyclic peptide is 1 mg / mL to 2000 mg / mL.

16. The method according to any one of claims 1 to 15, wherein, The step of contacting the cyclic peptide with the solvent is carried out at a temperature of -10°C to 120°C for 30 minutes to 12 weeks.

17. A method for screening a method for crystallizing a cyclic peptide, the method comprising the following steps (a) and (b): (a) A step of producing cyclic peptide crystals by the method according to any one of claims 1 to 16; and (b) A step of analyzing the crystals by powder X-ray crystallography.

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