Analogues of azabicyclo compounds

Abstract

The present invention provides a novel compound which is an analogue to be removed from an API or a preparation, and also provides a standard substance for an analogue to be used in the management of the quality of a pharmaceutical product. The analogue 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3, 3 '-di (propane-2-yl)-1' H-[1, 4 '-bipyrazolo [3, 4-b] pyridine]-1'-yl} benzamide analogue 2: 3-ethyl-4-fluorobenzamide analogue 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propane-2-yl)-1H-pyrazolo [3, 4-b] pyridine]-1 '-fluorobenzamide analogue 1: 3, and the analogue 2: 3: 4. 4: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo [3, 4-b] pyridin-1-yl} benzamide analogues 4: 3-ethyl-4-{14-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-13, 23, 33-tri (propan-2-yl)-31H-[11, 24: 21, 34-terpyrazolo [3, 4-b] pyridin-1-yl]-3: 3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo [3, 4-b] benzamide analogues. The preparation method comprises the following steps: preparing 5: 4, 4 '-(1H, 1' H-[4, 4 '-biimidazole]-1, 1'-diylbis {[3-(propan-2-yl)-1H-pyrazolo [3, 4-b] pyridine-4, 1-diyl]}) bis (3-ethylbenzamide) analogue 6: 4-{4, 6-bis [4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo [3, 4-b] pyridine]-31-yl} benzamide analogue; the 7: 4-{4, 6-bis [4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo [3, 4-b] pyridine-1-yl}-3-ethylbenzonitrile analogue has a structural formula shown in the description. The present invention relates to a compound represented by the following formula (I): 4-[4-ethoxy-3-(propane-2-yl)-1H-pyrazolo [3, 4-b] pyridine-1-yl]-3-ethylbenzamide analogue 8: 4-[4-ethoxy-3-(propane-2-yl)-1H-pyrazolo [3, 4-b] pyridine-1-yl]-3-ethylbenzamide analogue 9: 3-ethyl-4-[4-methoxy-3-(propane-2-yl)-1H-pyrazolo [3, 4-b] pyridine-1-yl] benzamide.

Description

Technical Field

[0001] The present invention relates to an analog of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (hereinafter also referred to as Compound 1) or a salt thereof, and a pharmaceutical composition for oral administration containing Compound 1 or a salt thereof as an active ingredient. Background Art

[0002] The quality of active pharmaceutical ingredients (API) must meet the standards set by the International Conference on Harmonization of Pharmaceutical Regulation (ICH). The standards are for impurities contained in API or preparations, such as analogs, residual solvents, and residual metals. Impurities in API or preparations are required to be removed to below the standard value.

[0003] In order to confirm that impurities have been removed from API or preparations, it is necessary to prepare and test these impurities as standard products or standard substances. Among impurities, analogs are organic compounds such as byproducts or decomposition products generated in the manufacturing process of API, products or decomposition products generated during the storage of API or preparations containing API, which can usually be detected by high performance liquid chromatography or thin layer chromatography.

[0004] Patent Document 1 and Non-Patent Document 1 disclose that 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (Compound 1) is useful as a preventive and / or therapeutic agent for cancer and the like based on HSP90 inhibition.

[0005] Patent Document 2 discloses that Compound 1 exhibits a combined effect with various antitumor agents.

[0006] Patent Document 3 discloses that Compound 1 exhibits an effect particularly when used in combination with an immune checkpoint inhibitor.

[0007] Patent Document 4 discloses a crystal form of Compound 1 that is useful as a pharmaceutical.

[0008] Patent Document 5 discloses that Compound 1 and the like are useful for treating diseases associated with IDO expression.

[0009] However, Patent Documents 1 to 5 and Non-Patent Document 1 neither disclose nor suggest analogs of Compound 1 that are used for quality control for mass production of an API of a quality suitable for pharmaceuticals.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: International Publication No. 2011 / 004610

[0013] Patent Document 2: International Publication No. 2015 / 046498

[0014] Patent Document 3: International Publication No. 2019 / 004417

[0015] Patent Document 4: International Publication No. 2016 / 181990

[0016] Patent Document 5: International Publication No. 2019 / 054465

[0017] Non-patent literature

[0018] Non-patent literature 1: J. Med. Chem. 2019, 62, 531-551 Summary of the invention

[0019] Technical problem to be solved by the invention

[0020] The technical problem to be solved by the present invention is to find a novel analogue derived from 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (Compound 1) or a salt thereof contained in a sample thereof, and to provide the novel analogue as a standard substance of the analogue used in the quality control of pharmaceuticals. In addition, the technical problem to be solved by the present invention is to provide a pharmaceutical composition for oral administration containing Compound 1 or a salt thereof that meets the standards specified by ICH.

[0021] Technical solutions for solving technical problems

[0022] The inventors of the present invention have conducted intensive studies and, as a result, have found an analogue derived from Compound 1 that can be used as a standard for confirming the quality of Compound 1 or a salt thereof as a pharmaceutical product.

[0023] That is, the present invention provides the following [1] to

[25] .

[0024] [1] An analogue of any one of 1 to 9 below or a salt thereof, or a combination thereof, which is used as a standard for quality management of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof,

[0025] Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide;

[0026] Analog 2: 3-ethyl-4-fluorobenzamide;

[0027] Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide;

[0028] Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide;

[0029] Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide);

[0030] Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile;

[0031] Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide;

[0032] Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide;

[0033] Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide.

[0034] [2] The analogue or salt thereof, or a combination thereof, according to [1], wherein the analogue used as the standard substance is any of the analogues 1 to 7.

[0035] [3] The analogue or salt thereof, or a combination thereof, according to [1], wherein the analogue used as the standard substance is any of the analogues 1 to 3.

[0036] [4] The analogue or salt thereof, or a combination thereof, according to [1], wherein the analogue used as the standard substance is any of the analogues 1 to 2.

[0037] [5] The analogue or salt thereof, or a combination thereof, according to [1], wherein the analogue used as the standard substance is the analogue 1.

[0038] [6] A pharmaceutical composition for oral administration, comprising 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof as an active ingredient, wherein the total content of the analogs 1 to 9 listed below is 1.0% or less.

[0039] Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide

[0040] Analog 2: 3-ethyl-4-fluorobenzamide

[0041] Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide

[0042] Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 33 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide

[0043] Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide)

[0044] Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile

[0045] Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide

[0046] Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide

[0047] Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide

[0048] [7] The pharmaceutical composition for oral administration according to [6], wherein the content of the analog 1 is 0.30% or less, and the content of each of the analogs 2 to 9 is 0.10% or less.

[0049] [8] A pharmaceutical composition for oral administration, comprising 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide as an active ingredient, wherein the content of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propan-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridin]-1'-yl}benzamide as analog 1 is 0.30% or less.

[0050] [9] A pharmaceutical preparation for oral administration, comprising the pharmaceutical composition for oral administration according to any one of [6] to [8].

[0051]

[10] 3-Ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propan-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide or a salt thereof.

[0052]

[11] 3-Ethyl-4-fluorobenzamide or its salt.

[0053]

[12] N-[1-(4-Carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof.

[0054] 〔13〕3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide or a salt thereof.

[0055]

[14] 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide) or a salt thereof.

[0056]

[15] 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile or a salt thereof.

[0057]

[16] 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide or a salt thereof.

[0058]

[17] 4-[4-Ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide or a salt thereof.

[0059]

[18] 3-Ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide or a salt thereof.

[0060]

[19] A method for producing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide, comprising the step of suspending water-containing wet crystals of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide in methyl acetate and heating and stirring the suspension.

[0061]

[20] A method for producing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide as described in

[19] , comprising: a step of suspending wet crystals of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide in methyl acetate and heating and stirring the mixture; and then adding the crystals to a methyl acetate / ethanol mixed solvent, suspending the mixture and heating and stirring the mixture.

[0062]

[21] Use of any analogue or salt of any of the following 1 to 9, or a combination thereof, as a standard for managing the quality of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof.

[0063] Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide

[0064] Analog 2: 3-ethyl-4-fluorobenzamide

[0065] Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide

[0066] Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide

[0067] Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide)

[0068] Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile

[0069] Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide

[0070] Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide

[0071] Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide

[0072]

[22] The use as described in

[21] , wherein the above-mentioned analogue is any analogue of the above-mentioned analogues 1 to 7.

[0073]

[23] The use as described in

[21] , wherein the above-mentioned analogue is any analogue of the above-mentioned analogues 1 to 3.

[0074]

[24] The use as described in

[21] , wherein the above-mentioned analogue is any analogue of the above-mentioned analogues 1 to 2.

[0075]

[25] The use as described in

[21] , wherein the above-mentioned analogue is the above-mentioned analogue 1.

[0076] Effects of the Invention

[0077] According to the present invention, by using an analogue derived from Compound 1 as a standard for quality control, the quality of a pharmaceutical composition containing Compound 1 or a salt thereof as an active ingredient can be maintained and managed. That is, according to the present invention, Compound 1 and a salt thereof of very high purity with quality suitable for pharmaceuticals can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 HPLC chromatogram of compound 1 of reference example 1

[0079] Figure 2 HPLC chromatogram of the standard product of analogue 1

[0080] Figure 3 HPLC chromatogram of the standard product of analogue 2 DETAILED DESCRIPTION

[0081] In the present invention, 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (Compound 1) is also known as TAS-116 or Pimitespib, and is a compound having a structure of the following Chemical Formula 1. As a method for producing Compound 1 or a salt thereof, methods described in, for example, Patent Document 1 and Non-Patent Document 1 are known.

[0082]

[0083] When compound 1 has isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, all isomers and mixtures thereof are included in compound 1 unless otherwise specified.

[0084] The compound names and structural formulas of analogs 1 to 9 derived from compound 1 newly discovered in the present invention are shown in the following Tables 1-1 to 1-3.

[0085] [Table 1-1]

[0086]

[0087] [Table 1-2]

[0088]

[0089] [Table 1-3]

[0090]

[0091] Analog 1 is sometimes also referred to as DBA.

[0092] Analog 2 is sometimes also referred to as FEBA.

[0093] Analog 3 is sometimes referred to as DBA-2.

[0094] Analog 4 is sometimes also referred to as TBA.

[0095] Analog 5 is sometimes also referred to as PZI-01-04.

[0096] Analog 6 is sometimes also referred to as AZI-04-05.

[0097] Analog 7 is sometimes also referred to as AZI-04-06.

[0098] Analog 8 is sometimes also referred to as EOABA.

[0099] Analog 9 is sometimes also referred to as MOABA.

[0100] Analogs 1 to 9 are all compounds that can be produced in the process of producing Compound 1. Analogs 1 to 9 and their salts can be said to be impurities that can be contained in the API and formulation of Compound 1.

[0101] In the present specification, the description of "analog 1", "analog 2", "analog 3", "analog 4", "analog 5", "analog 6", "analog 7", "analog 8", and "analog 9" may be intended to include "salts" and "solvates (such as hydrates)" of the analogs. In addition, analogs 1 to 9 also include their tautomers.

[0102] In the present specification, unless otherwise specified, a salt means a pharmaceutically acceptable salt, and examples thereof include a base addition salt and an acid addition salt.

[0103] Examples of the base addition salt include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-dibenzylethylenediamine salts.

[0104] Examples of the acid addition salt include inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbates, and trifluoroacetates; and sulfonates such as methanesulfonates, isethionates, benzenesulfonates, and p-toluenesulfonates.

[0105] The compound 1 or a salt thereof used in the present invention is preferably a free form of the compound 1 without forming a salt.

[0106] Batch production used in the manufacture of products or compounds is a method of adding a certain amount of raw materials and carrying out each process successively to produce a certain fixed amount of products or compounds at one time.

[0107] In batch production, the amount of raw materials added in one manufacturing is called 1 batch, for example, more than 1 kg, that is, the raw materials used in manufacturing a desired compound once are more than 1 kg, which is called mass production in this embodiment. In addition, the desired compound includes intermediates used in the manufacture of API in addition to API.

[0108] Whether the compound 1 or a salt thereof obtained in this way satisfies the quality of an API is determined by analyzing the compound 1 or a salt thereof. The determination is made in accordance with the standards described in ICH and the like.

[0109] The chemical purity used as a reference in this case is calculated by measurement using high performance liquid chromatography (hereinafter also referred to as HPLC), etc. The analogs can be identified by comparing the retention time of HPLC, mass spectrum, photodiode array (PDA) and these parameters of analogs 1 to 9 detected by the present invention.

[0110] Furthermore, these analogs 1 to 9 can also be quantitatively measured by any method using an external standard or an internal standard.

[0111] When these analogs 1 to 9 may be contained as impurities in a pharmaceutical product or a preparation, these analogs 1 to 9 are controlled by the guidelines of the International Conference on Harmonization of Pharmaceutical Regulations (ICH-Q3). The analysis of analogs 1 to 9 is very useful because it can confirm whether a pharmaceutical product or a preparation meets the standards of the guidelines.

[0112] These analogs 1 to 9 can be detected from compound 1 or a salt thereof by the analytical method for analogs described below. In addition, the present invention can use one or more of analogs 1 to 9 as standard products for quality control. It is preferred to use analogs 1 to 5 as standard products in quality control, and it is further preferred to use analogs 1 and 2 as standard products in quality control, and it is most preferred to use analog 1 as a standard product in quality control.

[0113] The analogues from compound 1 used in such standard products are high-purity products. Therefore, each analogue obtained by separation under the conditions of the HPLC can be used as a standard product. Therefore, the present invention can also be referred to as a method for producing the analogue characterized by separation from a sample containing compound 1 or a salt thereof. The analogues include analogues 1 to 9 mentioned above, preferably analogues 1 to 5, more preferably 1 and 2, and most preferably analogue 1.

[0114] So far, it is not known that compound 1 contains analogs 1 to 9. In addition, analogs 1 and 3 to 9 are novel substances. Therefore, the present invention includes analogs 1 to 9 used in the quality management of the original drug of compound 1 or its salt and the preparation containing compound 1 or its salt. In addition, analogs 1 to 9 used as standard substances in the impurity detection of the preparation containing compound 1 or its salt are also included.

[0115] <Analysis methods for analogues>

[0116] In this embodiment, the object of determination for confirming the presence of analogs 1 to 9 or their salts is API (compound 1 or its salt) and a preparation containing API. The preparation containing API may contain commonly used fluidizers, excipients, binders, disintegrants, lubricants, coating agents, colorants, flavoring agents, and flavoring agents.

[0117] Analogs 1 to 9 or salts thereof in the present embodiment can be used as standard substances for quality management by confirming the presence or absence of each analog in the stability of API or a preparation containing API and its manufacturing process by infrared absorption (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, HPLC, thin layer chromatography (TLC) or other chromatographic measurements.

[0118] For example, in IR spectroscopy, when measuring an analog in an API or a preparation, if the absorption band from compound 1 or its salt, or an excipient contained in the preparation, does not overlap with a portion of the absorption band from the analog or its salt, the presence of the analog in the API or the preparation can be confirmed.

[0119] In the NMR spectrum, when measuring an analog in an API or a preparation, if the peaks from Compound 1 or its salt, or excipients contained in the preparation, etc., do not overlap with the peaks of a part of the analog or its salt, the presence of the analog in the API or the preparation can be confirmed.

[0120] In HPLC, when measuring an analog in an API or a preparation, if the retention time of a peak derived from Compound 1 or its salt, or an excipient contained in the preparation, and a peak of a part of the analog or its salt do not overlap, the presence of the analog in the API or the preparation can be confirmed.

[0121] In TLC, when measuring an analog in an API or a preparation, if the Rf values ​​of points from compound 1 or its salt, or excipients contained in the preparation, and some points of the analog or its salt do not overlap, the presence of the analog in the API or the preparation can be confirmed.

[0122] In the present embodiment, the presence of analogs 1 to 9 or salts thereof in the API or a preparation containing the API can be confirmed by the above-mentioned measurement. However, measurement by HPLC is preferred from the viewpoint of being able to measure an extremely small amount of the analogs or salts thereof.

[0123] In addition, in the above-mentioned determination, it is required to prepare a standard product of the analog or its salt. The terms of standard product and standard substance are recorded in various definitions for each use in the Japanese Pharmacopoeia, but in this embodiment, "standard product" refers to a substance used as an indicator for confirming the presence of an analog contained in an API or a preparation. Therefore, the "standard product" in this embodiment includes not only the concept of standard product in the Japanese Pharmacopoeia, but also the concept of standard substance.

[0124] In this embodiment, the standard sample of the analog or its salt can be isolated from API, crude product, intermediate, etc., or synthesized separately when producing Compound 1 or its salt.

[0125] In addition, analogs that can be used as standard substances for quality management can be listed as raw materials or intermediate compounds, compounds that become byproducts during the manufacture of API, and compounds produced when the API is manufactured into preparations, etc., but as long as they are compounds that can be contained in the actual manufactured API or preparation, there is no particular limitation, and they can also be analogs that are not actually contained in the API or preparation. Therefore, in terms of the manufacture of API, such analogs are not only compounds actually contained in the API or preparation, but also compounds removed during the purification process of the API. Moreover, the compound 1 or its salt that can contain analogs in this embodiment is not limited to the products obtained by the above-mentioned manufacturing method.

[0126] The HPLC used in this embodiment can use a commonly available commercial product. HPLC includes at least a separation column and a detector.

[0127] In the present embodiment, the content of the analog contained in the API or the preparation can be calculated by the following formula based on the peak area of ​​the analog in HPLC measurement.

[0128] Analogue content (%) = analogue peak area / total peak area × 100

[0129] In the present embodiment, the resolution Rs of the peaks measured by HPLC represents the relationship between the retention times of the peaks on the chromatogram and the peak widths thereof, and is calculated using the following formula.

[0130] Rs=1.18×(tR2―tR1) / (W0.5h1+W0.5h2)

[0131] tR1, tR2: retention times of two substances used in the resolution determination, where tR1 < tR2.

[0132] W0.5h1, W0.5h2: peak width at the midpoint of the height of each peak.

[0133] Among them, tR1, tR2 and W0.5h1, W0.5h2 use the same unit respectively.

[0134] In the Japanese Pharmacopoeia, a resolution of 1.5 or more is considered to be a state in which the peaks are completely separated. In the present embodiment, a resolution of 1.5 or more can also be used as an indicator.

[0135] In this embodiment, the measurement conditions used for HPLC are not particularly limited as long as the separation degree between one analog selected from analogs 1 to 9 and compound 1 is 1.5 or more. In addition, the number of HPLC measurements is not particularly limited as long as it is one or more.

[0136] In this embodiment, the measurement conditions used in HPLC can appropriately set the gradient of the mobile phase, the silica gel column, the injection amount of the measurement sample, the presence or absence of the mobile phase cleaning agent, the measurement wavelength, the column temperature, the flow rate of the mobile phase, the mixer capacity of the HPLC device, etc.

[0137] In HPLC, there are known normal phase columns that use an organic phase as a mobile phase to separate compounds according to their polarity, and reverse phase columns that use an aqueous phase as a mobile phase to separate compounds. From the viewpoint of the physical properties of compound 1, reverse phase chromatography using a reverse phase column is preferred in this embodiment.

[0138] The mobile phase is as described later.

[0139] Generally, in HPLC measurement, the time when the measurement sample is injected (introduced) into the mobile phase and the detector starts detection is regarded as the time when the measurement starts. Hereinafter, in this embodiment, the time in HPLC measurement may be defined based on the time when the measurement starts.

[0140] The silica gel column for separation of HPLC that can be used in this embodiment can be selected from a silica gel column whose surface is modified with octadecylsilyl (ODS column or C18 column), a silica gel column whose surface is modified with octyl (C8 column), a silica gel column whose surface is modified with cyanopropyl (CN column), a silica gel column whose surface is modified with phenethyl (Ph column), a silica gel column whose surface is modified with aminopropyl (NH column), a silica gel column whose surface is modified with dihydroxypropyl (Diol column), a column filled with various polymers (polymer column), a column filled with ion exchange resin (ion exchange column), etc., preferably an ODS column.

[0141] As the ODS column, various columns can be used, which have different particle sizes, pore sizes, octadecylsilyl bonding methods, octadecylsilyl substitution degrees, etc. of silica gel. In the present embodiment, high-purity silica gel can be used, preferably an ODS column (capped ODS column) in which the remaining silanol is treated with a low-molecular silylating agent after octadecylation.

[0142] As the ODS column, various columns can be used that differ in silica gel particle size, pore size, method of bonding octadecylsilyl groups, degree of substitution of octadecylsilyl groups, and the like.

[0143] The average particle size of the silica gel is more preferably about 3 to 5 μm, for example. The average particle size of the silica gel can be measured by a laser diffraction method or the like.

[0144] The average pore size of silica gel is more preferably, for example, 10 to 12 nm. The average pore size of silica gel can be measured by a gas adsorption method or the like.

[0145] As the bonding form of the octadecylsilyl group in the silica gel, for example, a monomeric form, a polymerized form, etc. are preferable.

[0146] The degree of substitution of octadecylsilyl groups can be measured by various methods. The carbon content of silica gel is preferably, for example, 14% or more. In addition, the carbon content of silica gel is preferably, for example, 20% or less. The carbon content of silica gel can be measured by various methods.

[0147] As the mobile phase of HPLC in the present embodiment, it is preferable to use a mixed liquid of an organic phase and an aqueous phase.

[0148] The organic phase used in the mobile phase of HPLC is a liquid medium based on an organic solvent. As the above-mentioned organic solvent, non-polar solvents such as hexane, cyclohexane, heptane, diethyl ether, tetrahydrofuran, chloroform, dichloromethane, acetone, dimethyl sulfoxide, acetonitrile and the like can be used. These organic solvents can be used alone as one, or combined as more than two (for example, in the form of a mixed solvent) and used. As the organic solvent contained by the organic phase in the present embodiment, acetonitrile is preferred.

[0149] The organic phase may contain 50% by volume or less of water. The water content of the entire organic phase is preferably 40% by volume or less, more preferably 30% by volume or less, and particularly preferably 20% by volume or less.

[0150] The aqueous phase used in the mobile phase of HPLC is a liquid medium mainly composed of water. The entire amount of the liquid contained in the aqueous phase can be water.

[0151] In addition, the aqueous phase may contain 20% by volume or less of an organic solvent. In this case, the organic solvent used is not particularly limited as long as it can be uniformly mixed with water, and examples thereof include acetone, dimethyl sulfoxide, acetonitrile, formic acid, acetic acid, methanol, ethanol, isopropanol, etc., preferably acetonitrile.

[0152] The organic solvent contained in the aqueous phase may account for 50% by volume or less of the entire aqueous phase, preferably 10 to 50% by volume, and more preferably 20 to 40% by volume.

[0153] The pH of the mobile phase of HPLC is not particularly limited as long as analogs 1 to 9 or salts thereof can be detected and their contents can be calculated. The pH of the mobile phase of HPLC can be adjusted by adding the following buffer.

[0154] A buffer can be added to the mobile phase of HPLC from the viewpoint of reducing the influence of pH during measurement and improving reproducibility. For example, formic acid or its salt, acetic acid or its salt, citric acid or its salt, tartaric acid or its salt, phosphoric acid or its salt can be added as a buffer.

[0155] Examples of formic acid or its salt include formic acid, sodium formate, and ammonium formate. Examples of acetic acid or its salt include acetic acid and sodium acetate. Examples of citric acid or its salt include citric acid, monosodium citrate, disodium citrate, and trisodium citrate. Examples of tartaric acid or its salt include tartaric acid and sodium tartrate. Examples of phosphoric acid or its salt include phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. These buffers may be used alone or in combination of two or more.

[0156] The concentration of the buffer that can be used in the present invention can be appropriately adjusted as long as the buffer does not precipitate during high performance liquid chromatography measurement, and is preferably 1 to 50 mM, more preferably 3 to 30 mM, further preferably 5 to 20 mM, and particularly preferably 8 to 15 mM.

[0157] The buffer can be added to either the aqueous phase or the organic phase. Preferably, the buffer is added to the aqueous phase.

[0158] The concentration of the buffer that can be used in the present embodiment can be appropriately adjusted as long as it is a concentration at which the buffer does not precipitate during HPLC measurement.

[0159] In this embodiment, as the aqueous phase in the mobile phase, the above-mentioned solvents and buffers can be used, preferably an aqueous solution containing formic acid or its salt as a buffer, or an aqueous solution containing phosphoric acid or its salt as a buffer, and more preferably an aqueous solution of phosphate.

[0160] Generally, in HPLC measurement, by changing the composition of the mixed solution of the organic phase and the aqueous phase in the mobile phase, the analogue of interest can be appropriately separated. In this case, the analogue of interest can be measured by making the composition ratio of the mixed solution in the mobile phase constant (isocratic) or by changing the composition of the mixed solution continuously (gradient).

[0161] Usually, in reverse phase chromatography, the variation of the composition of the mixed solution of the organic phase and the aqueous phase in the mobile phase can be represented by a two-dimensional graph with the vertical axis being the ratio (%) of the organic phase in the entire mobile phase and the horizontal axis being the measurement time (minutes). That is, if it is isocratic, it is represented by a linear function with a slope of 0. If it is a gradient that causes the ratio of the organic phase to rise over time at a certain increasing ratio, it is represented by a linear function with a positive slope. If it is a gradient that causes the ratio of the organic phase to decrease over time at a certain decreasing ratio, it is represented by a linear function with a negative slope. By combining them, it is possible to maintain the separation of each peak while simultaneously allowing analogs with low polarity to be effectively eluted, and to be measured with a short retention time.

[0162] The increase ratio of the organic phase in the mobile phase, which is the “slope” of the linear function, can be expressed, for example, by the increase ratio of the organic phase per unit time, and can be calculated as follows.

[0163] The increase ratio of the organic phase per unit time = {(the ratio of the organic phase in the mobile phase at the end of the gradient) - (the ratio of the organic phase in the mobile phase at the start of the gradient)} ÷ (the time length between the start and end of the gradient)

[0164] For example, at the start of the measurement (0 minutes), the proportion of the organic phase is 10 volume % of the mobile phase. When the proportion of the organic phase is continuously increased and 10 minutes after the start of the measurement, the proportion of the organic phase becomes 30 volume % of the mobile phase, the increase rate of the organic phase per unit time is expressed as 2 volume % / minute.

[0165] In the present embodiment, the composition of the mobile phase and the presence or absence of changes therein are not particularly limited as long as the above-mentioned analogs can be measured.

[0166] In the present embodiment, the measurement time of HPLC is not particularly limited as long as the target analog can be measured, and examples thereof include 3 to 120 minutes, and preferably 10 to 60 minutes.

[0167] In the present embodiment, at the time of starting the HPLC measurement (0 minutes), the proportion of the aqueous phase is 50 to 100% by volume of the entire mobile phase.

[0168] In the present embodiment, when the API of Compound 1 is measured, the proportion of the aqueous phase at the start of HPLC measurement is 50 to 100% by volume, preferably 50 to 80% by volume, and more preferably 50 to 75% by volume of the entire mobile phase.

[0169] In the present embodiment, at the time when the HPLC measurement is completed, the proportion of the aqueous phase is 0 to 50% by volume of the entire mobile phase.

[0170] In the present embodiment, when the API of Compound 1 is measured, the proportion of the aqueous phase at the end of the HPLC measurement is 0 to 50% by volume, preferably 10 to 50% by volume, and more preferably 20 to 40% by volume of the entire mobile phase.

[0171] During the period from the start to the end of the HPLC measurement, the target analog can be measured by appropriately using an isocratic method, a gradient method, or a combination thereof.

[0172] In this embodiment, the solution injected into the mobile phase at the start of measurement by HPLC can be the solvent used in the mobile phase described above, preferably water or a buffer used in the aqueous phase of the mobile phase, acetonitrile, isopropanol, and a mixed solvent thereof.

[0173] In the present embodiment, the flow rate of the mobile phase in the column in the measurement by HPLC is not particularly limited as long as it is a rate that enables measurement, but is preferably 0.5 to 2.0 mL / min.

[0174] In the present embodiment, the detection wavelength of the measurement by HPLC is not particularly limited as long as it is a detectable wavelength, but is preferably 210 to 400 nm, and more preferably 220 nm.

[0175] In the present embodiment, the amount of the mobile phase solution injected at the start of measurement by HPLC is not particularly limited as long as it is a measurable amount, but is preferably 10 μL or more.

[0176] In addition, the HPLC in this embodiment can also appropriately use a mobile phase cleaning agent. The cleaning agent uses activated carbon in the protective column core (cartridge) to remove impurities or dust in the mobile phase. Along with this, the baseline noise of the chromatogram is reduced, so even a small amount of analogs from compound 1 can be appropriately detected and quantified.

[0177] In the present invention, an analogue derived from Compound 1 can be detected by mixing Compound 1 or a salt thereof with a solvent to prepare a sample, and injecting the sample as a measurement sample into a high performance liquid chromatography.

[0178] In the present invention, when compound 1 is isolated at a high purity such that the total content of analogs 1 to 9 is 1.0% or less, it is preferable to perform the following purification step by crystallization.

[0179] First, the water-containing wet crystals of compound 1 obtained by the method including the above steps are purified. The solvent used for purifying the wet crystals of compound 1 is preferably C6-C14 aromatic hydrocarbons, C1-C6 alcohols, C1-C6 esters and mixed solvents thereof, and more preferably methyl acetate.

[0180] In addition, the obtained wet crystals of compound 1 may be filtered and washed before entering the following step. The solvent used for filtering and washing is preferably water, C6-C14 aromatic hydrocarbons, C1-C6 alcohols, C1-C6 esters and mixed solvents thereof, and more preferably a mixed solvent of ethanol / water.

[0181] Next, the obtained compound 1 is purified to obtain a crystal of compound 1. The solvent used for further purification of compound 1 is preferably C6-C14 aromatic hydrocarbons, C1-C6 alcohols, C1-C6 esters and mixed solvents thereof, more preferably a mixed solvent of methyl acetate / ethanol.

[0182] When a solvent (mixed solvent) containing methyl acetate / ethanol is used as the solvent for further purification of Compound 1, the amount of methyl acetate can be used in a volume ratio of 0.01 to 100 times, preferably 0.1 to 50 times, more preferably 0.5 to 25 times or more, and even more preferably 1.0 to 10 times, relative to the amount of ethanol as the solvent ratio of the initial methyl acetate / ethanol mixed solution.

[0183] The method for producing compound 1 according to this embodiment is characterized by comprising the step of suspending the water-containing wet crystals of compound 1 in methyl acetate and heating and stirring. In addition, it is characterized by comprising the step of adding the obtained compound 1 to a methyl acetate / ethanol mixed solvent and suspending and heating and stirring.

[0184] Preferably, the method for producing compound 1 is as follows, characterized in that it includes a step of suspending the water-containing wet crystals of compound 1 in methyl acetate and heating and stirring, the method includes a step of adding the obtained compound 1 to a methyl acetate / ethanol mixed solvent, suspending, heating and stirring, and the yield of each batch of compound 1 is more than 1 kg.

[0185] More preferably, the method for producing compound 1 is characterized in that it includes a step of suspending the water-containing wet crystals of compound 1 in methyl acetate and heating and stirring, the method includes a step of adding the obtained compound 1 to a methyl acetate / ethanol mixed solvent, suspending, heating and stirring, and the yield of each batch of compound 1 is more than 1 kg.

[0186] Further preferred is the following method for producing compound 1, characterized in that it includes a step of suspending the water-containing wet crystals of compound 1 in methyl acetate and heating and stirring, the production method includes a step of adding the obtained compound 1 to a methyl acetate / ethanol mixed solvent, suspending, heating and stirring, and the output of each batch of compound 1 is 5 kg or more.

[0187] Further preferred is the following method for producing compound 1, characterized in that it includes a step of suspending the water-containing wet crystals of compound 1 with methyl acetate and heating and stirring, the production method includes a step of adding compound 1 to a methyl acetate / ethanol mixed solvent for suspending, heating and stirring, and the output of each batch of compound 1 is more than 10 kg.

[0188] Furthermore, a method for producing compound 1 is further preferred, characterized in that it includes a step of suspending compound 1 in a solvent containing methyl acetate and ethanol in an amount of methyl acetate in a volume ratio of 0.01 to 100 times the amount of ethanol and heating and stirring, and the yield of compound 1 per batch is 10 kg or more.

[0189] The pharmaceutical composition for oral administration of the present invention contains compound 1 or a salt thereof as an active ingredient. From the viewpoint of meeting the standards specified by ICH, in the pharmaceutical composition for oral administration of the present invention, the total content of the above analogs 1 to 9 is 1.0% or less, preferably 0.5% or less. In addition, in the pharmaceutical composition for oral administration, the content of analog 1 is 0.30% or less. In addition, in the pharmaceutical composition for oral administration, the individual contents of analogs 2 to 9 are all 0.10% or less.

[0190] In the pharmaceutical composition for oral administration of the present invention, the total content of the above analogs 1 to 9 is 0% to 1.0%. In addition, in the pharmaceutical composition for oral administration, the content of analog 1 is 0% to 0.30%. In addition, in the pharmaceutical composition for oral administration, the content of each of analogs 2 to 9 is 0% to 0.10%.

[0191] In addition, as a preferred embodiment of the pharmaceutical composition for oral administration of the present invention, the total content of the above analogs 1 to 9 is more than 0% and less than 1.0%, preferably more than 0% and less than 0.5%. In addition, in the pharmaceutical composition for oral administration, the content of analog 1 is more than 0% and less than 0.30%. In addition, in the pharmaceutical composition for oral administration, the individual content of analogs 2 to 9 is more than 0% and less than 0.10%.

[0192] The pharmaceutical composition for oral administration of the present invention can be formulated with a pharmaceutically acceptable carrier as required, and can be administered in various ways according to the purpose of prevention or treatment. Various administration methods can be prepared by conventional preparation methods known to those skilled in the art.

[0193] As pharmaceutically acceptable carriers, various conventional organic or inorganic carrier materials can be used as preparation raw materials, as excipients, binders, disintegrants, lubricants, colorants in solid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid preparations. In addition, preparation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0194] A preferred pharmaceutical composition for oral administration of the present invention is a tablet containing compound 1 or its salt and an excipient selected from lactose, corn starch, and crystalline cellulose, or a film-coated tablet having a film coating applied to the tablet. More preferably, it is a tablet containing compound 1 or its salt, lactose, corn starch, and crystalline cellulose, or a film-coated tablet having a film coating applied to the tablet. Further preferably, it is a tablet containing compound 1 or its salt, lactose, corn starch, hydroxypropyl cellulose, crystalline cellulose, and magnesium stearate, or a film-coated tablet having a film coating applied to the tablet. Particularly preferably, it is a film-coated tablet having a film coating composed of hydroxypropyl methylcellulose, polyethylene glycol 6000P (Macrogol 6000P), titanium oxide, and magnesium stearate applied to a tablet containing compound 1 or its salt, lactose, corn starch, hydroxypropyl cellulose, crystalline cellulose, and magnesium stearate.

[0195] When preparing a solid preparation for oral administration, an excipient, a binder as needed, a disintegrant, a lubricant, a colorant, a flavoring agent, a flavor corrective, etc. can be added to Compound 1 or a salt thereof, and then tablets, film-coated tablets, granules, powders, capsules, etc. can be manufactured by conventional methods.

[0196] When preparing a liquid preparation for oral administration, a solubilizing agent, an isotonic agent, a buffer, a preservative, and the like can be used in the preparation of Compound 1 or a salt thereof.

[0197] In addition, the daily dosage of the drug having the above-mentioned dosage form can be appropriately determined according to the patient's symptoms, body weight, age, sex, etc.

[0198] Example

[0199] The present invention will be described in more detail below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

[0200] Various reagents used in Examples and Comparative Examples were commercially available products unless otherwise specified.

[0201] Furthermore, the total content of analogs 1 to 9 and their salts contained in the free form of compound 1 was measured using high performance liquid chromatography.

[0202] Mass spectra were measured under the following conditions using LCMS-IT-TOF manufactured by Shimadzu Corporation for HRMS and SQD manufactured by Waters Corporation for LRMS, and are expressed as [M+H]+ values.

[0203] MS detection: ESI positive

[0204] The structures of some compounds were confirmed by 1H-NMR, and the meanings of the abbreviations are shown below.

[0205] s:singlet

[0206] d:doublet

[0207] t:triplet

[0208] q:quartet

[0209] sep: septet

[0210] dd: doublet of doublets

[0211] ddd: doublet of doublet of doublets

[0212] m: multiplet (multiplet)

[0213] brs: broad singlet

[0214] [Reference Example 1] Synthesis of Compound 1

[0215] Compound 1 was produced by the following production method.

[0216] (Step 1) 4-iodo-3-(propan-2-yl)-1-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyrrolidone Synthesis of pyridine

[0217] 4-iodo-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (6.53 kg) synthesized with reference to Example 100(1) of International Publication No. 2011 / 004610 was dissolved in N,N-dimethylformamide (27.6 kg), and 66% sodium hydride (0.933 kg) was added at about 0°C, followed by stirring for 30 minutes. Trityl chloride (6.66 kg) was added at about 0°C, followed by stirring for 30 minutes, and then stirred at about 25°C for 3.7 hours. A mixed solution of acetonitrile (14.2 kg), water (12.0 L) and 35% hydrochloric acid (0.24 kg) was added at about 40°C, followed by stirring for 30 minutes. Furthermore, a mixed solution of acetonitrile (4.5 kg) and water (23.0 L) was added at about 40°C, cooled to 0°C, and stirred for 13.8 hours. The crystals were separated and washed with a mixture of acetonitrile (29.4 kg) and water (15.0 L). The wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain dry crystals (11.68 kg). The dry crystals (11.6 kg) were added to a mixture of acetonitrile (23.7 kg) and water (12.1 L) and heated at about 75°C for 1 hour. The mixture was cooled to 0°C and stirred for 3.5 hours. The crystals were separated and washed with a mixture of acetonitrile (13 L) and water (7.0 kg). The wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain 4-iodo-3-(propane-2-yl)-1-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyridine.

[0218] (Step 2) 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propyl)-1H-imidazol-1-yl Synthesis of 2-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyridine

[0219] Dimethyl sulfoxide (74.0 kg) and 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole dihydrochloride (5.99 kg) which can be synthesized by referring to the method described in Non-Patent Document 1 (J. Med. Chem. 2019, 62, 531-551) were stirred and dissolved. Furthermore, sodium tert-butoxide (7.73 kg) was added at 25°C and stirred for 10 minutes. Tripotassium phosphate (4.49 kg) was added at about 20°C. 4-iodo-3-(propane-2-yl)-1-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyridine (11.2 kg) was added and stirred at about 125°C for 5.5 hours. The reaction solution was cooled to about 10°C, and a mixed solution of acetonitrile (24.1 kg) and water (3.77 kg) was added and stirred at about 0°C for 2.3 hours. A mixed solution of water (19.0 L) and 35% hydrochloric acid (4.40 kg) was added at about 0°C, and water (120 L) was further added. Stirring was performed at about 5°C for 10.7 hours. Crystals were separated and washed with water (56 L). The entire amount of the obtained wet crystals and water (220 L) were stirred at about 35°C for 1 hour. Crystals were separated and washed with water (170 L). The obtained wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyridine.

[0220] (Step 3) 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propyl)-1H-imidazol-1-yl Synthesis of (2-alkyl)-1H-pyrazolo[3,4-b]pyridine

[0221] Benzyltriethylammonium chloride (2.80 kg), 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1-(triphenylmethyl)-1H-pyrazolo[3,4-b]pyridine (11.2 kg) and water (0.440 kg) were added to acetonitrile (23.0 kg) and stirred. Methanesulfonic acid (7.83 kg) was added at about 40°C, and the mixture was stirred at about 45°C for 1.1 hours. Water (0.661 kg) was further added, and the mixture was stirred at about 45°C for 2.7 hours. The reaction solution was cooled, and water (87.0 L) was added at about 0°C, and the mixture was stirred for 2 hours. Celite (9.00 kg) was added and stirred. The solid was removed by filtration, and the residue was washed with water (100 L) and mixed with the filtrate. The obtained mixed solution was cooled, stirred at about 0°C for 11.9 hours, and filtered. The filtrate was added to an aqueous sodium carbonate solution prepared from water (49.3 L) and sodium carbonate (7.77 kg) at about 20°C, and stirred for 3.1 hours. The crystals were separated and washed with water (45.0 L). The obtained wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain dry crystals (5.42 kg). The obtained dry crystals (4.41 kg) and acetonitrile (35.3 kg) were stirred at about 80°C for 2.1 hours. The mixture was cooled and stirred at about 5°C for 1 hour. The crystals were separated and washed with acetonitrile (11.0 kg). The obtained wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine (4.26 kg).

[0222] (Step 4) Synthesis of Compound 1

[0223] Dimethyl sulfoxide (29.0 kg), 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine (3.91 kg), potassium carbonate (2.11 kg) and 3-ethyl-4-fluorobenzonitrile (5.69 kg) were stirred. The mixture was heated and stirred at about 125°C for 5.5 hours. The reaction solution was cooled, and ethyl acetate (79.5 kg) and water (39.0 L) were added and stirred. The mixture was allowed to stand to separate the organic layer and the aqueous layer. A sodium chloride aqueous solution prepared from sodium chloride (8.80 kg) and water (26.9 L) was added to the organic layer and stirred. The mixture was allowed to stand to separate the organic layer and the aqueous layer. The organic layer was passed through an activated carbon filter plate, and the activated carbon filter plate was washed with ethyl acetate (8.80 kg) and mixed with the filtrate. The filtrate and the washing liquid were mixed, and the obtained mixed liquid was concentrated under reduced pressure to obtain 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile as a concentrated liquid. Dimethyl sulfoxide (29.0 kg) was added to the entire amount of the obtained concentrated liquid and stirred to dissolve. The mixture was cooled, and an aqueous sodium hydroxide solution prepared from sodium hydroxide (0.051 kg) and water (0.330 kg) was added at about 15°C and stirred. A 35% hydrogen peroxide solution (3.71 kg) was added at about 15°C and stirred. Furthermore, an aqueous sodium hydroxide solution prepared from sodium hydroxide (0.025 kg) and water (0.170 kg) was added at about 20°C and stirred. A sodium thiosulfate aqueous solution prepared from sodium thiosulfate pentahydrate (1.39 kg) and water (12.1 L) was added, and the mixture was stirred at about 10° C. for 2 hours. Water (56.2 L) was further added, and the mixture was cooled and stirred at about 10° C. for 16.3 hours. The crystals were separated and washed with water (56.0 L) to obtain a crude compound 1 (13.56 kg) as wet crystals.

[0224] (Step 5) Purification of Compound 1

[0225] The crude compound 1 (13.56 kg) obtained was added to methyl acetate (111 kg) and stirred. Heat to reflux and stir for 10 hours. Cool and stir. Heat to reflux again and stir for 2.6 hours. Cool and stir at about 10°C for 2.9 hours. The crystals were separated and washed with methyl acetate (16.8 kg). The obtained wet crystals were dried under reduced pressure at an external temperature of 80°C to obtain a purified compound 1 (4.38 kg).

[0226] (Step 6) Purification of Compound 1

[0227] Add purified form 1 (4.17 kg) of compound 1 to a mixture of ethanol (59.0 kg) and water (8.30 L) and stir. Heat to dissolve the crystals at about 55°C. Filter the solution, wash with a mixture of ethanol (5.9 kg) and water (0.84 L), and mix the filtrate and the washing liquid. After the obtained mixed solution is concentrated under reduced pressure, add water (58.0 L). Cool and stir at about 20°C for 16 hours. Separate the crystals and wash with water (13.0 L). Dry the obtained wet crystals under reduced pressure at an external temperature of 50°C to obtain purified form 2 (3.98 kg) of compound 1.

[0228] (Step 7) Purification of Compound 1

[0229] Add the purified form 2 (3.00 kg) of compound 1 to a mixture of methyl acetate (22.3 kg) and ethanol (4.75 kg) and stir. Heat to reflux and stir for 6 hours. Add methyl acetate (16.7 kg) under heating to reflux. Cool and stir at about 25°C for 11 hours. Separate the crystals and wash with methyl acetate (8.45 kg). Dry the obtained wet crystals under reduced pressure at an external temperature of 80°C to obtain compound 1 (2.59 kg).

[0230] What you get 1 The data of H-NMR and MS are shown below.

[0231] 1 H-NMR (CDCl3) δ: 8.59 (1H, d, J = 4.8Hz), 7.97 (1H, d, J = 2.0Hz), 7.87 (1H, d, J = 1.3Hz), 7.84~7.75 (3H, m), 7.58 (1H, d, J=8.1Hz), 7.39 (1H, d, J=1.4Hz), 7.14 (1H, d, J=4.9Hz), 6.28 (1H, brs), 5.98 (1H, brs), 3.98 (3H, s), 3.18 (1H, sep, J=6.8Hz), 2.61 (2H, q, J=7.5Hz), 1.25 (6H, d, J=6.8Hz), 1.14 (3H, t, J=7.6Hz)

[0232] HRMS (ESI) m / z: 455.2310 [M+H]+

[0233] [Preparation Example 1] Synthesis of analog 1:

[0234] Analogue 1 was produced by the following production method.

[0235] (Step 1) 3-ethyl-4-[4-iodo-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine- Synthesis of 1-methyl]benzonitrile

[0236] 3-Ethyl-4-fluorobenzonitrile (6.23 g) was stirred with potassium carbonate (2.31 g) and dimethyl sulfoxide (26.8 mL) and heated to 110° C. 4-iodo-3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine (4 g) and dimethyl sulfoxide (0.8 mL) which can be synthesized with reference to Example 100 (1) of International Publication No. 2011 / 004610 were added thereto, and after stirring for 17.5 hours, the mixture was cooled to room temperature. Ethyl acetate (100 mL), water (20 mL) and 20% saline (10 mL) were added, stirred, and the insoluble matter was filtered. After stirring, the aqueous layer was removed to obtain an organic layer 1. Ethyl acetate (90 mL) and water (50 mL) were added to the insoluble matter, stirred, and the insoluble matter was filtered again, and the aqueous layer was removed to obtain an organic layer 2. The organic layer 1 and the organic layer 2 were mixed and concentrated under reduced pressure. The obtained residue was purified by normal phase silica gel column chromatography to obtain 3-ethyl-4-[4-iodo-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzonitrile (yield 2.57 g, yield 44.3%).

[0237] (Step 2) 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-1- 1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzonitrile Synthesis

[0238] 4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (2.22 g) obtained in step 3 of reference example 1 was stirred with 3-ethyl-4-[4-iodo-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzonitrile (2.00 g), potassium carbonate (0.7969 g) and dimethyl sulfoxide (12 mL). The temperature was raised to 130°C and cooled to room temperature after 21 hours. Ethyl acetate (100 mL) and water (50 mL) were added and stirred, and then the insoluble matter was filtered and the water layer was removed. Water (50 mL) was added to the obtained organic layer and stirred, and then the water layer was removed. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by normal phase silica gel chromatography and then by reverse phase chromatography to obtain 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propan-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzonitrile (yield 735.2 mg, yield 25.7%).

[0239] (Step 3) Synthesis of Analogue 1

[0240] Dimethyl sulfoxide (3.25 mL) and sulfolane (1.63 mL) were added to 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzonitrile (650 mg) obtained in step 2, and the mixture was stirred. After cooling to 0°C, 4N sodium hydroxide aqueous solution (27.3 μL) and 30% hydrogen peroxide aqueous solution (334.3 μL) were added, and then 4N sodium hydroxide aqueous solution (27.3 μL) was further added. 10% sodium thiosulfate aqueous solution (812.5 μL) was added, and after the temperature was raised to room temperature, 2N hydrochloric acid (13.5 μL) was added. Add 10% sodium thiosulfate aqueous solution (5.27 mL) and ethyl acetate (10 mL), stir, and separate the organic layer and the aqueous layer. Add ethyl acetate (5 mL) to the aqueous layer, stir, and remove the aqueous layer. Mix the organic layers, add water (5 mL) and stir, and then remove the aqueous layer. After drying the organic layer over sodium sulfate, concentrate under reduced pressure, and purify the resulting residue by normal phase silica gel chromatography. The resulting oily substance is recrystallized from ethanol / water. Filter the crystals and dry under reduced pressure at 50°C to obtain analog 1 (yield 433.3 mg, yield 64.7%).

[0241] What you get 1 The data of H-NMR and MS are shown below.

[0242] 1 H-NMR (CD2Cl2) δ: 8.68 (1H, d, J = 4.5Hz), 8.62 (1H, d, J = 5.0Hz), 7.94 (1H, d, J = 2.0Hz), 7.87 (1H, d, J = 1.5Hz), 7.78-7.80 (3H, m), 7.63 (1H, d, J = 5.0Hz), 7.58 (1H, d, J = 8.0Hz), 7.44 (1H, d, J = 1.5Hz), 7.26 (1H, d, J=5.0Hz), 6.35 (1H, brs), 5.82 (1H, brs), 3.94 (3H, s), 3.67 (1H, sep, J=7.0Hz), 3.26 (1H, sep , J=6.5Hz), 2.65 (2H, q, J=7.5Hz), 1.29 (6H, d, J=7.0Hz), 1.13 (3H, t, J=7.5Hz), 1.12 (6H, d, J=6.5Hz)

[0243] HRMS (ESI) m / z: 614.3095 [M+H]+

[0244] [Preparation Example 2] Synthesis of Analogue 2:

[0245] Dimethyl sulfoxide (18.63 mL) and sulfolane (9.31 mL) were added to commercially available 3-ethyl-4-fluorobenzonitrile (1.5016 g) and stirred. After cooling to 0°C, 4N sodium hydroxide aqueous solution (1.383 mL) and 30% hydrogen peroxide aqueous solution (1.392 mL) were added and stirred at 0°C for 1 hour. 10% sodium thiosulfate aqueous solution (10 mL) was added, and after stirring at room temperature, water (24 mL) was added and stirred at room temperature. The precipitate was filtered and washed with water. It was dried under reduced pressure to obtain analogue 2 (yield 1.1984 g, yield 71.3%).

[0246] What you get 1 The data of H-NMR and MS are shown below.

[0247] 1 H-NMR (CDCl3) δ: 7.73 (1H, dd, J=2.0, 7.2Hz), 7.62 (1H, ddd, J=2.4, 4.8, 8.4Hz), 7.06 (1H, dd, J=, 8.8, 9.2Hz), 5.95 (2H, brs), 2.71 (2H, q, J=7.6Hz), 1.25 (3H, t, J=7.6Hz)

[0248] LRMS (ESI) m / z: 168.2 [M+H]+

[0249] [Example 1] Analogue 1 as a standard

[0250] Accurately weigh about 25 mg of compound 1 obtained in the above reference example 1, add 0.01 mol / l phosphate buffer (pH3.5) / acetonitrile mixture (1:1) to dissolve, and accurately set to 100 mL as a sample solution. Accurately measure 1 mL of the solution, add 0.01 mol / L phosphate buffer (pH3.5) / acetonitrile mixture (1:1), and accurately set to 100 mL as a standard solution. Accurately measure 10 μL of each sample solution and standard solution, and test by liquid chromatography under the following conditions. The peak areas AT of each peak other than compound 1 of the sample solution and the peak area AS of compound 1 of the standard solution are determined by automatic integration and calculated by the following formula.

[0251] Amount of each analog (%) = AT × RF / AS

[0252] Total amount of analogs (%) = sum of the amounts of individual analogs (%)

[0253] RF: Sensitivity correction factor

[0254] Test conditions

[0255] Detector: UV spectrophotometer (measurement wavelength: 220nm)

[0256] Chromatographic column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm was filled with 5 μm octadecylsilylated silica gel for liquid chromatography [InertSustain C18 (GL Sciences Co., Ltd.) or an equivalent product].

[0257] Column temperature: fixed at 40°C

[0258] Mobile phase

[0259] Mobile phase A: 0.01 mol / L phosphate buffer (pH 3.5) / acetonitrile mixture (9:1)

[0260] Mobile phase B: acetonitrile / 0.01 mol / L phosphate buffer (pH 3.5) mixture (7:3)

[0261] Delivery of mobile phase: The mixing ratio of mobile phase A and B was changed as follows to control the concentration gradient.

[0262]

[0263] Flow rate: 1.0 mL per minute

[0264] Area measurement range: 40 minutes after sample solution injection

[0265] System suitability

[0266] Detection confirmation: Accurately weigh 1 mL of the standard solution and add 0.01 mol / L phosphate buffer (pH 3.5) / acetonitrile mixture (1:1) to accurately set to 20 mL. Confirm that the peak area of ​​compound 1 obtained from 10 μL of this solution is 3.5-6.5% of the peak area of ​​compound 1 in the standard solution.

[0267] System performance: When the above conditions are used for every 10 μL of the standard solution, the theoretical order and symmetry coefficient of the peak of compound 1 are greater than 6000 and less than 1.5, respectively.

[0268] Reproducibility of the system: When the test was repeated 6 times under the above conditions for each 10 μL of the standard solution, the relative standard deviation of the peak area of ​​Compound 1 was less than 2.0%.

[0269] Compound 1 obtained in the above Reference Example 1 was measured by HPLC using the above method.

[0270] The results are expressed in Figure 1 As a result, it was confirmed that the standard product of analogue 1 ( Figure 2) shows the same retention time peak. In addition, for the standard substance ( Figure 2 ) shows the peaks with the same retention time obtained for the analogs and the standard of analog 1 ( Figure 2 )Implementation 1 As a result of H-NMR measurement, it was confirmed that they were the same components.

[0271] Therefore, it was found that analog 1 is useful as a standard for confirming the quality of the API of compound 1. Figure 1 As a result, it was confirmed that the content of analog 1 in compound 1 was 0.3% or less.

[0272] In addition, a film-coated tablet having the composition shown in Table 2 and containing Compound 1 obtained by the same method as Reference Example 1 was prepared, and the content of Analogue 1 was measured to confirm that it was 0.3% or less.

[0273] [Table 2]

[0274]

[0275] [Example 2] Analogue 2 as a standard

[0276] The compound 1 obtained in the above-mentioned reference example 1 was measured by HPLC using the method described in Example 1 ( Figure 1 ), the results confirmed that the standard of analogue 2 ( Figure 3 ) show peaks with the same retention time.

[0277] Therefore, it was found that analog 2 is useful as a standard for confirming the quality of the API of compound 1. Figure 1 As a result, it was confirmed that the content of analogue 2 in compound 1 was 0.1% or less. In addition, the content of analogues other than analogues 1 and 2 was 0.1% or less.

[0278] Film-coated tablets of the composition shown in Table 2 were prepared containing Compound 1 obtained by the same method as Reference Example 1, and the content of Analog 2 was measured to be 0.1% or less. The content of analogs other than Analogs 1 and 2 was 0.1% or less.

Claims

1. Any one of the analogs or salts thereof described in 1 to 9 below, or a combination thereof, It is used as a standard substance for managing the quality of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof. Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide; Analog 2: 3-ethyl-4-fluorobenzamide; Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide; Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide; Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide); Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile; Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide; Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide; Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide.

2. The analogue or salt thereof, or a combination thereof according to claim 1, characterized in that: The analog used as the standard is any one of the analogs 1 to 7.

3. The analogue or salt thereof, or a combination thereof according to claim 1, characterized in that: The analog used as the standard substance is any one of the analogs 1 to 3.

4. The analogue or salt thereof, or a combination thereof according to claim 1, characterized in that: The analog used as the standard is any one of the analogs 1 to 2.

5. The analogue or salt thereof, or a combination thereof according to claim 1, characterized in that: The analog used as the standard was Analog 1.

6. A pharmaceutical composition for oral administration, characterized in that: Containing 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof as an active ingredient, the total content of the following analogs 1 to 9 is 1.0% or less, Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide; Analog 2: 3-ethyl-4-fluorobenzamide; Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide; Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide; Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide); Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile; Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide; Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide; Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide.

7. The pharmaceutical composition for oral administration according to claim 6, wherein: The content of the analogue 1 is less than 0.30%, and the content of each of the analogues 2 to 9 is less than 0.10%.

8. A pharmaceutical composition for oral administration, characterized in that: The composition comprises 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide as an active ingredient, and the content of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propan-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridin]-1'-yl}benzamide as analogue 1 is 0.30% or less.

9. A pharmaceutical preparation for oral administration, characterized in that: The pharmaceutical composition for oral administration according to any one of claims 6 to 8.

10. 3-Ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propan-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide or a salt thereof.

11. 3-Ethyl-4-fluorobenzamide or its salts.

12. N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof. 13.3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide or a salt thereof.

14. 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide) or a salt thereof.

15. 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile or a salt thereof.

16. 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide or a salt thereof.

17. 4-[4-Ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide or a salt thereof.

18. 3-Ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide or a salt thereof.

19. Use of any one of the analogs or salts thereof described in 1 to 9 below, or a combination thereof, as a standard substance for managing the quality of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof, Analog 1: 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3,3'-di(propane-2-yl)-1'H-[1,4'-bipyrazolo[3,4-b]pyridine]-1'-yl}benzamide; Analog 2: 3-ethyl-4-fluorobenzamide; Analog 3: N-[1-(4-carbamoyl-2-ethylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide; Analog 4: 3-ethyl-4-{1 4 -[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1 3 , 2 3 , 3 3 -Tri(propane-2-yl)-3 1 H-[1 1 , 2 4 :2 1 , 3 4 -terpyrazolo[3,4-b]pyridine]-3 1 -yl}benzamide; Analog 5: 4,4'-(1H,1'H-[4,4'-biimidazole]-1,1'-diylbis{[3-(propane-2-yl)-1H-pyrazolo[3,4-b]pyridine-4,1-diyl]})bis(3-ethylbenzamide); Analog 6: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzonitrile; Analog 7: 4-{4,6-bis[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-ethylbenzamide; Analog 8: 4-[4-ethoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]-3-ethylbenzamide; Analog 9: 3-ethyl-4-[4-methoxy-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide.

20. The use according to claim 19, characterized in that: The analog is any analog of Analogs 1 to 7.

21. The use according to claim 19, characterized in that: The analog is any analog of Analogs 1 to 3.

22. The use according to claim 19, characterized in that: The analog is any analog of the analogs 1 to 2.

23. The use according to claim 19, characterized in that: The analog is analog 1.

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