Salts of 2-methyl-2-thiazoline

Abstract

Provided is a solid derivative of 2-methyl-2-thiazoline, which is easy to handle when made into a formulation and is useful as a pharmaceutical raw material. The present invention provides a 1, 5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline, or a deuterated product thereof, a pharmaceutical composition containing the same, a preparation for preventing or treating hypoxic injury, ischemia-reperfusion injury, or inflammation, and a method for producing the 1, 5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline, or the deuterated product thereof.

Description

Technical Field

[0001] The present invention relates to a salt of 2-methyl-2-thiazoline useful as a drug, for example, an agent for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation, and a method for producing the same. Background Art

[0002] 2-Methyl-2-thiazoline (hereinafter sometimes referred to as "2-MT") represented by formula (I) is a compound useful as a drug, for example, an agent for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation (Patent Document 1).

[0003] [Chemistry 1]

[0004] However, 2-MT is a highly volatile liquid with a pungent odor, so it is difficult to handle when formulating. In addition, it is difficult to accurately measure the weight of 2-MT when weighing. Prior art literature Patent Literature Patent Document 1: International Publication No. 2019 / 177142 Summary of the invention Problem that the invention aims to solve

[0006] An object of the present invention is to provide a solid derivative of 2-MT which is easy to handle during formulation and is useful as a pharmaceutical raw material. Means to solve problems

[0007] The present inventors have conducted intensive studies to solve the above problems and have found that a salt of 2-MT and 1,5-naphthalene disulfonic acid (hereinafter referred to as "NDSA") or saccharin can be prepared as a solid having excellent handleability and stability for use as a pharmaceutical raw material, thereby completing the present invention.

[0008] It is known that deuterated compounds that replace the CH bonds at the metabolic sites of drug molecules with more stable CD bonds can delay metabolism due to the deuterium isotope effect and are difficult to decompose, while having little effect on the overall properties of the molecule and maintaining biological activity. According to the present invention, a deuterated product of NDSA salt or saccharin salt of 2-MT is provided.

[0009] That is, the present invention relates to the following. [1] 1,5-naphthalene disulfonate or saccharinate of 2-methyl-2-thiazoline or a deuterated salt thereof. [2] The salt according to [1], which is 1,5-naphthalene disulfonate or saccharinate of 2-methyl-2-thiazoline. [3] The salt according to [1] or [2], which is a crystal. [4] The salt according to [1], which is 1,5-naphthalene disulfonate of 2-methyl-2-thiazoline or a deuterated salt thereof. [5] The salt according to [4], which is 2-methyl-2-thiazoline hemi-1,5-naphthalenedisulfonate or a deuterated salt thereof. [6] The salt according to [5], which is a hydrate of 2-methyl-2-thiazoline hemi-1,5-naphthalenedisulfonate. [7] The salt according to [5] or [6], which is a crystal. [8] The salt according to [7], which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 17.2±0.2°, 17.9±0.2°, 18.7±0.2° and 22.6±0.2°. [9] The salt according to [7], which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 11.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 20.1±0.2°, 22.6±0.2° and 23.9±0.2°. [9A] The salt according to any one of [5] to [9], which has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 218°C±3°C, preferably 218°C±1°C in differential scanning calorimetry (DSC). [9B] The salt according to [9A], further having an endothermic peak with an extrapolated onset temperature (Onset temperature) of 108°C±3°C, preferably 108°C±1°C in differential scanning calorimetry (DSC).

[10] The salt according to [4], which is 2-methyl-2-thiazoline mono-1,5-naphthalene disulfonate or a deuterated salt thereof.

[11] The salt according to

[10] , which is a hydrate of mono-1,5-naphthalene disulfonate of 2-methyl-2-thiazoline.

[12] The salt according to

[10] or

[11] , which is a crystal.

[13] The salt according to

[12] , which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 18.5±0.2°, 22.6±0.2°, 22.9±0.2° and 23.4±0.2°.

[14] The salt according to

[12] , which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 11.9±0.2°, 14.4±0.2°, 18.5±0.2°, 22.6±0.2°, 22.9±0.2° and 23.4±0.2°. [14A] The salt according to any one of

[10] to

[14] , which has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 268°C±3°C, preferably 268°C±1°C in thermogravimetric / differential thermal analysis (TG / DTA). [14B] The salt described in [14A] further has endothermic peaks with extrapolated onset temperatures (Onset temperatures) of 115°C±3°C and 142°C±3°C, preferably 115°C±1°C and 142°C±1°C in thermogravimetric / differential thermal analysis (TG / DTA). [14C] The salt according to any one of [4] to

[14] , [9A], [9B], [14A] and [14B], wherein the purity of 1,5-naphthalene disulfonate of 2-methyl-2-thiazoline is 95% or more, preferably 97% or more, more preferably 98% or more, and even more preferably 99% or more.

[15] The salt according to [1], which is a saccharinate salt of 2-methyl-2-thiazoline or a deuterated salt thereof.

[16] The salt according to

[15] , which is a monosaccharide salt of 2-methyl-2-thiazoline or a deuterated salt thereof.

[17] The salt according to

[16] , which is an anhydrate of the monosaccharide salt of 2-methyl-2-thiazoline.

[18] The salt according to

[16] or

[17] , which is a crystal.

[19] The salt according to

[18] , which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 19.9±0.2° and 26.2±0.2°.

[20] The salt according to

[18] , which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 14.7±0.2°, 19.9±0.2°, 26.2±0.2° and 29.3±0.2°. [20A] The salt according to any one of

[15] to

[20] , which has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 131°C±3°C, preferably 131°C±1°C in thermogravimetric / differential thermal analysis (TG / DTA). [20B] The salt according to any one of

[15] to

[20] and [20A], wherein the purity of the saccharin salt of 2-methyl-2-thiazoline is 95% or more, preferably 97% or more, more preferably 98% or more, and even more preferably 99% or more.

[21] The deuterated compound according to [1], which is represented by formula (1) or formula (2).

[0010] Formula (1) [Chemistry 2]

[0011] Formula (2)

[0012] [Chemistry 3]

[0013]

[22] The deuterated compound according to [1], which is represented by formula (3).

[0014] Formula (3) [Chemistry 4]

[0015]

[23] A pharmaceutical composition comprising the salt or deuterated product thereof according to any one of [1] to

[22] and a pharmaceutically acceptable carrier.

[24] A preparation for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation, comprising the salt or deuterated form thereof according to any one of [1] to

[22] . [24A] The salt or deuterated product thereof according to any one of [1] to

[22] for use in preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation. [24B] Use of the salt according to any one of [1] to

[22] or a deuterated product thereof for the manufacture of a preparation for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation. [24C] A method for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation in a mammal, comprising administering to the mammal an effective amount of the salt according to any one of [1] to

[22] or a deuterated form thereof.

[25] A method for producing 1,5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline, which comprises mixing 2-methyl-2-thiazoline, 1,5-naphthalene disulfonic acid or saccharin and a solvent, and isolating the obtained solid of 1,5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline.

[26] A method for producing a deuterated saccharinate of 2-methyl-2-thiazoline, comprising mixing a saccharinate of 2-methyl-2-thiazoline and deuterated methanol, and isolating the deuterated saccharinate of 2-methyl-2-thiazoline.

[27] A method for producing a deuterated compound represented by formula (1) or (2), comprising mixing a deuterated compound of 2-methyl-d3-2-thiazoline and 1,5-naphthalene disulfonic acid in a solvent to produce a deuterated compound represented by formula (1) or (2). Formula (1)

[0016] [Chemistry 5]

[0017] Formula (2)

[0018] [Chemistry 6]

[28] A method for producing a deuterated compound represented by formula (3), comprising mixing a saccharinate salt of 2-methyl-2-thiazoline and deuterated methanol to produce the deuterated compound represented by formula (3). Formula (3)

[0020] [Chemistry 7]

[0021] Effects of the Invention

[0022] According to the present invention, a solid 2-MT salt having excellent handling and stability as a raw material drug of a medicine can be provided, and in particular, it is a crystalline salt. The 2-MT salt of the present invention has high storage stability and is stable even when stored under high humidity. In addition, since the 2-MT salt of the present invention is solid, the weight of the salt can be easily and accurately measured when weighing. The 2-MT salt of the present invention is useful as a raw material drug of a medicine.

[0023] The deuterated compound of the present invention can delay metabolism through the deuterium isotope effect, is difficult to be decomposed, and can maintain biological activity at the same time, because the CH bond is replaced by a more stable CD bond. Therefore, when used as a drug, the dosage and the number of administrations can be reduced, and the side effects are easily controlled. In addition, the deuterated compound can be used as a tracer or internal standard substance for biological analysis (such as drug dynamic analysis, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0024] [ Figure 1 ]X-ray powder diffraction (XRPD) pattern of the half-NDSA salt of 2-MT prepared in Example 1. [ Figure 2 ] The half NDSA salt of 2-MT prepared in Example 1 1 H-NMR spectrum (CD3OD). [ Figure 3 ] Comparison of the 2-MT·half NDSA salt prepared in Example 1 with the raw material 1 H-NMR spectrum (CD3OD). [ Figure 4 ] The half NDSA salt of 2-MT prepared in Example 1 13 C-NMR spectrum (CD3OD). [ Figure 5 ] The stability of the half NDSA salt of 2-MT prepared in Example 1 before and after the test 1H-NMR spectrum (CD3OD). [ Figure 6 ]Microscope photos of NDSA and 2-MT·half-NDSA salt (the numbers on the left indicate the magnification). [ Figure 7 ]Differential scanning calorimetry (DSC) chart of 2-MT·half-NDSA salt. [ Figure 8 ] XRPD spectra of NDSA (the first one), 2-MT·half NDSA salt (the second one), 2-MT·half NDSA salt after storage at room temperature for 7 days (the third one), and 2-MT·half NDSA salt after storage at 40℃ / 75% relative humidity for 7 days (the fourth one). [ Fig. 9 ]XRPD pattern of the mono-NDSA salt of 2-MT prepared in Example 2. [ Fig.10 ] The mono-NDSA salt of 2-MT prepared in Example 2 1 H-NMR spectrum (D2O). [ Fig.11 ] Thermogravimetric / differential thermal analysis (TG / DTA) thermogram of the mono-NDSA salt of 2-MT prepared in Example 2 (30-300°C, 10°C / min). [ Fig.12 ]XRPD pattern of the monosaccharide salt of 2-MT produced in Example 3. [ Fig.13 ]Compare the XRPD spectra of the monosaccharide salt of 2-MT produced in Example 3 and the raw material (saccharin). [ Fig.14 ] The monosaccharide salt of 2-MT produced in Example 3 1 H-NMR spectrum (D2O). [ Fig.15 ]TG / DTA thermogram of the monosaccharide salt of 2-MT produced in Example 3 (30-300°C, 10°C / min). [ Fig.16 ] The deuterated product of the monosaccharide salt of 2-MT prepared in Example 4 and the monosaccharide salt of 2-MT before deuteration 1 H-NMR spectrum (DMF-d7). [ Fig.17 ] The deuterated product of the monosaccharide salt of 2-MT prepared in Example 4 and the monosaccharide salt of 2-MT before deuteration 13 C-NMR spectrum (DMF-d7). [ Fig.18 ] The deuterated 2-MT (2-methyl-d3-2-thiazoline) prepared in Example 5 (1) and the protium 2-MT 1H-NMR spectrum (CDCl3). [ Fig.19 ] The deuterated 2-MT (2-methyl-d3-2-thiazoline) prepared in Example 5 (1) 13 C-NMR spectrum (DMF-d7). [ Fig. 20 ] The deuterated mono-NDSA salt of 2-MT prepared in Example 5 (2) and the half-NDSA salt of 2-MT 1 H-NMR spectrum (DMF-d7). [ Fig.21 ] The deuterated half NDSA salt of 2-MT prepared in Example 5 (2) and the half NDSA salt of 2-MT 1 H-NMR spectrum (DMF-d7). [ Fig. 22 ] The deuterated half NDSA salt of 2-MT prepared in Example 5 (2) and the half NDSA salt of 2-MT 13 C-NMR spectrum (DMF-d7). DETAILED DESCRIPTION

[0025] The present invention relates to a NDSA salt or saccharin salt of 2-MT.

[0026] [Chemistry 8]

[0027] Saccharin is a compound represented by the above formula.

[0028] The salt of the present invention is a solvate, for example, it can also be a hydrate. Examples of hydrates include: 0.5 hydrate, monohydrate, dihydrate, trihydrate, etc. In addition, the salt of the present invention can also be an anhydrate. In this specification, an anhydrate refers to a water content of 1.5 weight % or less, preferably 1 weight % or less based on Karl-Fischer method, differential scanning calorimetry (DSC) or thermogravimetric differential thermal analysis (TG / DTA).

[0029] In the salt of the present invention, the molar ratio of 2-MT:NDSA or saccharin is, for example, 2:1 to 1:2, and examples thereof include 2:1 and 1:1. The salts of the present invention may also be crystalline.

[0030] In one embodiment of the present invention, a NDSA salt of 2-MT is provided. In one embodiment of the present invention, the salt of the present invention is preferably a half NDSA salt of 2-MT or a mono NDSA salt of 2-MT. Half NDSA salt means a 1 / 2 NDSA salt, which means a salt having a molar ratio of 2-MT: NDSA of about 2:1. Mono NDSA salt means a salt having a molar ratio of 2-MT: NDSA of about 1:1. In one embodiment of the present invention, the salt of the present invention is preferably a hydrate of a half NDSA salt of 2-MT or a hydrate of a mono NDSA salt of 2-MT. Examples of hydrates include: 0.5 hydrate, monohydrate, dihydrate, trihydrate, etc. Preferred examples of the salt of the present invention include: a half NDSA salt monohydrate of 2-MT, a mono NDSA salt dihydrate of 2-MT, etc. The NDSA salt of 2-MT (including the half-NDSA salt of 2-MT, the hydrate of the half-NDSA salt of 2-MT, the mono-NDSA salt of 2-MT and the hydrate of the mono-NDSA salt of 2-MT) ​​may also be crystalline.

[0031] In one embodiment of the present invention, the half-NDSA salt of 2-MT preferably has an X-ray powder diffraction (XRPD) pattern having peaks at 2θ values ​​of 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, and 22.6±0.2°.

[0032] In one embodiment of the present invention, the half-NDSA salt of 2-MT more preferably has an XRPD pattern having peaks at 2θ values ​​of 11.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 20.1±0.2°, 22.6±0.2° and 23.9±0.2°.

[0033] In one embodiment of the present invention, the half-NDSA salt of 2-MT further preferably has an XRPD pattern having peaks at 2θ values ​​of 11.6±0.2°, 13.6±0.2°, 14.7±0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 20.1±0.2°, 22.6±0.2°, 22.7±0.2°, 23.9±0.2°, 27.5±0.2° and 28.2±0.2°.

[0034] In one embodiment of the present invention, the half NDSA salt of 2-MT is further preferably actually Figure 1 XRPD pattern shown.

[0035] In one embodiment of the present invention, the half NDSA salt of 2-MT is characterized in that it preferably has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 218°C ± 3°C, more preferably 218°C ± 1°C in differential scanning calorimetry (DSC). The peak temperature of the endothermic peak is preferably 222°C ± 3°C, more preferably 222°C ± 1°C.

[0036] In one embodiment of the present invention, the half NDSA salt of 2-MT is characterized in that it preferably further has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 108°C ± 3°C, more preferably 108°C ± 1°C in differential scanning calorimetry (DSC). The peak temperature of the endothermic peak is preferably 132°C ± 3°C, more preferably 132°C ± 1°C.

[0037] In one embodiment of the present invention, the half NDSA salt of 2-MT is characterized in that it is further preferred that it actually has Figure 7 DSC chart shown.

[0038] In one embodiment of the present invention, the mono-NDSA salt of 2-MT preferably has an X-ray powder diffraction (XRPD) pattern having peaks at 2θ values ​​of 18.5±0.2°, 22.6±0.2°, 22.9±0.2°, and 23.4±0.2°.

[0039] In one embodiment of the present invention, the mono-NDSA salt of 2-MT more preferably has an XRPD pattern having peaks at 2θ values ​​of 11.9±0.2°, 14.4±0.2°, 18.5±0.2°, 22.6±0.2°, 22.9±0.2° and 23.4±0.2°.

[0040] In one embodiment of the present invention, the mono-NDSA salt of 2-MT further preferably has an XRPD pattern having peaks at 11.9±0.2°, 14.4±0.2°, 14.9±0.2°, 15.3±0.2°, 17.2±0.2°, 18.5±0.2°, 19.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.4±0.2° and 24.0±0.2°.

[0041] In one embodiment of the present invention, the mono-NDSA salt of 2-MT is further preferably actually Fig. 9 XRPD pattern shown.

[0042] In one embodiment of the present invention, the mono-NDSA salt of 2-MT is characterized in that it preferably further has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 268°C ± 3°C, more preferably 268°C ± 1°C in thermogravimetric differential thermal analysis (TG / DTA). The peak temperature of the endothermic peak is preferably 279°C ± 3°C, more preferably 279°C ± 1°C.

[0043] In one embodiment of the present invention, the mono-NDSA salt of 2-MT is characterized in that it preferably further has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 115°C ± 3°C and 142°C ± 3°C, more preferably 115°C ± 1°C and 142°C ± 1°C in thermogravimetric differential thermal analysis (TG / DTA). The peak temperature of the endothermic peak is preferably 122°C ± 3°C and 157°C ± 3°C, more preferably 122°C ± 1°C and 157°C ± 1°C.

[0044] In one embodiment of the present invention, the mono-NDSA salt of 2-MT is characterized in that it is further preferred that it actually has Fig.11 TG / DTA thermogram shown.

[0045] The purity of the NDSA salt of 2-MT (including half-NDSA salt and mono-NDSA salt) is preferably 95% or more, more preferably 97% or more, further preferably 98% or more, and particularly preferably 99% or more.

[0046] In this specification, unless otherwise specified in terms of purity, 1 The purity was obtained by quantitative analysis using H-NMR (proton nuclear magnetic resonance).

[0047] In one embodiment of the present invention, saccharin salt of 2-MT is provided. In one embodiment of the present invention, the salt of the present invention is preferably a monosaccharin salt of 2-MT. The monosaccharin salt is a salt having a molar ratio of 2-MT:saccharin of about 1:1. In one embodiment of the present invention, the salt of the present invention is preferably an anhydrate of 2-MT monosaccharide salt. The saccharinate salt of 2-MT (including the monosaccharinate salt of 2-MT and the anhydrate of the monosaccharinate salt of 2-MT) ​​may also be crystalline.

[0048] In one embodiment of the present invention, the monosaccharide salt of 2-MT preferably has an X-ray powder diffraction (XRPD) pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 19.9±0.2° and 26.2±0.2°.

[0049] In one embodiment of the present invention, the monosaccharide salt of 2-MT more preferably has an XRPD pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 14.7±0.2°, 19.9±0.2°, 26.2±0.2° and 29.3±0.2°.

[0050] In one embodiment of the present invention, the monosaccharide salt of 2-MT further preferably has an XRPD pattern having peaks at 2θ values ​​of 6.8±0.2°, 12.8±0.2°, 13.8±0.2°, 14.7±0.2°, 16.6±0.2°, 19.0±0.2°, 19.9±0.2°, 20.7±0.2°, 25.7±0.2°, 26.2±0.2° and 29.3±0.2°.

[0051] In one embodiment of the present invention, the monosaccharide refined salt of 2-MT is further preferably actually Fig.12 XRPD pattern shown.

[0052] In one embodiment of the present invention, the monosaccharide refined salt of 2-MT is characterized in that it preferably further has an endothermic peak with an extrapolated onset temperature (Onset temperature) of 131°C ± 3°C, more preferably 131°C ± 1°C in thermogravimetric differential thermal analysis (TG / DTA). The peak temperature of the endothermic peak is preferably 134°C ± 3°C, more preferably 134°C ± 1°C.

[0053] In one embodiment of the present invention, the monosaccharide refined salt of 2-MT is characterized in that it is further preferred that it actually has Fig.15 TG / DTA thermogram shown.

[0054] The purity of saccharinate of 2-MT (including monosaccharinate) is preferably 95% or more, more preferably 97% or more, further preferably 98% or more, and particularly preferably 99% or more.

[0055] Deuteride The present invention also provides a deuterated product of NDSA salt or saccharin salt of 2-MT. The term "deuterated product" refers to a product in which at least one hydrogen (H) in the molecule is replaced by deuterium (denoted by 2 The deuteration rate of the deuterated product is preferably 90% or more, more preferably 95% or more, and further preferably 98% or more. The deuteration rate can be calculated by the following method. 1 The CHD2 abundance ratio was calculated from the integrated values ​​of the peaks corresponding to the methyl group of 2-MT before and after deuteration in the H-NMR spectrum, and the deuteration rate was calculated from the CHD2 abundance ratio.

[0056] The deuterated NDSA salt or saccharin salt of 2-MT is preferably a deuterated NDSA salt or deuterated saccharin salt of 2-methyl-d3-2-thiazoline in which the methyl group of 2-MT is substituted with a CD3 group. Preferred examples of the deuterated compound include deuterated compounds represented by the following formula (1), (2) or (3) or deuterated hydrates thereof.

[0057] [Chemistry 9]

[0058] [Chemistry 10] [Chemistry 11] Manufacturing method The salt of the present invention can be produced, for example, by mixing 2-methyl-2-thiazoline, 1,5-naphthalene disulfonic acid or saccharin and a solvent. The obtained solid can be isolated by known separation means such as filtration, centrifugation, crystallization, and recrystallization.

[0061] Commercially available 2-methyl-2-thiazoline, 1,5-naphthalene disulfonic acid, and saccharin can be used.

[0062] 1,5-naphthalenedisulfonic acid may be in the form of a hydrate, a potassium salt, a sodium salt, a calcium salt, etc. Examples thereof include 1,5-naphthalenedisulfonic acid tetrahydrate and 1,5-naphthalenedisulfonic acid disodium dihydrate.

[0063] Saccharin may be in the form of a hydrate, potassium salt, sodium salt, calcium salt, etc. Examples thereof include saccharin potassium, saccharin sodium, saccharin calcium, and the like.

[0064] Examples of the solvent include tetrahydrofuran, acetonitrile, ethanol, isopropanol, acetone, water, and mixtures thereof, but the solvent is not limited thereto.

[0065] In the embodiment of the present invention, a mixture of an organic solvent such as tetrahydrofuran, acetonitrile, ethanol, isopropanol, acetone and water can be used as the solvent. The water content in the solvent is preferably 5 to 30% v / v, more preferably 10 to 20% v / v.

[0066] When producing 1,5-naphthalene disulfonate, tetrahydrofuran, acetonitrile, a mixture of tetrahydrofuran and water, a mixture of acetonitrile and water, etc. can be preferably used as a solvent, and a mixture of tetrahydrofuran and water or a mixture of acetonitrile and water is more preferably used. The content of water in the solvent is preferably 5 to 30% v / v, more preferably 10 to 20% v / v.

[0067] When producing saccharin salt, acetonitrile, tetrahydrofuran, etc. can be preferably used as a solvent, and acetonitrile is more preferably used.

[0068] The volume of the solvent is not particularly limited, and the concentration of 2-MT in the solvent can be preferably 0.01 to 3 M, more preferably 0.05 to 2 M, and further preferably 0.3 to 1.5 M.

[0069] The mixing ratio of 2-MT and 1,5-naphthalene disulfonic acid or saccharin is preferably 0.1 to 5 mol, more preferably 0.3 to 3 mol, further preferably 0.5 to 2 mol, particularly preferably 0.5 to 1 mol, per 1 mol of 2-MT.

[0070] After mixing 2-methyl-2-thiazoline, 1,5-naphthalenedisulfonic acid or saccharin and a solvent, the mixture is preferably allowed to stand or stir. The temperature at which the mixture is allowed to stand or stir is not particularly limited, but is preferably -5°C to 35°C, more preferably 0°C to 30°C, and further preferably 5°C to 25°C. The time for which the mixture is allowed to stand or stir is not particularly limited, but is preferably 30 minutes to 2 days, and more preferably 1 to 24 hours.

[0071] Method for producing deuterated compounds (1) The deuterated product of saccharinate of 2-MT can be produced by, for example, mixing saccharinate of 2-MT and deuterated methanol and isolating the obtained deuterated product.

[0072] The volume of deuterated methanol used as a solvent is not particularly limited, and a volume such that the concentration of NDSA salt or saccharinate salt of 2-MT is preferably 30 to 300 mg / mL, more preferably 50 to 200 mg / mL, and further preferably 80 to 150 mg / mL can be used.

[0073] After mixing 2-MT saccharin salt and deuterated methanol, the mixture is preferably stirred. The temperature of the stirred mixture is not particularly limited, but is preferably 30 to 63° C., more preferably 40 to 63° C., and further preferably 50 to 60° C. The time for stirring the mixture is not particularly limited, but is preferably 30 minutes to 2 days, and more preferably 1 to 24 hours.

[0074] The obtained deuterated product can be isolated, for example, by distilling off the solvent from the reaction mixture, washing the obtained solid with an appropriate solvent (e.g., acetonitrile), and drying it under reduced pressure. The reduced pressure drying is preferably carried out at room temperature (about 15° C. to about 35° C.). The obtained deuterated product can also be isolated by known separation means such as filtration, centrifugation, crystallization, and recrystallization.

[0075] As the 2-MT saccharin salt, the 2-MT saccharin salt produced by the above-mentioned production method was used.

[0076] Method for producing deuterated compounds (2) The deuterated NDSA salt or saccharin salt of 2-MT can be produced, for example, by mixing the deuterated 2-MT (2-methyl-d3-thiazoline) and the deuterated NDSA or saccharin in a solvent.

[0077] As the solvent, tetrahydrofuran, acetonitrile, etc. can be preferably used, and tetrahydrofuran is more preferably used. Alternatively, deuterated methanol can be used as the solvent.

[0078] The volume of the solvent is not particularly limited, and the concentration of the deuterated 2-MT in the solvent can be preferably 20 to 300 mg / mL, more preferably 30 to 200 mg / mL, and even more preferably 40 to 150 mg / mL.

[0079] The mixing ratio of the deuterated 2-MT and the deuterated NDSA or saccharin is preferably 0.1 to 5 mol, more preferably 0.3 to 3 mol, further preferably 0.5 to 2 mol, and particularly preferably 0.5 to 1 mol of the deuterated NDSA or saccharin per 1 mol of the deuterated 2-MT.

[0080] Preferably, the deuterated form of 2-MT, the deuterated form of NDSA or saccharin and the solvent are mixed and then the mixture is stirred. The temperature at which the mixture is stirred is not particularly limited, but is preferably -5°C to 35°C, more preferably 0°C to 30°C, and further preferably 5°C to 25°C. The time for stirring the mixture is not particularly limited, but is preferably 30 minutes to 2 days, and more preferably 1 to 24 hours.

[0081] The obtained deuterated product can be isolated, for example, by distilling off the solvent from the reaction mixture, washing the obtained solid with an appropriate solvent (e.g., tetrahydrofuran), and drying it under reduced pressure. The reduced pressure drying is preferably carried out at room temperature (about 15° C. to about 35° C.). The obtained deuterated product can also be isolated by known separation means such as filtration, centrifugation, crystallization, and recrystallization.

[0082] When producing the deuterated mono-NDSA salt of 2-MT, the deuterated mono-NDSA salt of 2-MT can be further added with the deuterated mono-NDSA salt of 2-MT, and the mixture is mixed in a solvent to produce the deuterated mono-NDSA salt of 2-MT. As the solvent, tetrahydrofuran, acetonitrile, etc. are preferably used, and tetrahydrofuran is more preferably used. Alternatively, deuterated methanol can be used as the solvent.

[0083] The deuterated product of 2-MT (2-methyl-d3-thiazoline) can be prepared, for example, by reacting a deuterated product of 2-aminoethanethiol hydrochloride (DS-CH2-CH2-ND2·DCl) with deuterated acetonitrile in the presence of sodium deuteride according to the method described in Example 5 (1) described later. The deuterated product of 2-aminoethanethiol hydrochloride (DS-CH2-CH2-ND2·DCl) can be prepared, for example, by mixing 2-aminoethanethiol hydrochloride with heavy water according to the method described in Example 5 (1) described later.

[0084] The deuterated product of NDSA or saccharin can be produced, for example, by mixing NDSA or saccharin, deuterated methanol and heavy water according to the method described in Example 5 (2) described later.

[0085] Pharmaceutical composition 1,5-naphthalenedisulfonate or saccharinate of 2-methyl-2-thiazoline or a deuterated product thereof (hereinafter also referred to as the compound of the present invention) is useful as a pharmaceutical agent, for example, for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation.

[0086] In the present invention, the term "anoxia-induced injury" refers to a disease caused by hypoxia, for example, anoxia, cerebral hypoxia, neonatal hypoxia, hypoxic-ischemic encephalopathy, hypoxic-anoxia, ischemic hypoxia, congestive hypoxia, mountain sickness, cerebral infarction, myocardial infarction, renal failure, heart failure, diabetic vascular injury, occlusive arteriosclerosis, ulcer, spinal cord injury, optic nerve injury, optic cell injury, nerve injury, etc.

[0087] In the present invention, ischemia-reperfusion injury refers to the damage to the cells and tissues of the ischemic organ caused by reperfusion after blood flow is restored to the organ in an ischemic state. Examples include ischemia-reperfusion injury after reperfusion therapy for myocardial infarction, cerebral infarction, mesenteric vascular occlusion, etc., ischemia-reperfusion injury after organ transplantation, bedsores, etc.

[0088] In the present invention, inflammation refers to a pathological inflammatory state of the whole body or tissue caused by trauma, invasion of pathogens, stimulation of chemical substances, radiation damage, etc. Examples thereof include sepsis, encephalitis, meningitis, arteritis, sinusitis, rhinitis, pneumonia, bronchitis, oral ulcers, esophagitis, gastritis, enteritis, hepatitis, myositis, dermatitis, arthritis, nephritis, adrenalitis, lymphangitis, rheumatoid arthritis, psoriasis, osteoporosis, Crohn's disease, etc.

[0089] The compound of the present invention can be used as a preparation for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation by in vivo administration.

[0090] Investment method The compounds of the present invention can be administered to animals including humans that have hypoxic injury, ischemia-reperfusion injury, inflammatory disease or the possibility of disease, with the purpose of preventing damage or alleviating symptoms. The compounds of the present invention can be administered orally at a dose of 1 μg / kg to 5,000 mg / kg. Alternatively, the compounds of the present invention can be injected into the body at a dose of 1 μg / kg to 5,000 mg / kg by intradermal injection, subcutaneous injection, intramuscular injection, intravenous injection, intraarterial injection, intraspinal injection, intraperitoneal injection, etc. Alternatively, the compounds of the present invention can be administered nasally, pulmonary, transdermally or rectally at a dose of 1 μg / kg to 5,000 mg / kg. The frequency of administration can be a single administration or continuous administration at a certain interval, or continuous administration at different intervals. Animals as the subject of administration include mammals (humans, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, pigs, horses, monkeys, etc.).

[0091] When the compound of the present invention is used as a preparation for preventing or treating ischemia-reperfusion injury or inflammation (hereinafter also referred to as the preparation of the present invention), a pharmaceutically acceptable carrier may be mixed as needed. That is, the preparation of the present invention can be used as a composition (pharmaceutical composition) containing the compound of the present invention and a pharmaceutically acceptable carrier.

[0092] Specific examples of pharmaceutically acceptable carriers include, but are not limited to, antioxidants, preservatives, colorants, flavoring agents, diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, diluents, carriers, excipients and / or pharmaceutical adjuvants.

[0093] The dosage form of the preparation of the present invention is not particularly limited, and examples thereof include oral preparations, injections, suppositories, ointments, patches, inhalants, sprays, etc. These various administration forms can be produced by conventional preparation methods known to those skilled in the art.

[0094] Injections can be prepared by known methods in the art. For example, after being dissolved in a suitable solvent (a buffer solution such as physiological saline, PBS, sterile water, etc.), it can be sterilized by filtration using a filter membrane, etc., and then filled into a sterile container (such as an ampoule, etc.) to prepare an injection. In the injection, a conventional pharmaceutical carrier may also be included as needed. A method of administration utilizing a non-invasive catheter may also be used. As carriers that can be used in the present invention, there can be mentioned: neutral buffered physiological saline or physiological saline containing serum albumin, etc.

[0095] The present invention will be described in further detail below with reference to examples, but the present invention is not limited to the examples. Example

[0096] The abbreviations used in this specification have the following meanings. 2-MT: 2-Methyl-2-thiazoline NDSA:1,5-Naphthalene disulfonic acid THF: Tetrahydrofuran ACN: Acetonitrile

[0097] Tests were performed in the range of about 20-30 mg at molar ratios of 1:1 and 2:1 (2-MT:salifying agent).

[0098] X-ray powder diffraction (XRPD) XRPD analysis was performed using a Panalytical Empyrean diffractometer equipped with a CuX-ray tube and a PIXcel 1D-Medipix3 detection system. The sample was sandwiched between low-density PVC films at room temperature to analyze the sample in transmission mode. XRPD program (range 3-40 ° 2θ, step length 0.013 °, counting time 99 seconds, about 22 minutes of running time / counting time 49 seconds, about 11 minutes of running time / counting time 22 seconds, about 5 minutes of running time) was used. During data collection, the sample was rotated at 60 rpm. XRPD patterns were classified using HighScore Plus 2.2c / v4.9 software.

[0099] Differential Scanning Calorimetry (DSC) 2 to 3 mg of a sample was accurately weighed in an aluminum sample pan, and the measurement was performed within a measurement range of 30 to 250° C. at a temperature increase rate of 5° C. / min.

[0100] Thermogravimetry and differential thermal analysis (TG / DTA) Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC1STARe device. Calibration standards were indium and tin. The sample was accurately weighed in an aluminum sample pan on an analytical balance and inserted into a TG furnace. After stabilizing the heat flow signal at 30°C for 1 minute, it was heated to 300°C at a rate of 10°C / min under a nitrogen flow.

[0101] 1 H Nuclear Magnetic Resonance Spectroscopy (NMR) NMR analysis was performed using a Bruker 500 MHz instrument.

[0102] Example 1 Preparation of 2-methyl-2-thiazoline semi-1,5-naphthalene disulfonate 2-MT (470 μL, 501.5 mg) was placed in a volumetric flask (5 mL) and THF / water (82:18% v / v) was added to a concentration of 0.99 M. Typical aliquot = 249 μL, approximately 25 mg. NDSA tetrahydrate (1 molar equivalent) was added to the vial, and 2-MT (243-257 μL, 1 molar equivalent, THF / water (82:18% v / v)) was added and kept at room temperature (about 20°C) overnight. The solid was isolated by centrifugation and dried using filter paper. X-ray powder diffraction (XRPD), 1 The obtained solid was analyzed by H-NMR and differential scanning calorimetry (DSC). Figure 1 The main peaks are shown in Table 1.

[0103] [Table 1]

[0104] Physical property evaluation Confirmation of structure and residual solvent by NMR pass 1 H-NMR (CD3OD) and 13 C-NMR (CD3OD) for structural confirmation ( Figure 2 to Figure 4 ) As the measurement solvent, deuterated methanol was used, which can dissolve 2-MT·NDSA salt and does not overlap with the solvent peak. 1 H-NMR spectrum (CD3OD) Figure 2 Compared with the raw material 1 H-NMR spectrum (CD3OD) Figure 3 shown. 13 C-NMR spectrum (CD3OD) Figure 4 As shown. 1 The integrated value of H-NMR confirmed that the molar ratio of the obtained salt was 2 (2-MT:NDSA=2:1). 1 H-NMR confirmed that the residual amount of THF was below the detection limit (about 0.1% or less). 1 As a result of H-NMR, it was confirmed that no impurities were detected and the purity of the obtained salt was 99% or more.

[0105] Solubility When 2-MT·NDSA salt (20 mg) was added to phosphate buffered saline (PBS pH 7.2-7.4, Fujifilm Wako Pure Chemical Industries, Ltd. 164-18541, 1 mL) at room temperature, it was easily dissolved. 80 mg, 100 mg, and 100 mg of 2-MT·NDSA salt were further added to the solution. When dissolution was confirmed by visual inspection, since the dissolution residue was confirmed when the total amount was 200 mg, the solubility under the present conditions was 100 mg / mL to 200 mg / mL.

[0106] stability Add 2-MT·NDSA salt to the vial, heat to 40°C and let stand for 3 days.1 When the salt was measured by H-NMR, no peak change was observed, so it can be said that the 2-MT·NDSA salt is stable in a solid state at 40°C for 3 days (equivalent to 2 weeks at 25°C). 1 H-NMR spectrum (CD3OD) Figure 5 shown.

[0107] Crystallinity Microscopic observation and DSC measurement confirmed that the prepared 2-MT·NDSA salt was crystalline ( Figure 6 and Figure 7 ). Microscope photos of NDSA and 2-MT·NDSA salt are shown in Figure 2. Figure 6 The DSC graph of 2-MT·NDSA salt is shown in Figure 7 shown. Figure 7 The presence of two main peaks was confirmed on the DSC chart shown. The first endothermic peak had an extrapolated onset temperature (Onset temperature) of 107.76°C and a peak temperature of 131.53°C, and the second endothermic peak had an extrapolated onset temperature (Onset temperature) of 217.86°C and a peak temperature of 221.61°C. It is speculated that the peak on the low temperature side may be water. For this reason, the water content was measured using a moisture meter (Karl-Fischer (KF) method, volumetric method) and was 6.78%. In terms of molar ratio, it was confirmed that 2-MT: water was 1:1. Therefore, the obtained 2-MT·NDSA salt is considered to be a semi-1,5-naphthalene disulfonate monohydrate of 2-methyl-2-thiazoline represented by the following formula.

[0108] [Chemistry 12]

[0109] Deliquescent The petri dish containing 2-MT·NDSA salt was placed at a relative humidity of about 75% and allowed to stand for 23 hours in a thermostatic bath at 25° C. The absence of deliquescence was visually confirmed.

[0110] Humidity pressure test A prescribed amount of salt was added to the vial, which was not sealed and placed in a constant temperature chamber at 40°C / 75% relative humidity or at room temperature for 7 days for XRPD analysis. Figure 8 shown. Figure 8 The XRPD patterns of NDSA tetrahydrate (the first), 2-MT·half NDSA salt (the second), 2-MT·half NDSA salt after storage at room temperature for 7 days (the third), and 2-MT·half NDSA salt after storage at 40°C / 75% relative humidity for 7 days (the fourth) are shown. Figure 8 As shown, it was confirmed that the 2-MT·half-NDSA salt was physically stable after being stored at 40° C. / 75% relative humidity or at room temperature for 7 days.

[0111] Example 2 Preparation of 2-methyl-2-thiazoline mono-1,5-naphthalene disulfonate Add NDSA tetrahydrate (0.5 or 1 molar equivalent) to the vial, add ACN / water (86:14% v / v, 200-300 μL), and mix for about 5 minutes. Add 2-MT (about 23-25 ​​μL, 1 molar equivalent) and keep at room temperature (about 20°C) overnight. Isolate the solid by centrifugation and dry it with filter paper. X-ray powder diffraction (XRPD), 1 The obtained solid was analyzed by H-NMR and thermogravimetric / differential thermal analysis (TG / DTA). A 0.5 molar equivalent of NDSA sample was used, which exhibited an XRPD pattern similar to that of the half-NDSA salt of Example 1, and a half-NDSA salt was obtained. The XRPD pattern of 1 molar equivalent of NDSA is as follows Fig. 9 The main peaks are shown in Table 2. 1 H-NMR spectrum (D2O) Fig.10 As shown in the TG / DTA thermogram (30-300°C, 10°C / min), Fig.11 As shown. XRPD analysis confirmed that the prepared 2-methyl-2-thiazoline mono-1,5-naphthalene disulfonate was crystalline.

[0112] [Table 2]

[0113] according to 1 H-NMR analysis ( Fig.10 ) was used as the integral value, and the solid isolated from ACN / water (86:14% v / v) using 1 molar equivalent of NDSA was formed as a monosalt, forming 1:1 (2-MT:NDSA). 1 As a result of H-NMR, it was confirmed that no impurities were detected and the purity of the obtained salt was 99% or more.

[0114] TG / DTA analysis( Fig.11 ) indicates that a weight loss of about 7.81% is observed between about 66-205°C, which is equivalent to about 2.2 molar equivalents of water, suggesting that the monosalt is a dihydrate. Relevant endotherms are observed at an onset temperature of 114.78°C and a peak temperature of 121.80°C, and further endotherms are observed at an onset temperature of 142.36°C and a peak temperature of 157.21°C and an onset temperature of 267.73°C and a peak temperature of 279.12°C. Therefore, the obtained 2-MT·NDSA salt is considered to be a dihydrate of a mono-1,5-naphthalene disulfonate of 2-methyl-2-thiazoline represented by the following formula.

[0115] [Chemistry 13]

[0116] Example 3 Preparation of monosaccharide salt of 2-methyl-2-thiazoline Add saccharin (1 molar equivalent) to the vial, add ACN (100-200 μL), and mix for about 5 minutes. Add 2-MT (about 23-25 ​​μL, 1 molar equivalent) and keep at room temperature (about 20°C) overnight. Isolate the solid by centrifugation and dry it with filter paper. X-ray powder diffraction (XRPD), 1 The obtained solid was analyzed by H-NMR and thermogravimetric differential thermal analysis (TG / DTA). Fig.12 The main peaks are shown in Table 3. The XRPD pattern compared with the raw material (saccharin) is shown in Fig.13 shown. 1 H-NMR spectrum (D2O) Fig.14 TG / DTA thermal spectrum (30-300℃, 10℃ / min) Fig.15 XRPD analysis confirmed that the prepared 2-methyl-2-thiazoline monosaccharide salt was crystalline.

[0117] [Table 3]

[0118] according to 1 H-NMR analysis ( Fig.14 ) was confirmed to be a monosalt with a formation ratio of 1:1 (2-MT: saccharin). 1 As a result of H-NMR, it was confirmed that no impurities were detected and the purity of the obtained salt was 99% or more.

[0119] According to TG / DTA analysis ( Fig.15 ), and no weight loss was observed until melting was observed at the onset temperature of 131.43°C (possibly due to the onset of decomposition). This suggests that the monosalt is an anhydrate, which is different from 1 The results of H-NMR analysis were consistent. Therefore, the obtained monosaccharide refined salt was considered to be an anhydrate of monosaccharide refined salt of 2-methyl-2-thiazoline represented by the following formula.

[0120] [Chemistry 14]

[0121] Example 4 Preparation of deuterated monosaccharide salt of 2-methyl-2-thiazoline

[0122] [Chemistry 15]

[0123] Dissolve 2-MT monosaccharide (2.0 g) in deuterated methanol (20 mL) and heat with stirring at 60°C. Take a portion of the sample after 18 hours, confirm deuteration under NMR, and then distill off the solvent. Wash the obtained solid with cooled acetonitrile and dry under reduced pressure at room temperature overnight to obtain deuterated 2-MT monosaccharide (1.02 g). 1 H-NMR and 13 C-NMR confirmed that the saccharin salt ( Fig.16 and Fig.17 ).

[0124] After deuteration, 1 In the H-NMR spectrum, the integral value of the peak corresponding to the methyl group of 2-MT (2.21 ppm) changed from 3.01 to 0.58. The deuteration rate of the obtained saccharin salt of 2-MT was 96.73%. 13 In the C-NMR spectrum, it was confirmed that the peak (24.7 ppm) corresponding to the methyl group of 2-MT was coupled with CD.

[0125] according to 1 H-NMR and 13 As a result of C-NMR, it was confirmed that a deuterated monosaccharide salt of 2-MT (deuterated monosaccharide salt of 2-methyl-d3-2-thiazoline) was obtained (deuteration rate: 96.73%). 1 As a result of H-NMR, it was confirmed that no impurities were detected and the purity of the obtained salt was 99% or more.

[0126] [Chemistry 16]

[0127] 1 H-NMR(400MHz,DMF-d7)δppm8.15(dd,J 7’-6’ =7.3Hz,J 7’-5’ =1.2Hz,1H,7'),8.04-7.94(m,3H,4',5',6'),4.22(t,J 3-4 =8.5Hz,2H,3),3.45(t,J 4-3 =8.5Hz,2H,4).

[0128] [Chemistry 17]

[0129] 13C-NMR(100MHz,DMF-d7)δppm170.5(2),162.8(1')*,141.4(2'),135.4(5'),134 .8(6'),129.5(3'),125.1(7'),121.3(4'),63.4(3),34.4(4),19.0(quintet,J 1-D =20.3Hz,1). The peak of *162.8(1') may overlap with the carbonyl peak of DMF.

[0130] Example 5 Preparation of deuterated NDSA salt of 2-methyl-2-thiazoline (1) Production of deuterated 2-methyl-2-thiazoline (2-methyl-d3-2-thiazoline)

[0131] [Chemistry 18]

[0132] 2-Aminoethanethiol hydrochloride (5.68 g) was dissolved in heavy water (5.00 g) and stirred at room temperature for 3 days. The solvent was distilled off, and the obtained residue was dissolved in heavy water (5.00 g), and stirred at 50°C for 3 days. The solvent was distilled off, and sodium deuteride (300 mg) and deuterated acetonitrile (1.74 mL) were added to the obtained residue (deuterated product of 2-aminoethanethiol hydrochloride (DS-CH2-CH2-ND2·DCl)), and stirred at 80°C for 3 days. After cooling, the reaction solution was extracted with diethyl ether (5 mL×10). The organic layer was concentrated under normal pressure (room temperature to 50°C) to obtain a colorless oily deuterated product of 2-methyl-2-thiazoline (2-methyl-d3-2-thiazoline) (2.55 g, yield 74%). According to 1 H-NMR and 13 The results of C-NMR confirmed that the deuterated product of 2-methyl-2-thiazoline (2-methyl-d3-2-thiazoline) was obtained. Fig.18 and Fig.19 ).

[0133] [Chemistry 19]

[0134] 1 H-NMR(400MHz,CDCl3)δppm4.19(t,J 3-4 =8.3Hz,2H,3),3.30(t,J 4-3 =8.3Hz,2H,4).

[0135] [Chemistry 20]

[0136] 13 C-NMR(100MHz,DMF-d7)δppm166.9(2),64.7(3),34.6(4),19.5(quintet,J 1-D =20.4Hz,1).

[0137] (2) Production of deuterated NDSA salt of 2-methyl-2-thiazoline

[0138] [Chemistry 21]

[0139] Dissolve NDSA (4.5 g) in deuterated methanol (3.6 mL), add heavy water (1.5 mL) and stir, distill off the solvent to synthesize the deuterated NDSA. Use THF (13.3 mL) to dissolve the synthesized deuterated NDSA (1.6 g), add the deuterated 2-MT (2-methyl-d3-2-thiazoline) (0.607 g) and stir at room temperature overnight. Distill off the solvent, dry under reduced pressure, stir in THF (5 mL) and recover the solid. Dry under reduced pressure to obtain 1.4 g of solid. Determine the solid 1 In H-NMR, the peaks corresponding to CH2 (3.84, 4.45 ppm) were less than 2H. The synthesized NDSA salt (deuterated) was a mono-NDSA salt (deuterated) of 2-MT ( Fig. 20 ). Furthermore, deuterated 2-MT was added to synthesize NDSA salt (deuterated).

[0140] To the deuterated form of 2-MT (0.61 g), a solution of the mono-NDSA salt (deuterated form) of 2-MT dissolved in deuterated methanol (5.0 mL) was added. The mixture was stirred for 30 minutes and the solvent was distilled off. The mixture was dried under reduced pressure at room temperature overnight, and the resulting crystals (1.14 g) were stirred for 5 minutes under ice cooling using THF (5 mL) to wash the crystals. The crystals were recovered and dried under reduced pressure at room temperature overnight to obtain 1.09 g of the half-NDSA salt (deuterated form) of 2-MT. The half-NDSA salt (deuterated form) of 2-MT obtained was measured. 1 H-NMR and 13 C-NMR( Fig.21 and Fig. 22 ).

[0141] After deuteration, 1 In the H-NMR spectrum, the integral value of the peak corresponding to the methyl group of 2-MT (2.62 ppm) changed from 6 to 0.628. The deuteration rate of the deuterated product of the half-NDSA salt of 2-MT obtained was 98.27%. 13In the C-NMR spectrum, it was confirmed that the peak (23.2 ppm) corresponding to the methyl group of 2-MT was coupled with CD.

[0142] according to 1 H-NMR and 13 As a result of C-NMR, it was confirmed that a deuterated half-NDSA salt of 2-MT (deuterated half-NDSA salt of 2-methyl-d3-2-thiazoline) was produced (deuteration rate: 98.27%).

[0143] [Chemistry 22]

[0144] 1 H-NMR(400MHz,DMF-d7)δppm9.12(dd,J 2’-3’ =8.6Hz,J 2’-4’ =0.9Hz,2H,2'),8.12(dd,J 4’-3’ =7.2Hz,J 4’-2’ =1.1Hz,2H,4'),7.46(dd,J 3’-2’ =8.6Hz,J 3’-4’ =8.6Hz,2H,3'),4.44(t,J 3-4 =9.3Hz,2H,3),3.89(t,J 4-3 =9.4Hz,2H,4).

[0145] [Chemistry 23]

[0146] 13 C-NMR(100MHz,DMF-d7)δppm192.8(2),144.4(1'),130.4(5'),129.8(2'),124.7(4'),124.2(3'),54.4(3),32.8(4),17.3(quintet,J 1-D =20.5Hz,1). Industrial Applicability

[0147] According to the present invention, a solid 2-MT salt having excellent operability and stability as a pharmaceutical raw material is provided. The 2-MT salt of the present invention is useful as a pharmaceutical raw material. In addition, the deuterated 2-MT salt is useful as a tracer or internal standard substance for a pharmaceutical raw material or biological analysis (e.g., pharmacodynamic analysis, etc.).

[0148] This application is based on Japanese Patent Application No. 2022-077593 filed in Japan, the entire contents of which are incorporated herein by reference.

Claims

1. 1,5-naphthalene disulfonate or saccharinate of 2-methyl-2-thiazoline or deuterated salt thereof. 2 . The salt according to claim 1 , which is 1,5-naphthalene disulfonate or saccharinate of 2-methyl-2-thiazoline. The salt according to claim 1 , which is crystalline. The salt according to claim 1 , which is 1,5-naphthalene disulfonate of 2-methyl-2-thiazoline or a deuterated salt thereof. The salt according to claim 4, which is 2-methyl-2-thiazoline hemi-1,5-naphthalenedisulfonate or a deuterated salt thereof. The salt according to claim 5, which is a hydrate of 2-methyl-2-thiazoline hemi-1,5-naphthalenedisulfonate.

7. The salt according to claim 5, which is crystalline.

8. The salt according to claim 7, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 17.2±0.2°, 17.9±0.2°, 18.7±0.2° and 22.6±0.2°.

9. The salt according to claim 7, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 11.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.7±0.2°, 20.1±0.2°, 22.6±0.2° and 23.9±0.2°. 10 . The salt according to claim 4 , which is a mono-1,5-naphthalene disulfonate of 2-methyl-2-thiazoline or a deuterated salt thereof. The salt according to claim 10, which is a hydrate of mono-1,5-naphthalene disulfonate of 2-methyl-2-thiazoline.

12. The salt according to claim 10, which is crystalline.

13. The salt according to claim 12, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 18.5±0.2°, 22.6±0.2°, 22.9±0.2° and 23.4±0.2°.

14. The salt according to claim 12, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 11.9±0.2°, 14.4±0.2°, 18.5±0.2°, 22.6±0.2°, 22.9±0.2° and 23.4±0.2°.

15. The salt according to claim 1, which is a saccharinate salt of 2-methyl-2-thiazoline or a deuterated salt thereof.

16. The salt according to claim 15, which is a monosaccharide salt of 2-methyl-2-thiazoline or a deuterated salt thereof.

17. The salt according to claim 16, which is an anhydrate of the monosaccharinate salt of 2-methyl-2-thiazoline.

18. The salt according to claim 16, which is crystalline.

19. The salt according to claim 18, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 19.9±0.2° and 26.2±0.2°.

20. The salt of claim 18, which has an X-ray powder diffraction pattern having peaks at 2θ values ​​of 12.8±0.2°, 13.8±0.2°, 14.7±0.2°, 19.9±0.2°, 26.2±0.2°, and 29.3±0.2°.

21. The deuterated compound according to claim 1, which is represented by formula (1) or formula (2):

22. The deuterated compound according to claim 1, which is represented by formula (3):

23. A pharmaceutical composition comprising the salt or deuterated product thereof according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier.

24. A preparation for preventing or treating hypoxic injury, ischemia-reperfusion injury or inflammation, comprising the salt according to any one of claims 1 to 22 or a deuterated product thereof.

25. A method for producing 1,5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline, comprising mixing 2-methyl-2-thiazoline, 1,5-naphthalene disulfonic acid or saccharin and a solvent, and isolating the obtained solid of 1,5-naphthalene disulfonate or saccharin salt of 2-methyl-2-thiazoline.

26. A method for producing a deuterated product of a saccharinate salt of 2-methyl-2-thiazoline, comprising mixing a saccharinate salt of 2-methyl-2-thiazoline and deuterated methanol, and isolating the produced deuterated product of the saccharinate salt of 2-methyl-2-thiazoline.

27. A method for producing a deuterated compound represented by formula (1) or formula (2), comprising mixing 2-methyl-d3-2-thiazoline and a deuterated compound of 1,5-naphthalene disulfonic acid in a solvent to produce a deuterated compound represented by formula (1) or formula (2), 28. A method for producing a deuterated compound represented by formula (3), comprising mixing a saccharinate salt of 2-methyl-2-thiazoline and deuterated methanol to produce the deuterated compound represented by formula (3),

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