BR-122026002526-A2 - Triazine compound salt, crystal thereof, method of production thereof, uses thereof, aldosterone synthase inhibitor, and pharmaceutical composition.

BR122026002526A2BR 122026002526 A2BR122026002526 A2BR 122026002526A2BR-122026002526-A2

Abstract

The present invention provides a salt of a triazine compound that has an inhibitory action against aldosterone synthase and is useful as a drug, and especially as a drug to prevent or treat primary aldosteronism and the like, a crystal thereof, and a method for producing the same. Specifically, the present invention provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is hydrobromide, sulfate, succinate or tosylate and the like.

Inventors

Takafumi YAMAGAMI
Tomofumi Setsuta
Yoshihiro Sugiura
Naoko Ueda

Assignees

MITSUBISHI TANABE PHARMA CORPORATION

Dates

Publication Date: 20260310
Application Date: 20210915
Priority Date: 20200915

Claims (5)

1. Method for producing 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine represented by a Compound (10), characterized in that it is represented by the following reaction scheme: (where R1 and R2 each independently represent an amino protecting group) and comprising the following steps: (Step 1) a step of reacting Compound (2) with Compound (3) to produce Compound (4) or a salt thereof; (Step 2) a step of subjecting Compound (4) or a salt thereof to a deprotection reaction to produce Compound (5) or a salt thereof; (Step 3) a step of reacting Compound (5) or a salt thereof with Compound (7) to produce Compound (8) or a salt thereof; (Step 4) a step of subjecting Compound (8) or a salt thereof to a deprotection reaction to produce Compound (9) or a salt thereof; and (Step 5) a step of reacting Compound (9) or a salt thereof with an acetylating agent to produce Compound (10).
2. Compound, characterized by the fact that it is represented by formula (4) (where R1 and R2 each independently represent a protecting amino group) or a salt thereof.
3. Compound, characterized by the fact that it is represented by the formula (5) (where R2 represents an amino protecting group) or a salt thereof.
4. Compound, characterized by the fact that it is represented by the formula (8) (where R2 represents an amino protecting group) or a salt thereof.
5. Invention in any of its embodiments or in any applicable category of claim, for example, product or process or use, or any other type of claim encompassed by the matter initially described, disclosed or illustrated in the patent application; and/or Pharmaceutically acceptable salt, crystal, aldosterone synthase inhibitor, pharmaceutical composition, use or method characterized by one or more elements disclosed in this patent application; Compound, represented by any of the formulas below or a salt thereof: and/or Pharmaceutical composition, comprising the salt, crystal or aldosterone synthase inhibitor, as defined in any of claims 1 to 7, and a pharmaceutically acceptable additive; and/or Pharmaceutical composition, according to the above claim, which is for preventing or treating a disease whereby a pathological condition is expected to be improved by aldosterone synthase inhibition; and/or Use of the salt, crystal, or aldosterone synthase inhibitor as defined in any of claims 1 to 7, for the manufacture of a medicament, composition, or product to prevent or treat a disease where the pathological condition is expected to be improved by aldosterone synthase inhibition; and/or Use of a pharmaceutically acceptable salt, or crystal, or aldosterone synthase inhibitor, or pharmaceutical composition, or compound, as defined in any of the preceding claims, or in any part of this patent application, for the preparation of a medicament, composition, or product to prevent or treat a disorder, disease, or health condition.

Description

TECHNICAL FIELD [001] The present invention relates to a salt of a triazine compound that has an inhibitory action against aldosterone synthase and is useful as a medicament, and especially as a medicament for preventing or treating primary aldosteronism and the like, a crystalline form thereof and a method for producing the same. More specifically, the present invention relates to 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine (hereinafter also referred to as "Triazine Compound A") or a pharmaceutically acceptable salt thereof with excellent physical properties as an active pharmaceutical ingredient, a crystalline form thereof, a method for producing the same, a pharmaceutical composition comprising the same as an active ingredient, and taste. BACKGROUND OF THE TECHNIQUE [002] Patent Document 1 discloses a plurality of triazine decomposers or pharmacologically acceptable salts thereof having aldosterone synthase inhibitory activities, and Example 48 in said document discloses Triazine Compound A. However, Patent Document 1 does not disclose or suggest a specific salt or crystalline form of Triazine Compound A. [003] In addition, Patent Document 1 discloses the following method for producing Triazine compound A. LIST OF CITATIONS PATENT DOCUMENT Patent Document 1: WO 2015/163427 pamphlet SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION [004] The present invention provides novel salts of compound A deTriazine used in the prevention or treatment of primary aldosteronism and the like, their crystalline forms and an industrially advantageous method for producing said compound. WAYS TO SOLVE PROBLEMS [005] In order to solve the above problems, the present inventors seriously studied to obtain an active pharmaceutical ingredient having a specific level of quality suitable as a medicine, and they tried to obtain a salt. As a result, hydrobromide, sulfate, succinate or tosylate of Triazine compound A were found as salts that can produce excellent crystals that are excellent in terms of purity, thermal stability, hygroscopicity, deliquescence, chemical stability and safety, as well as in terms of handling. [006] Subsequently, the present inventors seriously studied the previous salts of Triazine compound A. As a result, they found that the hydrobromide of Triazine compound A exhibits stable pharmacokinetics under both increased and reduced gastric acid secretion. [007] Triazine compound A hydrobromide has unexpectedly excellent physical properties as an active pharmaceutical ingredient, as indicated above, and has also proven to have several crystalline forms. The present inventors have found that a Form A Hydrobromide crystal of Triazine compound A is the most preferred crystalline form among others in terms of stability and the like. However, problems such as polymorph incorporation, increased impurities, and increased residual solvent(s) were encountered depending on the amount of hydrogen bromide to be added in the crystallization step, crystallization temperature, and composition of the crystallization solvent, and the target crystal could not be produced reproducibly and stably. Thus, the present inventors also seriously studied the type, quantity, and proportion of reagents and solvents to be used in crystallization, as well as the crystallization procedure and the like. As a result, they found a method to efficiently produce the Form A Hydrobromide crystal of Triazine Compound A, which is a crystal with appropriate qualities as an active pharmaceutical ingredient, and completed the present invention. Furthermore, they found a method to produce stable crystalline forms with excellent qualities also from sulfate, succinate, and tosylate of Triazine Compound A, such as the Form A Hydrobromide crystal of Triazine Compound A. [008] Furthermore, the production intermediate compounds disclosed in Patent Document 1, namely Compounds (B), (C) and (E), were confirmed to have an explosive hazard as a result of differential scanning calorimetry. In addition, Compounds (B), (C) and (D) were confirmed to have a potential genotoxic hazard as a result of genotoxic hazard assessment by DEREK; MultiCASE. Namely, the production method disclosed in Patent Document 1 uses compounds with both an explosive hazard and a genotoxic hazard as production intermediate compounds and is therefore a disadvantageous production method for industrial-scale implementation. [009] Furthermore, Triazine compound A is a sparingly soluble compound, has physical properties similar to the insoluble and similar impurities produced in the intermediate step(s), therefore, purification, such as isolation in the final step, is not easy to perform, and it has been difficult to obtain Triazine compound A with appropriate qualities as an active pharmaceutical ingredient. [0010] Thus, the present inventors carried out several studies. As a result, they found an industrially advantageous method f