WO2022220599A1 - Crystal form of sphingosine-1-phosphate receptor agonist - Google Patents

Crystal form of sphingosine-1-phosphate receptor agonist Download PDF

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WO2022220599A1
WO2022220599A1 PCT/KR2022/005376 KR2022005376W WO2022220599A1 WO 2022220599 A1 WO2022220599 A1 WO 2022220599A1 KR 2022005376 W KR2022005376 W KR 2022005376W WO 2022220599 A1 WO2022220599 A1 WO 2022220599A1
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acid
chloro
pharmaceutically acceptable
crystalline form
acceptable salt
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PCT/KR2022/005376
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French (fr)
Korean (ko)
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김지윤
전슬아
김성원
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주식회사 엘지화학
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Priority to CN202280026343.8A priority Critical patent/CN117157283A/en
Publication of WO2022220599A1 publication Critical patent/WO2022220599A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystalline form of a sphingosine-1-phosphate receptor agonist, and more particularly, 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole- 5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof;
  • Sphingosine-1-phosphate is produced through the intracellular ceramide pathway, and ceramide, the starting material of this synthetic pathway, has two production pathways, namely, the de novo biosynthetic pathway and It is produced in cells through the degradation of sphingomyelin, a component of the cell membrane.
  • S1P levels in each tissue are regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatases).
  • S1P lyase and lysophospholipid phosphatases The produced substance S1P mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion- and tight junction assembly, and morphogenesis. it is known They are present in high concentrations (100-1000 nM) in plasma bound to albumin and other plasma proteins, whereas in tissues, they are present in low concentrations.
  • S1P binds to the S1P receptor, a G-protein coupled receptor, and exhibits various biological functions.
  • the sub-types of S1P receptors known to date are S1P1 to S1P5. ) receptor) 1, 5, 3, 6 and 8. These S1P receptors are responsible for leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vasoregulation and cardiovascular development ( It is known to be involved in various biological functions such as cardiovascular development.
  • crystal form with a different structure can be obtained depending on the recrystallization conditions during the drug manufacturing process, i.e., recrystallization solvent, drug concentration, heating and cooling rate, temperature, stirring rate, etc.
  • recrystallization solvent i.e., recrystallization solvent, drug concentration, heating and cooling rate, temperature, stirring rate, etc.
  • special attention must be paid to the control of the manufacturing process.
  • the difference in crystal structure is distinguished as an X-ray diffraction diagram. Chemical properties showing pharmacological effects do not change, only physical properties such as crystallinity, hygroscopicity, melting point, solubility, and dissolution rate change, so it has a very important meaning in terms of pharmaceuticals, like polymorphism (Morris, K. R. et al. , Int. J. Pharm., 108, 1994, 15-206).
  • the present invention is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalen-2-ylmethyl of the formula 1 It is intended to provide a crystalline form having pharmaceutically excellent properties of ]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof:
  • the present invention is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- provided is a crystalline form of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention as an active ingredient 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2-
  • a pharmaceutical composition comprising a crystalline form of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
  • -6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or Crystalline forms of pharmaceutically acceptable salts or solvates thereof are provided: 6.98 ⁇ 0.2°, 11.10 ⁇ 0.2°, 12.49 ⁇ 0.2°, 13.47 ⁇ 0.2°, 14.22 ⁇ 0.2°, 15.22 ⁇ 0.2°, 19.45 ⁇ 0.2° , 19.82 ⁇ 0.2°, 20.29 ⁇ 0.2°, 20.90 ⁇ 0.2°, 22.53 ⁇ 0.2°, 24.89 ⁇ 0.2°, 25.39 ⁇ 0.2°, 25.83 ⁇ 0.2° and 26.88 ⁇ 0.2°.
  • the crystalline form B is referred to as “crystalline form B”.
  • the crystalline form B has 3 or more, 5 or more, 7 or more, 9 or more or 10 or more characteristic peaks (2 ⁇ ) selected from the following X-ray diffraction pattern spectra: 6.98 ⁇ 0.1°, 11.10 ⁇ 0.1°, 12.49 ⁇ 0.1°, 13.47 ⁇ 0.1°, 14.22 ⁇ 0.1°, 15.22 ⁇ 0.1°, 19.45 ⁇ 0.1°, 19.82 ⁇ 0.1°, 20.29 ⁇ 0.1°, 20.90 ⁇ 0.1°, 22.53 ⁇ 0.1°, 24.89 ⁇ 0.1°, 25.39 ⁇ 0.1°, 25.83 ⁇ 0.1° and 26.88 ⁇ 0.1°.
  • the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, glue conic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid.
  • the pharmaceutically acceptable salt may be hydrochloric acid.
  • the solvate may be a hydrate.
  • the 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- Provided is a pharmaceutical composition comprising crystalline Form B of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
  • pharmaceutical composition may include other chemical ingredients such as carriers, diluents, excipients and the like in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary.
  • the pharmaceutical composition facilitates administration of the active compound into an organism.
  • Various techniques for administering a compound exist, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • carrier refers to a compound that facilitates the introduction of the compound into a cell or tissue.
  • DMSO dimethylsulfoxide
  • carrier facilitates the introduction of many organic compounds into cells or tissues of living organisms.
  • diluent is defined as a compound that is diluted in water to dissolve the compound as well as to stabilize the biologically active form of the compound. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for a buffered diluent to modify the biological activity of a compound.
  • pharmaceutically acceptable refers to a property that does not impair the biological activity and physical properties of a compound.
  • the crystalline form of the compound of Formula 1 may be formulated into various pharmaceutical dosage forms as desired.
  • the active ingredient specifically, the crystalline form B of the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, various agents that can be selected depending on the dosage form to be prepared Mix with a scientifically acceptable carrier.
  • the pharmaceutical composition according to the present invention may be formulated as an injectable preparation, an oral preparation, etc. as desired.
  • the crystalline form of the compound of formula (1) of the present invention may be formulated by a known method using a known pharmaceutical carrier and excipient, and then put into a unit dose form or a multi-dose container.
  • the form of the preparation may be in the form of a solution, suspension or emulsion in oil or aqueous medium, and may contain customary dispersing, suspending or stabilizing agents. Also, for example, it may be in the form of a dry powder that is used by dissolving it in sterile, pyrogen-free water before use.
  • the crystalline form of the compound of Formula 1 of the present invention may also be formulated in a suppository form using a conventional suppository base such as cocoa butter or other glycerides.
  • a solid dosage form for oral administration can be capsules, tablets, pills, powders and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with an enteric coating.
  • a solid dosage form can be prepared by mixing the crystalline form of the compound of formula 1 of the present invention with one or more inert diluents such as sucrose, lactose, starch, and the like, and a carrier such as a lubricant, disintegrant, binder, etc., such as magnesium stearate.
  • it may be formulated in a transdermal dosage form, for example, a lotion, ointment, gel, cream, patch or spray, and the like.
  • the pharmaceutical composition according to the present invention is suitable for preventing or treating sphingosine-1-phosphate receptor-related diseases.
  • the pharmaceutical composition may be used for the treatment of autoimmune disorders including multiple sclerosis.
  • the pharmaceutical composition can be used for the prevention or treatment of diseases caused by undesirable lymphocyte infiltration involving sphingosine-1-phosphate.
  • the pharmaceutical composition can be used for the prevention or treatment of immunomodulatory disorders.
  • the immunomodulatory abnormality is, for example, systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis autoimmune selected from the group consisting of sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma and autoimmune hepatitis; It may be a chronic inflammatory disease, but is not limited thereto.
  • prevention refers to reducing or eliminating the possibility of contracting a disease.
  • treatment means stopping, delaying, or alleviating the progression of a disease when used for an object showing symptoms of onset.
  • Crystalline Form B of din-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof has pharmacological activity as a sphingosine-1-phosphate receptor agonist, and at the same time has stability, such as thermal stability and storage stability. It has the same excellent pharmaceutical properties.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • crystalline form A A crystalline form (hereinafter referred to as "crystalline form A") of compound 1 having an X-ray powder diffraction (XRPD) pattern of 1 (156 g, two step yield 69.0%) was obtained.
  • XRPD X-ray powder diffraction
  • Form B was prepared by the following three methods.
  • Form A was dissolved in a 50:50 mixed solvent of ethanol and water, and then filtered through a 0.2 ⁇ m nylon filter through a glass vial. When the vial was opened and evaporated at room temperature, a crystalline white solid was obtained.
  • Form A was dissolved in a mixed solvent of tetrahydrofuran and water 5:1 to prepare a solution, and then cyclohexane, an anti-solvent, was slowly added. At this time, tetrahydrofuran/water mixed solvent and cyclohexane were used in a ratio of 1:20. After stirring at room temperature for 1 day, it was refrigerated for 3 days. If a precipitate formed, it was filtered through a 0.45 ⁇ m PVDF filter.
  • Form A was dissolved in a mixed solvent of methanol and methyl tert-butyl ether 70:30, and then heated to 35°C for a while. At this time, most of the solid was dissolved. It was filtered through a preheated 0.2 ⁇ m nylon filter and placed in a clean vial preheated to that temperature. The solution was then removed from the heating plate and allowed to cool to room temperature. Since no solid was formed in the vial, a crystalline white solid was obtained when the vial was evaporated at room temperature with the vial open.
  • XRPD analysis was performed using a Panalytical Xpert Pro MPD diffractometer using an incident beam of Cu radiation. After compacting a sample of about 20 to 30 mg to have a flat surface on a glass sample holder, the generator was set to 45kV (acceleration voltage), 40mA (filament emission), and then measured in reflection mode (not-spin). . Bragg angles (2 ⁇ ) in the range of 4 to 40° were measured with a step size of 0.026° and a Time per step condition of 51 seconds. XRPD patterns were classified and processed using HighScore Plus 2.2c software and the results are shown in Figure 1 and Table 2.
  • TGA/DSC combo analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. The sample was placed in an open aluminum pan, the pan was sealed, the lid pierced, and then inserted into the TG furnace. Heated under nitrogen at a rate of 10° C./min from 30° C. up to 250° C. The results are shown in FIG. 2 .
  • Hotstage microscopy was performed on a Leica DM LP microscope using a Linkman hot stage (model FTIR 600) with a TMS93 controller. Samples were observed using a lambda plate with crossed polarizers at either 10x0.22 or 20x0.40 magnification. A sample was placed on a cover slip and another coverslip was placed over the sample. The sample was visually observed as the stage was heated. A drop of mineral oil may be added to the sample in some cases to investigate outgassing. Images are from SPOT software v. Captured using a SPOT Insight color digital camera with 4.5.9 ( Figure 3).

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Abstract

The present invention relates to a crystal form of a sphingosine-1-phosphate receptor agonist and, more specifically, to a crystal form of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid of chemical formula 1 or a pharmaceutically acceptable salt or solvate thereof.

Description

스핑고신-1-인산 수용체 효능제의 결정형Crystalline form of sphingosine-1-phosphate receptor agonist
본 발명은 스핑고신-1-인산 수용체 효능제의 결정형에 관한 것으로, 보다 상세하게는 하기 화학식 1의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형에 관한 것이다:The present invention relates to a crystalline form of a sphingosine-1-phosphate receptor agonist, and more particularly, 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazole- 5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof;
[화학식 1][Formula 1]
Figure PCTKR2022005376-appb-img-000001
Figure PCTKR2022005376-appb-img-000001
스핑고신-1-인산(sphingosine-1-phosphate, S1P)은 세포내 세라미드 경로(intracellular ceramide pathway)를 통해서 생성되며, 이러한 합성 경로의 출발물질인 세라미드는 두 가지 생성 경로, 즉 de novo 생합성 경로와 세포막 구성물질인 스핑고미엘렌(sphingomyelin)의 분해(degradation)을 통해서 세포 내에 생성된다. 각 조직에서의 S1P level은 두 개의 생합성 스핑고신 키나제(sphingosine kinases; SphKs)와 두 개의 생분해 S1P 포스파타제(S1P lyase 및 lysophospholipid phosphatases)에 의해 조절되는데, 스핑고신이 스핑고신 키나제에 의해 인산화(phosphorylation)되면서 생성되는 물질인 S1P는 세포의 증식(proliferation), 세포골격 조직 및 이동(cytoskeletal organization and migration), 부착-(adherence-) 및 tight junction assembly, 그리고 형태발생(morphogenesis)과 같은 다양한 세포반응을 매개하는 것으로 알려져 있다. 이들은 혈장에서 알부민을 비롯한 다른 혈장 단백질에 결합된 형태로 높은 농도(100~1000 nM)로 존재하는 반면 조직에서는 낮은 농도로 존재하고 있다.Sphingosine-1-phosphate (S1P) is produced through the intracellular ceramide pathway, and ceramide, the starting material of this synthetic pathway, has two production pathways, namely, the de novo biosynthetic pathway and It is produced in cells through the degradation of sphingomyelin, a component of the cell membrane. S1P levels in each tissue are regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatases). The produced substance S1P mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion- and tight junction assembly, and morphogenesis. it is known They are present in high concentrations (100-1000 nM) in plasma bound to albumin and other plasma proteins, whereas in tissues, they are present in low concentrations.
S1P는 G-단백질 커플링된 수용체인 S1P 수용체에 결합하여 다양한 생물학적 기능을 나타내는데, 현재까지 알려진 S1P 수용체의 서브-타입은 S1P1~S1P5의 5 가지로 이들은 각각 내피 분화 유전자 수용체(endothelial differentiation gene (EDG) receptor) 1, 5, 3, 6 및 8로 명명된다. 이러한 S1P 수용체들은 백혈구 재순환(leukocyte recirculation), 신경세포 증식(neural cell proliferation), 형태 변형(morphological changes), 이동(migration), 내피 기능(endothelial function), 맥관긴장조절(vasoregulation) 및 심장혈관계 발생(cardiovascular development)과 같은 다양한 생물학적 기능에 관여하는 것으로 알려져 있다.S1P binds to the S1P receptor, a G-protein coupled receptor, and exhibits various biological functions. The sub-types of S1P receptors known to date are S1P1 to S1P5. ) receptor) 1, 5, 3, 6 and 8. These S1P receptors are responsible for leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vasoregulation and cardiovascular development ( It is known to be involved in various biological functions such as cardiovascular development.
한편, 새로운 약물의 물리 화학적 성질 규명은 효율적이고 성공적인 신약 개발에 필수적이며 특히 약물의 결정다형(polymorph) 및 의사결정다형 (pseudopolymorph)의 존재 여부 및 각각의 결정다형들의 물리화학적 성질의 차이를 연구함으로써 약제학적 측면에서 볼 때 보다 바람직한 약물결정형을 선택할 수 있다(Remington's Pharmaceutics, Chapter 75 Preformulation); (Byrn, S.R., Solid State Chemistry of Drugs, Academic Press, New York, 1982). 결정다형이 용액 내에 존재할 때에는 화학적으로 같은 물질이지만 고체 상태에서 이들은 각각의 X선 회절도가 확연히 다르며 여러 가지 물리화학적인 성질의 차이를 보여준다. 특히 각 결정다형의 용해속도의 차이에 의해 생체이용률에도 차이가 있을 수 있으며, 이들은 열역학적 안정성 측면에서도 예측하지 못한 성질을 보여준다.On the other hand, identification of the physicochemical properties of new drugs is essential for efficient and successful drug development. In particular, by studying the existence of polymorphs and pseudopolymorphs of drugs and differences in the physicochemical properties of each polymorph, From a pharmaceutical point of view, a more preferable drug crystalline form can be selected (Remington's Pharmaceutics, Chapter 75 Preformulation); (Byrn, S.R., Solid State Chemistry of Drugs, Academic Press, New York, 1982). When polymorphs exist in solution, they are chemically the same substance, but in the solid state, their respective X-ray diffraction diagrams are significantly different and show differences in various physicochemical properties. In particular, there may be differences in bioavailability due to the difference in dissolution rate of each polymorph, and they show unexpected properties in terms of thermodynamic stability.
특정 약물이 결정다형으로 존재할 경우 약물의 제조공정 중 재결정 조건 즉, 재결정 용매, 약물 농도, 가열 및 냉각 속도, 온도, 교반 속도 등의 여러 조건에 따라 구조가 상이한 결정형이 얻어질 수 있으므로 동일한 결정형을 얻기 위해서는 제조 공정관리에 특별한 주의가 요구된다. 결정구조의 차이는 X선 회절도로서 구별된다. 약리효과를 나타내는 화학적인 성질은 변화되지 않고 결정성, 흡습성, 융점, 용해성, 용해 속도 등의 물리적인 성질만 변화되므로 결정다형과 마찬가지로 약제학적 측면에서 매우 중요한 의미를 지닌다(Morris, K. R. et al., Int. J. Pharm., 108, 1994, 15-206).When a specific drug exists as a polymorph, a crystal form with a different structure can be obtained depending on the recrystallization conditions during the drug manufacturing process, i.e., recrystallization solvent, drug concentration, heating and cooling rate, temperature, stirring rate, etc. In order to achieve this, special attention must be paid to the control of the manufacturing process. The difference in crystal structure is distinguished as an X-ray diffraction diagram. Chemical properties showing pharmacological effects do not change, only physical properties such as crystallinity, hygroscopicity, melting point, solubility, and dissolution rate change, so it has a very important meaning in terms of pharmaceuticals, like polymorphism (Morris, K. R. et al. , Int. J. Pharm., 108, 1994, 15-206).
지금까지 본 발명이 속한 기술분야의 여러 문헌으로부터 알 수 있는 것은, 약물의 안정성, 흡습성 등 약제학적 특성의 개선을 위해 결정형에 따른 일반적인 경향이 없다는 사실이다. 결국, 각 약물에 대하여 최적의 약제학적 특성을 가진 형태를 결정하기 위해서는 부단한 연구를 통해 케이스 별로 수행되어야 하고, 예측이 불가능하며 오직 반복된 실험을 통해서만 확인할 수 있는 실험적 영역이다.What can be seen from various documents in the technical field to which the present invention belongs so far is the fact that there is no general tendency according to the crystalline form to improve pharmaceutical properties such as drug stability and hygroscopicity. After all, in order to determine the form with the optimal pharmaceutical properties for each drug, it must be carried out on a case-by-case basis through continuous research, and is an experimental area that cannot be predicted and can only be confirmed through repeated experiments.
본 발명은 하기 화학식 1의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 약제학적 우수성을 갖는 결정형을 제공하고자 하는 것이다:The present invention is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalen-2-ylmethyl of the formula 1 It is intended to provide a crystalline form having pharmaceutically excellent properties of ]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof:
[화학식 1][Formula 1]
Figure PCTKR2022005376-appb-img-000002
Figure PCTKR2022005376-appb-img-000002
상기 과제 해결을 위하여, 본 발명은 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형을 제공한다.In order to solve the above problems, the present invention is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- provided is a crystalline form of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof.
또한, 본 발명은 유효성분으로 상기 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형을, 약제학적으로 허용되는 담체와 함께 포함하는 약제학적 조성물을 제공한다.In addition, the present invention as an active ingredient 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- Provided is a pharmaceutical composition comprising a crystalline form of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
이하에서 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 측면에 따르면, 다음의 X선 회절 패턴 스펙트럼 중에서 선택되는 3개 이상, 5개 이상, 7개 이상, 9개 이상 또는 10개 이상의 특성 피크(2θ)를 갖는 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형이 제공된다: 6.98±0.2°, 11.10±0.2°, 12.49±0.2°, 13.47±0.2°, 14.22±0.2°, 15.22±0.2°, 19.45±0.2°, 19.82±0.2°, 20.29±0.2°, 20.90±0.2°, 22.53±0.2°, 24.89±0.2°, 25.39±0.2°, 25.83±0.2° 및 26.88±0.2°. 이하에서, 상기 결정형을 “결정형 B”라 명명한다.According to one aspect of the present invention, 1- [1-chloro having 3 or more, 5 or more, 7 or more, 9 or more, or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum. -6-(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or Crystalline forms of pharmaceutically acceptable salts or solvates thereof are provided: 6.98±0.2°, 11.10±0.2°, 12.49±0.2°, 13.47±0.2°, 14.22±0.2°, 15.22±0.2°, 19.45±0.2° , 19.82±0.2°, 20.29±0.2°, 20.90±0.2°, 22.53±0.2°, 24.89±0.2°, 25.39±0.2°, 25.83±0.2° and 26.88±0.2°. Hereinafter, the crystalline form is referred to as “crystalline form B”.
본 발명에 따른 일 구체예에서, 상기 결정형 B는 다음의 X선 회절 패턴 스펙트럼 중에서 선택되는 3개 이상, 5개 이상, 7개 이상, 9개 이상 또는 10개 이상의 특성 피크(2θ)를 갖는다: 6.98±0.1°, 11.10±0.1°, 12.49±0.1°, 13.47±0.1°, 14.22±0.1°, 15.22±0.1°, 19.45±0.1°, 19.82±0.1°, 20.29±0.1°, 20.90±0.1°, 22.53±0.1°, 24.89±0.1°, 25.39±0.1°, 25.83±0.1° 및 26.88±0.1°.In one embodiment according to the present invention, the crystalline form B has 3 or more, 5 or more, 7 or more, 9 or more or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectra: 6.98±0.1°, 11.10±0.1°, 12.49±0.1°, 13.47±0.1°, 14.22±0.1°, 15.22±0.1°, 19.45±0.1°, 19.82±0.1°, 20.29±0.1°, 20.90±0.1°, 22.53±0.1°, 24.89±0.1°, 25.39±0.1°, 25.83±0.1° and 26.88±0.1°.
상기 결정형 B를 시차주사열량(differential scanning calorimetry, DSC)을 이용한 분석시, 열중량 분석(thermogravimetric analysis)의 초기 중량 손실에 해당하는 약 91℃ 위치에서 넓은 흡열 피크가 관찰된다. 추가로 가열하면 약 142℃ (onset)에서 흡열이 관찰된다. 상기 결정형 B를 hot stage microscopy(HSM)를 하면 130.2-151.3℃ 내에서 녹는 현상이 관찰된다.When the crystalline Form B is analyzed using differential scanning calorimetry (DSC), a broad endothermic peak is observed at about 91° C., which corresponds to an initial weight loss in thermogravimetric analysis. Upon further heating, an endotherm is observed at about 142°C (onset). When the crystalline form B is subjected to hot stage microscopy (HSM), a melting phenomenon is observed within 130.2-151.3°C.
본 발명에 따른 일 구체예에서, 상기 약제학적으로 허용되는 염은 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산, 타타르산, 포름산, 시트르산, 아세트산, 트라이클로로아세트산, 트라이플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산으로 이루어진 그룹으로부터 선택될 수 있다. 본 발명에 따른 일 구체예에서 상기 약제학적으로 허용되는 염은 염산일 수 있다.In one embodiment according to the present invention, the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, glue conic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid. In one embodiment according to the present invention, the pharmaceutically acceptable salt may be hydrochloric acid.
본 발명에 따른 일 구체예에서, 상기 용매화물은 수화물일 수 있다.In one embodiment according to the present invention, the solvate may be a hydrate.
본 발명의 다른 측면에 따르면, 상기 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형 B를, 약제학적으로 허용되는 담체와 함께 포함하는 약제학적 조성물이 제공된다.According to another aspect of the present invention, the 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- Provided is a pharmaceutical composition comprising crystalline Form B of ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
본 발명에서 "약제학적 조성물"은 본 발명에 따른 활성 화합물에 추가하여 담체, 희석제, 부형제 등과 같은 다른 화학 성분들을 포함할 수 있다. 따라서, 상기 약제학적 조성물에는 필요에 따라 약제학적으로 허용되는 담체, 희석제, 부형제, 또는 이들의 조합이 포함될 수 있다. 약제학적 조성물은 생물체 내로 활성 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다.In the present invention, "pharmaceutical composition" may include other chemical ingredients such as carriers, diluents, excipients and the like in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. The pharmaceutical composition facilitates administration of the active compound into an organism. Various techniques for administering a compound exist, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
본 명세서에서 “담체(carrier)”란 세포 또는 조직 내로 화합물의 투입을 용이하게 하는 화합물을 의미한다. 예를 들어, 디메틸설폭사이드(DMSO)는 생물체의 세포 또는 조직 내로 많은 유기 화합물의 투입을 용이하게 하는 통상의 담체이다.As used herein, the term “carrier” refers to a compound that facilitates the introduction of the compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into cells or tissues of living organisms.
본 명세서에서 “희석제(diluent)”란 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 화합물로 정의된다. 완충액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 완충액은 인체 용액의 염 형태를 모방하고 있는 포스페이트 완충 식염수이다. 완충제 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 완충 희석제가 화합물의 생물학적 활성을 변형시키는 일은 드물다.As used herein, "diluent" is defined as a compound that is diluted in water to dissolve the compound as well as to stabilize the biologically active form of the compound. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for a buffered diluent to modify the biological activity of a compound.
본 명세서에서 “약제학적으로 허용되는(pharmaceutically acceptable)”이란, 화합물의 생물학적 활성과 물성들을 손상시키지 않는 성질을 의미한다.As used herein, “pharmaceutically acceptable” refers to a property that does not impair the biological activity and physical properties of a compound.
본 발명에서 화학식 1의 화합물의 결정형은 목적하는 바에 따라 다양한 약제학적 투여 형태로 제형화될 수 있다. 본 발명에 따른 약제학적 조성물을 제조하는 경우, 유효 성분, 구체적으로 화학식 1의 화합물, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형 B를, 제조하고자 하는 제형에 따라 선택될 수 있는 다양한 약제학적으로 허용되는 담체와 함께 혼합한다. 예를 들어, 본 발명에 따른 약제학적 조성물은 목적하는 바에 따라 주사용 제제, 경구용 제제 등으로 제형화될 수 있다.In the present invention, the crystalline form of the compound of Formula 1 may be formulated into various pharmaceutical dosage forms as desired. When preparing the pharmaceutical composition according to the present invention, the active ingredient, specifically, the crystalline form B of the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, various agents that can be selected depending on the dosage form to be prepared Mix with a scientifically acceptable carrier. For example, the pharmaceutical composition according to the present invention may be formulated as an injectable preparation, an oral preparation, etc. as desired.
본 발명의 화학식 1의 화합물의 결정형은 공지된 제약용 담체와 부형제를 이용하는 공지의 방법으로 제제화되어 단위 용량 형태 또는 다용량 용기에 내입될 수 있다. 제제의 형태는 오일 또는 수성 매질 중의 용액, 현탁액 또는 유화액 형태일 수 있으며, 통상의 분산제, 현탁제 또는 안정화제를 함유할 수 있다. 또한, 예를 들어, 사용 전에 무균, 발열물질이 제거된 물에 녹여 사용하는 건조 분말의 형태일 수도 있다. 본 발명의 화학식 1의 화합물의 결정형은 또한, 코코아버터 또는 기타 글리세리드와 같은 통상의 좌약 기제를 이용하여 좌약형으로 제제화될 수도 있다. 경구 투여용 고체투여 형태는 캅셀제, 정제, 환제, 산제 및 과립제가 가능하고, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장용피제로 제조하는 것이 바람직하다. 고체투여 형태는 본 발명의 화학식 1의 화합물의 결정형을 수크로오즈, 락토오스, 전분 등과 같은 하나 이상의 불활성 희석제 및 마그네슘 스테아레이트와 같은 윤활제, 붕해제, 결합제 등과 같은 담체와 혼합시킴으로써 제조할 수 있다. 또한, 경피(transdermal) 투여 형태로 제제화될 수 있고, 예를 들면 로션, 연고, 겔, 크림, 패취 또는 분무제 등으로 제형화될 수 있다.The crystalline form of the compound of formula (1) of the present invention may be formulated by a known method using a known pharmaceutical carrier and excipient, and then put into a unit dose form or a multi-dose container. The form of the preparation may be in the form of a solution, suspension or emulsion in oil or aqueous medium, and may contain customary dispersing, suspending or stabilizing agents. Also, for example, it may be in the form of a dry powder that is used by dissolving it in sterile, pyrogen-free water before use. The crystalline form of the compound of Formula 1 of the present invention may also be formulated in a suppository form using a conventional suppository base such as cocoa butter or other glycerides. A solid dosage form for oral administration can be capsules, tablets, pills, powders and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with an enteric coating. A solid dosage form can be prepared by mixing the crystalline form of the compound of formula 1 of the present invention with one or more inert diluents such as sucrose, lactose, starch, and the like, and a carrier such as a lubricant, disintegrant, binder, etc., such as magnesium stearate. In addition, it may be formulated in a transdermal dosage form, for example, a lotion, ointment, gel, cream, patch or spray, and the like.
본 발명에 따른 약제학적 조성물은 스핑고신-1-인산 수용체 관련 질환의 예방 또는 치료에 적합하다. 본 발명의 일 구체예에서, 상기 약제학적 조성물은 다발성 경화증을 포함하는 자가면역 장애의 치료에 사용될 수 있다. 본 발명에 따른 일 구체예에서, 상기 약제학적 조성물은 스핑고신-1-인산이 관여하는 바람직하지 않은 림프구 침윤에 의해 야기되는 질환의 예방 또는 치료에 사용될 수 있다. 본 발명에 따른 일 구체예에서, 상기 약제학적 조성물은 면역조정 이상의 예방 또는 치료에 사용될 수 있다. 본 발명에 따른 일 구체예에서, 상기 면역조정 이상은, 예를 들면 전신 홍반성 루프스(systemic lupus erythematosus), 만성 류마티스 관절염(chronic rheumatoid arthritis), 염증성 장질환(inflammatory bowel diseases), 다발성 경화증(multiple sclerosis), 근위축성 측색 경화증(amyotrophic lateral sclerosis, ALS), 동맥경화증(arteriosclerosis), 죽상동맥경화증(atherosclerosis), 피부경화증(scleroderma) 및 자가면역성 간염(autoimmune hepatitis)으로 이루어진 그룹으로부터 선택되는 자가면역 또는 만성 염증 질환일 수 있으나 이에 제한되는 것은 아니다.The pharmaceutical composition according to the present invention is suitable for preventing or treating sphingosine-1-phosphate receptor-related diseases. In one embodiment of the present invention, the pharmaceutical composition may be used for the treatment of autoimmune disorders including multiple sclerosis. In one embodiment according to the present invention, the pharmaceutical composition can be used for the prevention or treatment of diseases caused by undesirable lymphocyte infiltration involving sphingosine-1-phosphate. In one embodiment according to the present invention, the pharmaceutical composition can be used for the prevention or treatment of immunomodulatory disorders. In one embodiment according to the present invention, the immunomodulatory abnormality is, for example, systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis autoimmune selected from the group consisting of sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma and autoimmune hepatitis; It may be a chronic inflammatory disease, but is not limited thereto.
본 명세서에서 “예방”이란 질병에 걸릴 가능성을 감소시키거나 가능성을 제거하는 것이다.As used herein, “prevention” refers to reducing or eliminating the possibility of contracting a disease.
본 명세서에서 “치료”란 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단, 지연 또는 완화시키는 것을 의미한다.As used herein, “treatment” means stopping, delaying, or alleviating the progression of a disease when used for an object showing symptoms of onset.
본 발명의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형 B는 스핑고신-1-인산 수용체 효능제로서의 약리 활성을 가짐과 동시에 안정성, 예를 들면 열 안정성 및 저장 안정성과 같은 뛰어난 약제학적 특성을 갖는다.1-[1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperi of the present invention Crystalline Form B of din-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, has pharmacological activity as a sphingosine-1-phosphate receptor agonist, and at the same time has stability, such as thermal stability and storage stability. It has the same excellent pharmaceutical properties.
도 1은 결정형 B의 X선 분말 회절(XRPD) 스펙트럼이다.1 is an X-ray powder diffraction (XRPD) spectrum of Form B.
도 2는 결정형 B의 열중량 분석(TGA)/시차주사열량(DSC) 분석 결과이다.2 is a thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) analysis results of Form B.
도 3은 결정형 B의 hot stage microscopy 결과이다.3 is a hot stage microscopy result of Form B.
도 4는 결정형 B의 슬러리화 전/후의 X선 분말 회절(XRPD) 스펙트럼을 비교한 결과이다.4 is a comparison result of X-ray powder diffraction (XRPD) spectra before and after slurrying of Form B.
이하에서 본원 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 하나 이상의 구체예를 예시적으로 설명하기 위한 것일 뿐 발명의 범위가 이들에 의해서 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only of one or more embodiments, and the scope of the invention is not limited thereto.
제조예 1: 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산 염산염의 합성Preparation 1: 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalen-2-ylmethyl] -p Synthesis of peridine-4-carboxylic acid hydrochloride
1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산 에틸에스터를 국제공개번호 WO 2014/129796 A1호의 제조예 153-1에 기재된 방법에 따라 합성하고, 에스터를 NaOH로 가수분해하고, HCl로 산성화시킨 다음 결정화하여 염산염(이하에서 “화합물 1”이라 한다)을 얻었다.1-[1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4 -Carboxylic acid ethyl ester was synthesized according to the method described in Preparation Example 153-1 of International Publication No. WO 2014/129796 A1, the ester was hydrolyzed with NaOH, acidified with HCl, and then crystallized to form a hydrochloride (hereinafter “compound 1”) was obtained.
제조예 2: 기본 결정형의 제조Preparation Example 2: Preparation of basic crystalline form
반응기에 화합물 1(226 g, 0.46 mol), 에탄올(1.13 L, 5 fold), 물(0.57 L, 2.5 fold) 및 NaOH(32 g, 0.80 mol)를 투입하였다. 내부온도 45℃에서 60분 동안 가열한 뒤 내부온도를 28℃로 냉각시켰다. 반응 혼합물에 디클로로메탄(DCM)(340 ml, 1.5 fold)를 투입 후 6 N HCl(167 ml, 1.00 mol)를 50 분간 천천히 적가하여 용액의 pH를 2.5로 산성화시킨 뒤　에틸 아세테이트(EtOAc)(0.23 L, 1 fold)를 투입하여 결정화를 진행하였다. 내부온도를 5℃로 냉각하고 30분간 숙성 후 여과한 뒤 물 (1.13 L, 5 fold)로 2회, 메틸 tert-부틸 에테르(MTBE)(0.50 L, 3 fold)로 1회 세척하여 다음의 표 1의 XRPD(x-ray powder diffraction) 패턴을 갖는 화합물 1의 결정형(이하에서 “결정형 A”라 한다)(156 g, two step yield 69.0%)를 수득하였다.Compound 1 (226 g, 0.46 mol), ethanol (1.13 L, 5 fold), water (0.57 L, 2.5 fold) and NaOH (32 g, 0.80 mol) were added to the reactor. After heating at an internal temperature of 45°C for 60 minutes, the internal temperature was cooled to 28°C. After dichloromethane (DCM) (340 ml, 1.5 fold) was added to the reaction mixture, 6 N HCl (167 ml, 1.00 mol) was slowly added dropwise over 50 minutes to acidify the pH of the solution to 2.5, and then ethyl acetate (EtOAc) (0.23) L, 1 fold) was added to proceed with crystallization. After cooling the internal temperature to 5℃, aging for 30 minutes, filtration, washing twice with water (1.13 L, 5 fold) and once with methyl tert-butyl ether (MTBE) (0.50 L, 3 fold) A crystalline form (hereinafter referred to as "crystalline form A") of compound 1 having an X-ray powder diffraction (XRPD) pattern of 1 (156 g, two step yield 69.0%) was obtained.
[표 1][Table 1]
Figure PCTKR2022005376-appb-img-000003
Figure PCTKR2022005376-appb-img-000003
실시예 1: 결정형 B의 제조Example 1: Preparation of Form B
다음의 3가지 방법으로 결정형 B를 제조하였다.Form B was prepared by the following three methods.
(1) 결정형 A를 에탄올과 물 50:50 혼합용매에 녹인 후, 0.2 μm 나일론 필터를 통해 유리 바이알로 여과하였다. 바이알을 개방시킨 상태에서 상온에서 증발시켰을 때 결정형의 흰 고체를 수득하였다.(1) Form A was dissolved in a 50:50 mixed solvent of ethanol and water, and then filtered through a 0.2 μm nylon filter through a glass vial. When the vial was opened and evaporated at room temperature, a crystalline white solid was obtained.
(2) 결정형 A를 테트라하이드로퓨란과 물 5:1 혼합용매에 녹여 용액상태로 제조한 후, 반용매인 사이클로헥세인을 천천히 추가하였다. 이때 테트라하이드로퓨란/물 혼합용매와 사이클로헥세인은 1:20 비율로 사용되었다. 상온에서 1일동안 교반 후 3일 동안 냉장보관하였다. 침전물이 생기면 0.45 μm PVDF 필터를 통해 여과하였다.(2) Form A was dissolved in a mixed solvent of tetrahydrofuran and water 5:1 to prepare a solution, and then cyclohexane, an anti-solvent, was slowly added. At this time, tetrahydrofuran/water mixed solvent and cyclohexane were used in a ratio of 1:20. After stirring at room temperature for 1 day, it was refrigerated for 3 days. If a precipitate formed, it was filtered through a 0.45 μm PVDF filter.
(3) 결정형 A를 메탄올과 메틸 tert-부틸 에테르 70: 30 혼합용매에 녹인 후, 35℃로 잠깐 동안 가열하였다. 이때 대부분의 고체가 용해되었다. 예열된 0.2 μm 나일론 필터를 통해 여과하여 해당 온도에서 예열된 깨끗한 바이알에 넣었다. 그 다음 용액을 가열판에서 제거하고 상온으로 냉각되도록 하였다. 바이알 내에 고체가 생성되지 않아, 바이알을 개방시킨 상태에서 상온에서 증발시켰을 때 결정형의 흰 고체를 수득하였다.(3) Form A was dissolved in a mixed solvent of methanol and methyl tert-butyl ether 70:30, and then heated to 35°C for a while. At this time, most of the solid was dissolved. It was filtered through a preheated 0.2 μm nylon filter and placed in a clean vial preheated to that temperature. The solution was then removed from the heating plate and allowed to cool to room temperature. Since no solid was formed in the vial, a crystalline white solid was obtained when the vial was evaporated at room temperature with the vial open.
실시예 2: 결정형 B의 분석Example 2: Analysis of Form B
(1) XRPD (x-ray powder diffraction)(1) XRPD (x-ray powder diffraction)
XRPD 분석은 Cu 방사선 입사빔을 사용하는 Panalytical Xpert Pro MPD 회절계를 사용하여 수행되었다. 약 20~30 mg의 시료를 glass sample holder에 평평한 표면을 갖도록 다져 올려놓은 후, 기기의 generator를 45kV(acceleration voltage), 40mA(filament emission)로 설정한 후 reflection mode (not-spin)로 측정하였다. 0.026°의 스텝 사이즈(step size) 및 51초의 Time per step 조건으로 4~40°범위의 Bragg 각(2θ)을 측정했다. XRPD 패턴은 HighScore Plus 2.2c 소프트웨어를 사용하여 분류 및 처리되었고 결과를 도 1 및 표 2에 나타내었다.XRPD analysis was performed using a Panalytical Xpert Pro MPD diffractometer using an incident beam of Cu radiation. After compacting a sample of about 20 to 30 mg to have a flat surface on a glass sample holder, the generator was set to 45kV (acceleration voltage), 40mA (filament emission), and then measured in reflection mode (not-spin). . Bragg angles (2θ) in the range of 4 to 40° were measured with a step size of 0.026° and a Time per step condition of 51 seconds. XRPD patterns were classified and processed using HighScore Plus 2.2c software and the results are shown in Figure 1 and Table 2.
(2) TGA/DSC combination (thermogravimetric analysis/differential scanning calorimetry)(2) TGA/DSC combination (thermogravimetric analysis/differential scanning calorimetry)
TGA/DSC 콤보 분석은 Mettler-Toledo TGA/DSC3+ 분석기를 사용하여 수행되었다. 시료를 열린 알루미늄 팬에 넣고, 팬을 밀봉한 뒤 뚜껑을 뚫은 다음 TG 용광로에 삽입했다. 질소하에서 10℃/분의 속도로 30℃에서 최대 250℃까지 가열하였다. 결과를 도 2에 나타내었다.TGA/DSC combo analysis was performed using a Mettler-Toledo TGA/DSC3+ analyzer. The sample was placed in an open aluminum pan, the pan was sealed, the lid pierced, and then inserted into the TG furnace. Heated under nitrogen at a rate of 10° C./min from 30° C. up to 250° C. The results are shown in FIG. 2 .
(3) HSM (hot stage microscopy)(3) HSM (hot stage microscopy)
핫스테이지 현미경 검사는 Leica DM LP 현미경에서 TMS93 컨트롤러와 함께 Linkman 핫 스테이지(모델 FTIR 600)를 사용하여 수행되었다. 샘플은 10x0.22 또는 20x0.40 배율에서 교차 편광판이 있는 람다 플레이트를 사용하여 관찰되었다. 샘플은 커버 슬립에 놓고 또 다른 커버 슬립을 샘플 위에 놓았다. 스테이지가 가열되면서 샘플이 시각적으로 관찰되었다. 가스 방출을 조사하기 위해 일부 경우 샘플에 미네랄 오일 한 방울이 추가될 수 있다. 이미지는 SPOT 소프트웨어 v. 4.5.9와 함께 SPOT Insight 컬러 디지털 카메라를 사용하여 캡처되었다(도 3).Hotstage microscopy was performed on a Leica DM LP microscope using a Linkman hot stage (model FTIR 600) with a TMS93 controller. Samples were observed using a lambda plate with crossed polarizers at either 10x0.22 or 20x0.40 magnification. A sample was placed on a cover slip and another coverslip was placed over the sample. The sample was visually observed as the stage was heated. A drop of mineral oil may be added to the sample in some cases to investigate outgassing. Images are from SPOT software v. Captured using a SPOT Insight color digital camera with 4.5.9 (Figure 3).
(4) 결과(4) Results
XRPD분석결과, 결정형으로 구성된 화합물임을 확인할 수 있었으며, 구체적인 값은 하기 표 1에 나타내었다.As a result of XRPD analysis, it was confirmed that the compound was in a crystalline form, and specific values are shown in Table 1 below.
[표 2][Table 2]
Figure PCTKR2022005376-appb-img-000004
Figure PCTKR2022005376-appb-img-000004
DSC 결과, TGA의 초기 중량 손실에 해당하는 약 91℃ 위치에서 넓은 흡열 피크가 관찰되었다. 추가로 가열하면 약 142℃ (onset)에서 흡열이 관찰되는데, 이는 HSM 관찰을 기반으로 한 탈수된 고체의 용융 때문일 가능성이 높았다. 결정형 B는 결정형 A의 수화물일 가능성이 높았고, TGA의 초기 무게 감소는 약 2.3 몰의 H2O에 해당한다.As a result of DSC, a broad endothermic peak was observed at about 91° C. corresponding to the initial weight loss of TGA. Upon further heating, an endotherm was observed at about 142 °C (onset), most likely due to melting of the dehydrated solid based on HSM observations. Form B was most likely a hydrate of Form A, and the initial weight loss of TGA corresponds to about 2.3 moles of H 2 O.
HSM 결과 130.2-151.3℃ 내에서 녹는 현상이 관찰되었다.As a result of HSM, a melting phenomenon was observed within 130.2-151.3°C.
결정형 B를 seed로 사용하여 결정형 A와 함께 50:50 EtOH/H2O (결정형 B가 생성된 용매 조건, 생성방법은 Fast evaporation)에서 상온에서 9일간 교반하였고, 분리된 고체는 결정형 A와 일치하였다.Using crystalline form B as a seed, it was stirred for 9 days at room temperature in 50:50 EtOH/H 2 O (solvent conditions in which crystalline form B was produced, fast evaporation) together with crystalline form A, and the separated solid was identical to crystalline form A did.

Claims (9)

  1. 다음의 X선 회절 패턴 스펙트럼 중에서 선택되는 3개 이상의 특성 피크(2θ)를 갖는 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형:1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)- having three or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum A crystalline form of 3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof:
    6.98±0.2°, 11.10±0.2°, 12.49±0.2°, 13.47±0.2°, 14.22±0.2°, 15.22±0.2°, 19.45±0.2°, 19.82±0.2°, 20.29±0.2°, 20.90±0.2°, 22.53±0.2°, 24.89±0.2°, 25.39±0.2°, 25.83±0.2° 및 26.88±0.2°.6.98±0.2°, 11.10±0.2°, 12.49±0.2°, 13.47±0.2°, 14.22±0.2°, 15.22±0.2°, 19.45±0.2°, 19.82±0.2°, 20.29±0.2°, 20.90±0.2°, 22.53±0.2°, 24.89±0.2°, 25.39±0.2°, 25.83±0.2° and 26.88±0.2°.
  2. 제1항에 있어서, 다음의 X선 회절 패턴 스펙트럼 중에서 선택되는 3개 이상의 특성 피크(2θ)를 갖는 것을 특징으로 하는 결정형:The crystalline form according to claim 1, characterized in that it has at least three characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectra:
    6.98±0.1°, 11.10±0.1°, 12.49±0.1°, 13.47±0.1°, 14.22±0.1°, 15.22±0.1°, 19.45±0.1°, 19.82±0.1°, 20.29±0.1°, 20.90±0.1°, 22.53±0.1°, 24.89±0.1°, 25.39±0.1°, 25.83±0.1° 및 26.88±0.1°.6.98±0.1°, 11.10±0.1°, 12.49±0.1°, 13.47±0.1°, 14.22±0.1°, 15.22±0.1°, 19.45±0.1°, 19.82±0.1°, 20.29±0.1°, 20.90±0.1°, 22.53±0.1°, 24.89±0.1°, 25.39±0.1°, 25.83±0.1° and 26.88±0.1°.
  3. 제1항에 있어서, 상기 약제학적으로 허용되는 염이 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산, 타타르산, 포름산, 시트르산, 아세트산, 트라이클로로아세트산, 트라이플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산으로 이루어진 그룹으로부터 선택되는 것을 특징으로 하는 결정형.According to claim 1, wherein the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid , lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid.
  4. 제3항에 있어서, 상기 약제학적으로 허용되는 염이 염산인 것을 특징으로 하는 결정형.The crystalline form according to claim 3, wherein the pharmaceutically acceptable salt is hydrochloric acid.
  5. 제1항에 있어서, 상기 용매화물이 수화물인 것을 특징으로 하는 결정형.The crystalline form according to claim 1, wherein the solvate is a hydrate.
  6. 제1항의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형을, 약제학적으로 허용되는 담체와 함께 포함하는, 다발성 경화증을 포함하는 자가면역 장애의 치료용 약제학적 조성물.The 1-[1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperi of claim 1 A pharmaceutical composition for the treatment of autoimmune disorders including multiple sclerosis, comprising a crystalline form of din-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
  7. 제1항의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형을, 약제학적으로 허용되는 담체와 함께 포함하는, 스핑고신-1-인산이 관여하는 바람직하지 않은 림프구 침윤에 의해 야기되는 질환의 예방 또는 치료용 약제학적 조성물.The 1-[1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperi of claim 1 By undesirable lymphocyte infiltration involving sphingosine-1-phosphate comprising a crystalline form of din-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier A pharmaceutical composition for preventing or treating a disease caused.
  8. 제1항의 1-[1-클로로-6-(3-클로로-1-아이소프로필-1H-인다졸-5-일메톡시)-3,4-디하이드로-나프탈렌-2-일메틸]-피페리딘-4-카르복실산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물의 결정형을, 약제학적으로 허용되는 담체와 함께 포함하는, 면역조정 이상의 예방 또는 치료용 약제학적 조성물.The 1-[1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperi of claim 1 A pharmaceutical composition for the prevention or treatment of immunomodulatory disorders, comprising a crystalline form of din-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier.
  9. 제8항에 있어서, 상기 면역조정 이상이 전신 홍반성 루프스, 만성 류마티스 관절염, 염증성 장질환, 다발성 경화증, 근위축성 측색 경화증(ALS), 동맥경화증, 죽상동맥경화증, 피부경화증 및 자가면역성 간염으로 이루어진 그룹으로부터 선택되는 자가면역 또는 만성 염증 질환인 것을 특징으로 하는 약제학적 조성물.9. The method of claim 8, wherein the immunomodulatory abnormality consists of systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma and autoimmune hepatitis. A pharmaceutical composition, characterized in that it is an autoimmune or chronic inflammatory disease selected from the group.
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EP1826197A1 (en) * 2004-12-13 2007-08-29 Ono Pharmaceutical Co., Ltd. Aminocarboxylic acid derivative and medicinal use thereof
WO2008064320A2 (en) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
KR20140104376A (en) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
US10166250B2 (en) * 2009-08-05 2019-01-01 Biogen Ma Inc. Bicyclic aryl sphingosine 1-phosphate analogs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1826197A1 (en) * 2004-12-13 2007-08-29 Ono Pharmaceutical Co., Ltd. Aminocarboxylic acid derivative and medicinal use thereof
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
WO2008064320A2 (en) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity
US10166250B2 (en) * 2009-08-05 2019-01-01 Biogen Ma Inc. Bicyclic aryl sphingosine 1-phosphate analogs
KR20140104376A (en) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent

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