WO2022220600A1 - Forme cristalline d'un agoniste du récepteur de la sphingosine-1-phosphate - Google Patents

Forme cristalline d'un agoniste du récepteur de la sphingosine-1-phosphate Download PDF

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Publication number
WO2022220600A1
WO2022220600A1 PCT/KR2022/005377 KR2022005377W WO2022220600A1 WO 2022220600 A1 WO2022220600 A1 WO 2022220600A1 KR 2022005377 W KR2022005377 W KR 2022005377W WO 2022220600 A1 WO2022220600 A1 WO 2022220600A1
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Prior art keywords
acid
chloro
pharmaceutically acceptable
crystalline form
acceptable salt
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PCT/KR2022/005377
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English (en)
Korean (ko)
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김지윤
전슬아
박기숙
김성원
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주식회사 엘지화학
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Priority to CN202280026441.1A priority Critical patent/CN117120426A/zh
Publication of WO2022220600A1 publication Critical patent/WO2022220600A1/fr

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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- to a crystalline form of 5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt 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 an object to provide a crystalline form of ]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof with pharmaceutical superiority:
  • 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 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 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 its Crystalline forms of the pharmaceutically acceptable salts are provided: 8.93 ⁇ 0.2o, 9.17 ⁇ 0.2o, 9.49 ⁇ 0.2o, 13.36 ⁇ 0.2o, 13.81 ⁇ 0.2o, 15.04 ⁇ 0.2o, 16.15 ⁇ 0.2o, 17.41 ⁇ 0.2o , 18.07 ⁇ 0.2o, 18.59 ⁇ 0.2o, 19.56 ⁇ 0.2o, 20.75 ⁇ 0.2o, 21.26 ⁇ 0.2o, 21.70 ⁇ 0.2o, 22.66 ⁇ 0.2o, 24.72 ⁇ 0.2o, 25.65 ⁇ 0.2o, 27.19 ⁇ 0.2o and 31.10 ⁇ 0.2
  • the crystalline form III 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: 8.93 ⁇ 0.1o, 9.17 ⁇ 0.1o, 9.49 ⁇ 0.1o, 13.36 ⁇ 0.1o, 13.81 ⁇ 0.1o, 15.04 ⁇ 0.1o, 16.15 ⁇ 0.1o, 17.41 ⁇ 0.1o, 18.07 ⁇ 0.1o, 18.59 ⁇ 0.1o, 19.56 ⁇ 0.1o, 20.75 ⁇ 0.1o, 21.26 ⁇ 0.1o, 21.70 ⁇ 0.1o, 22.66 ⁇ 0.1o, 24.72 ⁇ 0.1o, 25.65 ⁇ 0.1o, 27.19 ⁇ 0.1o and 31.10 ⁇ 0.1o.
  • thermogravimetric analysis TGA
  • DSC differential scanning calorimetry
  • 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.
  • the pharmaceutically acceptable salt may be hydrochloric acid.
  • 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 III of ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt 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 III of the compound of Formula 1 or a pharmaceutically acceptable salt thereof
  • various pharmaceutically acceptable carriers that can be selected depending on the dosage form to be prepared mix with
  • 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.
  • Form III of din-4-carboxylic acid or a pharmaceutically acceptable salt thereof has pharmacological activity as a sphingosine-1-phosphate receptor agonist and at the same time has excellent pharmaceutical properties such as stability, e.g. thermal stability and storage stability.
  • thermogravimetric analysis TGA
  • 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 A was dissolved in dimethyl sulfoxide to prepare a solution, and then acetonitrile was slowly added.
  • dimethyl sulfoxide and isopophyl alcohol 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.
  • XRPD analysis was performed using a Panalytical Xpert Pro MPD diffractometer using an incident Cu radiation beam. 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.
  • DSC was measured using a Mettler Toledo DSC1 system. A sample of about 2-5 mg was weighed and placed in 40 ⁇ L Al crucible (flat-bottomed aluminum pan with one pin-hole lid) to make one pin hole. Thereafter, the sample was heated from 25° C. to 350° C. at a rate of 10° C./min to measure DSC. During the measurement, nitrogen gas was supplied to the inside of the instrument at a rate of 70 mL/min to prevent the inflow of oxygen and other gases. Data collection and evaluation were performed using the software STARe (FIG. 2).
  • the TGA was measured using a Mettler Toledo TGA/DSC 1 module. Approximately 4-8 mg of the sample was weighed and placed in 100 ⁇ L Al crucible (flat-bottomed aluminum crucibles). Thereafter, the TGA was measured by heating the sample from 30°C to 350°C at a rate of 10°C/min. During the measurement, nitrogen gas was supplied to the inside of the instrument at a rate of 80 mL/min to prevent the inflow of oxygen and other gases. Data collection and evaluation were performed using the software STARe (FIG. 2).

Abstract

La présente invention concerne une forme cristalline d'un agoniste du récepteur de la sphingosine-1-phosphate et, plus particulièrement, une forme cristalline de l'acide 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylméthoxy)-3,4-dihydro-naphtalén-2-ylméthyl]-pipéridine-4-carboxylique de formule chimique 1 ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/KR2022/005377 2021-04-14 2022-04-13 Forme cristalline d'un agoniste du récepteur de la sphingosine-1-phosphate WO2022220600A1 (fr)

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Application Number Priority Date Filing Date Title
CN202280026441.1A CN117120426A (zh) 2021-04-14 2022-04-13 鞘氨醇-1-磷酸酯受体激动剂的结晶形式

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KR20210048828 2021-04-14
KR10-2021-0048828 2021-04-14

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WO2022220600A1 true WO2022220600A1 (fr) 2022-10-20

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1826197A1 (fr) * 2004-12-13 2007-08-29 Ono Pharmaceutical Co., Ltd. Dérivé d'acide aminocarboxylique et applications thérapeutiques dudit dérivé
WO2008064320A2 (fr) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Analogues d'hydrindane ayant une activité agoniste de récepteur de sphingosine-1-phosphate
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물
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 (fr) * 2004-12-13 2007-08-29 Ono Pharmaceutical Co., Ltd. Dérivé d'acide aminocarboxylique et applications thérapeutiques dudit dérivé
US20080200535A1 (en) * 2006-08-25 2008-08-21 Asahi Kasei Pharma Corporation Amine Compounds
WO2008064320A2 (fr) * 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Analogues d'hydrindane ayant une activité agoniste de récepteur de sphingosine-1-phosphate
US10166250B2 (en) * 2009-08-05 2019-01-01 Biogen Ma Inc. Bicyclic aryl sphingosine 1-phosphate analogs
KR20140104376A (ko) * 2013-02-20 2014-08-28 주식회사 엘지생명과학 스핑고신-1-인산 수용체 효능제, 그의 제조방법 및 그를 활성성분으로서 함유하는 약제학적 조성물

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KR20220142383A (ko) 2022-10-21
TWI812166B (zh) 2023-08-11
CN117120426A (zh) 2023-11-24
TW202302564A (zh) 2023-01-16

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