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WO2025080049A1 - Composé pour inhiber l'atx, son procédé de préparation et composition pharmaceutique destinée à être utilisée dans la prévention ou le traitement de maladies liées à l'activité de l'atx le contenant en tant que principe actif - Google Patents

Composé pour inhiber l'atx, son procédé de préparation et composition pharmaceutique destinée à être utilisée dans la prévention ou le traitement de maladies liées à l'activité de l'atx le contenant en tant que principe actif Download PDF

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Publication number
WO2025080049A1
WO2025080049A1 PCT/KR2024/015527 KR2024015527W WO2025080049A1 WO 2025080049 A1 WO2025080049 A1 WO 2025080049A1 KR 2024015527 W KR2024015527 W KR 2024015527W WO 2025080049 A1 WO2025080049 A1 WO 2025080049A1
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Prior art keywords
methyl
chlorophenyl
ylidene
phenoxy
dioxopyrrolidin
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Korean (ko)
Inventor
오광석
임채조
이규양
이병호
이정현
최준영
서호원
장우대
이미영
고준수
찬드라세카란라마크리쉬난
이주용
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Arontier Co Ltd
Korea Research Institute of Chemical Technology KRICT
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Arontier Co Ltd
Korea Research Institute of Chemical Technology KRICT
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Publication of WO2025080049A1 publication Critical patent/WO2025080049A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present disclosure relates to a compound having a specific structure having excellent ATX inhibitory activity and a method for preparing the same.
  • the present disclosure also relates to a pharmaceutical composition for preventing or treating a disease associated with ATX activity, comprising the compound according to the present disclosure as an active ingredient. That is, the present disclosure also relates to a pharmaceutical use for preventing or treating a disease associated with ATX activity.
  • ATX inhibitors The need for the development of ATX inhibitors is that in genetically engineered mice in which the expression of the ATX gene (Enpp2) was suppressed systemically or tissue-specifically, the incidence of liver fibrosis, hepatic steatosis, and hepatocellular carcinoma was significantly reduced (Brandon et al., PLoS one, 2019, 14, e0208099), and when the ATX-LPA signaling pathway was suppressed by administering an ATX inhibitor, a significant reduction in liver fibrosis and fatty liver was confirmed in various NASH disease animal models (Bain et al., J Pharmacol Exp Ther, 2017, 360, 1-13, Jiang et al., Eur J Med Chem, 2020, 187, 111904).
  • the problem that the present disclosure seeks to solve is to provide compounds having ATX (Autotaxin) inhibitory activity, pharmaceutical compositions containing them as active ingredients, and pharmaceutical uses thereof.
  • ATX Autotaxin
  • X is H or halogen
  • n 0 or 1
  • Y is H, -COOR 1 , -CONR 1 R 2 , , -CN, OR 3 , or And,
  • halogen and “halo” as used herein mean fluorine, chlorine, bromine or iodine.
  • Examples of pharmaceutically acceptable acid addition salts include salts derived from relatively non-toxic organic acids, including acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like, as well as hydrogen chloride, hydrogen bromide, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogen iodide or phosphorous acid and the like.
  • isotopic variant means a compound that contains an unusual ratio of isotopes at one or more of the atoms that make up the compound.
  • an isotopic variant of a compound may be radiolabeled, for example, the hydrogen atoms may be selected from hydrogen, deuterium and tritium, and may contain carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc.
  • polymorph means a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical, and/or spectral properties. Differences in physical properties include, but are not limited to, stability (e.g., heat or light stability), compressibility and density (important for formulation and product manufacturing), and solubility (which may affect bioavailability).
  • stability e.g., heat or light stability
  • compressibility and density important for formulation and product manufacturing
  • solubility which may affect bioavailability
  • Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., tablet fragments stored as a kinetically favored polymorph transform to the thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • chemical reactivity e.g., differential oxidation, such as faster discoloration when composed of one polymorph than when composed of another polymorph
  • mechanical properties e.g., tablet fragments stored as a kinetically favored polymorph transform to the thermodynamically more stable polymorph
  • tablettes of one polymorph are more susceptible to degradation at high humidity.
  • Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash than another polymorph, for example due to its shape or particle size distribution.
  • solvent compound as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof, which comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in formulation, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc.
  • the compound of the present disclosure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can be obtained by performing a reaction according to step 1 below to obtain an intermediate compound; and performing a reaction according to step 2 below to obtain a compound represented by chemical formula 2.
  • X, A, Y and m are as defined above.
  • the compounds of the specific structure of the present disclosure have excellent ATX inhibitory activity, they can be usefully used for the prevention or treatment of various liver diseases including fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH).
  • liver diseases including fatty liver, liver fibrosis, cirrhosis, liver failure, hepatitis, liver cancer, chronic liver disease, nonalcoholic fatty liver (NAFL), and nonalcoholic steatohepatitis (NASH).
  • the solid target compound was obtained in a yield of 2.347 g (11.338 mmol) of 74% by the same method as step 1 of Example 3, except that 1.77 ml (16.826 mmol) of 3-chloroaniline was used.
  • Step 3 Preparation of (Z)-4-(2-(1-(2-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid
  • Example 7 44 mg (0.098 mmol) of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoic acid prepared was dissolved in 6 ml of ethanol, and a catalytic amount of sulfuric acid was added. The mixture was stirred under reflux for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with water and brine, and dried over Na 2 SO 4 . The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 49 mg (0.089 mmol) of the solid target compound in a 99% yield.
  • the solid target compound was obtained in a yield of 170 mg (0.421 mmol) of 62% by the same method as step 2 of Example 1, except that 149 mg (0.678 mmol) of 2-(benzyloxy)benzaldehyde was used.
  • the solid target compound was obtained in a yield of 144 mg (0.484 mmol) of 62% by the same method as step 2 of Example 1, except that 180 ⁇ l (0.784 mmol) of benzaldehyde was used.
  • Step 3 Preparation of (Z)-1-(3-chlorophenyl)-3-(2-((4-(protidine-1-protonyl)benzyl)oxy)benzylidene)pyrrolidine-2,5-dione
  • the solid target compound was obtained in a yield of 25 mg (0.056 mmol) of 41% in the same manner as in Step 2 of Example 5, except that 35 mg (0.137 mmol) of 4-(2-formylphenoxy)methylbenzamide prepared in Step 1 was used.
  • the target compound was obtained in a yield of 41 mg (0.124 mmol) of 63% by the same method as step 2 of Example 15, except that 21 ⁇ l (0.234 mmol) of aniline was used.
  • Step 2 Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-phenylbenzamide
  • the solid target compound was obtained in a yield of 42 mg (0.080 mmol) of 65% in the same manner as in Step 2 of Example 5, except that 41 mg (0.124 mmol) of 4-((2-formylphenoxy)methyl)-N-phenylbenzamide prepared in Step 1 was used.
  • Step 1 Preparation of naphthalen-1-yl 4-((2-formylphenoxy)methyl)benzoate
  • Step 1 of Example 15 100 mg (0.395 mmol) of 4-((2-formylphenoxy)methyl)benzoic acid, 68 mg (0.468 mmol) of 1-naphthol, 121 mg (0.585 mmol) of DCC, and 24 mg (0.195 mmol) of DMAP were dissolved in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 32 hours. After completion of the reaction, the mixture was extracted with dichloromethane, washed with water, and dried over Na 2 SO 4 . The filtrate, concentrated under reduced pressure, was purified by combi flash to obtain 154 mg (0.390 mmol) of the target compound in a 99% yield.
  • Step 1 Preparation of naphthalen-2-yl 4-((2-formylphenoxy)methyl)benzoate
  • Step 2 Preparation of naphthalen-2-yl(Z)-4-(2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)benzoate
  • the solid target compound was obtained in a yield of 612 mg (2.264 mmol) in 99% by the same method as step 1 of Example 1, except that 320 mg (2.62 mmol) of 3-hydroxybenzaldehyde was used.
  • the target compound was obtained in a yield of 40 mg (0.124 mmol) of 64% in the same manner as in Example 12, except that 50 mg (0.195 mmol) of 4-((3-formylphenoxy)methyl)benzoic acid prepared in Step 2 above was used.
  • the solid target compound was obtained in a yield of 463 mg (1.713 mmol) in 79% by the same method as in Step 1 of Example 1, except that 320 mg (2.62 mmol) of 4-hydroxybenzaldehyde was used.
  • the solid target compound was obtained in a yield of 406 mg (1.584 mmol) in 93% in the same manner as in Example 2, except that 460 mg (1.702 mmol) of methyl 4-((4-formylphenoxy)methyl)benzoate prepared in Step 1 was used.
  • the target compound was obtained in a yield of 72 mg (0.223 mmol) of 57% in the same manner as in Example 12, except that 100 mg (0.390 mmol) of 4-((4-formylphenoxy)methyl)benzoic acid prepared in Step 2 above was used.
  • Step 2 of Example 15 The same procedure as in Step 2 of Example 15 was followed, except that 50 mg (0.195 mmol) of 4-((3-formylphenoxy)methyl)benzoic acid prepared in Step 2 of Example 22 and 117 ⁇ l (0.234 mmol) of 2 M methylamine in THF were used, to obtain the target compound (50 mg (0.186 mmol) in a 95% yield).
  • the solid target compound was obtained in a yield of 54.9 mg (0.119 mmol) of 67% in the same manner as in Step 2 of Example 5, except that 48 mg (0.178 mmol) of 4-((4-formylphenoxy)methyl)-N-methylbenzamide prepared in Step 1 was used.
  • the target compound was obtained in a yield of 50 mg (0.176 mmol) in 90% using the same method as in step 2 of Example 15, except that 117 ⁇ l (0.234 mmol) of 2 M ethylamine in methanol was used.
  • Step 2 Preparation of (Z)-4-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-propylbenzamide
  • the target compound was obtained in a yield of 46 mg (0.148 mmol) of 76% by the same method as step 2 of Example 15, except that 31 ⁇ l (0.293 mmol) of tert-butylamine was used.
  • the solid target compound was obtained in a yield of 555 mg (2.053 mmol) in 94% by the same method as in Step 1 of Example 1, except that 500 mg (2.18 mmol) of methyl 3-(dimethyl)benzoate was used.
  • Step 4 Preparation of (Z)-3-(2-(1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)-N-methylbenzamide
  • the solid target compound was obtained in a yield of 15 mg (0.033 mmol) of 29% in the same manner as in Step 2 of Example 5, except that 30 mg (0.111 mmol) of 3-((2-formylphenoxy)methyl)-N-methylbenzamide prepared in Step 3 was used.
  • step 1 Except that 40 mg (0.12 mmol) of pentyl 4-((2-formylphenoxy)methyl)benzoate prepared in step 1 was used, the same method as step 2 of Example 5 was followed to obtain 45 mg (0.08 mmol) of the solid target compound in a yield of 73%.
  • the target compound was obtained in a yield of 112 mg (0.33 mmol) of 84% by the same method as step 1 of Example 20, except that 33 ⁇ l (0.47 mmol) of 2,2,2-trifluoroethanol was used.
  • Step 2 Preparation of 2,2,2-trifluoroethyl (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate
  • the target compound was obtained in a yield of 70 mg (0.21 mmol) of 55% by the same method as step 1 of Example 20, except that 51 ⁇ l (0.47 mmol) of 2-pentanol was used.
  • the target compound was obtained in a yield of 55 mg (0.09 mmol) of 71% by the same method as step 1 of Example 20, except that 55 mg (0.16 mmol) of 5-((t-butyldiphenylsilyl)oxy)pentane-1-ol was used.
  • Step 1 Preparation of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate
  • the solid target compound was obtained in a yield of 24 mg (0.05 mmol) of 33% in the same manner as in Example 43, except that 32 mg (0.19 mmol) of methyl 6-(hydroxymethyl)picolinate was used.
  • the solid target compound was obtained in a yield of 78 mg (0.24 mmol) in the same manner as in Example 2, except that 150 mg (0.43 mmol) of methyl 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinate prepared in step 1 of Example 43 was used.
  • the solid target compound was obtained in a yield of 9 mg (0.02 mmol) in the same manner as in Step 2 of Example 5, except that 12 mg (0.04 mmol) of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinic acid prepared in Step 1 of Example 46 was used.
  • the solid target compound was obtained in a yield of 63 mg (0.15 mmol) of 71% in the same manner as in Step 2 of Example 5, except that 50 mg (0.21 mmol) of 4-((2-formylphenoxy)methyl)benzonitrile prepared in Step 1 was used.
  • Step 2 Preparation of (E)-6-(4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)phenyl))nicotinamide
  • the solid target compound was obtained in a yield of 28 mg (0.05 mmol) of 60% in the same manner as in Step 2 of Example 5, except that 30 mg (0.09 mmol) of 6-(4-((2-formylphenoxy)methyl)phenyl)nicotinamide prepared in Step 1 was used.
  • the solid target compound was obtained in a yield of 177 mg (0.62 mmol) of 64% by the same method as in Step 1 of Example 1, except that 350 mg (0.97 mmol) of methyl 4-(bromomethyl)-2-((t-butyldimethylsilyl)oxy)benzoate was used.
  • Step 2 Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-methoxybenzonitrile
  • the solid target compound was obtained in a yield of 60 mg (0.13 mmol) of 87% in the same manner as in Step 2 of Example 5, except that 40 mg (0.15 mmol) of 4-((2-formylphenoxy)methyl)-2-methoxybenzonitrile prepared in Step 12 above was used.
  • the target compound was obtained in a yield of 23 mg (0.06 mmol) of 8% by the same method as step 1 of Example 1, except that 250 mg (0.70 mmol) of methyl 3-(bromomethyl)-4-((t-butyldimethylsilyl)oxy)benzoate was used.
  • Step 2 Preparation of methyl (E)-4-((t-butyldimethylsilyl)oxy)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)benzoate
  • the solid target compound was obtained in a yield of 27 mg (0.06 mmol) of 67% in the same manner as in Step 2 of Example 5, except that 22 mg (0.09 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzonitrile prepared in Step 1 was used.
  • the solid target compound was obtained in a yield of 38 mg (0.09 mmol) at 72% in the same manner as in Step 2 of Example 5, except that 27 mg (0.12 mmol) of 3-((2-formylphenoxy)methyl)benzamide prepared in Step 1 was used.
  • the solid target compound was obtained in a yield of 23 mg (0.09 mmol) in the same manner as in Step 1 of Example 50, except that 100 mg (0.35 mmol) of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate prepared in Step 1 of Example 51 was used.
  • the solid target compound was obtained in a yield of 28 mg (0.06 mmol) of 89% in the same manner as in Step 2 of Example 5, except that 20 mg (0.07 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzamide prepared in Step 1 was used.
  • the solid target compound was obtained in 59 mg (0.22 mmol) of a 62% yield in the same manner as in Example 2, except that 100 mg (0.35 mmol) of methyl 4-((2-formylphenoxy)methyl)-2-hydroxybenzoate prepared in step 1 of Example 51 was used.
  • Step 2 Preparation of (E)-4-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2-hydroxybenzoic acid
  • the solid target compound was obtained in a yield of 10 mg (0.02 mmol) of 28% in the same manner as in Step 2 of Example 5, except that 22 mg (0.08 mmol) of 4-((2-formylphenoxy)methyl)-2-hydroxybenzoic acid prepared in Step 1 was used.
  • the solid target compound was obtained in 171 mg (0.57 mmol) of 74% yield by the same method as step 1 of Example 1, except that 200 mg (0.77 mmol) of methyl 3-(bromomethyl)-4-methoxybenzoate was used.
  • Step 2 Preparation of methyl (E)-3-((2-((1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-4-methoxybenzoate
  • the solid target compound was obtained in a yield of 48 mg (0.10 mmol) in 97% by the same method as in step 2 of Example 5, except that 30 mg (0.10 mmol) of methyl 3-((2-formylphenoxy)methyl)-4-methoxybenzoate prepared in step 1 was used.
  • the solid target compound was obtained in a yield of 25 mg (0.09 mmol) in the same manner as in Example 2, except that 100 mg (0.33 mmol) of methyl 3-((2-formylphenoxy)methyl)-4-methoxybenzoate prepared in step 1 of Example 58 was used.
  • the solid target compound was obtained in a yield of 17 mg (0.03 mmol) of 45% in the same manner as in Step 2 of Example 5, except that 23 mg (0.08 mmol) of 3-((2-formylphenoxy)methyl)-4-methoxybenzoic acid prepared in Step 2 was used.
  • Example 10 The structures of the compounds prepared in the above examples are summarized in Table 1 below.
  • the example number is the compound number.
  • the compound prepared in Example 10 is Compound 10.
  • ATX autotaxin, hereinafter referred to as ATX
  • the experiment was conducted based on the fluorescence excitation analysis method (FS-3 based ATX kinetic assay) through phospholipid bond cleavage in the artificial substrate FS-3 provided by Echelon (Salt Lake City, Utah, United States).
  • the buffer solution was prepared as reaction buffer (224.0 mM NaCl, 80.0 mM Tris-HCl (pH 8.0), 8 mM KCl, 1.6 mM MgCl 2 , 1.6 mM CaCl 2 , 1.6 mg/mL fatty acid free BSA), and 5 ⁇ M of substrate (FS-3) and 125 nM of enzyme ATX (echelon; E-4000) were prepared.
  • 125 nM ATX and 10 ⁇ M substrate were diluted to 1.25 nM (final reaction concentration: 1 nM) and 5 ⁇ M (final reaction concentration: 0.5 ⁇ M), respectively.
  • the buffer solution used in all dilution and preparation processes is the reaction buffer solution.
  • the prepared samples were dispensed into 384 microplates (Multiwell 384 well plates, #3572, Corning Life Sciences, Lowell, MA, USA) using a 16-channel pipette (multi 16-channel, Finnpipette, Thermo Scientific, Essex, UK) with a total reaction volume of 2.5 ⁇ l per well.
  • a negative control 2.5 ⁇ l of 5% DMSO, 2.5 ⁇ l of substrate solution, and 20 ⁇ l of reaction buffer were used.
  • As a positive control 2.5 ⁇ l of 5% DMSO, 2.5 ⁇ l of substrate solution, and 20 ⁇ l of ATX solution were used.
  • As an experimental group 2.5 ⁇ l of derivative compound, 2.5 ⁇ l of substrate solution, and 20 ⁇ l of ATX solution were used.
  • the compounds of the present example were confirmed to exhibit excellent Autotaxin (ATX) inhibitory effects, and thus can be usefully used for the prevention or treatment of diseases related to ATX activity.
  • ATX Autotaxin

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Abstract

La présente invention concerne un composé ayant une activité inhibitrice de l'autotaxine (ATX), une composition pharmaceutique le comprenant en tant que principe actif, et ses utilisations pharmaceutiques. Le composé selon la présente invention présente une excellente activité inhibitrice de l'ATX et peut être utilisé efficacement pour prévenir ou traiter des maladies liées à l'activité d'ATX.
PCT/KR2024/015527 2023-10-13 2024-10-14 Composé pour inhiber l'atx, son procédé de préparation et composition pharmaceutique destinée à être utilisée dans la prévention ou le traitement de maladies liées à l'activité de l'atx le contenant en tant que principe actif Pending WO2025080049A1 (fr)

Applications Claiming Priority (2)

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KR10-2023-0137161 2023-10-13
KR1020230137161A KR20250053629A (ko) 2023-10-13 2023-10-13 Atx 저해용 화합물, 이의 제조방법 및 이를 유효성분으로 포함하는 atx 활성 관련 질환의 예방 또는 치료용 약학적 조성물

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WO2025080049A1 true WO2025080049A1 (fr) 2025-04-17

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PCT/KR2024/015527 Pending WO2025080049A1 (fr) 2023-10-13 2024-10-14 Composé pour inhiber l'atx, son procédé de préparation et composition pharmaceutique destinée à être utilisée dans la prévention ou le traitement de maladies liées à l'activité de l'atx le contenant en tant que principe actif

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KR (1) KR20250053629A (fr)
WO (1) WO2025080049A1 (fr)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALBAKHIT SULTAN D., MUTLAQ DAKHIL ZUGHAYIR, AL-SHAWI ALI A. A.: "Antibacterial, Antifungal, and Antitumor Properties of 2,5-Pyrrolidinedione Derivatives", CHEMISTRY AFRICA, vol. 6, no. 6, 1 December 2023 (2023-12-01), pages 2933 - 2944, XP093303009, ISSN: 2522-5758, DOI: 10.1007/s42250-023-00710-7 *
CHUPAKHIN EVGENY, GECHT MARTHA, IVANOV ALEXANDER, KANTIN GRIGORY, DARIN DMITRY, KRASAVIN MIKHAIL: "(E)-3-arylidene-4-diazopyrrolidine-25-diones: Preparation and use in RhII-catalyzed X–H insertion reactions towards novel, medicinally important michael acceptors", SYNTHESIS, THIEME CHEMISTRY, vol. 53, no. 7, 11 January 2021 (2021-01-11), pages 1292 - 1300, XP009562357, ISSN: 0039-7881, DOI: 10.1055/s-0040-1706556 *
DATABASE REGISTRY 12 July 2015 (2015-07-12), XP093303012, Database accession no. 1799012-59-1 *
RIEMER NASTJA, SHIPMAN MICHAEL, WESSIG PABLO, SCHMIDT BERND: "Iterative Arylation of Itaconimides with Diazonium Salts through Electrophilic Palladium Catalysis: Divergent β-H-Elimination Pathways in Repetitive Matsuda–Heck Reactions", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, UNITED STATES, vol. 84, no. 9, 3 May 2019 (2019-05-03), United States, pages 5732 - 5746, XP093303007, ISSN: 0022-3263, DOI: 10.1021/acs.joc.9b00627 *
YASEEN HUSSAIN; CLAIRE EMPEL; RENE M. KOENIGS; PANKAJ CHAUHAN: "Carbene Formation or Reduction of the Diazo Functional Group? An Unexpected Solvent‐Dependent Reactivity of Cyclic Diazo Imides", ANGEWANDTE CHEMIE, VERLAG CHEMIE, HOBOKEN, USA, vol. 62, no. 40, 24 August 2023 (2023-08-24), Hoboken, USA, pages n/a - n/a, XP072503002, ISSN: 1433-7851, DOI: 10.1002/anie.202309184 *

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