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WO2023090829A1 - Composé de faible poids moléculaire pour la régulation de l'interaction mll1-wdr5 et son utilisation - Google Patents

Composé de faible poids moléculaire pour la régulation de l'interaction mll1-wdr5 et son utilisation Download PDF

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Publication number
WO2023090829A1
WO2023090829A1 PCT/KR2022/018027 KR2022018027W WO2023090829A1 WO 2023090829 A1 WO2023090829 A1 WO 2023090829A1 KR 2022018027 W KR2022018027 W KR 2022018027W WO 2023090829 A1 WO2023090829 A1 WO 2023090829A1
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Prior art keywords
methyl
compound
imidazol
dihydro
trifluoromethyl
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Korean (ko)
Inventor
태현섭
이빛
김현주
이미진
양홍주
최종윤
김윤란
하형호
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Elgen Therapeutics Inc
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Elgen Therapeutics Inc
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a pharmaceutical composition for anticancer containing a double-ringed low-molecular compound as an active ingredient and a method for preparing the same.
  • Histone methylation plays an important role in a number of biological processes, and histone modifications are important for epigenetic regulation.
  • H3K4 is methylated by several histone methyltransferases, including SET1a, SET1b, and SET1, which is composed of MLL (mixed-lineage leukemia protein) 1–4 (Guillermo, S. et al. ., 2013).
  • SET1a histone methyltransferases
  • SET1b histone methyltransferases
  • MLL1 is a key protein that maintains the expression of selected target Hox genes required for proper embryonic development, including hematopoiesis, myogenesis, and neurogenesis (Argiropoulos, B. et al ., 2007; Lim , DA et al ., 2009).
  • Wild-type MLL1 functions by forming a core multiprotein complex with four components required for maximal enzymatic activity of H3K4 methylation: MLL1, WDR5, RbBP5 and ASH2L (Dou, Y. et al. , 2006).
  • MLL1 alone has weak H3K4 methyltransferase activity, but when it forms a core complex with WDR5, RbBP5 and ASH2L, H3K4 methyltransferase activity is greatly enhanced, and WDR5 and RbBP5 are essential for MLL1 activity.
  • MLL1 gene rearrangement abnormalities account for 5-10% of acute myeloid leukemia (AML) in adults and 70% of acute lymphoblastic (ALL) cases in infants (Ayton, PM et al ., 2001). In most cases, one MLL1 allele results in chromosome translocation, resulting in the expression of oncogenic MLL1 fusion proteins such as MLL1-AF9, MLL1-AF4 and MLL1-ENL (Dou, Y. et al ., 2008 ).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic
  • the MLL1 fusion protein which lacks the carboxyl terminal SET domain and thus has no H3K4 histone methyltransferases (HMTs) activity, cannot induce leukemia by itself, and requires wild-type MLL1 to cause leukemia. enzymatic activity is required (Thiel, AT et al ., 2010). Wild-type MLL1 binds to the regulatory regions of Hox genes in its amino-terminal fragment, while its catalytic-carboxyl-terminal domain catalyzes H3K4 methylation through interaction with WDR5 and upregulates target gene transcription (Thomas, AM et al ., 2005; Akihiko, Y. et al ., 2004). Oncogenic MLL1 fusion proteins are known to regulate the transcription of multiple oncogenes including Hox and MEIS1.
  • WDR5 is related to the initiation, development, and maintenance of disease, and is overexpressed in various carcinomas such as leukemia, hepatocellular carcinoma, and breast cancer, and is associated with poor prognosis in clinical practice.
  • WD40 iterations form a propeller fold with seven blades and each blade is composed of four anti-parallel sheets. This structural feature can act as a useful adapter for interacting with other proteins because WDR5 has many exposed surfaces (Raymond, CT et al ., 2009).
  • WDR5 is not only an essential part of the WRAD complex, but also binds directly to the Myc oncoprotein family (c-, L-, N-Myc) and binds to the WBM site of WDR5 and Myc-box IIIb at the amino terminal site of Myc (Thomas , L R et al ., 2020).
  • the various proteins that interact with WDR5 play a variety of biological roles, such as reproduction, development, immunity, neural and humoral regulation.
  • Myc is one of the representative proto-oncogenes involved in cell proliferation and apoptosis, and is an essential transcription factor that affects cancer development and growth. It is known to be (Hessmann, E. et al ., 2016). Myc and WDR5 interactions are required for Myc-mediated induction of components for ribosome and protein production, and have been implicated extensively in inducing tumorigenesis. Although partial genetic inhibition of Myc is known to prolong tumor regression and survival in several tumor models such as lung adenocarcinoma (Soucek, L. et al ., 2013), the development of substances that inhibit Myc is technically challenging. Due to difficulties, there are no commercially available clinical inhibitors.
  • the method of disrupting the protein-protein interaction of MLL1-WDR5 using small molecules is not only effective in inhibiting MLL enzymatic activity and down-regulating Hox gene expression to block disease progression, but also by inhibiting Myc. It can be a good therapeutic agent for treating Myc-induced tumors.
  • An object of the present invention is to provide a pharmaceutical composition for anticancer containing a bicyclic low-molecular compound as an active ingredient and a method for preparing the same.
  • the present invention relates to a compound comprising a bicyclic low-molecular-weight compound of Formula 1 below, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.
  • A is substituted with -C(O)- or -C(OH)-;
  • R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,
  • substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH- tert- butoxycarbonyl, -N (C 1 -C 3 alkyl) -tert- butoxycarbonyl, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy , halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[( CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 al
  • substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert- butoxycarbonyl, -NH- tert- butoxycarbonyl , -N(C 1 -C 3 alkyl)- tert- butoxycarbonyl, C 1 -C 6 alkyl amino, and benzyloxy;
  • R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,
  • the substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);
  • R 3 is a substituted or unsubstituted 3-6 membered heterocycloalkyl or a substituted or unsubstituted 4-10 membered heteroaryl;
  • the present invention relates to a compound comprising a bicyclic low-molecular-weight compound of Formula 2 below, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.
  • A is substituted with -C(O)- or -C(OH)-;
  • R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,
  • substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH- tert- butoxycarbonyl, -N (C 1 -C 3 alkyl) -tert- butoxycarbonyl, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy , halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[( CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 al
  • substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert- butoxycarbonyl, -NH- tert- butoxycarbonyl , -N(C 1 -C 3 alkyl)- tert- butoxycarbonyl, C 1 -C 6 alkyl amino, and benzyloxy;
  • R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,
  • the substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);
  • R 3 is substituted with Formula 2-1, Formula 2-2, or Formula 2-3.
  • R 4 is substituted with hydrogen, tert- butoxycarbonyl, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;
  • R 5 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy; do.
  • the present invention is a chroman-4-one derivative, wherein R 2 in the compound of Formula 2 is substituted with Formula 3-1 or Formula 3-2, an enantiomer, a diastereomer, a stereoisomer, a hydrate, or a solvate thereof. , a prodrug or a pharmaceutically acceptable salt thereof.
  • R 2 is substituted with Formula 3-1 or Formula 3-2.
  • R 6 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy or methyl-(C 1 -C 2 alkoxy) 1-5 is replaced,
  • R 8 is independently one or more selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy, or acetamido. substituted with a substituent;
  • X is N, CH, or C
  • n is an integer from 0 to 2:
  • the chroman-4-one derivative compound of the present invention was prepared by the same method as Scheme 1 to 22 below.
  • Benzaldehyde corresponding to the starting material 8-bromo-6-methylchroman-4-one compound was reacted under a para-toluenesulfonic acid catalyst to synthesize a benzylidene compound, and an asymmetric alcohol through an asymmetric hydrogenation reaction with a ruthenium catalyst.
  • compound was synthesized.
  • an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, and then products (Compounds 1 to 22) were obtained through an alkylation reaction with a corresponding amine and a Suzuki coupling with a corresponding boronic acid compound.
  • a benzylidene compound was synthesized by reacting tert-butyl (4-formylcyclohexyl) carbamate with 8-bromo-6-methylchroman-4-one compound as a starting material in the presence of a pyrrolidine base.
  • An asymmetric ketone compound was synthesized through an asymmetric hydrogenation reaction.
  • Intermediate compounds were then synthesized through bromination, and then products (Compounds 23 to 29) were obtained through alkylation with the corresponding amine and Suzuki coupling with the corresponding boronic acid compound.
  • the starting material, 8-bromo-6-methylchroman-4-one compound, (4-fluorophenyl)boronic acid was subjected to a condensation reaction with Suzuki coupling and benzaldehyde under a palladium catalyst, followed by hydrogen substitution and reduction, followed by a ruthenium catalyst.
  • An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction.
  • an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, and then a product (Compound 37) was obtained through an alkylation reaction with imidazole amine.
  • the starting material 4-chloro-3-hydroxybenzaldehyde
  • ethyl bromovalerate in the presence of a base
  • a condensation reaction and a reduction reaction were conducted with the corresponding chromanone to synthesize an intermediate.
  • An intermediate was synthesized through an alkylation reaction with the corresponding imidazole amine, followed by a protection reaction of imine, a Suzuki reaction with the corresponding boronic acid, and a hydrolysis reaction of esters to obtain products (Compounds 46 to 51).
  • the starting material 4-fluoro-3-hydroxybenzaldehyde
  • a condensation reaction was conducted with the corresponding chromanone under an acidic condition to synthesize an intermediate.
  • An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction using a ruthenium catalyst.
  • an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, followed by an alkylation reaction with the corresponding amine, followed by a protection reaction of imine, a Suzuki reaction with the corresponding boronic acid, and a hydrolysis reaction of ester to obtain product 52.
  • product No. 53 was obtained through a Suzuki reaction with the corresponding boronic acid and a ruthenium-catalyzed asymmetric hydrogenation reaction, and the synthesized intermediate methyl 2-(2-fluoro-5-formylphenoxy) After a condensation reaction with chromanone corresponding to acetate, product 54 was obtained through Suzuki reaction with corresponding boronic acid.
  • An intermediate was synthesized by carrying out a condensation reaction between methyl 2-fluoro-5-formylbenzoate as a starting material and the corresponding chromanone under acidic conditions.
  • An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction with a ruthenium catalyst, and then an intermediate compound was synthesized through an oxidation reaction and a bromination reaction.
  • Products (Compounds 55 to 58) were obtained through Suzuki reaction and ester hydrolysis.
  • Compound 73 was obtained through a condensation reaction with chromanone corresponding to 4-methoxypicolinaldehyde as a starting material, a ruthenium-catalyzed asymmetric hydrogenation reaction, and an oxidation reaction.
  • Compound 80 was obtained through Suzuki reaction with boronic acid corresponding to the starting material 8-bromo-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one, and then the corresponding A condensation reaction with benzaldehyde and a ruthenium-catalyzed asymmetric hydrogenation reaction were performed.
  • a product (Compound 82) was obtained through an oxidation reaction and a deprotection reaction under acidic conditions. Weinrebamide produced through coupling of 6-chloro-4-methylpicolinic acid with hydroxylamine is reduced, and then intermediates are synthesized through the corresponding chromanone condensation reaction, and ruthenium-catalyzed asymmetric hydrogenation and oxidation reactions to obtain compound 81.
  • the starting material (6-bromo-5-fluoropyridin-2-yl)methanol, was subjected to a palladium-catalyzed coupling reaction with the corresponding amine, and then an intermediate was synthesized through an oxidation reaction.
  • a product was obtained through a condensation reaction and a deprotection reaction with the corresponding chromanone.
  • Product 93 was obtained through ruthenium-catalyzed asymmetric hydrogenation, oxidation, and deprotection to obtain products (Compounds 91 to 100).
  • the compound represented by Formula 1 is a compound characterized in that it is any one selected from the group of compounds or its enantiomer, diastereomer or stereoisomer, hydrate, solvate, prodrug or pharmaceutical thereof. It relates to acceptable salts.
  • alkyl refers to a single-bonded straight or branched hydrocarbon group having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert- butyl, 1-methylpropyl, pentyl and hexyl.
  • alkoxy refers to an oxygen group to which a single bonded straight or branched saturated hydrocarbon having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms is bonded, and includes methoxy, ethoxy, propoxy, n-butoxy, tert -butoxy, 1-methylpropoxy and the like.
  • Boc means tert -butoxycarbonyl
  • halo and “halogen” are used in their conventional sense to refer to fluoro, chloro, bromo or iodo substituents.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a halo group, and the alkyl and halo groups are as defined above.
  • haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group have been replaced with a halo group, and halo and alkoxy are as defined above.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.
  • the pharmaceutically acceptable salt means a salt or complex of Formula 1 having a desired biological activity.
  • examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , salts formed with organic acids such as benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid.
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • acetic acid e.g., oxalic acid, tarta
  • the compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl esters (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandeloates and diphenylacetate).
  • the compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer using a chroman-4-one derivative.
  • the cancer means solid cancer or blood cancer
  • the solid cancer means brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, Glioma, glioblastoma, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharynx cancer, tonsil cancer, thyroid cancer, oral cancer, esophageal cancer, eye cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, lung adenocarcinoma , lung cancer, lung squamous cell carcinoma, pleural cancer, mediastinal tumor, breast cancer, male breast cancer, abdominal tumor, stomach cancer, gastric mastoid, liver cancer, hepato
  • the blood cancer may be selected from the group consisting of acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, childhood lymphoma, malignant lymphoma, multiple myeloma, or aplastic anemia, but is not particularly limited thereto.
  • compositions according to the present invention may be formulated in a suitable form together with a generally used pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans.
  • the composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the compound of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized or preservatives, stabilizers, hydrating agents or emulsification accelerators, salts or buffers for osmotic pressure control, and other therapeutic agents. It can be mixed with water together with useful substances to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form.
  • a pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection.
  • the dose depends on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used, and the prescription It will depend on judgment, etc.
  • dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
  • composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cancer.
  • the present invention relates to an anti-cancer pharmaceutical composition containing a low-molecular-weight bicyclic compound as an active ingredient and a method for preparing the same, and the composition containing the low-molecular-weight derivative as an active ingredient can be usefully used as a composition for preventing or treating cancer.
  • Step 2 tert-butyl (S,E)-(3-((3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4 Preparation of -oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene)carbamate
  • step 4) tert - butyl (S)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl Preparation of )methyl)cyclohexyl)carbamate
  • Step 2 Preparation of tert-butyl 4-(((R)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate
  • Step 4) 8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one manufacture of
  • Step 2) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-( Preparation of bromomethyl)chroman-4-one
  • Step 3 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-( Preparation of (2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one
  • Step 4) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-(1-ethyl- Preparation of 3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one
  • step 4) tert - Preparation of butyl (Z)-(1-((8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate
  • Step 8) methyl 2-(2-(2-(2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) Preparation of methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)acetate
  • Step 9) methyl (Z)-2-(2-(2-(2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3 Preparation of -dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)acetate
  • step 1 of the synthesis of compound 38 ethyl bromovalerate (0.6 mL, 3.832 mmol) was used instead of methyl bromoacetate to prepare a product (920 mg, quant.).
  • step 2 of the synthesis of compound 38 ethyl 5-(2-chloro-5-formylphenoxy)pentanoate (1072 mg, 3.35 mmol) was added instead of methyl 2-(2-chloro-5-formylphenoxy)acetate.
  • the product (958 mg, 52% yield) was prepared using
  • Step 5 ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 Preparation of ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate
  • Step 1) ethyl (Z)-5-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1- Preparation of yl) methyl) -4-oxochroman-3-yl) methyl) -2-chlorophenoxy) pentanoate
  • Step 2) ethyl (Z)-5-(5-((6-((2-((tert - butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4- Preparation of oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate
  • the reaction mixture was extracted with CH 2 Cl 2 , washed with NH 4 Cl, dried over MgSO 4 and concentrated under reduced pressure.
  • Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy)acetate (3385 mg, 7.705 mmol) and Molecular sieves 4 ⁇ (300 mg) in CH 2 Cl 2 (60 mL) was stirred for 10 minutes, and then N-methylmorpholine N-oxide (NMO, 903 mg, 7.705 mmol) and tetrapropylammonium perute Nate (TPAP, 271 mg, 0.771 mmol) was added at 0°C and stirred at room temperature for 3 h.
  • NMO N-methylmorpholine N-oxide
  • TPAP tetrapropylammonium perute Nate
  • the black reaction mixture was filtered through celite with a diethyl ether solvent, and the filtrate was concentrated under reduced pressure.
  • the concentrate was purified by MPLC (ethyl acetate:n-heptane, 20%) to obtain the target product (2828 mg, 84%).
  • Step 7) methyl (S,Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol- Preparation of 1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate
  • Step 8) methyl (S,Z)-2-(5-((6-((2-((tert - butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4- Preparation of oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate
  • Step 9) (S,Z)-2-(5-((6-((2-((tert - butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4- Preparation of oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid
  • Step 1) methyl (E)-2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3 Preparation of -(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)phenoxy)acetate
  • Step 2) methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl Preparation of -3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate
  • Step 2) methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl) Preparation of -1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate
  • step 2 of the synthesis of compound 52 methyl 2-(2-chloro-5-formylphenoxy)acetate was replaced with methyl 2-fluoro-5-formylbenzoate (17 g, 93.3 mmol) to obtain the product (10.23 g). , 55% yield) was prepared.
  • Step 7) methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- Preparation of 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate
  • step 4 of the synthesis of compound 38 methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate was replaced by 8 -Bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one (15.5 g, 48.44 mmol) was used to prepare the product (13.33 g, 81.8% yield).
  • Compound 61 (435 mg, 43% yield) was prepared.
  • step 1 of the synthesis of compound 65 methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5000 mg, 26.938 mmol) and tert- butyl azetidine-3 were used instead of methyl 6-chloro-4-methylpicolinate.
  • the product (4.13 g, 68% yield) was prepared using -yl(methyl)carbamate (5519 mg, 29.632 mmol).
  • Step 1) methyl 6-(3-((tert - Preparation of butoxycarbonyl) (methyl) amino) azetidin-1-yl) -4-methylpicolinate
  • tert- butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate 800 mg, 2.602 mmol
  • 100 mg of CH 2 Cl 2 (10 mL) solution is stirred for 10 min.
  • NMO N-methylmorpholine N-oxide
  • TPAP tetrapropylammonium perruthenate
  • the black mixture was filtered through celite and washed with diethyl ether. After concentration under reduced pressure, the concentrate was purified by MPLC (ethyl acetate:n-heptane, 20%) to obtain the target product (386 mg, 49%).
  • step 4) tert - butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)- Preparation of 1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate
  • Step 2) (3S,4S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl- Preparation of 3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-ol
  • step 2 of the synthesis of compound 65 methyl 2-(4- ( tert The product (4.6 g, 66% yield) was prepared using -butoxycarbonyl)piperazin-1-yl)-6 - methylpyrimidine-4-carboxylate (7 g, 22.89 mmol).
  • step 3 of the synthesis of compound 65 tert- butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate was replaced with tert- butyl 4-
  • the product (2 g, 50% yield) was prepared using (4-(hydroxymethyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (4 g, 12.98 mmol).
  • step 4) tert - butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H- Preparation of pyrazol-4-yl) -4-oxochroman-3-ylidene) methyl) pyrimidin-2-yl) piperazine-1-carboxylate

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Abstract

La présente invention concerne une composition pharmaceutique anticancéreuse contenant un dérivé bicyclique de faible poids moléculaire en tant que principe actif et son procédé de préparation, et la composition contenant le dérivé bicyclique en tant que principe actif peut être utile en tant que composition pour la prévention ou le traitement du cancer.
PCT/KR2022/018027 2021-11-17 2022-11-15 Composé de faible poids moléculaire pour la régulation de l'interaction mll1-wdr5 et son utilisation Ceased WO2023090829A1 (fr)

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KR20210158352 2021-11-17
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KR1020220152080A KR102795782B1 (ko) 2021-11-17 2022-11-14 Mll1-wdr5 상호작용을 조절하는 저분자 화합물 및 이의 용도
KR10-2022-0152080 2022-11-14

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056580A1 (fr) * 2000-02-01 2001-08-09 Rutgers, The State University Compositions de polygonum odoratum pour la prevention et le traitement d'affections
US20060074127A1 (en) * 2004-09-21 2006-04-06 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US20080070918A1 (en) * 2006-08-24 2008-03-20 Huang Kenneth H Dihydropyridazine, Tetrahydropyridine, Chromanone, and Dihydronaphthalenone Derivatives
CN102949388A (zh) * 2011-08-29 2013-03-06 苏州同立医药技术有限公司 异黄酮类成分及其制备的药物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056580A1 (fr) * 2000-02-01 2001-08-09 Rutgers, The State University Compositions de polygonum odoratum pour la prevention et le traitement d'affections
US20060074127A1 (en) * 2004-09-21 2006-04-06 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US20080070918A1 (en) * 2006-08-24 2008-03-20 Huang Kenneth H Dihydropyridazine, Tetrahydropyridine, Chromanone, and Dihydronaphthalenone Derivatives
CN102949388A (zh) * 2011-08-29 2013-03-06 苏州同立医药技术有限公司 异黄酮类成分及其制备的药物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEMIRAYAK SEREF; YURTTAS LEYLA; GUNDOGDU-KARABURUN NALAN; KARABURUN AHMET CAGRI; KAYAGIL ISMAIL: "New chroman-4-one/thiochroman-4-one derivatives as potential anticancer agents", SAUDI PHARMACEUTICAL JOURNAL, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 7, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 1063 - 1072, XP085273906, ISSN: 1319-0164, DOI: 10.1016/j.jsps.2017.04.040 *

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