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WO2025162405A1 - Dérivé de phénol et son utilisation pharmaceutique - Google Patents

Dérivé de phénol et son utilisation pharmaceutique

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Publication number
WO2025162405A1
WO2025162405A1 PCT/CN2025/075292 CN2025075292W WO2025162405A1 WO 2025162405 A1 WO2025162405 A1 WO 2025162405A1 CN 2025075292 W CN2025075292 W CN 2025075292W WO 2025162405 A1 WO2025162405 A1 WO 2025162405A1
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WO
WIPO (PCT)
Prior art keywords
oxo
methyl
dichloro
oxy
chlorophenyl
Prior art date
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Pending
Application number
PCT/CN2025/075292
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English (en)
Chinese (zh)
Inventor
罗群
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Individual
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Individual
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Publication of WO2025162405A1 publication Critical patent/WO2025162405A1/fr
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Classifications

    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]

Definitions

  • the present invention relates to a phenol derivative, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the phenol derivative, the isomer thereof, the deuterated product thereof or a pharmaceutically acceptable salt thereof, and use of the pharmaceutical composition in preparing a drug for treating a disease associated with THR- ⁇ agonist activity.
  • Thyroid hormone is synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland.
  • Thyroid hormone plays a very important role in regulating body growth, development, metabolism and matrix balance.
  • Thyroid hormones There are two main types of thyroid hormones, 3,5,3'-triiodo-L-thyroxine (T3) and thyroxine (T4).
  • T3 and T4 produced by the thyroid gland are under negative feedback control, and thyroid-stimulating hormone (TSH) is responsible for normal thyroid function and thyroid hormone secretion.
  • TSH is synthesized in the anterior pituitary gland, and its secretion is controlled by thyroid-releasing hormone (TRH) synthesized in the hypothalamus.
  • Thyroid hormones exert their functions by binding to thyroid hormone receptors (THRs).
  • THRs belong to a large family of nuclear receptors that regulate the expression of target genes.
  • THR ⁇ is primarily found in heart tissue and plays a crucial role in regulating cardiac function.
  • the THR ⁇ subtype is primarily expressed in the liver and pituitary gland, regulating cholesterol metabolism and thyroid-stimulating hormone secretion.
  • thyroid hormone At normal levels, thyroid hormone (TH) maintains body weight, metabolic rate, body temperature, mood, and regulates serum cholesterol. Thyroid hormones have been used to regulate serum cholesterol. However, the cardiac side effects of natural thyroid hormones preclude their use for the treatment of high cholesterol and obesity. Animal studies with selective knockout of the THR gene, as well as studies of selective THR ligands, suggest that these cardiac side effects of thyroid hormones can be attributed to THR ⁇ .
  • the thyroid hormone receptor pathway regulates lipid metabolism, including cholesterol, triglycerides, and lipoproteins. Clinically, it has been shown that lowering low-density cholesterol will reduce the incidence of cardiovascular and cerebrovascular diseases.
  • the therapeutic use of thyroid hormone itself is limited by adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity.
  • a thyroid hormone analogue if it can avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormone, may be used to treat responsive diseases, such as metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.
  • responsive diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.
  • metabolic diseases including obesity, hyperlipidemia, hypercholesterolemia, diabetes and other conditions such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, etc.
  • NASH non-alcoholic
  • Nonalcoholic fatty liver disease is also a type of metabolic disorder caused by excessive accumulation of triglycerides in the liver, which can further damage liver cells and trigger inflammation, leading to nonalcoholic fatty liver disease (NASH).
  • NASH patients are usually also accompanied by type 2 diabetes, high cholesterol, high blood lipids and obesity. NASH patients have a higher probability of developing cirrhosis, liver failure, and eventually liver cancer. There is currently a lack of effective drugs to treat NASH.
  • the function of thyroid hormones in regulating lipid metabolism makes the thyroid receptor pathway a potential target for the treatment of NASH and NAFLD. It has been confirmed in animals that thyroid hormone analogs can significantly reduce the level of liver fat in animals.
  • Selective THR ⁇ agonists can be used to circumvent the cardiac side effects of conventional THR receptor agonists, selectively activating only THR ⁇ , improving cellular lipid metabolism, and exerting cholesterol and blood lipid lowering functions.
  • selective THR ⁇ agonists may also inhibit the thyroid axis, leading to side effects such as depression, fatigue, and osteoporosis. Therefore, it is necessary to develop a selective THR ⁇ agonist that activates THR ⁇ but reduces the inhibitory effect on the thyroid axis, thereby circumventing the side effects associated with thyroid axis inhibition.
  • Patents such as WO03094845, WO2007009913, WO2010122980, and WO2011038207 disclose several THR receptor agonists, all of which are designed and developed based on the natural THR receptor ligand, T3. Given this background, there remains a need to develop selective THR ⁇ receptor agonists that possess the beneficial therapeutic effects of thyroid hormones while avoiding the adverse cardiac side effects.
  • This invention also involves structural modification of T3, the natural ligand for the THR receptor.
  • T3 the natural ligand for the THR receptor.
  • some of the compounds described herein are highly enriched in the liver, a target organ, further reducing their distribution in the heart, thereby potentially reducing clinical side effects.
  • the inventors unexpectedly discovered that some of the modified compounds retain good THR ⁇ receptor agonist or binding activity, and the compounds of this invention have enhanced selectivity for THR ⁇ .
  • the present invention provides a phenol derivative, its isomer, its deuterated form, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition comprising the phenol derivative, its isomer, its deuterated form, or a pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition in the treatment of diseases associated with THR- ⁇ agonist activity.
  • a phenol derivative an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, wherein the phenol derivative has a structure represented by formula (I):
  • X is -CH 2 -, -(CH 2 ) n O-, -(CH 2 ) n S-, -O(CH 2 ) n -, -S(CH 2 ) n -, -(CH 2 ) n NH-, -NH(CH 2 ) n -;
  • R 1 and R 2 are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkoxy, and may be arbitrarily substituted by halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkoxy;
  • Z and Z1 are each independently -O- or -NH-;
  • R 3 and R 4 are each independently hydrogen, C 1 -C 8 alkyl, unsubstituted phenyl, phenyl substituted with at least one substituent selected from halogen, phenyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, unsubstituted naphthyl, -CH 2 OC(O)-R 6 , or -C(RR 0 )C(O)OR 7 ;
  • R 3 , R 4 and the -ZP(O)-Z 1 - connected thereto form the following six-membered ring:
  • R 8 is a 5-10 membered aryl group, which may be substituted by at least one substituent selected from halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and C 1 -C 6 alkoxy;
  • a 5-10 membered heteroaryl group containing one or two heteroatoms selected from N, S, and O may be substituted by at least one substituent selected from halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and C 1 -C 6 alkoxy;
  • R 5 is hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl
  • R 6 and R 7 are each independently hydrogen or C 1 -C 8 alkyl
  • R and R 0 are each independently hydrogen, C 1 -C 8 alkyl, which may be substituted by halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, or optionally substituted aryl;
  • Het is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heteroaromatic ring, and includes the following groups:
  • R9 and R10 are each independently hydrogen, C1 - C8 alkyl, C3 - C7 cycloalkyl, heterocycle, or aryl; R9 and R10 , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted by deuterium, halogen, C1 - C6 alkyl, halogenated C1 - C6 alkyl, C3 - C7 cycloalkyl, C1 - C6 alkoxy, heterocycle, or aryl;
  • R 11 , R 12 , R 13 , R 14 , and R 15 are each independently hydrogen, deuterium, -C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl;
  • R 16 and R 17 are each independently hydrogen, -C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl;
  • Z 2 , Z 3 , and Z 3′ are each independently —N— or —CH—;
  • n 0, 1, 2, or 3.
  • the phenol derivative includes the following structure:
  • a pharmaceutical composition comprising the phenol derivative according to claim 1 or 2, its isomer, its deuterated product or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition as described above for use in the preparation of a medicament for treating THR ⁇ -related diseases, wherein the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • a phenol derivative, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof wherein the phenol derivative has a structure represented by formula (II):
  • Het 1 is selected from a 5-12 membered aromatic ring, a naphthalene ring, a thiophene ring, a pyrrole ring, a 5-12 membered aromatic heterocycle, a 5-12 membered heterocyclic aromatic ring, and includes the following groups:
  • X 1 is -CH 2 -, -(CH 2 ) m O-, -(CH 2 ) m S-, -O(CH 2 ) m -, -S(CH 2 ) m -, -(CH 2 ) m NH-, -NH(CH 2 ) m -;
  • Z 4 , Z 5 , and Z 6 are each independently -CH- or -N-;
  • R 18 and R 19 are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkoxy, and may be arbitrarily substituted by halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkoxy;
  • R 20 and R 21 are each independently hydrogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, heterocycle, or aryl; R 20 and R 21 , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, which may be arbitrarily substituted by deuterium, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, heterocycle, or aryl;
  • R 22 and R 23 are each independently hydrogen, deuterium, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, heterocycle, or aryl; R 22 and R 23 , together with the carbon atom to which they are attached, form a 4-10 membered ring, a 5-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring, and may be arbitrarily substituted with halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, heterocycle, or aryl;
  • R 24 , R 25 , R 26 , R 27 , and R 28 are each independently hydrogen, deuterium, C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl;
  • R 29 and R 30 are each independently hydrogen, -C 1 -C 8 alkyl, or C 3 -C 7 cycloalkyl;
  • Q includes the following groups:
  • R 31 and R 32 are each independently hydrogen, halogen, -NH 2 , cyano, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, or C 1 -C 6 alkoxy, and may be arbitrarily substituted by halogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl;
  • Z 7 and Z 8 are each independently -CH- or -N-;
  • n 0, 1, 2, or 3.
  • the phenol derivative includes the following structure:
  • a pharmaceutical composition comprising the phenol derivatives, isomers thereof, deuterated derivatives thereof or pharmaceutically acceptable salts thereof as described above.
  • the use in the preparation of a medicament for treating THR ⁇ -related diseases is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • the disease is selected from the group consisting of at least one of the following: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • alkyl refers to groups such as, but not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • aryl refers to an aromatic system, which can be a single ring or multiple aromatic rings that are fused or linked together so that at least a portion of the fused or linked rings form a conjugated aromatic system.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and tetrahydronaphthyl.
  • Aryl groups can be optionally substituted, such as aryl or heterocycle substituted with one to four groups selected from the group consisting of halogen, -CN, -OH, -NO2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxyl, alkylamino, or arylthio.
  • substituted means that the referenced group may be substituted with one or more additional groups, wherein the additional groups are individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl, thiocarbonyl, nitro, haloalkyl, fluoroalkyl and amino, including mono- and di-substituted amino groups and protected derivatives thereof.
  • additional groups are individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsul
  • halogen means chlorine, fluorine, bromine or iodine.
  • halo means chloro, fluoro, bromo or iodo.
  • haloalkyl means an alkyl group as defined above which is substituted by one or more halogen atoms.
  • pharmaceutically acceptable salt means that the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc.; or with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-p-toluenesulfonic acid, camphoric acid, dodecylsulf
  • the present invention provides a drug comprising a derivative, isomer, deuterated product, or pharmaceutically acceptable salt thereof of the structure of formula (I) of the present invention as an active ingredient.
  • the drug may further contain one or more carriers, including conventional diluents, binders, excipients, fillers, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and the like, and, if necessary, flavoring agents, sweeteners, and the like.
  • the drug of the present invention can be prepared in various forms, including tablets, powders, granules, capsules, oral solutions, and injections. Each of these dosage forms can be prepared according to conventional methods in the pharmaceutical field.
  • the present invention provides a drug comprising a derivative, isomer, deuterated form thereof, or pharmaceutically acceptable salt thereof of the structure represented by formula (II) as an active ingredient.
  • the drug may further comprise one or more carriers, including conventional pharmaceutical diluents, binders, excipients, fillers, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, and the like. Flavoring agents, sweeteners, and the like may also be added, if necessary.
  • the drug can be prepared in various forms, including tablets, powders, granules, capsules, oral solutions, and injections. Each of these dosage forms can be prepared according to conventional pharmaceutical methods.
  • the present invention provides a derivative of the structure of formula (I), an isomer, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, for use in preparing a medicament for treating THR ⁇ -related diseases, wherein the disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • the disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • the present invention provides a derivative of the structure of formula (II), an isomer, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, for use in preparing a medicament for treating THR ⁇ -related diseases, wherein the disease is selected from the group consisting of: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • the disease is selected from the group consisting of: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic fatty liver disease (NASH), atherosclerosis, and hypothyroidism.
  • Step 3 (2,6-Dimethyl-4-((triisopropylsilyl)oxy)phenyl)(3-fluoro-5-isopropyl-4-(methoxymethoxy)phenyl)methanol
  • Step 4 4-((3-Fluoro-5-isopropyl-4-(methoxymethoxy)phenyl)(hydroxy)methyl)-3,5-dimethylphenol
  • Step 5 4-(3-Fluoro-5-isopropyl-4-(methoxymethoxy)benzyl)-3,5-dimethylphenol
  • Step 7 (4-(3-Fluoro-4-hydroxy-5-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)phosphonic acid
  • the reaction solution is filtered to remove solids, the filter cake is washed with 200 mL of dichloromethane, and the filtrate is extracted with dichloromethane.
  • the organic layers are combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a brown solid, which is then separated by column chromatography to obtain 1.7 g of a yellow solid.
  • Step 3 Diethyl (3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenoxy)methyl)phosphate
  • Step 4 Diethyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphate
  • Step 5 (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)phosphoric acid
  • Step 4 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile
  • Step 5 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one
  • Step 6 6-(2,6-dichloro-4-hydroxybenzyl)-4-isopropylpyridazin-3(2H)-one
  • Step 7 Diethyl (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonate
  • Step 8 (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenoxy)methylphosphonic acid
  • step 7 Under magnetic stirring, 0.4 g of the intermediate of step 7 was added, 6 mL of dichloromethane was measured and placed in a 25 mL clean, dry three-necked flask. The system was cooled to 0 ° C in an ice-salt bath, and 2.7 g of trimethylsilyl bromide was slowly added dropwise. After the addition was complete, the ice bath was removed and the system was naturally returned to room temperature for 6 hours. TLC monitored the reaction to be complete. 0.5 mL of tap water was added dropwise and stirred at room temperature for 10 minutes to quench the system. A white solid precipitated. The dichloromethane was removed under reduced pressure.
  • Example 36 4-(4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)-2,6-dichlorobenzyl)phthalazin-1(2H)-one
  • Example 40 4-(2,6-dichloro-4-((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)-2-methylphthalazin-1(2H)-one
  • Step 4 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)benzamide
  • Step 1 (3,5-Dichloro-4-((2-(methylcarbamoyl)phenoxy)methyl)phenoxy)methyl)phosphonic acid
  • Step 2 2-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphin-2-yl)methoxy)benzyl)oxy)-N-methylbenzamide
  • Example 64 4-((2,6-dichloro-4-(((2R,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide
  • Example 65 4-((2,6-dichloro-4-(((2S,4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxophosphin-2-yl)methoxy)benzyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxamide
  • Step 1 Ethyl (Z)-(2-cyano-2-(2-(3,5-dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)hydrazono)acetyl)carbamate
  • Step 2 2-(3,5-dimethyl-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Step 4 (Z)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)hydrazone)acetyl)carbamate
  • step 3 raw materials are added to 10.0mL of acetic acid and 20.0mL of saturated hydrochloric acid. 0.48g of sodium nitrite is weighed and dissolved in 20.0mL of water and slowly added dropwise to the reaction system. After the addition is complete, the ice-salt bath reaction is continued for 1h until the system is clear to obtain a light yellow solution. Under ice-salt bath, 1.1g of (2-cyanoacetyl) ethyl carbamate is directly added to the diazonium chloride solution. After stirring in an ice bath for 1h, sodium acetate solution is slowly added dropwise to the system. After the system is stirred for 4h, the reaction is complete, and a large amount of yellow solid is precipitated. The filter cake is washed with water and petroleum ether under reduced pressure and dried to obtain 1.1g of the target product.
  • Step 5 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Step 6 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid
  • Step 7 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Step 1 Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)hydrazono)acetyl)carbamate
  • Step 2 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4-5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • step 1 Add 3.94 g of the intermediate of step 1 to 100 mL of glacial acetic acid, and then add 5.3 g of sodium acetate. After the addition is complete, the temperature of the reaction system is raised to 110°C. After the reaction is completed for 4 hours, the heating is stopped and the mixture is cooled to room temperature. Clean water is added to precipitate a large amount of solid. Filter under reduced pressure to obtain a solid. Wash the filter cake with water and dry it to obtain 2.8 g of the target product.
  • Step 3 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3,5-dioxo-2,3,4-5-tetrahydro-1,2,4-triazine-6-carboxylic acid
  • Step 4 6-amino-2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Step 1 N-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)acetamide
  • Step 2 4-(4-amino-2,6-dichlorophenoxy)-2-methylphthalazin-1(2H)-one
  • Step 3 Ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)hydrazone)acetyl)carbamate
  • Step 4 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
  • Step 5 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid
  • Step 6 6-amino-2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Step 1 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid methyl ester
  • Step 2 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(hydroxymethyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • 0.6 g of the product from step 1 was dissolved in 10 mL of tetrahydrofuran, and then 0.2 g of sodium borohydride was added. The temperature was raised to 60°, and methanol was slowly added dropwise until no gas was generated. The reaction was heated for 4 h. After the reaction was complete, 20 mL of water was added and the pH was adjusted to 6 with dilute hydrochloric acid. The organic layers were extracted with ethyl acetate, combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.41 g of the target compound.
  • Step 3 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Step 1 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbaldehyde
  • reaction solution was added to 20 mL of ice water, extracted with ethyl acetate, and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated. It was purified by preparative chromatography to obtain 0.15 g of the target product.
  • Step 2 2-(3,5-dichloro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)oxy)phenyl)-6-(difluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione
  • Streptavidin-d2 indirectly labels the SRC2-2 coactivator peptide by binding to the biotin tag.
  • the THR ⁇ -LBD can form a heterodimer, THR ⁇ -LBD/RXRa.
  • Agonist binding to the THR ⁇ -LBD/RXR ⁇ causes conformational changes in the THR ⁇ -LBD, thereby increasing the heterodimer's ability to recruit the SRC2-2 coactivator peptide.
  • this decreases the distance between the d2-labeled SRC2-2 coactivator peptide and the Eu-anti-GST antibody, increasing the THR-FRET signal.
  • the effects of different compound concentrations on THR ⁇ activity can be used to assess the compound's agonistic ability.
  • This application uses MGL-3196, ALG-055009 and T-501 as control compounds to illustrate the biological activities of the compounds of the present invention.
  • the experimental results are shown in Table 1.
  • Example 66 to Example 103 of the present invention have better binding to THR ⁇ than the reference compounds MGL-3196, ALG-055009, and T-501.
  • the compounds of the present invention 1-44 have better selectivity for THR ⁇ / ⁇ than the reference compound VK-2809.
  • Example 105 Drug metabolism experiment of prodrug in SD rats
  • At least 0.2 mL of blood was collected from the tail vein or jugular vein, and the anticoagulant was sodium heparin.
  • the surface is washed with physiological saline, wiped dry with medical gauze, placed in a labeled small ziplock bag, and stored below -40°C until testing.

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Abstract

La présente invention concerne un dérivé de phénol, un isomère, un composé deutéré ou un sel pharmaceutiquement acceptable de celui-ci. Le dérivé de phénol a une structure telle que représentée dans la formule (I), les définitions de X, R1-R5, Z et Z1 étant détaillées dans la description. De plus, la présente invention concerne en outre une composition pharmaceutique contenant le dérivé de phénol, un isomère, un composé deutéré, ou un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation de la composition pharmaceutique dans la préparation d'un médicament pour le traitement de maladies liées à l'activité agoniste de THR-β.
PCT/CN2025/075292 2024-02-01 2025-01-26 Dérivé de phénol et son utilisation pharmaceutique Pending WO2025162405A1 (fr)

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WO2021032218A1 (fr) * 2019-08-19 2021-02-25 苏州闻天医药科技有限公司 COMPOSÉ AGONISTE DU RÉCEPTEUR THR-β HÉTÉROCYCLIQUE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2021121210A1 (fr) * 2019-12-16 2021-06-24 江苏恒瑞医药股份有限公司 Dérivé à cycles condensés et son procédé de préparation et utilisation médicale associée
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CN118290483A (zh) * 2023-01-05 2024-07-05 烟台药物研究所 一种哒嗪酮类化合物及其应用
CN119080829A (zh) * 2023-06-06 2024-12-06 石家庄迪斯凯威医药科技有限公司 一种新型化合物及其药物组合物和用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882327A (zh) * 2003-11-19 2006-12-20 症变治疗公司 含磷的新的拟甲状腺素药
WO2006128058A2 (fr) * 2005-05-26 2006-11-30 Metabasis Therapeutics, Inc. Composes thyromimetiques utilises pour traiter les maladies hepatiques graisseuses
CN101189248A (zh) * 2005-05-26 2008-05-28 症变治疗公司 新型含磷拟甲状腺素药
CN111320609A (zh) * 2018-12-13 2020-06-23 拓臻股份有限公司 一种THRβ受体激动剂化合物及其制备方法和用途
CN111909137A (zh) * 2019-05-10 2020-11-10 深圳微芯生物科技股份有限公司 一种哒嗪酮衍生物及其应用
WO2021032218A1 (fr) * 2019-08-19 2021-02-25 苏州闻天医药科技有限公司 COMPOSÉ AGONISTE DU RÉCEPTEUR THR-β HÉTÉROCYCLIQUE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2021121210A1 (fr) * 2019-12-16 2021-06-24 江苏恒瑞医药股份有限公司 Dérivé à cycles condensés et son procédé de préparation et utilisation médicale associée
CN114907401A (zh) * 2021-02-08 2022-08-16 江苏天士力帝益药业有限公司 一种亚甲基双苯酚类磷配体衍生物，它们的制备与治疗用途
CN118290483A (zh) * 2023-01-05 2024-07-05 烟台药物研究所 一种哒嗪酮类化合物及其应用
CN119080829A (zh) * 2023-06-06 2024-12-06 石家庄迪斯凯威医药科技有限公司 一种新型化合物及其药物组合物和用途

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