CN114591300A - Heterocyclic compounds as THR beta agonists and uses thereof - Google Patents
Heterocyclic compounds as THR beta agonists and uses thereof Download PDFInfo
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- CN114591300A CN114591300A CN202111465804.5A CN202111465804A CN114591300A CN 114591300 A CN114591300 A CN 114591300A CN 202111465804 A CN202111465804 A CN 202111465804A CN 114591300 A CN114591300 A CN 114591300A
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Abstract
The invention belongs to the field of medicinal chemistry, and relates to heterocyclic compounds serving as THR beta agonists and application thereof, in particular to a compound shown in a formula I, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating and/or preventing THR related diseases. The compound of the present invention has excellent THR beta-modulating activity and high selectivity, and is highly expected to be a therapeutic agent for diseases related to THR modulation.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to heterocyclic compounds serving as THR beta agonists or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, a preparation method thereof, pharmaceutical compositions containing the compounds, and application of the compounds or the compositions in treating and/or preventing THR related diseases.
Background
About 17 million people worldwide are affected by nonalcoholic fatty liver disease (NAFLD), and the incidence of NAFLD in China is remarkably increased from 1998 to 2018 (Jianghua and Feng, Hepatology, 2020, 5, 1851-. Therefore, the development of drugs for targeted therapy of NAFLD aiming at the pathological features and disease development mechanism of NAFLD is urgently needed (Monica a and Jacob c. journal of Hepatology, 2017, 68, 362-375).
NAFLD is a clinical pathological syndrome with histological changes in the liver similar to alcoholic liver disease, but without a history of excessive alcohol consumption. The pathological changes are manifested as simple fatty liver, steatohepatitis, hepatic fibrosis, cirrhosis and liver cancer as the course of disease progresses (Monica A and Jacob C. journal of Hepatology, 2017, 68, 362-375). Among them, Nonalcoholic Steatohepatitis (NASH) is the second process of NAFLD, and the main pathologies are steatosis of liver cells, ballooning lesion of liver cells, inflammation with punctate necrosis, and liver fibrosis of various degrees (susannen and Daniel, Nature Review Gastroenterology Hepatology, 2018, 15, 349-. NASH, if not effectively treated and controlled, can eventually evolve into cirrhosis and Liver cancer, a critical step in the diversion of hepatic steatosis to Liver cancer (Abdul M Oseini and Arun j. sanyal, Liver International, 2017, 37, 97-103).
Thyroid receptors (THRs) are divided into two subtypes, an α subtype (THR α) and a β subtype (THR β). Wherein THR α has 3 kinds of variable shears, which are THR α 1, THR α 2, and THR α 3, respectively; THR β has 3 kinds of variable shears, THR β 1, THR β 2, and THR β 3(Tania M and Aniket R, Nature Reviews, 2014, 10, 582-91), respectively. THR α is mainly distributed in the heart and brain, etc., and THR β is mainly distributed in the skeletal muscle and liver, etc. (Tania M and Aniket R, Nature Reviews, 2014, 10, 582-91). Among them, THR β expression level is high in hepatocytes (Rashmi and Yanyun, Physiology Review, 2014, 94, 355-82). The thyroid hormone T3 regulates the expression of multiple target genes after activating THR β in hepatocytes: increasing the expression of CPT-1(carnitine palmityltransferase-1), and promoting the transport of long-chain fatty acid to mitochondria and beta oxidation; reducing the expression of L-FABP (lipid-type fatty acid-binding protein), SREBP-1C (sterol alignment protein-1C) and ApoC3(apolipoprotein C3), promoting the expression of ApoA1(apolipoprotein A1) and PGC-1a (peroxisome promoter-activated receptor gamma activator-1a), and reducing the synthesis and accumulation of lipids in hepatocytes by regulating the lipid transporters; increasing LDL-R and CYP7a1 expression, promoting cholesterol efflux and bile acid synthesis, and decreasing intracellular cholesterol levels in hepatocytes (Marta. and amedeeo, Frontiers in Endocrinology, 2018, 8, 382). Preclinical studies have shown that THR β agonists significantly reduce liver lipid accumulation in NASH animal mouse models induced by high fat diet, reduce body weight of model mice, reduce inflammation and fibrosis of the liver in NASH mice, and ameliorate metabolic disorders associated with insulin resistance in NASH mice (AASLD, 2017, potter 1969). Meanwhile, THR beta agonists also show better effect of reducing liver lipid accumulation in clinical phase 2 experiment (Stephen and Mustafa, Lancet, 2019, 394, 2012-2024). Patients treated with MGL-3196 (oral 80mg, once daily) (n-78) had a significant reduction in liver lipid accumulation (MRI-PDFF assay) after 12 and 36 weeks of dosing compared to placebo patients (n-38) (Stephen and Mustafa, Lancet, 2019, 394, 2012-2024). Therefore, activation of THR β in hepatocytes is a potential target for treatment of NASH. There is a need to develop further THR β agonists for the prevention or treatment of THR β -related diseases.
Disclosure of Invention
One object of the present invention is to provide a compound having THR modulating activity represented by the general formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein R is1Selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halot-butyl, cyclopropylalkyl, alkylcyclopropyl, halocyclopropyl and azetidinyl;
R2、R3each independently selected from halogen and alkyl; and
x is selected from O, CH2S, SO and SO2。
It is another object of the present invention to provide a process for preparing the compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.
It is a further object of the present invention to provide a composition comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and a pharmaceutically acceptable carrier, and a composition comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug and another drug or drugs.
Still another object of the present invention is to provide a method for treating and/or preventing THR-related diseases by using the compound of formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention, and the use of the compound of formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug of the present invention in the preparation of drugs for treating and/or preventing THR-related diseases.
Aiming at the above purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound represented by formula I, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,
wherein R is1Selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halot-butyl, cyclopropylalkyl, alkylcyclopropyl, halocyclopropyl and azetidinyl;
R2、R3each independently selected from halogen and alkyl; and
x is selected from O, CH2S, SO and SO2。
In some preferred embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R1selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halotert-butyl, cyclopropyl C1-6Alkyl radical, C1-6Alkyl cyclopropyl, halo cyclopropyl and azetidinyl;
further preferably, R1Selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halogenated tert-butyl, cyclopropyl C1-3Alkyl radical, C1-3Alkyl cyclopropyl, halo cyclopropyl and azetidinyl;
even more preferably, R1Selected from the group consisting of ethyl, trifluoroethyl, difluoroethyl, fluoroethyl, hydroxyisopropyl, isobutyl, trifluoro-tert-butyl, difluoro-tert-butyl, fluoro-tert-butyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, methylcyclopropyl, ethylcyclopropyl, propylcyclopropyl, trifluoro-cyclopropyl, difluorocyclopropyl, fluorocyclopropyl and azetidinyl.
In some preferred embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R2、R3each independently selected from fluorine, chlorine, bromine, iodine and C1-6An alkyl group;
further preferably, R2、R3Each independently selected from fluorine, chlorine, bromine, iodine and C1-3An alkyl group;
even more preferably, R2、R3Each independently selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl and propyl;
in some particular embodiments, the compounds of general formula I according to the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein R1Is selected from
In some preferred embodiments, the compounds of formula I above according to the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein R2、R3Each independently is chlorine.
In some preferred embodiments, the compounds of formula I above according to the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein X is oxygen and R is2、R3Each independently is chlorine.
In some preferred embodiments, the compounds of formula I above according to the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, wherein X is oxygen and R is2、R3Each independently of the other is chlorine, R1Is selected from
The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
in another aspect, the invention provides a process for the preparation of a compound of the general formula (la) of the invention, for example:
when X is O, the compound of formula I of the present invention has a structure as shown in formula Ia below, and the compound of formula Ia of the present invention can be prepared by the following preparation method:
1) reacting the compound of formula 1 with the compound of formula 2 to obtain a compound of formula 3;
2) reacting the compound of the formula 3 with the compound of the formula 4 to obtain a compound of a formula 5;
3) reacting the compound shown in the formula 5 to obtain a compound shown in a formula 6;
4) reacting the compound of formula 6 with the compound of formula 7 to obtain a compound of formula 8;
5) the compound of the formula 8 is subjected to cyclization reaction to prepare a compound of a formula Ia;
wherein Y is halogen, preferably selected from chlorine, bromine and iodine; r4Is an alkyl group, preferably C1-6Alkyl, more preferably C1-3An alkyl group; r1、R2、R3Having the definition as described above for formula I.
The other compounds of formula I of the present invention may be prepared by reference to the preparation of formula Ia or by other techniques customary to those skilled in the art.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, further comprising one or more agents selected from the group consisting of: one or more Angiotensin Converting Enzyme (ACE) inhibitors such as enalapril, captopril, ramipril, lisinopril, and quinapril; or angiotensin II receptor blockers (ARBs), such as losartan, olmesartan and irbesartan; or antihypertensive agents such as amlodipine, nifedipine, felodipine, and the like; antibiotics, analgesics, antidepressants and/or anxiolytics, and the like.
In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, for use in the treatment and/or prevention of a THR-associated disease.
In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or the isomer, the pharmaceutically acceptable salt, the solvate, the crystal or the prodrug thereof, which is useful for treating and/or preventing a THR β agonist-related disease.
In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a use of the compound represented by general formula I, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, or a prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing a THR-related disease. In some embodiments, the THR associated disease or condition includes, but is not limited to: neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, tumors, metabolic disorders, and the like, and particularly, THR-related diseases include: kidney diseases (e.g., diabetic nephropathy, end-stage renal disease, chronic kidney disease, etc.), fibrotic diseases (e.g., lung, renal fibrosis, etc.), cardiovascular diseases (e.g., heart failure, etc.), respiratory diseases (e.g., Chronic Obstructive Pulmonary Disease (COPD), pulmonary hypertension, acute lung injury, etc.), acute and chronic liver diseases (e.g., nonalcoholic steatohepatitis (NASH), Alcoholic Hepatitis (AH), liver fibrosis, etc.), neurodegenerative diseases (e.g., alzheimer's disease, parkinson's disease, etc.), hyperlipidemia, atherosclerosis, hypercholesterolemia, hypothyroidism, and tumors (e.g., thyroid cancer, etc.).
In some embodiments, the present invention provides a use of the compound represented by the general formula I of the present invention or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating and/or preventing THR-related diseases. In some embodiments, the THR associated disease or condition includes, but is not limited to: obesity, hypertension, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis, fatty liver, bone disease, thyroid shaft alteration, atherosclerosis, cardiovascular disorders, tachycardia, hyperactivity, thyroid dysfunction, goiter, attention deficit hyperactivity disorder, learning disorders, mental retardation, hearing impairment, delayed bone age, neurological or psychiatric disorders, or thyroid cancer.
In some embodiments, the THR of the invention is THR β.
Description of the terms
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, and isotopes of carbon include12C、13C and14c, isotopes of oxygen including16O and18o, and the like.
The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine. "halo" in the context of the present invention means substituted by fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.
"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.
"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
"isomers" of the present invention are compounds having the same molecular formula but differing in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms. Stereoisomers are isomers whose atoms differ in their spatial arrangement. Stereoisomers that are not mirror images of each other are diastereomers and stereoisomers that are non-overlapping mirror images of each other are enantiomers. When the compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively) by the R-and S-sequencing rules of Cahn and Prelog, or by methods in which molecules rotate the plane of polarized light. The chiral compound may exist as a single enantiomer or a mixture thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".
The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.
The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As mentioned above, the in vivo effects of the compounds of formula (I) may also be exerted via precursor compound ("prodrug") metabolism. The "prodrug" of the present invention refers to a compound which is converted into a compound of the formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into a compound of the formula (I) by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into a compound of the formula (I) by a hydrolysis reaction of gastric acid or the like, or the like.
The "crystal" in the present invention is a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, and is different from an amorphous solid having no such regular internal structure.
The term "pharmaceutical composition" as used herein is intended to encompass a mixture comprising any one of the compounds of the present invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.
The "pharmaceutically acceptable carrier" of the present invention means a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.
"excipient" in the context of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials used in the following examples are all commercially available unless otherwise specified.
Example 1: 2- [3, 5-dichloro-4- (5- (1-methylcyclopropyl) -6-oxo-1, 6-dihydro-pyridazin-3-yloxy) -phenyl ] -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
Step 1: synthesis of 3, 6-dichloro-4- (1-methylcyclopropyl) pyridazine
To a 250mL two-necked flask were added 3, 6-dichloropyridazine (6.00g,40mmol), 1-methylcyclopropane-1-carboxylic acid (6.00g,60mmol), silver nitrate (3.40g,20mmol) and 60mL of water at room temperature, followed by warming the reaction to 55 deg.C, adding trifluoroacetic acid (2.32g,20mmol) at that temperature, then slowly adding ammonium persulfate (13.68g,60mmol), stirring at that temperature for 10 minutes, and warming to 70 deg.C. Stirring overnight, and after the reaction was completed, the reaction system was cooled to room temperature. While the mixture was chilled in an ice bath, ammonia was added to adjust the pH to 8, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration, concentration and silica gel column chromatography (petroleum ether: ethyl acetate 10:1) gave 3.46g of a white solid, yield: and 43 percent. MS (ESI) M/z 203.0[ M + H ]]+.
Step 2: synthesis of 3, 5-dichloro-4- ((6-chloro-5- (1-methylcyclopropyl) pyridazin-3-yl) oxy) aniline
Into a 100mL two-necked flask were charged 3, 6-dichloro-4- (1-methylcyclopropyl) pyridazine (3.40g,17mmol), 4-amino-2, 6-dichlorophenol (3.00g,17mmol), cuprous iodide (1.62g,8.5mmol), anhydrous potassium carbonate (9.40g,68mmol) and 30mL of anhydrous N, N-dimethylformamide, and the mixture was heated to 90 ℃ for overnight reaction. After the reaction, cooling to room temperature, adding water for quenching, adjusting the pH value to 3, adding ethyl acetate, removing solid particles by suction filtration, extracting an aqueous phase by using ethyl acetate, washing an organic phase by using brine, and drying by using anhydrous sodium sulfate. Filtration, concentration and silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) gave 3.20g of a yellow solid, yield: and 55 percent. MS (ESI) M/z344.0[ M + H ]]+.
And step 3: synthesis of 6- (4-amino-2, 6-dichlorophenoxy) -4- (1-methylcyclopropyl) pyridazin-3 (2H) -one
To a 100mL two-necked flask were added 3, 5-dichloro-4- ((6-chloro-5- (1-methylcyclopropyl) pyridazin-3-yl) oxy) aniline (3.20g,9.3mmol), anhydrous sodium acetate (2.68g,32.6mmol) and 20mL glacial acetic acid, and reacted at 100 ℃ overnight. After the reaction is completed, partial acetic acid is removed by rotary evaporation, water is added, ethyl acetate is used for extraction, and the organic phase is respectively washed by saturated sodium bicarbonate solution, water and saturated saline solution. The organic phase was concentrated by rotary drying and used directly in the next step. The product of the previous step, 10mL of methanol, 20mL of water and sodium hydroxide (7.44g,186mmol) were added to a two-necked flask, and the reaction was allowed to warm to 100 ℃ for 24 hours. After cooling to room temperature, the methanol was removed, the pH was adjusted to 5, extracted with ethyl acetate, the organic phase was washed with brine and dried over anhydrous sodium sulfate. Filtration, concentration and silica gel column chromatography (petroleum ether: ethyl acetate 1:1) gave 1.28g of a grey solid, yield: 42 percent. MS (ESI) M/z 326.0[ M + H ]]+.
And 4, step 4: synthesis of ethyl (2-cyano-2- (2- (3, 5-dichloro-4- ((5- (1-methylcyclopropyl) -6-oxo-1, 6-dihydropyridazin-3-yl) oxy) phenyl) hydrazino) acetyl) carbamate
To a 50mL round bottom flask was added 6- (4-amino-2, 6-dichlorophenoxy) -4- (1-methylcyclopropyl) pyridazin-3 (2H) -one (1.28g,3.9mmol), 18mL concentrated hydrochloric acid and 20mL water, cooled to 0 deg.C, and then 2mL sodium nitrite (0.36g,5.2mmol) solution was slowly added dropwise for reaction for 30 minutes. Into another reactor were charged N-cyanoacetylurethane (0.62g,3.9mmol), 12mL of pyridine and 12mL of water, and the reaction solution in the first flask was poured quickly at 0 ℃ and the reaction was continued for 30 minutes. After the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 1.20g of a crude productThe product was used directly in the next step. MS (ESI) M/z 493.1[ M + H ]]+.
And 5: synthesis of 2- [3, 5-dichloro-4- (5- (1-methylcyclopropyl) -6-oxo-1, 6-dihydro-pyridazin-3-yloxy) -phenyl ] -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
The product of the previous step (1.20g,2.4mmol), anhydrous sodium acetate (0.98g,12mmol) and 3mL of glacial acetic acid were added to a two-necked flask, and the temperature was raised to 120 ℃ for reaction for 2 hours. After the reaction was completed, most of the solvent was spin-dried, water was added, ethyl acetate was extracted, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.62g of a crude product, of which 0.3g was purified by a separation preparation platform to obtain 22mg of a pale yellow solid. Yield: 4 percent. MS (ESI) M/z 444.9[ M-H ]]-.1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.78(s,2H),7.43(s,1H),1.36(s,3H),1.20(s,2H),0.69(s,2H).
Example 2: 2- [3, 5-dichloro-4- (5-sec-butyl-6-oxo-1, 6-dihydro-pyridazin-3-yloxy) -phenyl ] -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
The title compound was obtained by the same procedure as in example 1, except that 1-methylcyclopropane-1-carboxylic acid as a starting material was replaced with 2-methylbutyric acid. MS (ESI) M/z 449.1[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ13.27(br,1H),12.23(s,1H),7.78(s,2H),7.45(s,1H),2.90(dd,J＝13.6,6.9Hz,1H),1.73–1.63(m,1H),1.56–1.45(m,1H),1.17(d,J＝6.9Hz,3H),0.86(t,J＝7.4Hz,3H).
Example 3: 2- [3, 5-dichloro-4- (5-ethyl-6-oxo-1, 6-dihydro-pyridazin-3-yloxy) -phenyl ] -3, 5-dioxo-2, 3,4, 5-tetrahydro- [1,2,4] triazine-6-carbonitrile
The title compound was obtained by the same procedure as in example 1, except that 1-methylcyclopropane-1-carboxylic acid as a starting material was replaced with propionic acid. MS (ESI) M/z 421.0[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),7.78(s,1H),7.47(s,1H),7.15(s,2H),2.56–2.46(m,2H),1.18(t,J＝8.0Hz,3H)..
Experimental example 1 THR alpha and THR beta receptor activation experiment
1. Experimental Material
The experiment is completed by Kanglong formation (Beijing) new drug technology company Limited. The positive control was MGL-3196(Resmetirom), supplied by Conlon chemical company.
Preparation of compound: the compounds of the invention and control compounds prepared in the above examples were each prepared in DMSO as a 6mM solution for use.
The experimental materials are shown in the following table
2. Experimental methods
2.1. 6mM of the compound of the example of the present invention and the control compound, which were prepared, were diluted 3-fold with DMSO, respectively, for 10 doses in 10 gradients, 6000, 2000, 666.67, 222.22, 74.07, 24.69, 8.23, 2.74, 0.91, 0.30. mu.M, as 100 Xsolution (final reaction concentration of 60, 20, 6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.0091, 0.0030. mu.M)
2.2. All 100 × solutions were diluted to 4 × solutions with DMSO, respectively;
2.3. add 5. mu.L of the 4 Xsolution to 384 well plates, respectively;
2.4. separately, 5. mu.L of TR α LBD or TR β LBD (TR α LBD if the test compound is active on THR α, or TR β LBD if the test compound is active on THR β) and 5. mu.L of RXR α are added to each well;
2.5. mu.L of each reaction solution (Biotin-SRC2-2, Europium anti-GST and streptavidin-d2) was added to each well.
2.6. Incubating for 4h at normal temperature in dark place;
2.7. fluorescence values were read at 665nM and 615 nM.
3. Data analysis method
3.1. Per hole according to the formula Ratio665nm/615nm-RatiobackgroundCalculating the Ratio value of each hole
3.2. Calculate% Activity per well according to the following equation
3.3. Calculation of the respective Compound EC50Value and Compound Selectivity (Selectivity. beta./alpha.)
EC50: fitting the log of% Activity of each well to the corresponding concentration (dose response-variable slope, Graphpad 8.0) to obtain EC50The value is obtained.
Since THR α is expressed in high abundance in the heart, activation of THR α in the heart will lead to myocardial hypertrophy, thereby bringing a serious safety risk, and therefore, it is necessary to calculate the selectivity of the compound for THR β:
Selectivityβ/α＝(EC50 THRα/EC50 THRβ)*(Emax THRβ/Emax THRα)
summary data for each compound is shown in table 1:
TABLE 1
The experimental data show that the compound has better agonism on THR beta and weak agonism on THR alpha, and is a THR beta high-selectivity agonist.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.
Claims (10)
1. A compound shown in general formula I or isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof
Wherein R is1Selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halot-butyl, cyclopropylalkyl, alkylcyclopropyl, halocyclopropyl and azetidinyl;
R2、R3each independently selected from halogen and alkyl; and
x is selected from O, CH2S, SO and SO2。
2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
R1selected from ethyl, haloethyl, hydroxyisopropyl, isobutyl, halotert-butyl, cyclopropyl C1-6Alkyl radical, C1-6Alkyl cyclopropyl, halo cyclopropyl and azetidinyl.
3. The compound according to claim 1 or its isomer, pharmaceutically acceptableAn acceptable salt, solvate, crystal or prodrug, wherein R1Is selected from
4. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R2、R3Each independently selected from fluorine, chlorine, bromine, iodine and C1-6An alkyl group.
5. The compound according to any one of claims 1 to 4, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R2、R3Each independently is chlorine.
6. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein X is oxygen and R is2、R3Each independently is chlorine.
7. The compound according to any one of claims 1 to 6, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein X is oxygen and R is2、R3Each independently of the other is chlorine, R1Is selected from
8. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:
9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
10. Use of a compound according to any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment and/or prevention of a THR associated disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020114093384 | 2020-12-04 | ||
| CN202011409338 | 2020-12-04 |
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| CN114591300A true CN114591300A (en) | 2022-06-07 |
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| CN202111465804.5A Pending CN114591300A (en) | 2020-12-04 | 2021-12-03 | Heterocyclic compounds as THR beta agonists and uses thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024141104A1 (en) * | 2022-12-31 | 2024-07-04 | 南京知和医药科技有限公司 | New pyridazine compound, and pharmaceutical composition and use thereof |
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2021
- 2021-12-03 CN CN202111465804.5A patent/CN114591300A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024141104A1 (en) * | 2022-12-31 | 2024-07-04 | 南京知和医药科技有限公司 | New pyridazine compound, and pharmaceutical composition and use thereof |
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