WO2023279280A1 - Inhibiteur de fbpase n-(arylsulfonyl)-indole-2-carboxamide et son utilisation - Google Patents

Inhibiteur de fbpase n-(arylsulfonyl)-indole-2-carboxamide et son utilisation Download PDF

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WO2023279280A1
WO2023279280A1 PCT/CN2021/104953 CN2021104953W WO2023279280A1 WO 2023279280 A1 WO2023279280 A1 WO 2023279280A1 CN 2021104953 W CN2021104953 W CN 2021104953W WO 2023279280 A1 WO2023279280 A1 WO 2023279280A1
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substituted
membered aromatic
compound
aromatic heterocycle
nitrogen
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Chinese (zh)
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徐柏玲
申竹芳
周洁
刘率男
扈金萍
纪文明
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中国医学科学院药物研究所
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention discloses 1-methyl-7-chloro-4-((methoxyaryl heteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide FBPase inhibitors with new structure , and its preparation method and pharmaceutical composition and use.
  • the present invention relates to N-acylsulfonamide FBPase inhibitors represented by general formula I and general formula II and their salts, their preparation methods, compositions containing one or more such compounds, and such compounds
  • the use in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase and the use in the preparation of drugs for preventing and/or treating diabetes.
  • Diabetes mellitus is a chronic metabolic disease regulated by multiple genes, mainly manifested as persistent hyperglycemia and glucosuria. Sustained hyperglycemia can lead to many complications, such as retinal, renal, nervous system lesions and vascular complications (New. Engl. J. Med., 2010, 362: 1090-1101). Patients with hyperglycemia are often accompanied by hyperlipidemia.
  • the number of people suffering from diabetes in China ranks first in the world. According to the latest survey of "Prevalence and Control of Adult Diabetes in China", the prevalence of diabetes in Chinese adults aged 18 and above has reached 11.6%, and the prevalence of prediabetes is even higher. It reached 50.1%.
  • Diabetes is divided into insulin-dependent (type I) and non-insulin-dependent (type II), of which type II diabetes accounts for 90% to 95% of the total number of diabetic patients.
  • Biological studies have shown that the main pathological basis of diabetes is insufficient insulin secretion, insulin resistance and increased hepatic glucose production.
  • Most antidiabetic drugs currently in clinical use increase insulin secretion (such as: sulfonylureas and glinide insulin secretagogues), or by preventing peripheral insulin resistance (such as: thiazolidinedione insulin sensitization agent) to treat diabetes.
  • Endogenous glucose production is the main cause of elevated fasting blood glucose in diabetic patients.
  • Endogenous glucose mainly comes from the liver, and gluconeogenesis and glycogenolysis are the two main ways to produce glucose in the liver.
  • the gluconeogenesis pathway is one of the main causes of elevated blood sugar in patients with type II diabetes. Therefore, reducing the production of endogenous glucose by regulating the gluconeogenesis pathway has become a new strategy for the development of anti-type II diabetes drugs with new mechanisms of action.
  • Gluconeogenesis is the process of converting three-carbon precursors such as glycerol and lactic acid into glucose under the catalysis of various enzymes.
  • Fructose 1,6-bisphosphatase, fructose 6-phosphatase and pyruvate carboxylase play key roles in gluconeogenesis; among them, fructose 1,6-bisphosphatase (FBPase) catalyzes the fructose -1,6-bisphosphate conversion to fructose-6-phosphate is one of the rate-controlling steps in the gluconeogenesis pathway; thus, fructose-1,6-bisphosphatase is a potential new mechanism of action for antidiabetic drug target.
  • Fructose-1,6-bisphosphatase inhibitors are potential novel mechanisms of antidiabetic drugs.
  • MB07803 is a phosphodiamide prodrug of thiazole compounds, and is currently in phase II clinical research (US, 225259A1[P].2007-09-27. ).
  • 2012-2014 through high-throughput screening, He et al.
  • FBPase inhibitors with various structural types, so far, only one FBPase inhibitor (MB07083) is in phase II clinical research in the form of a phosphonic acid diamide prodrug.
  • the present invention is based on the N-acyl sulfonamide inhibitors obtained earlier (patent application number: 2016101058649), the salt of the 4-position substituent of the indole ring, the 2-position sulfonamide substituent, and the acyl sulfonamide Structural modification is carried out to obtain FBPase inhibitors with high activity, and/or reasonable physicochemical properties (such as increased solubility), and/or druggability.
  • the present invention designs and synthesizes 1-methyl-7-chloro-4-((methoxyarylheteroyl)amino)-N-(arylsulfonyl)-indole-2-carboxamide and its salts with a new structure
  • the FBPase-like inhibitors have laid a structural foundation for obtaining FBPase inhibitors with good pharmacokinetic properties and which can be administered orally.
  • the present invention aims to find a novel orally effective antidiabetic drug which has strong inhibitory activity on FBP enzyme and good druggability.
  • the technical problem solved by the present invention is to provide formula I, I-A and formula II, the N-acyl sulfonamide FBPase inhibitor shown in II-A, its preparation method, the composition containing one or more such compounds, and the The use of the compound in the preparation of FBPase inhibitors or drugs for treating diseases related to FBPase, and the use in the preparation of drugs for preventing and/or treating diabetes.
  • the present invention provides the following technical solutions:
  • the first aspect of the technical solution of the present invention is to provide such as general formula I, IA and formula II, N-acyl sulfonamide derivatives shown in IIA:
  • A, B, D, E are independently selected from CR or N;
  • R is selected from H, F, Cl, CH 3 , OCH 3 ;
  • Ar 1 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A, B, D, E are independently selected from CR or N;
  • R is selected from H, F, Cl, CH 3 , OCH 3 ;
  • M 1 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • Ar 1 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A', B', D', E' are independently selected from CR' or N;
  • R' is selected from H, F, Cl, CH 3 , OCH 3 ;
  • Ar 2 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • A', B', D', E' are independently selected from CR' or N;
  • R' is selected from H, F, Cl, CH 3 , OCH 3 ;
  • M2 is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • Ar 2 is selected from the following groups or structural fragments:
  • Phenyl, substituted phenyl, non-substituted nitrogen-containing six-membered aromatic heterocycles including pyridine, pyrimidine, pyridazine, pyrazine), substituted nitrogen-containing six-membered aromatic heterocycles (six-membered aromatic heterocycles including pyridine, pyrimidine , pyridazine, pyrazine);
  • substituent is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclopropyl methylene, cyclobutyl, halogen substituted C1-4 straight chain Or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), F, Cl, Br, NO 2 , CN, methylenedioxy Base, ORs 1 , NRs 2 Rt 1 , CONRs 3 Rt 2 ;
  • Rs 1 , Rs 2 , Rs 3 , Rt 1 , Rt 2 are independently selected from H, C1-4 straight chain or branched chain alkyl (including methyl, ethyl, propyl, isopropyl, butyl group, isobutyl), halogen substituted C1-4 straight chain or branched chain alkyl (including CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CF 2 CH 3 , CH 2 CH 2 CF 3 ), Cyclopropyl, cyclopropyl methylene, cyclobutyl;
  • the benzene ring and the nitrogen-containing six-membered aromatic heterocycle can be mono-substituted or multi-substituted;
  • the six-membered aromatic heterocycle can contain one N atom or multiple nitrogen atoms
  • the halogen includes F, Cl, Br.
  • preferred compounds include but are not limited to the following compounds:
  • the second aspect of the technical solution of the present invention is to provide a preparation method for the compound described in the first aspect.
  • the technical solution adopted includes the following steps: in the presence of sodium ethylate and ethyl trifluoroacetate, 2-bromo-5-chloro-benzene Compound 1 was prepared by reacting formaldehyde with ethyl azidoacetate.
  • compound 1 underwent ring closure reaction at 180°C to obtain 4-bromo-7-chloro-1-H-indole-2 -Ethyl carboxylate, then methylated at the indole-1-position under the condition of cesium carbonate to give 4-bromo-7-chloro-1-methyl-indole-2-carboxylate ethyl ester; then the compound
  • the coupling reaction of 3 with the substituted arylamine under palladium catalysis gives compounds 4 and 4', and the corresponding compounds 5 and 5' with carboxyl at the 2-position are obtained after hydrolysis.
  • Reagents and reaction conditions (a) ethyl azidoacetate, ethyl trifluoroacetate, sodium, ethanol, -15°C to 0°C; (b) o-dichlorobenzene, 180°C; (c) methyl iodide, cesium carbonate , DMF, rt; (c) Ar 1 -NH 2 , Pd 2 (dba) 3, Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e ) Ar 2 -S(O) 2 -NH 2 , HATU, DMAP, Et 3 N, rt; (g) alkali metal or alkaline earth metal base, water, rt.
  • the third aspect of the technical solution of the present invention provides a pharmaceutical composition, which includes the compound described in the first aspect of the technical solution of the present invention and a commonly used pharmaceutical carrier.
  • the present invention also provides a pharmaceutical composition with the compound of the present invention as an active ingredient, and the composition includes at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems.
  • the pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • formulations are prepared according to methods well known to those skilled in the art.
  • the excipients used in the manufacture of tablets, capsules, and coatings are commonly used auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and solvents used in liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oil Such as corn oil, peanut oil, olive oil and so on.
  • the preparation containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments and the like.
  • Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agents can be water, ethanol, iso Propanol, etc.
  • binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrants can be dry starch, microcrystalline cellulose, low-substi
  • Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or a soft capsule.
  • the active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules.
  • Various diluents, binders, wetting agents, disintegrants, and glidants used in the preparation of tablets of the compound of the present invention can also be used in the preparation of capsules of the compound of the present invention.
  • water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators and osmotic pressure regulators in this field can be added.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations, if necessary.
  • the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.
  • the dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc.
  • the suitable daily dosage range of the compound of the present invention is 0.01-500 mg/Kg body weight, preferably 0.1-300 mg/Kg body weight.
  • the above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.
  • the compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
  • the fourth aspect of the technical solution of the present invention provides the use of the compound described in the first aspect of the present invention in the preparation of FBPase inhibitors and in the preparation of drugs for the prevention and/or treatment of diseases and disorders related to FBPase.
  • Said application is characterized in that the diseases and diseases related to FBPase are selected from diabetes, chronic complications of diabetes, hyperlipidemia and obesity.
  • the diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, nervous system lesions and vascular complications, local ischemic heart disease or atherosclerosis.
  • Described hyperlipidemia includes high glyceride and high cholesterol ester.
  • NMR nuclear magnetic resonance
  • HRMS high resolution mass spectroscopy
  • the reagents used in the experiment were chemically or analytically pure.
  • the solvents used are analytically pure, and the anhydrous solvents used are obtained from the solvent purification system produced by INNOVATIVE TECHNOLOGY in the United States. Other solvents are untreated unless otherwise specified.
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (350 mg, 1.113 mmol) was dissolved in toluene (30 mL), and Pd 2 (dba) 3 ( 255mg, 0.28mmoll), Xantphos (325mg, 0.56mmol), then Na 2 CO 3 (353mg, 3.341mmol) was dissolved in (7.5mL) water and added to the reaction solution, 2-amino-6-methoxypyridine (413mg , 3.339mmol) into the reaction flask, reflux reaction 20h.
  • the compound 1-methyl-4-((6-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid (2g, 6.04mmol) was dissolved in DCM (40mL ), add HATU (4.59g, 12.08mmol), DMAP (737mg, 6.04mmol), TEA (2.61mL, 18.12mmol) and p-methoxybenzenesulfonamide (2.265mg, 12.08mmol), stir at room temperature for about 1h, DCM (50 mL) was added, washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution, and water, a solid precipitated, suction filtered, the filter cake was washed with water, and DCM to obtain 1.2 g of a khaki solid.
  • 1-methyl-4-((4-methoxypyridin-2-yl)amino)-7-chloro-indole-2-carboxylic acid 100 mg, 0.30 mmol was dissolved in dry DCM, Add HATU (207mg, 0.54mmol), DMAP (20mg, 0.15mmol) and TEA (92mg, 0.91mmol) sequentially, stir well and add p-methoxybenzenesulfonamide (102mg, 0.54mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine.
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (190 mg, 0.60 mmol) was dissolved in toluene (20 mL), and Pd 2 (dba) 3 was added in sequence (55mg, 0.06mmol), Xantphos (70mg, 0.12mmol) and Na 2 CO 3 (191mg, 1.80mmol, 3mL H 2 O), after stirring well, 2-methoxy-5-aminopyridine (224mg, 1.80 mmol) was added, and the reaction was refluxed for 7h, and the raw material disappeared completely.
  • Ethyl 1-methyl-4-((6-methoxypyridin-3-yl)amino)-7-chloro-indole-2-carboxylate (110 mg, 0.31 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (62mg, 1.53mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 98 mg of a light yellow-green solid was obtained, with a yield of 97%.
  • the compound 1-methyl-7-chloro-4-bromo-indole-2-carboxylic acid ethyl ester (750 mg, 2.39 mmol) was dissolved in toluene (40 mL), and Pd 2 (dba) 3 ( 547mg, 0.6mmol), Xantphos (694mg, 1.2mmol), then Na 2 CO 3 (847mg, 7.99mmol) was dissolved in (10mL) water and added to the reaction solution, 2-methoxy-4-aminopyrimidine (1g, 7.99mmol) into the reaction flask, reflux reaction 20h.
  • 1-methyl-4-((2-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylic acid 75 mg, 0.23 mmol was dissolved in dry DCM, Add HATU (156mg, 0.41mmol), DMAP (15mg, 0.12mmol) and TEA (70mg, 0.69mmol) sequentially, stir well and then add p-methoxybenzenesulfonamide (77mg, 0.41mmol), react at 35°C for 30min and stop After the reaction, the solvent was distilled off and then washed with dilute hydrochloric acid, water, and brine.
  • Ethyl 1-methyl-4-((4-methoxypyrimidin-6-yl)amino)-7-chloro-indole-2-carboxylate (95 mg, 0.26 mmol) was dissolved in THF/EtOH (1/ 2, v/v, 12mL), add NaOH solution (53mg, 1.32mmol, 2mL H 2 O), react overnight at room temperature, evaporate the solvent after stopping the reaction, add a small amount of water, adjust the pH to 2 with 1M hydrochloric acid, and precipitate a solid. After filtration and drying, 85 mg of a light yellow-green solid was obtained, with a yield of 96%.
  • the bacterial solution was centrifuged at 4°C and 5500rpm for 5 minutes, the supernatant was discarded, and the precipitate (bacterial cells) was added to FBPase Tris-Buffer to resuspend the bacterial cells.
  • the cells were disrupted by ultrasonication, and then centrifuged at 12,000 rpm for 1 min at 4°C. The supernatant was collected, assayed for enzyme activity, and stored at -80°C after aliquoting.
  • Measuring principle of FBPase activity Utilize the coupling reaction of FBPase with phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, and use a spectrophotometer to detect the concentration of the reaction product to reflect the activity of the enzyme.
  • the reaction consumes NADP + to generate NADPH, and the change of absorbance at 340nm directly reflects the activity of the enzyme.
  • FBPase Tris-Buffer 100mM Tris, 2mM MgCl 2 , 0.1mM EDTA, pH 7.5
  • inhibitors final concentration 0.08uM, 0.4uM, 2uM or 10uM
  • FBPase final concentration 0.72unit
  • the reaction substrate mixture final concentration 0.2 mM NADP + , 0.01 units phosphoglucose isomerase, 0.01 units glucose-6-phosphate dehydrogenase and 0.2 mM FBP
  • NADPH absorbance value of the reaction product
  • Example (IC 50M ) Example (IC 50M ) 1 8.30 ⁇ 10 -8 2 1.50 ⁇ 10 -8 3 4.78 ⁇ 10 -8 4 1.81 ⁇ 10 -8 5 4.49 ⁇ 10 -8 6 3.05 ⁇ 10 -8 7 9.70 ⁇ 10 -8 8 2.71 ⁇ 10 -8
  • Adopt normal male ICR mice fast overnight, get zero o'clock blood sample (-120min) in the morning of the next day, thereafter, give embodiment compound 2 (Example 2, 150mg/kg) or positive drug metformin ( Met, 150mg/kg), the blank control group was replaced by water.
  • the post-administration blood sample was collected (0 min), and the gluconeogenesis substrate sodium pyruvate (2 g/kg) was orally administered orally, and the mouse blood sample was collected after 30 min of intragastric administration of sodium pyruvate (30 min).
  • Glucose concentration in blood samples was measured by GOD method. Compare each group 0min and 30min blood glucose difference with normal control group to compare whether there is statistical difference, measure the hypoglycemic activity of compound.
  • Experimental example 2-2 Evaluation of the antidiabetic activity of the compound of Example 2 on type 2 diabetic KKAy mice
  • Spontaneous type 2 diabetic KKAy mice male, 4-5 weeks old, were purchased from Beijing Huafukang Biotechnology Co., Ltd., and were bred in the SPF animal room of the Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 mice/box, with free access to water. They were fed with high-fat feed for about 3 weeks, and they were randomly divided into groups, 10 in each group.
  • MAIN OUTCOME MEASURES non-fasting blood glucose (PBG), fasting blood glucose (FBG), percent increase in blood glucose at 30 minutes of OGTT test, blood triglyceride (TG), blood total cholesterol (TC) and body weight.
  • Gavage water was used as the model control group
  • gavage compound Example 2 100 mg/kg and 200 mg/kg suspension was used as the administration group
  • gavage compound metformin 150 mg/kg suspension was used as the positive control group.
  • Oral administration once a day for 35 consecutive days.
  • the fasting blood glucose level of the mice was dynamically monitored. The fasting blood glucose was measured on the 21st day, the random blood glucose was measured on the 27th day, and the glycosylated hemoglobin level was measured on the 33rd day.
  • Compound Example 2 can significantly reduce the fasting blood glucose level (Table 2) of spontaneous type 2 diabetes KKAy mice; it can also significantly reduce the random blood glucose level (Table 3) of KKAy mice; and make KKAy The level of glycated hemoglobin in the mice was significantly reduced (Table 4).
  • mice were randomly divided into 2 groups, the intravenous injection group of the compound of Example 2 and the oral administration group, each group of 3 rats were given the compound of Example 2 (3mg/kg) by intravenous injection in 2min, 5min , 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h each time point was taken from the orbital venous plexus, and the rats were orally given the compound of Example 2 (30mg/kg) after At 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h, blood was collected from the orbital venous plexus at each time point, and the blood was collected into a heparin-anticoagulated EP tube and placed on ice , after centrifugation at 8000r/min ⁇ 5min, separate the plasma for later use.
  • Standard curve of the compound of Example 2 Take 50 ⁇ l of SD rat blank plasma, add 480 ⁇ l of acetonitrile, and then add 10 ⁇ l of methanol solution of the compound of Example 2 at different concentrations to make the final concentration 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10000, 20000, 50000ng/ml, mix well, 14000r/min ⁇ 5min high-speed centrifugation twice, take 5 ⁇ l of supernatant for HPLC-MS/MS analysis.
  • control group no inhibitor
  • positive inhibitor group the positive inhibitor group
  • test compound inhibition group 10 ⁇ M
  • three parallel samples were set up in each group. Add the inhibitor into human liver microsomes and incubate together with the probe substrates of each subtype, measure the metabolites generated by the probe substrate, and compare with the control group to reflect the degree of inhibition of the inhibitor on the isozyme.
  • CYP1A2, 2D6, 2C9, 2C19, 3A4, 2E1 substrate concentration and incubation time were phenacetin 50 ⁇ M/30min, dextromethorphan 5 ⁇ M/10min, diclofenac sodium 20 ⁇ M/10min, mephenytoin 40 ⁇ M/ 30min, midazolam 5 ⁇ M/5min, chlorzoxazone 80 ⁇ M/20min.
  • CYP1A2, 2D6, 2C9, 2C19, 3A4, and 2E1 isoenzyme positive inhibitors were as follows: furafylline 10 ⁇ M, quinidine 2 ⁇ M, sulfabenzopyrazole 5 ⁇ M, ticlopidine 5 ⁇ M, ketoconazole 1 ⁇ M, two Sodium ethyl disulfide ammonium formate 50 ⁇ M.
  • the metabolic inhibition rates of positive inhibitors to CYP1A2, 2C19, 2C9, 2D6, 3A4, and 2E1 probe substrates were 61.23%, 93.52%, 76.81%, 89.77%, 93.82%, and 80.37%.
  • the substrate has obvious inhibitory effect.
  • the inhibitory activity of the test compound on each subtype is weaker than that of the positive control inhibitor, and has good safety.
  • the results are shown in Table 6.

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Abstract

La présente invention concerne un inhibiteur de 1-méthyl-7-chloro-4-((méthoxyaryle hétéroyle)amino)-N-(arylsulfonyl)-indole-2-carboxamide FBPase ayant une nouvelle structure, son procédé de préparation, une composition pharmaceutique et une utilisation de celui-ci. En particulier, la présente invention concerne un inhibiteur de N-acylsulfonamide FBPase et un sel de celui-ci représenté par la formule générale I et la formule générale II, un procédé de préparation de celui-ci, une composition contenant un ou plusieurs de ces composés, l'utilisation de tels composés dans la préparation d'un inhibiteur de FBPase ou d'un médicament pour le traitement de maladies liées à la FBPase, et une utilisation de celui-ci dans la préparation d'un médicament pour la prévention et/ou le traitement du diabète.
PCT/CN2021/104953 2021-07-07 2021-07-07 Inhibiteur de fbpase n-(arylsulfonyl)-indole-2-carboxamide et son utilisation WO2023279280A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1505613A (zh) * 2000-10-10 2004-06-16 ʷ��˿�������ȳ�ķ���޹�˾ 取代的吲哚、含这类吲哚的药物组合物及它们作为PPAR-γ结合剂的用途
CN107098846A (zh) * 2016-02-26 2017-08-29 中国医学科学院药物研究所 N-酰基磺酰胺类FBPase抑制剂、其制备方法、药物组合物及用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1505613A (zh) * 2000-10-10 2004-06-16 ʷ��˿�������ȳ�ķ���޹�˾ 取代的吲哚、含这类吲哚的药物组合物及它们作为PPAR-γ结合剂的用途
CN107098846A (zh) * 2016-02-26 2017-08-29 中国医学科学院药物研究所 N-酰基磺酰胺类FBPase抑制剂、其制备方法、药物组合物及用途

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Title
ZHOU JIE, BIE JIANBO, WANG XIAOYU, LIU QUAN, LI RONGCUI, CHEN HUALONG, HU JINPING, CAO HUI, JI WENMING, LI YAN, LIU SHUAINAN, SHEN: "Discovery of N -Arylsulfonyl-Indole-2-Carboxamide Derivatives as Potent, Selective, and Orally Bioavailable Fructose-1,6-Bisphosphatase Inhibitors—Design, Synthesis, In Vivo Glucose Lowering Effects, and X-ray Crystal Complex Analysis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 18, 24 September 2020 (2020-09-24), US , pages 10307 - 10329, XP093021549, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c00726 *

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