WO2020114457A1 - Inhibiteur de fbpase de sel n-acyl sulfonamide, son procédé de préparation, sa composition pharmaceutique et ses applications - Google Patents

Inhibiteur de fbpase de sel n-acyl sulfonamide, son procédé de préparation, sa composition pharmaceutique et ses applications Download PDF

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WO2020114457A1
WO2020114457A1 PCT/CN2019/123301 CN2019123301W WO2020114457A1 WO 2020114457 A1 WO2020114457 A1 WO 2020114457A1 CN 2019123301 W CN2019123301 W CN 2019123301W WO 2020114457 A1 WO2020114457 A1 WO 2020114457A1
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substituted
heterocyclic ring
linear
membered aromatic
unsubstituted
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PCT/CN2019/123301
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Chinese (zh)
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徐柏玲
申竹芳
周洁
刘率男
别建波
李燕
李荣翠
崔国楠
扈金萍
盛莉
孙淑娟
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中国医学科学院药物研究所
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Priority to CN201980088460.5A priority Critical patent/CN113272276A/zh
Publication of WO2020114457A1 publication Critical patent/WO2020114457A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • 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
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—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
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an N-acyl sulfonamide salt-type FBPase inhibitor represented by formula I, and a preparation method thereof, a composition containing one or more compounds of this type, and the compounds in the inhibition of FBPase and treatment of diseases related to FBPase, And use in the preparation, prevention, and/or treatment of diabetes drugs.
  • Diabetes is a chronic metabolic disease regulated by multiple genes, mainly manifested by persistent hyperglycemia and diabetes. Persistent hyperglycemia can lead to many complications, such as retinal, renal, nervous system diseases, and vascular complications. The incidence of diabetes in China is growing rapidly. It is predicted that there are more than 92 million people with diabetes in China, and about 148 million people are at high risk of diabetes (New. Engl. J. Med., 2010, 362:1090-1101).
  • Diabetes is divided into two types, 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 for diabetes is insufficient insulin secretion, insulin resistance and increased liver glucose production.
  • drugs used clinically one is for insufficient insulin secretion, such as: sulfonylurea and glinide insulin secretagogues; the other is to improve insulin resistance, such as: thiazolidinedione insulin sensitizers . So far, no anti-diabetic drugs that reduce endogenous glucose production have been used clinically. Metformin can reduce hepatic glucose output, but the molecular target of action is unclear.
  • Endogenous glucose mainly comes from the liver.
  • the liver There are two ways for the liver to produce glucose, one is the endogenous synthesis of glucose, that is, gluconeogenesis; the other is glycogenolysis of the liver. Therefore, by regulating the gluconeogenesis pathway and reducing the production of endogenous glucose, it is a potential new strategy to develop new mechanisms of action for anti-diabetic drugs.
  • Gluconeogenesis is the process of converting three-carbon precursors such as lactic acid, glycine and glycerol into glucose under the catalytic action of various enzymes.
  • fructose-1,6-bisphosphatase Frazier-1,6-bisphosphatase, FBPase
  • FBPase fructose-1,6-bisphosphatase
  • This catalytic reaction is one of the rate-controlling steps of endogenous glucose production, inhibits the activity of FBPase, can reduce the production of endogenous glucose, and lowers blood glucose levels. Therefore, FBPase inhibitors may become a new mechanism of action of anti-diabetic drugs, especially in reducing fasting blood glucose levels, has more significant significance.
  • MB07803 is a prodrug of thiazole-based diacid phosphate, currently in Phase II clinical research (US,225259A1[P].2007-09-27. ).
  • the invention designs and synthesizes N-acylsulfonamide salt compounds as FBPase inhibitors, which lays a structural foundation for obtaining FBPase inhibitors with good pharmacological properties and can be administered orally.
  • the sulfonamide salt compounds of the present patent application have higher solubility, in vivo exposure and oral bioavailability than the prototype compounds.
  • the present invention aims to find new anti-diabetic drugs with strong anti-diabetic activity, good pharmacokinetic properties, and effective oral administration.
  • the technical problem solved by the present invention is to provide N-acyl sulfonamide salt derivatives represented by formula I, a preparation method thereof, a pharmaceutical composition, and its use in the preparation of FBPase inhibitors and its potential pharmaceutical use, and in the preparation of anti-diabetic drugs Use in.
  • the present invention provides the following technical solutions:
  • R is selected from the following atoms or groups, including
  • Ar 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 linear or branched alkane Group, halogen substituted C1-4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa′ 1 , SRa′ 2 , NRa′ 3 Rb′ 1 , COORa′ 4 , CONRa′ 5 Rb′ 2 , NRa′ 6 COORb′ 3 , SO 2 NRa′ 7 Rb′ 4 , NRa′ 8 CORb′ 5 , (CH 2 )nNRa′ 9 Rb′ 6 , (CH 2 )nORa′ 10 , Where Ra′ 1 , Ra′ 2 , Ra′ 3 , Rb′ 1 , Ra′ 4 , Ra
  • Ar 2 is selected from the following groups or structural fragments:
  • M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • R is preferably selected from Cl and NO 2 .
  • preferred compounds of the present invention include, but are not limited to, compounds represented by the general formula (I-A):
  • Ar 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 linear or branched alkane Group, halogen substituted C1-4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa′ 1 , SRa′ 2 , NRa′ 3 Rb′ 1 , COORa′ 4 , CONRa′ 5 Rb′ 2 , NRa′ 6 COORb′ 3 , SO 2 NRa′ 7 Rb′ 4 , NRa′ 8 CORb′ 5 , (CH 2 )nNRa′ 9 Rb′ 6 , (CH 2 )nORa′ 10 , Where Ra′ 1 , Ra′ 2 , Ra′ 3 , Rb′ 1 , Ra′ 4 , Ra
  • Ar 2 is selected from the following groups or structural fragments:
  • M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • preferred compounds of the present invention include, but are not limited to, compounds represented by the general formula (I-A-a):
  • R A can be a single substitution or multiple substitutions
  • R A can be independently selected from the following groups or structural fragments:
  • Ra′ 1 , Ra′ 2 , Ra′ 3 , Rb′ 1 , Ra′ 4 , Ra′ 5 , Rb′ 2 , Ra′ 6 , Rb′ 3 , Ra′ 7 , Rb′ 4 , Ra′ 8 , Rb′ 5 , Ra′ 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl;
  • Ar 2 is selected from the following groups or structural fragments:
  • M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • preferred compounds of the present invention include, but are not limited to, compounds represented by the general formula (I-A-b):
  • R B may be a mono-substituted, or a multi-substituted
  • R B can be independently selected from the following groups or structural fragments:
  • Ra′ 1 , Ra′ 2 , Ra′ 3 , Rb′ 1 , Ra′ 4 , Ra′ 5 , Rb′ 2 , Ra′ 6 , Rb′ 3 , Ra′ 7 , Rb′ 4 , Ra′ 8 , Rb′ 5 , Ra′ 9 , Rb′ 6 , Ra′ 10 are independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropyl Methylene, cyclobutyl, cyclopentyl;
  • Ar 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocyclic ring, substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from C1-4 linear or branched alkane Group, halogen substituted C1-4 linear or branched alkyl, F, Cl, Br, NO 2 , CN, methylenedioxy, ORa′ 1 , SRa′ 2 , NRa′ 3 Rb′ 1 , COORa′ 4 , CONRa′ 5 Rb′ 2 , NRa′ 6 COORb′ 3 , SO 2 NRa′ 7 Rb′ 4 , NRa′ 8 CORb′ 5 , (CH 2 )nNRa′ 9 Rb′ 6 , (CH 2 )nORa′ 10 , Where Ra′ 1 , Ra′ 2 , Ra′ 3 , Rb′ 1 , Ra′ 4 , Ra
  • M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).
  • preferred compounds include but are not limited to:
  • a second aspect of the technical solution of the present invention is to provide a method for preparing the compound described in the first aspect.
  • the technical solution adopted includes the following steps:
  • 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 -Br, Pd 2 (dba) 3 , Xantphos, sodium carbonate, toluene, water, 100°C; (d) sodium hydroxide, THF, ethanol, water, rt; (e) Ar 2 -S(O) 2 -OH, HATU, DMAP, Et 3 N, rt; (g) alkali or alkaline earth metal alkali, water, 80°C;
  • R, Ar 1 , Ar 2 and M described therein are the same as the definitions of the compounds described in the first aspect of the present invention.
  • a third aspect of the technical solution of the present invention is to provide a pharmaceutical composition comprising the compound described in the first aspect of the technical solution of the present invention and a common pharmaceutical carrier.
  • the present invention also provides a pharmaceutical composition using the compound of the present invention as an active ingredient, the composition comprising 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 microparticle delivery systems.
  • the pharmaceutical composition can be prepared according to methods known in the art.
  • the compound of the present invention may be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to make any dosage form suitable for human or animal use.
  • the content of the compound of the present invention in its pharmaceutical composition is usually 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be intestinal or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, 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 form can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and double emulsion), suspension, injection (including water injection, powder injection and infusion), eye drops Agents, nasal drops, lotions, liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, oral disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping 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 ordinary preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • auxiliary materials used in the manufacture of tablets, capsules, and coating agents are conventional auxiliary agents, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and liquid dosage forms.
  • the solvents used are, for example, water, ethanol, propylene glycol, and vegetable oil. Such as corn oil, peanut oil, olive oil and so on.
  • the preparations containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrating agents, preservatives, flavoring agents, coloring agents, and the like.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, isopropyl Propyl alcohol, etc.
  • the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl alcohol Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch,
  • the 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 of the compound of the present invention can also be made into granules or pellets with diluent, binder, disintegrant, and then placed in hard or soft capsules.
  • Various diluents, binders, wetting agents, disintegrating agents, glidants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of solubilizer, co-solvent, pH regulator, and osmotic regulator commonly used in the art 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 regulator can It is sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents may also be added to the pharmaceutical preparations.
  • preservatives may also be added to the pharmaceutical preparations.
  • fragrances may also be added to the pharmaceutical preparations.
  • flavoring agents may also be added to the pharmaceutical preparations.
  • the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
  • the dosage of the compound pharmaceutical composition of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the administration route and the 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 dosage may be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and the administration regimen including the use of other treatments.
  • the compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
  • the fourth aspect of the technical solution of the present invention is to provide the use of the compound described in the first aspect of the present invention in the preparation of FBPase inhibitors and the preparation of drugs for preventing and/or treating diseases and disorders related to FBPase.
  • the application is characterized in that the diseases and conditions related to FBPase are selected from diabetes, chronic complications of diabetes and obesity.
  • the diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retina, kidney, neuropathy and vascular complications, ischemic heart disease or atherosclerosis.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or high resolution mass spectrometry (HRMS).
  • NMR nuclear magnetic resonance
  • HRMS high resolution mass spectrometry
  • the NMR measurement is Varian mercury 300 or Varian mercury 400
  • the measurement solvent is CDCl 3 , DMSO-d 6 , acetone-d 6 , CD 3 OD
  • the internal standard is TMS
  • the chemical shift is given in ppm.
  • Thermo Exactive Plus mass spectrometer was used for the measurement of Ms.
  • mp is the melting point given in °C. The temperature is not corrected.
  • Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • the reagents used in the experiment were chemically pure or analytically pure.
  • the solvents used are all analytically pure.
  • the anhydrous solvents used are obtained from the solvent purification system produced by INNOVATIVE TECHNOLOGY in the United States. Other solvents are not treated unless otherwise specified.
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Spontaneous type 2 diabetic ZDF rat male, 8 weeks old, certificate number: No. 11400700293700, purchased from Beijing Viton Lihua Experimental Animal Technology Co., Ltd., license number SYXK (Beijing) 2014-0023, raised in China SPF animal house, Institute of Medicine, Academy of Medical Sciences, 4 animals/cage, free drinking water.
  • High-quality rat feed 5008 (referred to as purina) was fed for about 7 weeks, and the type 2 diabetes model was used for pharmacodynamic evaluation studies.
  • Normal ZDF control rat male, 8 weeks old, certificate number: No. 11400700293705, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number SYXK (Beijing) 2014-0023, raised in the Chinese Academy of Medical Sciences Institute SPF animal house. After about 7 weeks of normal maintenance feed feeding, it was used as a normal control group of ZDF for the experiment, 4 animals/cage, free drinking water.
  • ZDF rats were fed with high fat for about 7 weeks, and were predicted and grouped by multiple indicators.
  • the main observation indicators are: random blood glucose, fasting blood glucose, insulin tolerance (Insulin tolerance test, ITT) experiment 40% blood glucose drop percentage, blood triglyceride (TG) and total cholesterol (TC), and body weight.
  • ITT insulin tolerance test
  • the animals were administered by gavage, and the control group was gavaged with the corresponding volume of 0.5% CMC-Na solution once a day for 35 consecutive days.
  • Example 2 Weigh 4.5g of the compound of Example 1, put it in a mortar, grind it, suspend with 0.5% CMC-Na distilled water, and bring the volume to 150ml. According to 0.5ml/100g body weight, the dosage is 150mg/kg.
  • the dosage is 150mg/kg.
  • ⁇ -Quant microplate reader MQX200, American BIO-TEK company), air oscillator (HZQ-C, Harbin Dongming Medical Instrument Factory), low-temperature high-speed centrifuge (3-18K, German SIGMA company), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multifunctional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 5ml syringe (State-owned Shanghai Medical Laser Instrument Factory), injection needle (Lengpai, 0.5 ⁇ 20).
  • Glucose (Sinopharm Group Chemical Reagent Co., Ltd., 20141016), blood glucose determination GOD enzyme (sigma), glycated hemoglobin determination kit (Beijing Haomai Bioengineering Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561) insulin ( Eli Lilly Suzhou Pharmaceutical Co., Ltd., H0219).
  • HbA1c Glycated hemoglobin
  • Example 1 After sodium pyruvate was administered, the compound of Example 1 had a stronger gluconeogenesis inhibitory ability than the Con group in terms of the curve area under blood glucose time.
  • Spontaneous type 2 diabetic KKAy mice female, 11-12 weeks old, certificate number: No. 11401300055400, purchased from Beijing Huafukang Biotechnology Co., Ltd., license number SCXK ( ⁇ ) 2014-0004, raised in SPF animal house, Institute of Materia Medica, Chinese Academy of Medical Sciences, 5 animals/cage, free drinking water. It was fed with high-fat feed for about 10 weeks. After the formation of type 2 diabetes model, it was used for pharmacodynamic evaluation research.
  • KKAy mice were fed with high fat for about 10 weeks, and multi-index prediction and grouping were performed.
  • the main observation indicators are: random blood glucose, fasting blood glucose, insulin tolerance (Insulin tolerance test, ITT) experiment 40min blood glucose drop percentage, blood triglyceride (TG), blood total cholesterol (TC) and body weight.
  • Three dose groups were set, and 150 mg, 300 mg, and 600 mg of the compound of Example 1 were weighed, placed in a mortar, ground, suspended with 0.5% CMC-Na distilled water, and made to a volume of 30 ml.
  • the administration volume is 0.1ml/10g, that is, the dosage is 50mg/kg, 100mg/kg and 200mg/kg.
  • the administration volume is 0.1ml/10g, that is, the dose is 100mg/kg.
  • the administration volume is 0.1ml/10g, that is, the dose is 150mg/kg.
  • ⁇ -Quant microplate reader MQX200, American BIO-TEK company), air oscillator (HZQ-C, Harbin Dongming Medical Instrument Factory), low-temperature high-speed centrifuge (3-18K, German SIGMA company), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multifunctional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 0.25ml syringe (State-owned Shanghai Medical Laser Instrument Factory, B05-19-U), injection needle (Lengpai, 0.5 ⁇ 20).
  • MQX200 American BIO-TEK company
  • HZQ-C Harbin Dongming Medical Instrument Factory
  • low-temperature high-speed centrifuge 3-18K, German SIGMA company
  • water bath DK- 8D, Shanghai Yiheng Technology Co., Ltd.
  • multifunctional microplate reader
  • Glucose (Sinopharm Group Chemical Reagent Co., Ltd., 20141016), blood glucose determination GOD enzyme (sigma), glycated hemoglobin determination kit (Beijing Haomai Bioengineering Co., Ltd., A5911), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561), insulin (Lilly Suzhou Pharmaceutical Co., Ltd., H0219).
  • Random blood glucose and fasting blood glucose levels of mice were measured on the 20th day of administration.
  • the compound of Example 1 compared with the model control group (Con), the compound of Example 1 had a lowering effect on the blood glucose level of KKAy mice at doses of 50, 100, and 200 mg/kg, and the random blood glucose decreased by 13% , 21% (P ⁇ 0.05), 49% (P ⁇ 0.01); the decrease in fasting blood glucose was -3.7%, 10.4%, 35.4% (P ⁇ 0.001).
  • the compound of Example 3 reduced the random blood glucose of KKAy mice at a dose of 100 mg/kg by 18.4% (P ⁇ 0.05). It is equivalent to the compound of Example 1 (100 mg/kg) at the same dose.
  • mice Male, weighing 20-25g, were purchased from the Institute of Zoology, Chinese Academy of Medical Sciences, 5 per cage.
  • Animals were randomly grouped according to body weight before the experiment and fasted overnight (12h). Then they were randomly grouped according to body weight and divided into the compound group of Example 1, the compound group of Example 2, the normal group, and the metformin group.
  • the compound of the test compound and the positive control drug metformin were given by single gavage, and the normal group was given an equal volume of water. Two hours later, the sodium pyruvate tolerance test was conducted.
  • the administration volume is 0.1ml/10g. That is, the administration dose is 150mg/kg.
  • the administration volume is 0.1ml/10g. That is, the administration dose is 150mg/kg.
  • ⁇ -Quant microplate reader MQX200, American BIO-TEK company), air oscillator (HZQ-C, Harbin Dongming Medical Instrument Factory), low-temperature high-speed centrifuge (3-18K, German SIGMA company), water bath (DK- 8D, Shanghai Yiheng Technology Co., Ltd.), multifunctional microplate reader (Synergy2, BIO-TEK), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch number 302101) , 0.25ml syringe (State-owned Shanghai Medical Laser Instrument Factory, B05-19-U), hypodermic needle (Lengpai, 0.5 ⁇ 20).
  • MQX200 American BIO-TEK company
  • HZQ-C Harbin Dongming Medical Instrument Factory
  • low-temperature high-speed centrifuge 3-18K, German SIGMA company
  • water bath DK- 8D, Shanghai Yiheng Technology Co., Ltd.
  • Glucose (Sino Medicine Group Chemical Reagent Co., Ltd., 20141016), blood glucose determination GOD enzyme (sigma), sodium pyruvate (Beijing Bailingwei Technology Co., Ltd., 297561).
  • Sodium pyruvate tolerance test On the day of the experiment, blood was collected from the tip of the tail (0 min). Afterwards, the test compound and the positive control drug metformin were administered by intragastric administration, respectively, and the normal group was given an equal volume of water (0.1mL/10gb.w.). Two hours later, sodium pyruvate (3.0g/kg, 0.1mL/10gb.w.) was given by gavage, blood was collected from the tip of the tail at 40 and 90 minutes after sodium pyruvate load, and blood glucose was measured at each time point.
  • Example 1 The compound of Example 1 was dissolved in DMSO (3 mg/mL) and diluted with acetonitrile containing internal standard (YHP836, 200 ng/mL) to a working solution with a concentration of 5, 10, 25, 50, 200, 400, 800, 1000 ng/mL.
  • Compound P and the compound of Example 1 were formulated with 0.5% CMC (containing Tween 80) as a 15 mg/mL suspension for oral administration; with 20% HP- ⁇ -CD as a 0.15 mg/mL solution for intravenous injection.
  • CMC containing Tween 80
  • Chromatography column Zobax C18 (50mm ⁇ 2.1mm, 3.5 ⁇ m); column temperature: 30°C, mobile phase: methanol/water gradient; flow rate: 0.2mL/min; negative ion scanning, MRM detection m/z498 ⁇ 108(bjb -2936), m/z 465 ⁇ 297 (internal standard YHP836).
  • the plasma pharmacokinetic parameters were calculated using WinNonlin software.
  • the rats After oral administration of the compound of Example 1 and compound P (150 mg/kg), the rats absorbed faster, and the blood drug concentration maintained a high level from 1 to 12 hours, and the average blood drug peak concentrations were 85 and 305 ⁇ g/mL, respectively. After oral administration of the compound of Example 1 (150 mg/kg) in rats, the exposure in vivo was about 4 times that of its prototype compound. Oral administration of the compound of Example 1 (150 mg/kg) has a bioavailability >100%.

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Abstract

L'invention concerne un composé tenant lieu d'inhibiteur de FBPase et, plus particulièrement, un composé FBPase de formule I. L'invention concerne en outre un procédé de préparation dudit composé de formule I, une ou plusieurs compositions obtenues à partir de celui-ci, le composé agissant comme médicament pour le traitement de maladies associées à la FBPase et les applications dudit composé dans la préparation d'un médicament pour la prévention et/ou le traitement du diabète.
PCT/CN2019/123301 2018-12-05 2019-12-05 Inhibiteur de fbpase de sel n-acyl sulfonamide, son procédé de préparation, sa composition pharmaceutique et ses applications WO2020114457A1 (fr)

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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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US9023847B2 (en) * 2009-08-07 2015-05-05 Merck Patent Gmbh Azaheterocyclic compounds
JPWO2014123203A1 (ja) * 2013-02-06 2017-02-02 京都薬品工業株式会社 糖尿病治療薬

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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