Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/80—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/04—Carbocyclic radicals
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a C-aryl glycoside derivative, a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, a preparation method and use thereof.
• Diabetes is a type of metabolic disease characterized by high blood sugar. The current global incidence rate is increasing year by year. Among them, 90% of patients with diabetes are type 2 diabetes, caused by excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia (Pharmaceutical Progress, 2003, 27: 88-91).
• the most commonly used drugs for type 2 diabetes include sulfonylureas, biguanides, ⁇ -carbonase inhibitors, and insulins, which have good glycemic and hypoglycemic effects, but are accompanied by many Drug-related adverse reactions, such as weight gain, decreased insulin secretion, hypoglycemia, gastrointestinal side effects, etc. Therefore, it is necessary to develop a safer, more effective, orally available anti-diabetic drug.
• SGLTs Sodium-glucose co-transporters
• SGLT-1 is mainly distributed in the small intestine, kidney, heart and brain, and its main physiological function is to complete the absorption of glucose in the small intestine.
• SGLT-2 is specifically distributed in the renal proximal convoluted tubule S1, responsible for about 90% glucose reabsorption, and the remaining 10% is completed by SGLT-1 located in the proximal convoluted tubule S3. Therefore, it can inhibit the activity of SGLT-2. It specifically blocks the reabsorption of glucose by the kidneys and lowers the blood sugar by excreting excess glucose in the urine without the risk of weight gain and hypoglycemia.
• SGLT especially SGLT2 inhibitors
• SGLT2 inhibitors are promising candidates for antidiabetic drugs (Handlon, AL, Expert Opin. Ther. Patents (2005) 15(11): 1531-1540; Am JPhysiol Renal Physiol, 2001, 280:10 -18).
• SGLT-2 inhibitors that have been approved for marketing by the US Food and Drug Administration include Cangoliflozin of Johnson & Johnson's Johnson & Johnson Pharmaceuticals (approved on March 29, 2013), AstraZeneca and Bristol-Myers Squibb Dapagliflozin (approved on January 8, 2014), Boehringer Ingelheim and Eli Lilly and Company's Empagliflozin are currently only awarded by the European Medicines Agency's Committee on Human Pharmaceutical Products (CHMP). Listing approval (approved on March 21, 2014).
• the technical problem to be solved by the present invention is to provide a C-aryl glycoside derivative, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof which has an inhibitory effect on a sodium-dependent glucose transporter (SGLT). , its pharmaceutical composition, preparation method and application.
• SGLT sodium-dependent glucose transporter
• the present invention relates to a C-aryl glycoside derivative, a stereoisomer, an isotopically substituted derivative, a prodrug or a pharmaceutically acceptable salt thereof, of formula I;
• X is O or S
• Z is CH 2 , S, O or a single bond
• Y is a bicyclic group; the bicyclic group is preferably a C 5-8 cycloalkyl group and a C 6 aryl group, a C 5-8 cycloalkyl group and a C 3-5 heteroaryl group, a C 3-7 heterocycloalkyl group.
• the bicyclic group may be substituted at any position by one or more of the following groups: H, alkyl, CN, halogen, CF 3 , OH, amino, C 2 -6 alkynyl, C 2-6 alkenyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocyclic Alkyloxy, heterocycloalkylalkyl, heterocycloalkylalkoxy, alkylamino, carbonyl, COOH, COOR 7 , COR 7 , CONR 7 R 7a , -NHCOR 7 , -NHSO 2 R 7
• R 1 is H, halogen, CN, alkyl, alkoxy, haloalkoxy, OCD 3 , OC 2 D 5 or CF 3 ;
• R 2 is H, alkyl, halogen, CF 3 , CN, OH, amino, alkoxy, haloalkoxy, OCD 3 , OC 2 D 5 , C 2-6 alkynyl, C 2-6 alkenyl, ring Alkyl, heterocycloalkyl, alkylamino, carbonyl, COOH, COOR 7 , COR 7 , CONR 7 R 7a , -NHCOR 7 , -NHSO 2 R 7 , aryl, heteroaryl, alkylsulfonyl, aryl a sulfamoyl group or a heteroarylsulfonyl group;
• R 7 and R 7a are each independently selected from an alkyl group, a cycloalkyl group or a heterocycloalkyl group, or R 7 and R 7a together with the N atom to which they are attached form a 3-7 membered heterocycloalkyl group.
• said halogen is preferably chlorine.
• the 3-7 membered heterocycloalkyl group may further contain 1 to 3 atoms or groups.
• the 3-7 membered heterocycloalkyl group may be substituted with an alkyl group and/or a methanesulfonyl group.
• the C 3-7 heterocycloalkyl group and the C 6 aryl group are preferably a C 4-6 heterocycloalkyl group and a C 6 aryl group.
• the C 3-5 heteroaryl and C 6 aryl group is preferably a C 3-4 heteroaryl group and a C 6 aryl group.
• Y is more preferably (but not limited to) any one of the following Y1 to Y24:
• R 3 , R 4 , R 5 , R 6 , R 6a , R 6b and R 6c are each independently H, alkyl, CN, halogen, CF 3 , OH, amino, C 2-6 alkynyl, C 2-6 alkenyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, heterocycloalkyl, heterocycloalkyloxy, hetero Cycloalkylalkyl, heterocycloalkylalkoxy, alkylamino, carbonyl, COOH, COOR 7 , COR 7 , CONR 7 R 7a , -NHCOR 7 , -NHSO 2 R 7 , aryl, heteroaryl, An alkylsulfonyl group, an arylsulfonyl group or a heteroarylsulfonyl group;
• R 3 , R 4 , R 5 , R 6 , R 6a, R 6b and R 6c may be further substituted by any of the following groups: alkyl, halogen, CF 3 , OH, CN, amino, alkoxy or Haloalkoxy;
• the R 6a and R 6b may also form a 3-8 membered cycloalkyl group or a 3-8 membered heterocycloalkyl group together with the atom to which they are attached.
• the 3-8 membered heterocycloalkyl group preferably contains 1-3 of the following atoms or groups: N, O, S, SO and SO 2 .
• the 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl can be substituted with an alkyl group and/or a halogen.
• the Y is preferably More preferred *The carbon labeled is chiral carbon, which includes racemic, S or R type.
• the C-aryl glycoside derivative as shown in Formula I is preferably IA, IB or IC.
• the above IB and IC formulas include the S-type absolute configuration, the R-type absolute configuration, and the racemic form of the carbon labeled *.
• the C-aryl glycoside derivative as shown in Formula IA is preferably:
• the C-aryl glycoside derivative as shown in Formula IB is preferably:
• the C-aryl glycoside derivative as shown by the formula IC is preferably:
• the C-aryl glycoside derivative as shown in Formula I is any of the following compounds I-1 to I-148:
• the present invention also provides a preparation method of the C-aryl glycoside derivative as shown in Formula I, which is any of the following methods:
• Method 1 The preparation method comprises the following steps: in a solvent, the compound 1-f is subjected to a deacetylation protecting group reaction under the action of a base;
• Method 2 The preparation method comprises the following steps: 1) in a solvent, under the action of a condensing agent, compound 2-g and Performing the Mitsunobu reaction; 2), in the solvent, the compound 2-f obtained in the step 1) is subjected to a deacetylation protecting group reaction under the action of a base;
• Method 3 The preparation method comprises the following steps: 1. In the solvent, under the action of a base, the compound 3-g and Mixing, carrying out a nucleophilic substitution reaction; 2. In a solvent, the compound 3-f obtained in the step 1 is subjected to a deacetylation protecting group reaction under the action of a base;
• V is chlorine, bromine or iodine; the remaining groups and letter definitions are as described above.
• the conditions and steps of the deacetylation protecting group reaction may be the conditions and steps of the conventional deacetylation protecting group reaction in the art, and the present invention particularly preferably has the following reaction conditions: the solvent is preferably methanol or methanol. a mixed solvent of tetrahydrofuran and water; when a mixed solvent is used, the volume ratio of methanol, tetrahydrofuran and water is preferably 4:1:0.5 to 0.5:1:0.5, and the solvent is preferably used in an amount of 5 to 15 mL/mmol of compound 1-f.
• the solvent is preferably methanol or methanol.
• a mixed solvent of tetrahydrofuran and water when a mixed solvent is used, the volume ratio of methanol, tetrahydrofuran and water is preferably 4:1:0.5 to 0.5:1:0.5, and the solvent is preferably used in an amount of 5 to 15 mL/mmol of compound 1-f.
• the base is preferably an alkali metal alkoxide or an alkali metal hydroxide; the base is more preferably sodium methoxide or lithium hydroxide; the molar ratio of the base to the compound 1-f is preferably 0.1:1 to 2:1.
• the temperature of the reaction is preferably 10 to 30 ° C; the reaction can be detected by TLC, generally when the compound 1-f disappears as the end of the reaction, preferably 0.5 to 12 hours; after the reaction is completed,
• the product may be further purified by post-treatment, preferably comprising the steps of: adjusting the pH of the reaction system to 6-8 with acetic acid, removing the solvent under reduced pressure, and preparing the plate or silicon with a thin layer of solid residue. Purified by column chromatography.
• the steps and conditions for purifying the thin layer preparation plate or purifying the silica gel column chromatography may be the steps and conditions for purification of a thin layer preparation plate or silica gel column chromatography which are conventional in the art.
• the deacetylation protecting group is preferably a sodium methoxide and methanol system, or a lithium hydroxide, methanol, tetrahydrofuran or water system.
• the lithium hydroxide, methanol, tetrahydrofuran and water systems the volume ratio of methanol, tetrahydrofuran and water is preferably 4:1:0.5 to 0.5:1:0.5.
• the preparation method of the compound 1-f can be a conventional method for such a reaction in the art, and preferably includes the following steps: in the solvent, the compound 1-e is subjected to an acetyl protecting reaction, followed by recrystallization;
• the acetyl protecting reaction can be a conventional acetyl protecting reaction in the art, and the reaction conditions and steps thereof can be referred to J. Med. Chem. 2008, 51, 1145 - 1149.
• the following conditions are particularly preferred in the present invention:
• the solvent is preferably dichloromethane; the solvent is preferably used in an amount of 5 to 20 mL / mmol of compound 1-e; in the acetyl protecting reaction, the acetyl protecting agent is preferably acetic anhydride; the acetyl protecting reagent
• the molar ratio to the compound 1-e is preferably 5:1 to 20:1.
• the solvent used is preferably an aqueous ethanol solution having a volume concentration of 50% or more and less than 100%, or absolute ethanol.
• the amount of the recrystallized ethanol used is preferably from 3 to 10 mL/mmol of compound 1-e.
• the temperature of the recrystallization is preferably from 50 to 100 °C.
• the preparation method of the compound 1-e can be a conventional method of such a reaction in the art, and preferably comprises the steps of: 1-d and triethylsilane and boron trifluoride etherate in a solvent; The system is mixed and subjected to a reduction reaction;
• the solvent may be a solvent commonly used in such reactions in the art, preferably a mixture of dichloromethane and acetonitrile.
• the solvent mixture wherein the volume ratio of the dichloromethane to the acetonitrile is preferably 1:1 to 2:1.
• the amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL / mmol of the compound 1-d.
• the molar ratio of triethylsilane to boron trifluoride diethyl ether is preferably 1:1 to 1.5:1.
• the molar ratio of the triethylsilane to the compound 1-d is preferably from 1.5:1 to 3:1.
• the temperature of the reduction reaction is preferably -20 ° C to 10 ° C.
• the progress of the reaction can be detected by HPLC or TLC, generally as the end point of the reaction when the compound 1-d disappears, preferably 2 to 5 hours.
• the product may be further purified by post-treatment, preferably including the following steps: after quenching with a saturated aqueous solution of sodium hydrogencarbonate, the reaction system is extracted with an organic solvent, the organic phase is dried, and the organic solvent is removed under reduced pressure to give a compound.
• 1-e The compound 1-e obtained by the above work-up is usually used in the next reaction without purification.
• the preparation method of the compound 1-d can be a conventional method for such a reaction in the art, and can be referred to J. Med. Chem. 2008, 51, 1145 - 1149.
• the present invention preferably includes the following steps. : In the solvent, the compound 1-c is mixed with the alkali metal lithium reagent at -78 ° C to -60 ° C for 0.5 to 1 hour, and then with 2,3,4,6-tetra-O-(trimethylsilane Base)-D-glucopyranone (preparation method can be referred to: J. Med. Chem. 2008, 51, 1145-1149) mixed reaction for 0.5 to 2 hours (preferably 1 hour), 10 to 30 ° C, and then with A Mixing sulfonic acid in methanol to carry out the reaction;
• Q is bromine or iodine.
• the solvent may be a solvent commonly used in such reactions in the art, and a mixed solvent of tetrahydrofuran and toluene is preferred.
• the volume ratio of tetrahydrofuran to toluene is preferably 1:1 to 1:4.
• the organolithium reagent is preferably tert-butyllithium or n-butyllithium; when R 2 is CN, the organolithium reagent is preferably tert-butyllithium.
• the molar ratio of the organolithium reagent to the compound 1-c is preferably from 0.9:1 to 2:1.
• the molar ratio of the 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone to the compound 1-c is preferably 1:1 to 1.5:1.
• the molar concentration of the methanolic solution of methanesulfonic acid is preferably 0.5 to 1.2 mol/L.
• the molar ratio of the methanesulfonic acid to the compound 1-c is preferably from 1.2:1 to 3.0:1.
• the progress of the reaction can be detected by HPLC or TLC, generally as the end of the reaction when compound 1-c disappears.
• the preparation method of the compound 1-c preferably comprises the steps of: mixing a compound 1-b with a triethylsilane and a boron trifluoride diethyl ether system in a solvent to carry out a reduction reaction;
• Q is bromine or iodine.
• the solvent may be a solvent commonly used in such reactions in the art, preferably a mixed solvent of 1,2-dichloroethane and acetonitrile, wherein the volume ratio of 1,2-dichloroethane to acetonitrile is preferably 1:2. 2:1.
• the amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL / mmol of the compound 1-b.
• the molar ratio of triethylsilane to boron trifluoride diethyl ether is preferably from 1.2:1 to 3:1.
• the molar ratio of the triethylsilane to the compound 1-b is preferably from 1.5:1 to 4:1.
• the temperature of the reaction is preferably 0 to 30 °C.
• the progress of the reduction reaction can be detected by HPLC or TLC, generally as the end point of the reaction when the compound 1-b disappears.
• the product may be further purified by a post-treatment step.
• the post-treatment step preferably comprises: quenching the reaction with a saturated aqueous solution of sodium hydrogencarbonate, extracting the reaction system with an organic solvent, and drying the organic phase. The organic solvent is removed by pressure to give the compound 1-e.
• the compound 1-e can be purified by silica gel column chromatography or recrystallization.
• the method for preparing the compound 1-c preferably comprises the steps of: first mixing the compound 1-b with a sodium borohydride and a methanol system; After the reduction reaction, the reaction is carried out by mixing with triethylsilane and a boron trifluoride diethyl ether system to obtain a compound 1-c.
• the sodium borohydride and methanol system can be a sodium borohydride methanol system conventional in the art, wherein the molar ratio of sodium borohydride to compound 1-b is preferably 1:1 to 3:1; It does not affect the progress of the reaction, and preferably 5 to 20 mL/mmol of compound 1-b.
• the preparation method of the compound 1-b preferably comprises the following steps: in the solvent, in the presence of a base, the compound 1-a and Mixing and performing a nucleophilic substitution reaction;
• Q is bromine or iodine.
• the solvent may be a conventional solvent used in such a reaction in the art, preferably N,N-dimethylformamide.
• the amount of the solvent is generally such that the reaction is not affected, and preferably 2 to 20 mL/mmol of the compound 1-a.
• the base may be an alkali metal alkoxide, preferably potassium t-butoxide.
• the molar amount of the base is preferably 0.9 to 2.5 times the compound 1-a. Said
• the molar ratio to the compound 1-a is preferably 1.0:1 to 2.0:1.
• the temperature of the reaction is preferably 20 to 50 °C.
• the progress of the reaction can be detected by HPLC or TLC, generally as the end point of the reaction when the compound 1-a disappears, preferably 1 to 18 hours.
• the product may be further purified by a post-treatment step, preferably including the following post-treatment step: after diluting the reaction system with an organic solvent, the organic phase is washed with water and saturated brine, dried, and the solvent is evaporated to give compound 1 -b, which is purified by silica gel column chromatography or recrystallization.
• the method and conditions for column chromatography or recrystallization can be selected according to the methods and conditions conventionally used in the art for column chromatography or recrystallization.
• the solvent used for the recrystallization is preferably an aqueous ethanol solution having a volume concentration of 50% or more and less than 100%, or absolute ethanol.
• the solvent is preferably used in an amount of from 2 to 50 mL/mmol.
• the compound 2-g in the second method, in the step 1), can be produced by a conventional method in the art, for example, reference: WO2011/048148A2.
• the solvent may be a solvent commonly used in such reactions in the art, preferably tetrahydrofuran.
• the amount of the solvent used generally does not affect the progress of the reaction, and is preferably 5-20 ml/mmol of compound 2-g.
• the condensing agent may be a condensation reagent system commonly used in such reactions in the art, preferably triphenylphosphine and diethyl azodicarboxylate (DEAD), or triphenylphosphine and diisopropyl azodicarboxylate ( DIAD).
• the molar ratio of the triphenylphosphine to diethyl azodicarboxylate is preferably 1:1 to 1.5:1.
• the molar ratio of the triphenylphosphine and diisopropyl azodicarboxylate is preferably 1:1 to 1.5:1.
• the molar ratio of the condensing agent to the compound 2-g is preferably 1:1 to 3:1. Said The molar ratio to the compound 2-g is preferably 1:1 to 3:1.
• the reaction temperature of the Mitsunobu reaction is preferably 0 ° C to 30 ° C.
• the progress of the reaction can be detected by TLC or HPLC, generally as the end point of the reaction when the compound 2-g disappears, preferably 2-15 hours.
• the product may be further purified by a post-treatment step.
• the post-treatment step preferably comprises the steps of: after diluting the reaction system with an organic solvent, washing the organic phase with an aqueous solution of ammonium chloride and saturated brine, and drying. The solvent was removed under reduced pressure to give Compound 2- g.
• the steps and conditions for purifying the silica gel column chromatography can be selected according to the steps and conditions for purification by silica gel column chromatography which are conventional in the art.
• the conditions and steps of the deacetylation protecting group reaction may be the conditions and steps of the conventional deacetylation protecting group reaction in the art, and the preferred conditions of the present invention are the same as those in the above method 1.
• the conditions and procedures for the deacetylation protecting group are the same.
• the compound 3-g can be produced by a conventional method in the art, for example, reference: WO2011/048148A2.
• the solvent may be a solvent commonly used in such reactions in the art, preferably a N,N-dimethylformamide solution or dimethyl sulfoxide.
• the amount of the solvent generally does not affect the progress of the reaction, and is preferably 5 to 20 mL/mmol of the compound 3-g.
• the base is preferably cesium carbonate or potassium carbonate.
• the molar ratio of the base to the compound 3-g is preferably from 1 to 2.5. Said The molar ratio to the compound 3-g is preferably from 1 to 2.5.
• the temperature of the nucleophilic substitution reaction is preferably from 40 ° C to 65 ° C.
• the progress of the nucleophilic substitution reaction can be detected by HPLC or TLC, generally as the end point of the reaction when the compound 3-g disappears, preferably 2-15 hours.
• the product may be further purified by post-treatment.
• the post-treatment preferably comprises the steps of: after diluting the reaction system with ethyl acetate, washing the organic phase with an aqueous solution of ammonium chloride and saturated brine, and drying. The solvent was removed under reduced pressure to give compound 3- g, which was purified from silica gel.
• the steps and conditions for purifying the silica gel column chromatography can be selected according to the steps and conditions for purification by silica gel column chromatography which are conventional in the art.
• the conditions and steps of the deacetylation protecting group reaction may be the conditions and steps of the conventional deacetylation protecting group reaction in the art, and the preferred conditions of the present invention are the same as those described in the above method 1.
• the conditions and steps of the deacetylation protecting group are the same.
• the compounds involved can be prepared by the above method 1.
• the invention further relates to compounds of any of the following structures:
• compound f can be compound 1-f, compound 2-f or compound 3-f.
• alkyl refers to a saturated straight or branched hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, for example: methyl, ethyl, n-propyl Base, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4,4-dimethylpentyl, 2,2,4 - Trimethylpentyl, undecyl, dodecyl, and various isomers thereof and the like.
• cycloalkyl refers to a monocyclic, bicyclic or tricyclic hydrocarbon group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds), preferably a 3-10 membered monocycloalkyl group.
• a 5-8 membered monocycloalkyl group for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl , borneol, decahydronaphthyl, bicyclo [2.2.1] heptenyl and the like.
• C 5-8 cycloalkyl refers to a cycloalkyl group containing from 5 to 8 carbon atoms.
• heterocycloalkyl refers to a non-aromatic cyclic group consisting of a carbon atom and a heteroatom consisting of a hetero atom selected from nitrogen, oxygen or sulfur, including one or two double bonds, which is a cyclic group.
• the group may be a monocyclic, bicyclic or tricyclic group, preferably a 3-10 membered heterocycloalkyl group, more preferably a 5-8 membered heterocycloalkyl group, most preferably a 5-8 membered monocyclic heterocycloalkyl group.
• the number of hetero atoms in the heterocycloalkyl group is preferably 1 or 2, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may be optionally oxidized.
• the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
• C 3-7 heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing from 3 to 7 carbon atoms, wherein the number of heteroatoms is from 1 to 2.
• C 4-6 heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing 4 to 6 carbon atoms, wherein the number of heteroatoms is 1-2.
• cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
• cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
• heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
• heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
• alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
• alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
• cycloalkylalkoxy refers to a group formed by a hydrogen on an alkyl group in a cycloalkyl substituted alkoxy group.
• cycloalkylalkoxy includes the definitions of the above cycloalkyl and alkoxy groups.
• heterocycloalkylalkoxy refers to a group formed by a heterocycloalkyl substituted hydrogen on an alkyl group in an alkoxy group.
• heterocycloalkylalkoxy includes the definitions of the above heterocycloalkyl and alkoxy.
• alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
• C 2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and includes ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
• alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
• C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl and 3-methylbutynyl.
• aryl refers to any stable 6-10 membered monocyclic or bicyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
• C 6 aryl group means a 6-membered monocyclic aromatic groups such as phenyl.
• heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A bicyclic structure, preferably a 5-6 membered heteroaryl group.
• the number of hetero atoms is preferably 1 or 2, including carbazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1 , 3] dioxolane, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.
• C3-5 heteroaryl refers to a monocyclic heteroaryl group containing 3-5 carbon atoms, wherein the number of heteroatoms is 1-2.
• C3-4 heteroaryl refers to a monocyclic heteroaryl group containing from 3 to 4 carbon atoms, wherein the number of heteroatoms is 1-2.
• bicyclic group refers to a fused ring structure or a fused ring structure in which two cyclic structures share two adjacent atoms, and the cyclic structure may contain an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic ring. alkyl. At least one of the rings of the bicyclic structure referred to in the present invention is an aromatic ring.
• C 5-8 cycloalkyl-C 6 aryl group examples include, but are not limited to, benzocyclobutene, 2,3-dihydro-1-H-indole, 1, 2, 3, 4-tetrahydronaphthalene, 6,7,8,9-tetrahydro-5H-benzo[7]bornene, 6,9-dihydro-5H-benzo[7]bornene or 5,6,7, Specific examples of 8,9,10-hexahydrobenzo[8]bornene; C 5-8 cycloalkyl and C 3-5 heteroaryl include, but are not limited to, 2,3-cyclopentenopyridine, Specific implementation of 5,6-dihydro-4H-cyclopentyl[B]thiophene or 5,6-dihydro-4H-cyclopentyl[B]furan; C 4-6 heterocycloalkyl-C 6 aryl Examples include, but are not limited to, 2,3-dihydrobenzofuran
• bicyclic groups When one of the bicyclic groups is a non-aromatic ring, it is preferred to pass any carbon source on the non-aromatic ring.
• the pendant group is bonded to the side group W shown by the structure of the formula I, and the non-aromatic ring is preferably a cycloalkyl group or a heterocycloalkyl group.
• both of the bicyclic groups are aromatic, it is preferred to be bonded to the pendant group W of the structure of formula I via any carbon atom on both rings, and the aromatic ring may be an aryl or heteroaryl group.
• the "bicyclic group" described in the present invention includes the above definitions for "aryl", “heterocycloalkyl”, “cycloalkyl” and “heteroaryl”.
• halogen means fluoro, chloro, bromo or iodo.
• haloalkyl refers to an alkyl group optionally substituted by halogen.
• haloalkyl embraces the definitions of the above halo and alkyl.
• haloalkoxy refers to an alkoxy group optionally substituted by halogen.
• haloalkoxy includes the definitions of the above halo and alkoxy.
• amino means -NH 2
• alkylamino refers to at least one amino hydrogen atoms are substituted by alkyl.
• alkylamino embraces the definitions of alkyl and amino groups described above.
• sulfonyl refers to -SO 2 -.
• alkylsulfonyl refers to a sulfonyl group -SO 2 alkyl group between the core structure - are connected.
• alkylsulfonyl embraces the definitions of alkyl and sulfonyl groups described above.
• arylsulfonyl means a sulfonyl group -SO 2 aryl groups between the core structure and - connected.
• arylsulfonyl embraces the definitions of the above aryl and sulfonyl groups.
• heteroarylsulfonyl group refers to a sulfonyl group -SO 2 aryl and heteroaryl between the core structure - are connected.
• heteroarylsulfonyl embraces the definitions of the above sulfonyl and heteroaryl.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising the C-aryl glycoside derivative, an isotope-substituted derivative, a pharmaceutically acceptable salt thereof and/or a prodrug thereof, as shown in Formula I, and a pharmaceutically acceptable Acceptable excipients.
• the stereoisomers include enantiomers and diastereomers.
• the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
• the pharmaceutical composition may further comprise other types of drugs or other types of therapeutic agents for treating diabetes.
• the prodrug refers to a prodrug capable of releasing the active compound of the present invention after administration to an organism by various routes.
• the prodrugs include, but are not limited to, esters and hydrates of C-aryl glycoside derivatives of formula I and the like.
• the adjuvant may be a pharmaceutically acceptable carrier, diluent and/or excipient, and the like.
• the invention further relates to the use of a C-aryl glycoside derivative of the formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described for the preparation of an SGLT inhibitor.
• the invention further relates to the use of a C-aryl glycoside derivative, a pharmaceutically acceptable salt thereof, of the formula I, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a SGLT-mediated related disorder.
• the SGLT-mediated related diseases generally include: diabetes (including type II and type I), diabetic complications, obesity, hypertensive diseases, and any metabolic diseases associated with diabetes.
• the C-aryl glycoside derivative as shown in Formula I, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be further used in combination with a second therapeutic agent.
• the second therapeutic agent is preferably one or more of a diabetes therapeutic agent, a diabetic complication therapeutic agent, a lipid lowering therapeutic agent, an obesity therapeutic agent, and a hypertensive therapeutic agent.
• the preferred method of the method described above is:
• room temperature means 10 to 30 °C.
• the reagents and starting materials used in the present invention are commercially available.
• the positive progress of the present invention is that the aryl glycoside derivative of the present invention has a very good inhibitory effect on SGLT-2 and can effectively treat SGLT-mediated related diseases, and is a novel anti-diabetic drug.
• the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
• the detection wavelength is 214 nm or 254 nm.
• the chiral preparation of the compounds of the present invention uses chiral high performance liquid chromatography (Chiral HPLC) and supercritical fluid chromatography (SFC), and the following five separation conditions of A, B, C, D and E are available:
• the optical rotation of the compound of the present invention was measured using a RUDOLPH Automatic Polarimeter, and the light source was D light, and the sample cell length was 1 cm.
• the thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
• Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
• D-gluconic acid ⁇ -lactone (100.0 g, 0.56 mol) was dissolved in tetrahydrofuran (700 mL), triethylamine (511 g, 5.05 mol) was added under ice bath, and trimethylchlorosilane (427 g, 3.93 mol) was added dropwise. After about 1 hour, the dropwise addition was completed, and the mixture was stirred for 2 hours in an ice bath, and the mixture was stirred at room temperature overnight. Ethyl acetate (2 L) was added and washed with a saturated aqueous solution of sodium hydrogen sulfate (1 L), water (1 L) and brine (1 L ⁇ 2).
• the 2-vinylbenzaldehyde (2.0 g, 15.3 mmol) prepared in the step 1 was dissolved in a mixed solvent of tetrahydrofuran (14 mL) and methanol (14 mL), and the hydroboration was added in portions at 0 °C.
• Sodium (1.15 g, 30.3 mmol) was stirred at room temperature for 2 h.
• Ethyl acetate (50 mL) was added, washed with a saturated aqueous
• the solvent was evaporated under reduced pressure to give (2-vinylbenzene)methanol (2.0 g, yield: 100%).
• the 2-(2-propenyl)benzaldehyde (11.8 g, 80 mmol) obtained in the step 2 was dissolved in methanol (95 mL), cooled to 0 to 5 ° C, and sodium borohydride (3.67 g, 97 mmol) was added portionwise. After the addition, the reaction was carried out for 2 hours, and the reaction was quenched by the addition of 2M hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 3), and the organic phase was washed with brine (100 mL) The residue was purified by silica gel column chromatography (EtOAc (EtOAc:EtOAc)
• the (2-(2-propenyl)benzene)methanol (7.0 g, 47.2 mmol) prepared in the step 3 was dissolved in dichloromethane (70 mL), cooled to 0 to 5 ° C in an ice bath, and chlorine was added dropwise to the system.
• the sulfoxide (6.2 g, 52.3 mmol) was added, and the reaction was incubated for 1 hour.
• a saturated aqueous solution of sodium bicarbonate (20 mL) was added and extracted with dichloromethane (50 mL ⁇ 3). Washing, The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]
• the 1-(chloromethyl)-2-(2-propenyl)benzene (7.5 g, 45 mmol) obtained in the step 4 was dissolved in a mixed solvent of acetone (75 mL) and water (18.5 mL) under ice-protection. The mixture was cooled to 0 to 5 ° C, and N-methylmorpholine-N-oxide (15.8 g, 135 mmol) and osmium tetroxide (0.04 g, 0.02 mmol) were sequentially added to the system, and the mixture was reacted at room temperature for 16 hours.
• AD-mix- ⁇ (4.5 g) was mixed with tert-butanol (10 mL) and water (10 mL), and cooled to 0 ° C dropwise to add 2-benzyl acetate (500 mg, 3.5 mmol), and the mixture was stirred at 0 ° C.
• the reaction mixture was quenched with sodium sulphate and EtOAc (EtOAc)EtOAc.
• EtOAc EtOAc
• Step 3 (R)-2-(1-Hydroxy-2-((triisopropylsilyloxy)ethyl)acetic acid benzyl acetate
• Step 4 (R)-2-(1-(Methanesulfonyloxy)-2-((triisopropylsilyloxy)ethyl)acetic acid benzyl ester
• AD-mix- ⁇ (34.6 g) was dissolved in tert-butanol/water (260 mL, 1:1), cooled to 0 ° C, and the compound 1-(chloromethyl)-2-vinylbenzene (4.0 g, 26.2 mmol, dissolved in 5 mL of tert-butanol), and the mixture was stirred at 0 ° C for 2 hours.
• the reaction was quenched with anhydrous sodium sulphate (39 g), ethyl acetate (100 mL ⁇ 2), and the organic phase was combined and washed with water and brine. After drying over anhydrous sodium sulfate, the mixture was filtered and evaporated to ethylamine (jjjjjjj
• Step 1 3-Fluorophenyl allyl ether
• Step 3 Preparation of 3-fluorophenyl allyl ether (10 g, 66 mmol) and N,N-diethylaniline (15 mL) were stirred at 225 ° C for 2 hours, cooled to room temperature, (250 mL) was diluted, and the organic phase was washed with 6N hydrochloric acid (100 mL) and brine. It was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified mjjjjjjjjj 40%) is a pale yellow oil, 2-allyl-3-fluorophenol (2.2 g, yield 22%) as pale yellow oil.
• 2-fluorophenyl allyl ether (5.0 g, 32 mmol) prepared in the first step was dissolved in N-methyl The pyrrolidone (50 mL) was heated to 225 ° C for 3 hours, cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure of solvent gave 2- allyl-6-fluorophenol (5.0 g, yield: 100%) as a yellow oil.
• the 2-allyl-6-fluorophenol prepared in the step 2 was dissolved in chloroform (5.0 g, 32.9 mmol), and m-chloroperoxybenzoic acid (7.6 g, 32.9 mmol, 75%) was added.
• the reaction mixture was heated under reflux for 3 hours, and then cooled to room temperature.
• the mixture was washed with saturated sodium hydrogen sulfate, water and brine, and dried over anhydrous sodium sulfate.
• the solvent was evaporated under reduced pressure, and the crude crystals was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted g, yield: 38%) as a pale yellow oil.
• Step 4 (5-Bromo-2-chlorophenyl)(4-((7-fluoro-2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)methanone
• Step 1 4-Bromo-2-((4-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)(hydroxy)methyl)benzonitrile
• the compound of Example 38 was prepared by substituting the bromopropyl bromide in Step 1 with 3-bromo-2-methylpropene in the procedure of the compound of Example 18.
• the compound of Example 39 was obtained by substituting the bromopropyl bromide in Step 1 with 3-bromo-2-methylpropane.
• Step 1 (3R, 4S, 5S, 6R)-2-(4-chloro-3-(4-((7-fluoro-2,3-dihydrobenzofuran-2-yl)methoxy)benzyl) Phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol
• Step 3 (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)-6-(4-chloro-3-(4-((7-fluoro-2,3-dihydrobenzene) And furan)-2-yl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetyl ester
• Step 4 (2S,3R,4R,5S,6S)-2-(4-Chloro-3-(4-((7-fluoro-2,3-dihydrobenzofuran-2-yl)methoxy) Benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
• the I-38 retention time RT 3.23 min (e.e. value: 100%) was measured by chiral analysis condition C.
• I-24 obtained by the resolution of Example 57 and I-24 synthesized by the synthesis of Example 103 were uniformly mixed in a ratio of 1:1, and then the mixed sample was determined according to the chiral analysis condition A.
• Product retention time RT 4.78 min (e.e. value: 98%).
• Examples 66-70 were synthesized by the synthesis of the compound of Example 65.
• Step 1 (2R, 3R, 4R, 5S, 6S)-2-(Acetoxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H -pyran-3,4,5-triyltriacetyl ester
• Step 2 (2R, 3R, 4R, 5S, 6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyridyl Norm-3,4,5-triyltriacetyl ester
• Step 1 (2R,3R,4R,5S,6S)-2-(Acetoxymethyl)6-(3-(4-((2,3-dihydrobenzofuran-2-yl)methoxy) Benzyl)-4-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetyl ester
• Examples 78-79 were synthesized by the synthesis of the compound of Example 77, and the corresponding alcohol.
• n-Hexyllithium n-hexane was added dropwise to a solution of 2-(3-fluorophenyl)tetrahydro-2H-pyran (6 g, 30.6 mmol) in tetrahydrofuran (60 mL) obtained in Step 1 at -78 °C
• the solution 2.5 M, 14 mL, 36.7 mmol
• N,N-dimethylformamide 6 g, 91.3 mmol
• Example 80 A mixture of 5-fluoro-2-hydroxybenzaldehyde (0.85 g, 6.07 mmol) and potassium carbonate (1.68 g, 12.1 mmol) obtained in Example 80 was heated to 60 ° C, and ethyl bromoacetate was added to the mixture. 1.27 g, 7.58 mmol), the mixed system was stirred at 60 ° C for 1 hour, heated to 60 ° C, and stirred for 10 hours. It was diluted with ethyl acetate (50 mL), washed with aq. The solvent was evaporated under reduced pressure.yield purified crystals eluted elution Light yellow solid.
• Step 1 (2R, 3R, 4R, 5S, 6S)-2-(Acetoxymethyl) 6-(3-(4-(benzofuran-2-ylmethoxy)benzyl)-4-chloro Phenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetyl ester
• Examples 92 to 103 were synthesized by the synthesis of the compound of Example 91, and the corresponding bromo or chloro compound.
• I-23 retention time RT 4.09 min (e.e. value: 100%) was determined by chiral analysis method A.
• Compound I-23 can be synthesized according to the synthesis method of the compound of Example No. 77.
• Compound I-24 can be synthesized according to the method for synthesizing the compound of Example No. 77.
• Effect Example 1 Absorption test of [ 14 C]-AMG in Flp-in CHO cells stably expressing human sodium ion-dependent glucose-absorbing ion channels I and II (SGLT-1 and SGLT-2 activity screening test)
• cDNA clones of human SGLT-1 and SGLT-2 were purchased from OriGene. After obtaining the sequence information, the pcDNA5/FRT vector was constructed by a conventional molecular biological method, and then the expression plasmid was introduced into Flp-in CHO cells by Lipofetamin2000 lipofection. Transfected cells Hygromycin resistance screening was performed, and single cell clones were screened by gradient dilution after 4-5 weeks. The expression of SGLT-1 and SGLT-2 was detected by RT-PCR and functional assay, and the high-absorption signal cell line was selected for subsequent experiments.
• the Flp-in CHO cell line stably expressing SGLT-1 and SGLT-2 was cultured, and the medium composition was: F12 medium (purchased by Invitrogen), 500 ⁇ g/ml hygromycin (purchased by Calbiochem), and 10% fetal bovine serum ( Invitrogen purchased).
• the cells in the T75 flask were washed three times with phosphate buffer (purchased by Invitrogen), then 5 mL of trypsin-EDTA solution (purchased by Invitrogen), and the flask was gently shaken to make all The cells were exposed to the digestive juice, and after the cells were detached, the medium was added and the cells were blown into a single cell suspension using a 10 mL pipette. The cell density was adjusted to 3 ⁇ 10 5 /mL, and then inoculated into a 96-well wall-white cell culture plate (purchased by Corning Co., Ltd.) in an amount of 100 ⁇ L/well.
• phosphate buffer purchased by Invitrogen
• trypsin-EDTA solution purchased by Invitrogen
• the absorption test can be carried out after the cells in the well plate are cultured overnight. After inoculation of the cells for at least 12 hours, 150 ⁇ L/well of the absorption solution KRH-NMG (120 mM N-methyl-D-glucosamine (NMG), 4.7 mM potassium chloride, 1.2 mM magnesium chloride, 2.2 mM calcium chloride, 10 mM) Hydroxyethylpiperazine ethanesulfonic acid (HEPES), pH 7.4 containing 1 mM Tris) was washed once.
• KRH-NMG 120 mM N-methyl-D-glucosamine (NMG), 4.7 mM potassium chloride, 1.2 mM magnesium chloride, 2.2 mM calcium chloride, 10 mM
• HEPES Hydroxyethylpiperazine ethanesulfonic acid
• the corresponding compound I 5 ⁇ L/well was added to ensure a concentration of dimethyl sulfoxide of 1% (volume concentration).
• the plate to which the compound was added was cultured in a 37 ° C incubator for one hour.
• 150 ⁇ L of ice-cold wash solution 120 mM sodium chloride, 4.7 mM potassium chloride, 1.2 mM magnesium chloride, 2.2 mM calcium chloride, 10 mM hydroxyethylpiperazine ethanesulfonic acid (HEPES) was added to each well.
• 0.5 mM phlorizin, pH 7.4 with 1 mM Tris to terminate the absorption test.
• mice (C57 mouse sex male; supplier: Shanghai Slack Laboratory Animal Co., Ltd.) (body weight greater than 20 g) were administered gastrointestinal administration test compound I (10 mg/Kg) and then administered gastrointestinally Glucose (5g/Kg), the test C57 mice were placed in a metabolic cage, and the total amount of urine was collected within 24 hours.
• the metabolic cage was rinsed with 5 mL of normal saline, and the mice were free during collection of urination (24 hours). Take water and food. After collecting the urine sample, it is frozen immediately, and then the glucose content in the urine sample is detected. Finally, the total urine sugar output of the animal is calculated according to the total urine volume, and then the urine sugar discharge amount of 200 mg body weight within 24 hours is changed according to the weight of the mouse (mg ).
• the results (average of 6 mice) are shown in Table 2.
• Urine sugar excretion (mg/200mg weight/24h) A 1536.5 I-1 1646.9 I-22 3106.6 I-36 1723.1
• A: Empagliflozin (Chinese name: Rigliflozin, CAS No.: 864070-44-0) is a known aryl glycoside SGLT-2 inhibitor, and the specific structure is listed in Effect Example 1.

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