CN104250239B - The polycyclic carboxylic acid derivates of fragrance - Google Patents

The polycyclic carboxylic acid derivates of fragrance Download PDF

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CN104250239B
CN104250239B CN201410109434.5A CN201410109434A CN104250239B CN 104250239 B CN104250239 B CN 104250239B CN 201410109434 A CN201410109434 A CN 201410109434A CN 104250239 B CN104250239 B CN 104250239B
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CN104250239A (en
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吴永谦
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BEIJING TIANXINYUAN PHARMACEUTICAL SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd
Beijing Sihuan Pharmaceutical Co Ltd
Beijing Ao He Research Institute Co Ltd
Jilin Shengtong Chemical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to pharmaceutical technology field, be specifically related to fragrance polycyclic carboxylic acid derivates class GPR40 receptor stimulating agent, its pharmaceutically acceptable salt, its ester or its stereoisomer, the wherein R shown in formula (I)1、R2、R3、R4、R5It is defined as in the description with X；The invention still further relates to the preparation method of these compounds, pharmaceutical preparation and pharmaceutical composition, and described compound and pharmaceutical composition in preparation as GPR40 receptor stimulating agent for preventing and/or treating the application in the medicine of diabetes.

Description

Aromatic polycyclic carboxylic acid derivatives
1. Field of the invention
The invention belongs to the technical field of medicines, and particularly relates to an aromatic polycyclic carboxylic acid derivative GPR40 receptor agonist, pharmaceutically acceptable salts, esters and stereoisomers thereof, a preparation method, a pharmaceutical preparation and a pharmaceutical composition of the compounds, and application of the compounds serving as GPR40 receptor agonist in preparation of medicines for preventing and/or treating diabetes.
2. Background of the invention
Recent studies have shown that GPR40 receptor agonists are a new drug for the treatment of type II diabetes, with an improved glycemic control effect similar to that of glimepiride, but with a significantly lower risk of causing hypoglycemia.
Type II diabetes is the most common type of diabetes. Currently, about 1.5 million people in the united states suffer from diabetes, 90% of which are type II diabetes. The degree of harm to the general health of human populations has been at position 3 of chronic non-infectious diseases. With the rapid development of economy and improvement of material life of people in China, China has become one of the countries with the highest number of patients with diabetes. Diabetes and complications thereof become a major public health problem in the world of the 21 st century, and according to the results of national diabetes epidemiological investigation in 2007-2008, in Chinese people with the age of more than or equal to 20 years, the prevalence rates of diabetes and pre-diabetes are 9.7% and 15.5%, respectively, so that it is estimated that about 9240 ten thousand adults in China currently suffer from diabetes, which is 4 times that in 2003.
The disease is mainly caused by the reduction of the body's response to insulin, resulting in the rise of blood sugar and various chronic diseases. Only about 1/2 in type II diabetics can control blood glucose at a desirable level.
Free fatty acid receptor 1(FFAR1), otherwise known as G protein-coupled receptor 40(GRP40), plays a key role in stimulating and regulating insulin production. The mechanism by which Free Fatty Acids (FFA) cause an increase in intracellular calcium ion concentration via GPR 40: the increase of the glucose concentration accelerates the metabolism of glucose in cells, causes the ATP/ADP level in cytosol to rise, closes ATP-dependent potassium ion channels, causes the depolarization of cell membranes, and activates the opening of L-type calcium ion channels. FFA then stimulates a seven-transmembrane receptor GPR40 on a cell membrane, and the information of circulating phosphatidylinositol is transferred to a path, thereby stimulating calcium ions to be released on an endoplasmic reticulum, further opening an L-type calcium ion channel, causing the calcium ions to flow in the outside of the cell, greatly increasing the calcium ion concentration in the cell, and further leading to the insulin secretion. When postprandial blood glucose and fatty acids rise, FFAR1 lowers blood glucose levels by stimulating the release of insulin from the beta cells of the islets of langerhans. The drug, which is capable of activating FFAR1, effectively controls blood glucose levels by helping the diabetic release more insulin.
GPR40 receptor agonists, which are novel oral drugs that enhance insulin secretion in a glucose-dependent manner, act by stimulating insulin secretion from the beta cells of the islets of langerhans, but only when most needed by the patient, e.g. when glucose and fatty acids rise in the blood after meals, i.e. when blood glucose levels are normal, do not have any effect on insulin secretion. Therefore, GPR40 receptor agonists are both effective in controlling elevated blood glucose and minimizing the risk of hypoglycemia.
Given the frequent hypoglycemia associated with many medications (e.g., glimepiride, etc.) treatment, GPR40 receptor agonist treatment is less at risk of hypoglycemia. This indicates that there is a clear advantage in targeting FFAR1 for the treatment of type II diabetes.
The safety and efficacy of long-term clinical trials will also demonstrate that GPR40 receptor agonists may play a part in drug therapy in type II diabetes.
By using GPR40 receptor agonists, diabetes with the same pathogenesis can be effectively treated, and to date, there are no new drugs formally marketed that target GPR 40. WO2008001931 (published japanese 2008.01.03) discloses the TAK-875 racemate, a drug developed by Takeda in phase III of clinical trials, for the treatment of diabetes, with a definite therapeutic effect. Therefore, the research and development of the GPR40 agonist with stronger pharmacological activity, higher safety and better selectivity has very important significance for treating the type II diabetes mellitus, and has huge market.
Because GPR40 receptor agonist compounds participate in various physiological processes in human bodies, the GPR40 receptor agonist compounds can also be closely related to other various diseases. Therefore, the study of potent and low-toxicity agonists of GPR40 is of great interest for the treatment of diabetes, particularly type II diabetes, and related indications such as obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, Alzheimer's disease, parkinson's disease, stroke, and certain cancers (e.g., breast cancer).
3. Summary of the invention
The invention aims to solve the technical problem of providing an aromatic polycyclic carboxylic acid derivative GPR40 receptor agonist for preparing medicaments for preventing and/or treating diabetes and the like.
The technical scheme of the invention is as follows:
a compound of formula (I), pharmaceutically acceptable salts, esters and stereoisomers thereof:
wherein R is1Is a hydrogen atom, C optionally substituted by substituents1-6Alkyl, amino or 3-14 membered cycloalkyl, said substituents being selected from C1-6Alkyl, halogen atom, hydroxy, amino or halogeno C1-6An alkyl group;
x is a bond or-NH-, or R1And X and to which they are attached-S (O)2-forming a 3-14 membered cyclic structure optionally substituted by a substituent selected from the group consisting of halogen atom, hydroxy, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylcarbonyl group;
R2、R3、R4、R5each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group or C optionally substituted by a substituent1-6Alkyl, said substituents being selected from the group consisting of pro-halogensSon, hydroxy, amino, halogeno C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkylsulfonyl group.
The compound shown in the general formula (I), the pharmaceutically acceptable salt, ester and stereoisomer thereof have the following structure shown in the general formula (II):
wherein R is1Is a hydrogen atom, C optionally substituted by substituents1-6Alkyl, amino or 3-14 membered cycloalkyl, said substituents being selected from C1-6Alkyl, halogen atom, hydroxy, amino or halogeno C1-6An alkyl group;
x is a bond or-NH-, or R1And X and to which they are attached-S (O)2-forming a 3-14 membered cyclic structure optionally substituted by a substituent selected from the group consisting of halogen atom, hydroxy, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylcarbonyl group;
R2、R3、R4、R5each independently selected from a hydrogen atom, a halogen atom, a hydroxyl group or C optionally substituted by a substituent1-6An alkyl group, the substituent being selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a halogenated C group1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkylsulfonyl group.
The preferable technical scheme of the compound shown in the general formula (I) and the pharmaceutically acceptable salt, ester and stereoisomer thereof is as follows:
wherein R is1Is C optionally substituted by a substituent1-4Alkyl, amino or 3-7 membered cycloalkyl, said substituents being selected from C1-4Alkyl, fluorine, chlorine, hydroxy, amino or halogeno C1-4An alkyl group;
x is-NH-, or R1And X and to which they are attached-S (O)2-forming a 5-8 membered cyclic structure optionally substituted by a substituent selected from the group consisting of halogen atom, hydroxy, amino, C1-4Alkyl, halo C1-4Alkyl or C1-4An alkoxy group;
R2、R3、R4、R5each independently selected from a hydrogen atom, a halogen atom or C1-4An alkyl group.
The preferable technical scheme of the compound shown in the general formula (I) and the pharmaceutically acceptable salt, ester and stereoisomer thereof is as follows:
wherein R is1Is C optionally substituted by a substituent1-4An alkyl group, an amino group or a 3-to 7-membered cycloalkyl group, the substituent being selected from a methyl group, an ethyl group, a fluorine atom, a chlorine atom, a hydroxyl group or an amino group;
x is-NH-, or R1And X and to which they are attached-S (O)2-forming a 5-6 membered cyclic structure optionally substituted by a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a hydroxyl group, an amino group, a trifluoromethyl group, a methoxy group or an ethoxy group;
R2、R3、R4、R5each independently selected from hydrogen atom or C1-4An alkyl group.
The preferable technical scheme of the compound shown in the general formula (I) and the pharmaceutically acceptable salt, ester and stereoisomer thereof is as follows:
wherein R is1Is methyl, ethyl, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
x is-NH-, or R1And X and to which they are attached-S (O)2-forming 1, 1-dioxoisothiazolidine, 1-dioxo-1, 2, 5-thiadiazolidine, 1-dioxo-1, 2, 3-thiadiazolidine or 1, 1-dioxo-1, 2, 4-thiadiazolidine optionally substituted by a substituent selected from a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group or a methoxy group;
R2、R3is methyl; r4、R5Is a hydrogen atom.
Particularly preferred compounds include:
the term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.
Said "C" of the present invention1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.
The "halo C" of the present invention1-6Alkyl "means one or more" halogen atoms "substituted" C1-6A group derived from one or more hydrogen atoms on an alkyl group, said "halogen atom" and "C1-6Alkyl "is as defined above. The "halo C" of the present invention1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.
"C" according to the invention1-6Alkoxy radical, C1-6Alkylcarbonyl group, C1-6Alkylsulfonyl "means with C1-6alkyl-O-, C1-6alkyl-C (O) -, C1-6alkyl-SO2A group attached by a formula wherein "C1-6Alkyl "is as defined above. Book (I)"C" of the invention1-4Alkoxy radical, C1-4Alkylcarbonyl group, C1-4Alkylsulfonyl "means a specific example containing 1 to 4 carbon atoms among the above examples.
The 3-14 membered cycloalkyl refers to a 3-14 membered cyclic group with all ring atoms being carbon atoms, and comprises a 3-8 membered cycloalkyl and an 8-14 membered fused cycloalkyl; the 3-7 membered cycloalkyl group in the invention refers to a specific example of the 3-14 membered cycloalkyl group having 3-7 ring atoms;
3-8 membered cycloalkyl, refers to saturated cyclic alkyl groups containing 3-8 carbon atoms, specific examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 1-pentylcyclopropyl, 1, 2-diethylcyclobutyl, 1-methylcyclobutyl, 1-butylcyclobutyl, 1, 3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclopentyl, etc.
8-14 membered fused cyclic alkyl refers to saturated fused cyclic structures containing 8-14 ring atoms joined by two or more ring structures sharing two adjacent atoms with each other, specific examples include, but are not limited to: and the like.
The "3-14 membered cyclic structure" of the present invention means a cyclic group containing 3-14 ring atoms (wherein at least one heteroatom is contained), said heteroatom is nitrogen, oxygen and sulfur, etc., and includes carbon atom, nitrogen atom and sulfur atom which can be oxo-substituted, including 3-8 membered heterocyclic group, 6-14 membered fused heterocyclic group, 5-8 membered heteroaryl group, 6-14 membered fused heteroaryl group. The 5-8 membered cyclic structure of the present invention means a specific example of the 3-14 membered cyclic structure containing 5-8 ring atoms. The 5-6 membered cyclic structure of the present invention means a specific example of the 3-14 membered cyclic structure containing 5-6 ring atoms.
A3-8 membered heterocyclic group means a cyclic group containing 3 to 8 ring atoms (wherein at least one heteroatom is contained), and specific examples include, but are not limited to, aziridine, diazepane, azetidine, 1, 2-diazetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, ethylene oxide, dioxirane, epithioethane, oxetane, 1, 2-dioxetane, thietane, tetrahydrofuran, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyran, 1, 4-dioxane, 1, 3-oxathiane, oxaziridine, tetrahydrooxazole, tetrahydroisooxazole, thiazolidine, isothiazoline, 1,2, 3-thiadiazolidine, 1,2, 4-thiadiazolidine, 1,2, 5-thiadiazolidine, morpholine, 2H-aziridine, 3H-diazacyclopropene, azetidine, 1, 2-diazacyclobutene, dihydropyrrole, 4, 5-dihydroimidazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, 1,2, 4-triazole, 2-pyridone, 4-pyridone, 1, 2-diazepatriene, 1, 3-diazepatriene, 1, 4-dihydro-1, 4-diazacyclooctatriene, 1, 2-dithiocyclobutene, 2, 5-dihydrothiophene, 1, 2-dithiocyclopentene, 1, 3-dithiocyclopentene, 2H-pyran, 2H-aziridine, 3H-diazacyclopropene, 3-diazacyclopropene, 1, 2-diazacyclo-triazole, 1, 2-pyridone, 1,2-, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran-4-one, 4, 5-dihydrooxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 4, 5-dihydrothiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, and the like.
The 6-to 14-membered fused heterocyclic group means a fused ring structure having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two adjacent atoms with each other, and includes carbon atoms, nitrogen atoms and sulfur atoms which may be oxo, and specific examples include, but are not limited to, octahydro-benzo [ d ] imidazole, decahydroquinolyl, octahydrobenzothiophene, octahydrobenzofuran, hexahydrothienoimidazole, hexahydrofuroimidazole, 4H-1, 3-benzoxazine, 4, 6-dihydro-1H-furo [3,4-d ] imidazole, 4, 6-dihydro-1H-thieno [3,4-d ] imidazole, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazole, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole, and the like.
The 5-to 8-membered heteroaryl group means a cyclic group having an aromatic ring containing 5 to 8 ring atoms (at least one hetero atom therein), and specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, and the like, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,3, 4-triazinyl, 1,2,4, 5-tetrazinyl, oxepinyl, thiepinyl, azepinyl, 1, 3-diazepinyl, and azepinyl.
The 6-to 14-membered fused heteroaryl group means an unsaturated aromatic fused ring structure having 6 to 14 ring atoms (wherein at least one heteroatom is contained) formed by two or more ring structures sharing two adjacent atoms to each other, and specific examples include, but are not limited to: benzofuranyl, benzoisotropfuranyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, and the like.
The above compounds of the present invention can be synthesized using the methods described in the following schemes and/or other techniques known to those of ordinary skill in the art, but are not limited to the following methods:
the abbreviations used in the present invention have the following meanings:
the THF is tetrahydrofuran, and the THF is tetrahydrofuran,
ADDP is an azodicarbonyl dipiperidine,
the PE is petroleum ether, and the mixture is,
EA is ethyl acetate and the mixture is reacted with ethyl acetate,
the DCM is the methylene chloride, and the DCM is the methylene chloride,
boc is tert-butyloxycarbonyl, and the Boc is tert-butyloxycarbonyl,
TFA is trifluoroacetic acid.
The reaction equation is as follows:
the reaction steps are as follows:
step 1: synthesis of intermediate 1
Adding the raw material 1, the raw material 2 with the equivalent weight and the ADDP with the equivalent weight of 1.5 into a proper amount of tetrahydrofuran, adding the tri-n-butylphosphine with the equivalent weight of 1.5 in an ice bath, heating to room temperature after the dropwise addition is finished, continuously reacting for a period of time, and separating and purifying to obtain the intermediate 1.
Step 2: synthesis of intermediate 2
Dissolving the intermediate 1 in a proper solvent, and removing a protecting group to obtain an intermediate 2.
And step 3: synthesis of intermediate 3
Dissolving the intermediate 2 in a proper solvent, adding excessive triethylamine, dropwise adding 1.1 equivalent of the raw material 3 under ice bath, finishing dropping in a short time, heating to room temperature, and continuously reacting for a period of time. Separating and purifying to obtain an intermediate 3.
And 4, step 4: synthesis of intermediate 4
Adding the intermediate 3, equivalent raw material 4, palladium acetate, triphenyl phosphorus, tetrabutyl ammonium bromide and excessive potassium phosphate into a proper amount of tetrahydrofuran, and performing reflux reaction for a period of time under the protection of nitrogen. Separating and purifying to obtain an intermediate 4.
And 5: synthesis of intermediate 5
Adding the intermediate 4, the raw material 5 and the ADDP into a proper amount of solvent, adding tri-n-butylphosphonium in an ice bath, and heating to room temperature after dropwise addition. After the reaction is continued for a while, the intermediate 5 is obtained by separation and purification.
Step 6: synthesis of Compounds of formula (I)
Dissolving the intermediate 5 in a proper amount of THF/MeOH mixed solvent, slowly adding an aqueous solution of a basic compound, and stirring for a period of time at a certain temperature. Separating and purifying to obtain the compound of the invention.
Wherein R in the above reaction equation1、R2、R3、R4、R5And X is as defined above.
The invention claims "pharmaceutically acceptable salts" of the compounds of formula (I) including alkali metal salts, alkaline earth metal salts, inorganic base salts, organic base salts, inorganic acid salts, organic acid salts, amino acid salts, and the like.
The "ester" of the compound represented by the general formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound represented by the formula (I), and an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound represented by the formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.
Examples of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, or a solvate of a stereoisomer thereof include, but are not limited to, a hydrate.
The "stereoisomers" of the compounds of the general formula (I) of the present invention are classified into conformational isomers and configurational isomers, and configurational isomers are also classified into cis-trans isomers and optical isomers. "stereoisomers" refers to compounds of the invention when they contain one or more asymmetric centers, each of which independently produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention.
The compound of the present invention may be used in combination with one or more other drugs, which may be a drug for treating diabetes, a drug for treating diabetic complications, a drug for treating hyperlipidemia, an antihypertensive drug, an anti-obesity drug, a diuretic, a chemotherapeutic drug, an immunotherapeutic drug, an anti-inflammatory drug, an antithrombotic drug, a therapeutic drug for osteoporosis, celluloses, an anti-dementia drug, a therapeutic drug for pollakiuria or urinary incontinence, a therapeutic drug for dysuria, or the like.
The compound shown in the formula (I), the pharmaceutically acceptable salt, the ester or the stereoisomer thereof can be combined with two or more than two pharmaceutical active ingredients or one or more than two pharmaceutical carriers to form a pharmaceutical composition. The pharmaceutical composition can be prepared into a conventional pharmaceutical preparation used clinically, and can be used for patients needing the treatment in an oral or parenteral mode. Such as tablet, granule, capsule, powder, injection, inhalant, sublingual preparation, syrup, gel, ointment, suppository, lotion, nasal drop, spray, transdermal preparation, etc. These preparations can be prepared by conventional methods by adding pharmaceutically acceptable carriers such as excipient, binder, moisturizer, disintegrator, thickener, etc. Such as lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light silica, and the like.
The compounds represented by the general formula (I), pharmaceutically acceptable salts, esters and stereoisomers thereof can be administered to mammals, such as humans, by oral, parenteral (intravenous, intramuscular, subcutaneous or rectal), pulmonary, topical, etc. administration. The amount of the compound of the present invention in the pharmaceutical formulation is from 0.01 to about 100% by weight relative to the actual formulation. The dose varies depending on the administration subject, administration route, disease, disorder and the like, and for example, the compound of the present invention (as an active ingredient) can be orally administered to a diabetic patient (body weight: about 60kg) in the following doses: about 0.01 to 30mg/kg body weight per day, preferably about 0.1 to 20mg/kg body weight per day, more preferably about 1 to 20mg/kg body weight per day. The dose may be administered once a day or divided into several administrations.
The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof shows an excellent GPR40 receptor function-modulating effect in mammals, and is useful as a modulator relating to the physiological function of the GPR40 receptor, or a prophylactic and/or therapeutic agent for preventing and/or treating the pathology or disease of the GPR40 receptor.
Specifically, the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof is useful as an insulin secretion regulator (preferably an insulin secretagogue), a hypoglycemic agent and an islet beta cell protective agent.
In particular, the present invention provides a compound represented by the formula (i), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, which is useful as an insulin secretagogue depending on blood glucose levels, based on the GPR40 receptor agonist activity thereof. This is different from sulfonylureas, and the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof of the present invention is useful as an insulin secretagogue which does not cause hypoglycemia.
The compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof can be used as a medicament for preventing and/or treating diabetes and related diseases, wherein the related diseases comprise impaired glucose tolerance, ketosis, acidosis, diabetic complications (such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macroangiopathy and diabetic gangrene), macular edema, hyperlipidemia, obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes mellitus, insulin allergy caused by lipoatrophy, insulinoma, lipotoxicity, hyperinsulinemia, metabolic syndrome, immunological diseases, inflammatory diseases, multiple sclerosis, acute renal failure and the like. In addition, diabetes includes type I diabetes, type II diabetes, gestational diabetes, and obese diabetes. Hyperlipidemia includes hypertriglyceridemia, hypercholesterolemia, hypo-high density lipoproteinemia, postprandial hyperlipidemia, etc.
The compound of formula (i), its pharmaceutically acceptable salt, its ester or its stereoisomer of the present invention can be used as a medicament for the prevention and/or treatment of Diabetes, borderline type, Impaired Glucose tolerance, IFG (Impaired Fasting Glucose), and IFG (Impaired Fasting hyperglycaemia) according to the new diagnostic criteria reported by ADA (American Diabetes Association), WHO and the japan Diabetes Association. In addition, the present invention provides a compound of formula (i), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, which can prevent the development of borderline type, Impaired Glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting hyperglycemia) into diabetes.
The advantageous effects of the compounds of the present invention are further illustrated below by experiments, but this should not be understood as the compounds of the present invention have only the following advantageous effects.
EXAMPLE 1 calcium flux assay of GPR40 transfected cell line with the Compounds of the invention
Purpose of the experiment: the efficacy of the compounds of the invention and LA (linoleic acid) in the activation of hGPR40 was evaluated using a HEK293 cell line stably expressing human hGPR40 to detect calcium flux signals induced by the compounds of the invention using a FLIPR instrument.
And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
comparison products: control LA (linoleic acid); reference substance TAK-875 racemate, and its structural formula isThe control TAK-875, whose formula is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03).
Experimental reagent:
the experimental steps are as follows:
(1) cell culture
The day before calcium flux assay, low passage numbers of hGPR40 cells were plated at 8000 cells/well and 50. mu.L/well in 384-well assay plates. At 37 ℃ 5% CO2The culture was carried out overnight in an incubator.
(2) Gradient dilution of compound
Preparing a dilution buffer solution:
buffer 1: 25mL of HBSS (containing 20 mM HEPES) + 250. mu.L of 10% BSA, 0.1% BSA buffer was prepared
Buffer 2: 19.7 mL Buffer1+0.3 mL DMSO, 1.5% DMSO Buffer was prepared.
Compound dilution:
1) a proper amount of a test sample and a control TAK-875 racemate (3.01 mg) are accurately weighed and dissolved in DMSO to prepare a sample with the concentration of 10 mM.
2) Test and control TAK-875 racemates at 10mM were diluted to 3mM with DMSO.
3) Transferring 2.5. mu.L of a sample with a concentration of 3mM, adding 148. mu.L of buffer solution for dilution to prepare a mother solution, transferring 40. mu.L of the mother solution, adding 80. mu.L of buffer solution 2, sequentially diluting according to a gradient of 1:3, and obtaining 10 concentration points with a maximum concentration of 50. mu.M. Dilutions were first performed in 96-well plates and subsequently transferred to 384-well plates, duplicate wells.
4)10 u L LA and 22 u L DMSO make concentration 1mol/L solution, 10 u L solution is added 20 u LDMSO diluted into 300 mM solution, 1 u L300 Mm LA/DMSO solution is added 100u L DMSO diluted into 3mM solution, 2.5 u L3 mM LA/DMSO solution, added 148 u L buffer solution 1 solution, make mother liquor, transfer 40 u L mother liquor, add 80 u L buffer solution 2, in order according to 1:3 gradient dilution, total 10 concentration points, the highest concentration 50 u M. Dilutions were first performed in 96-well plates and subsequently transferred to 384-well plates, duplicate wells.
(3) FLIPR calcium flux detection
Preparation of calcium dye: 10mL of HBSS (20 mM HEPES) +1 tube calcium dye + 100. mu.L of 10% BSA.
Loading of calcium dye into cells:
1) the 384 well plates plated with cells were removed from the incubator and the medium was discarded.
2) Calcium dye was added to 384-well plates at 40. mu.L/well.
3) The 384 well plates were returned to the incubator and incubated for 1 h.
FLIPR detection:
1) the 384 well plates plated with cells and the 384 well plates with compounds were placed in the corresponding positions in the cabinet above the FLIPR.
2) The FLIPR protocol was set such that the compound was added to the cells in 10. mu.L volumes per well, giving a maximum final concentration of 10. mu.M compound and a final concentration of 0.3% DMSO.
High control: 10 μ M TAK-875 control.
Low control: control without compound.
3) And operating the instrument to obtain a calcium flow detection curve.
Data processing and results
The raw data were fitted with XLFit to give the EC for each compound and control50And efficacy value. Wherein EC50Values are given by fitting curves, efficacy = maximum/(High control-Lowcontrol) × 100% obtained by compound fitting, results are shown in tables 1-3.
EC50The value: half maximal effect concentration, i.e. the concentration that causes 50% of the maximal effect.
TABLE 1 calcium flux assay results for Compound 1 of the present invention
LA is one of the natural ligands of GPR40, EC acting in vitro50At higher concentrations, the compounds of the invention act on GPR40, compete with LA after entering into the body, and show the binding capacity of the compounds with GPR40 by comparing with the relative activity value of LA. Relative activity value>80, full agonist, relative activity value<80, is a partial agonist.
And (4) experimental conclusion: as is clear from the data in tables 1,2,3, 4 and 5, the compounds EC according to the invention50The value is equivalent to that of a TAK-875 racemate, the relative activity value is equivalent to that of the TAK-875 racemate, and the compound is a complete agonist, so that the agonistic effect of the compound on GPR40 is obvious.
Experimental example 2 detection of GTPgS binding ability of the Compounds of the present invention on GPR40 transfected cell line
And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
comparison products: the control TAK-875, whose formula is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03).
Experimental reagent:
the experimental steps are as follows:
(1) extraction of cell membranes
1. 100 dishes of cells were collected and digested with PBS-EDTA.
2. The cells were resuspended in 5-fold TE (Tris-EDTA) solution. 1000g, centrifuging at 4 ℃ for 10min, collecting supernatant at 26000g, and centrifuging at 4 ℃ for 30 min.
3. The supernatant was discarded, resuspended in 5-fold TE, 26000g, and centrifuged at 4 ℃ for 30 min.
4. The supernatant was discarded, resuspended and diluted to 30mL with 5-fold TE.
5. Protein concentrations were determined by Bradford method and diluted to 1mg/mL and dispensed into l-2mL centrifuge tubes for storage at-80 ℃.
(2) Dilution of Compounds
Compounds were diluted in DMSO in 5-fold gradients to compound stocks.
(3) Cell membrane dilution (1 mg/mL to 0.035 mg/mL)
1. Preparing a detection solution: 23mL of buffer (50 mM Hepes, 160mM NaCl, 10mM MgCl2, 1mM EDTA) + 230. mu.L 10% BSA (without free fatty acids) + 4.6. mu.L saponin (50mg/mL) + 11.5. mu.L LGDP (5 mM)) was placed in ice water.
2. 0.8mL of the cell membrane solution with a concentration of 1mg/mL was added to 23mL of the detection solution and diluted to a concentration of 0.035 mg/mL.
3. To the above 2.0 cell membrane solution was added 23. mu.L of 100nM35S-GTPgS, final concentration 0.1 nM.
(4) Binding reaction
1. Two Corning96 hole U plates (catalog # 3605) were taken and labeled recovery plate1and recovery plate2.
2. Taking 1. mu.L of the compound mother liquor diluted in gradient to corresponding wells of the reaction plate1and 2 (final concentrations of the compounds are 10, 2, 0.4, 0.08, 0.016, 0.003, 0.0006, 0.0001, 0.00003 and 0.000001. mu.M, respectively)
3. Add 1. mu.L 10mM Unlabeled GTPgS to the corresponding wells of the action plate1and the action plate2.
4. 99. mu.L of a 3.3 cell membrane dilution (0.035 mg/mL membrane, 0.1nM membrane) was added35S-GTPgS) into corresponding holes of the interaction plate1and the interaction plate2.
5. The reaction plate was sealed with topseal.
6.1000 spin for 1 min, shake for 2 min.
The reaction was carried out at 7.4 ℃ for 1.5h and at room temperature for 1 h.
(5) Termination of the reaction
The Cell membranes were collected by Cell Harvester (Perkin Elmer) using GF/B plates, which were then washed 10 times with buffer and dried by an electric blower (10 min).
(6) Detection of
1. The plate was bottom-sealed and 50. mu.L/well of Microscint40 scanning fluid solution was added and incubated for 2 h.
2. Plates were placed on a TopCount-NXT reading.
Data processing:
IC50fitting with XLFit, Y = (A + ((B-A)/(1+ ((C/X) ^ D)))), Y is the reading of the isotope (cpm), X is the logarithmic value of the compound concentration, A is the lowest value of the curve, B is the highest value of the curve, and C is the IC50The value, D, is hillslope.
Data processing and results:
TABLE 5 binding ability assay results of Compounds 5 and 6 of the present invention
And (4) conclusion:
binding potency of the compounds of the invention to human GPR40 experiments indicated that the binding potency of Compound 5 was superior to that of the control compound TAK-875, and that the binding potency of Compound 6 was comparable to that of the control compound TAK-875.
Experimental example 3 in vivo pharmacokinetic determination of the Compound of the invention
1. Design of experiments
2. Test article
Some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
dissolution scheme: dissolving the compound 1-4 with 20% DMF, 20% PEG400 and 60% sterile water for injection;
compound 5IV was treated with 2% DMSO +20% (40% HP- β -CD) +78% sterile water for injection PO 2% klucel LF +0.1% Tween;
compound 6IV was treated with 5% DMSO +20% (40% HP- β -CD) +75% sterile water for injection PO 2% klucel LF +0.1% Tween.
Preparing concentration: 0.5 mg/mL (IV: solution; PO: suspension with compounds 1,2,3, 4 as solution, and compounds 5,6 as suspension)
Internal standard 1 for compound 1: dapagliflozin (Dapagliflozin) with the structurePrepared according to the method of patent WO03099836a1 (published as 2003.12.04) and dissolved with MTBE.
Internal standard 2 for compounds 2,3, 4,5, 6: TAK-875 racemate prepared according to the method of patent WO2008001931 (published as 2008.01.03). The internal standard used for compounds 2,3, 4 was dissolved with MTBE; the internal standard used for compounds 5,6 was dissolved in ethyl acetate.
3. Device
The instrument equipment comprises: compounds 1,2,3, 4 were purified using API4000 LC-MS/MS; API3000 LC-MS/MS for compounds 5 and 6
A chromatographic column: waters XbridgeTMC18 (2.10×50 mm,5 μm)
4. Blood collection
Collecting rat blood: fixing animals, heating the tail part of the animal in a water bath kettle 10min before each time point, collecting about 100 mu L of whole blood through tail veins, and placing the collected blood into an anticoagulant tube containing heparin sodium. Blood samples were centrifuged at 8000rpm at 4 ℃ for 6 min to obtain plasma samples, which had to be prepared within 30min after blood collection. Plasma was stored in a-80 ℃ freezer prior to testing.
5. Experimental methods
(1) Taking out the sample to be tested from the refrigerator, naturally melting at room temperature (-80 ℃), and vortexing for 5 min;
(2) precisely transferring 20 mu L of sample into a 1.5mL EP tube;
(3) adding 600. mu.L of internal standard solution (containing internal standard TAK-875 racemate 25 ng/mL);
(4) after vortexing at 1500 rpm for 10min, centrifuging for 5 min (12000 rpm);
(5) precisely transferring 400. mu.L of the supernatant to a 96-well plate, N2Blow-dry, add 200 μ L of reconstituted solution (acetonitrile: water =1:1), vortex and mix well, and analyze by LC-MS/MS.
6. Data processing method
The test substance (plasma sample) concentration was outputted using Analyst 1.5.1 from AB. Microsoft Excel calculates parameters such as mean value, standard deviation, coefficient of variation and the like (analysis 1.5.1 is directly output without calculation), and PK parameters are calculated by adopting Pharsight Phoenix 6.2 software. Calculating the formula: f% = AUCinf-po*Doseiv/AUCinf-iv*Dosepo。
Table 6 rat PK assessment results for test compounds following intravenous bolus dosing of compounds
Table 7 rat PK assessment results for test compounds following gavage administration of compounds
Table 8 rat PK assessment results for test compounds following intravenous bolus dosing of compounds
TABLE 9 rat PK evaluation results of test compounds after gastric gavage
Wherein, T1/2Represents the half-life; AUClastArea under curve when representing drug0→t(ii) a CL represents clearance; vss represents apparent volume of distribution; cmaxRepresents the peak blood drug concentration; t ismaxRepresents the peak time of blood drug; f% represents the absolute bioavailability.
7. Conclusion of the experiment
As can be seen from tables 6,7, 8 and 9, the PK parameters of the compounds of the invention measured by IV and PO in rats were comparable to the exposure to IV (AUC) of the TAK-875 racemate or TAK-875, with compounds 1,3,4 having a volume of distribution (Vss) superior to that of the TAK-875 racemate; the half-life of the compounds 5 and 6 is better than that of TAK-875, and the clearance rate (CL) is equivalent; peak concentration of PO administration (C)max) And the exposure (AUC) is equivalent to that of a TAK-875 racemate or TAK-875, wherein the bioavailability of the compound 5 is superior to that of the TAK-875, the compound can be used for treating diseases such as diabetes and the like, and the oral bioavailability of the compound is better than that of the TAK-875, so that the compound has better clinical application prospect.
Experimental example 4 study of the Effect of the Compound of the present invention on apoptosis of HepG2 cells
And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
comparison products: a positive control staurosporine (commercially available); reference substance TAK-875 racemate, and its structural formula isA control TAK-875, the formula of which is as described above, prepared according to the method of patent WO2008001931 (published as 2008.01.03); AMG-837, the structural formula is:structure of compound QComprises the following steps:prepared according to the method in Journal of Medicinal Chemistry (2012),55(8), 3756-.
Cell line:
experimental reagent:
the instrument comprises the following steps:
an enzyme-labeling instrument: perkin Elmer-Envision Multilabel Reader
The experimental steps are as follows:
(1)37℃，5% CO2HepG2 cells were cultured in L-glutamine-containing MEM medium containing 10% FBS, 100U/mL penicillin, and 100 mg/mL streptomycin under conditions to achieve 80% confluency between cells.
(2) Cells were digested with pancreatin, centrifuged at 1000rpm for 4 minutes, resuspended in fresh medium containing 0.5% FBS, and seeded at an adjusted cell concentration to 384 plates. A total of 1000 cells per well of 22.5. mu.L, 3 duplicate wells.
(3) The cells were cultured for 24h to prepare 10-fold compound solution, 2.5. mu.L of 10-fold compound solution (total volume 25. mu.L) was added to each well, the final concentration of compound was 30. mu.M, and 1 concentration of each compound was added to each well, 3 wells.
a) Solvent comparison: cells added with 0.3% DMSO.
b) Control of the medium: cells without added compound.
c) Blank control: cells were not added for instrument zeroing.
(4)37℃，5% CO2The cells were treated with the drug under conditions for 24 h.
(5) Add 25. mu.L of Caspase-GloR 3/7 reagent to each well and mix gently in a microplate shaker.
(6) The plate was sealed with a sealing film, protected from light, and incubated at room temperature for 30 min.
(7) The light absorption was measured with a microplate reader.
Calculating the formula:
caspase activity = (average of absorbance of compound-average of blank control)/(average of medium control-average of blank control)
Statistical analysis: the p-value represents the difference in the T-test between the medium and compound groups.
TABLE 10 results of experiments on the apoptosis of HepG2 by the compounds of the present invention
TABLE 10-1 results of experiments on apoptosis of HepG2 by the inventive compounds 5,6
And (4) conclusion: the structure of a positive control compound Q of a GPR40 series reported in the literature is unmodified and has cytotoxicity.
The effect of the compounds 1,2,3 and 4 on HepG2 cell apoptosis is equivalent to that of the marketed drug TAK-875 racemate or TAK-875, and the toxic effect on liver cells is equivalent.
Experimental example 5 Effect of the Compounds of the present invention on cell proliferation of HepG2
And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
comparison products: positive control sorafenib (commercially available); reference substance TAK-875 racemate, and its structural formula isA control TAK-875, the formula of which is as described above, prepared according to the method of patent WO2008001931 (published as 2008.01.03); AMG-837, the structural formula is:compound Q has the structure:prepared according to the method in Journal of Medicinal Chemistry (2012),55(8), 3756-.
Cell lines
Experimental reagent:
the instrument comprises the following steps:
an enzyme-labeling instrument: EnVision2104 Multilable Reader
The experimental steps are as follows:
(1)37℃，5% CO2HepG2 cells were cultured in L-glutamine-containing MEM medium containing 10% FBS, 100U/mL penicillin, and 100 mg/mL streptomycin under conditions to achieve 80% confluency between cells.
(2) Cells were digested with pancreatin, centrifuged at 1000rpm for 4 minutes, resuspended in fresh medium containing 0.5% FBS, and seeded in 96-well plates at adjusted cell concentrations. A total of 2500 cells per well of 90uL, 3 duplicate wells.
(3) Culturing the cells for 24h, preparing 10 times of compound solution, and adding 10 mu L of 10 times of compound solution into each hole (the total volume is 100 mu L); the final concentration of the compound was 30. mu.M, and the final concentration of sorafenib was 5. mu.M.
a) Solvent comparison: cells added with 0.3% DMSO.
b) Control of the medium: cells without added compound.
c) Blank control: cells were not added for instrument zeroing.
(4)37℃，5% CO2Cells were treated with drug under conditions for 72 h.
(5) The plates were then allowed to equilibrate for 30min at room temperature.
(6) Add 100. mu.L CellTiter-Reagent。
(7) Shaking and mixing for 2min to dissolve the cells.
(8) The plate was equilibrated at room temperature for 10min to stabilize the signal.
(9) The light absorption was measured using an EnVision2104 multifunctional microplate reader.
Calculating the formula:
cell viability = (mean compound light absorption value-mean blank control)/(mean medium control value-mean blank control value) × 100
TABLE 11 results of experiment on proliferation of HepG2 cells by the compounds of the present invention
TABLE 11-1 results of cell proliferation experiments of Compounds 5 and 6 of the present invention against HepG2
And (4) conclusion: the effect of the compounds 1,2,3 and 4 on cell viability in a cell proliferation experiment of HepG2 is equivalent to that of a TAK-875 racemate, and the effect of the compounds 5 and 6 on cell viability is equivalent to that of the TAK-875 and toxic effect on liver cells is equivalent to that of the liver cells.
Experimental example 6 intraperitoneal glucose tolerance test of compound of the present invention
And (3) testing the sample: some of the compounds of the invention, each prepared according to the methods of the examples of the invention;
comparison products: reference substance TAK-875 racemate, and its structural formula isThe control TAK-875, whose formula is as described above, was prepared according to the method of patent WO2008001931 (published as 2008.01.03).
The experimental method comprises the following steps:
accurately weighing the sample and a 0.5% methyl cellulose solution as a solvent. All were prepared as 3mg/mL solutions.
2.750g of glucose was adjusted to 25mL with water for injection, and 4 parts were added.
After 1 week of quarantine, male SD rats are fasted without water supply overnight, and after weighing, the SD rats are randomly divided into a normal control group, a solvent control group, a test article group and a control article group according to the weight, wherein the dosages of the SD rats are 30mg/kg, and the SD rats are divided into 6 groups, and each group comprises 5 rats, as shown in the following table. After the compound solution or the solvent is orally taken for 1 hour, 1g/kg of glucose solution is injected into the abdominal cavity, the administration volume is 10mL/kg, the tail vein is punctured by a disposable syringe before (-60min), before (0min) and 10, 20, 30, 60 and 120min after the administration of glucose respectively, blood is taken, 3 mu L of blood is taken by a pipette, the blood is dripped on a test paper of a blood glucose determinator, the concentration of blood glucose is determined, and the reading is recorded.
Grouping and dosing
Individual blood glucose values for each animal were plotted in a scatter plot using Excell. Adopting a WinNonLin software NCA model to calculate AUC, calculating the blood glucose inhibition rate according to the delta AUC, using SPSS13.0 software to carry out One-Way ANOVA test, carrying out statistical analysis between groups on the delta AUC, and considering that P <0.05 has significant difference.
Calculating the formula:
blood glucose inhibition rate = (vehicle control group AUC average value-administration group AUC average value)/(vehicle control group AUC average value-normal control group AUC average value) × 100%.
The experimental results are as follows:
TABLE 12 inhibition of blood glucose in rats by compounds
The value of P is compared with that of a solvent control group, and the value of P is less than 0.05, which has statistical significance.
TABLE 13 inhibition of blood glucose in rats by compounds
TABLE 14 inhibition of blood glucose in rats by compounds
The value of P is compared with that of a solvent control group, and the value of P is less than 0.05, which has statistical significance.
And (4) conclusion: the blood sugar reducing levels of the compounds 3 and 4 are superior to that of a TAK-875 racemate, the blood sugar reducing level of the compound 1 is equivalent to that of the TAK-875 racemate, the blood sugar reducing level of the compound 5 is superior to that of the TAK-875 racemate, and the compound has an obvious blood sugar reducing effect.
4. Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example preparation of the Synthesis of 12- (6- ((2',6' -dimethyl-4 '- (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)
(1) Preparation of 4- (chloromethyl) -7-hydroxy-2H-benzopyran-2-one
M-diphenol (27.5g, 250mmol) is placed in acetic acid (60mL) and heated to 50 ℃ for dissolution and standby, 4-chloroacetoacetic acid ethyl ester (20.5g, 125mmol) is dissolved in acetic acid (20mL) and cooled in an ice water bath, concentrated sulfuric acid (10mL) is slowly added, then the acetic acid solution of m-diphenol is added in the ice water bath, the mixture is stirred for 1h at room temperature, and then the reaction is carried out for 3h at 60 ℃. After the reaction was complete, water (300mL) was added, the mixture was stirred at room temperature for 1h, filtered under reduced pressure, and the resulting white solid was washed three times with water (100mL) and dried to give the product (17.6g, 67% yield).
(2) Preparation of 2- (6-hydroxybenzofuran-3-yl) acetic acid
Sodium hydroxide (1.35g, 34mmol) was dissolved in water (8mL), and an aqueous solution (6mL) in which 4- (chloromethyl) -7-hydroxy-2H-benzopyran-2-one (2.5g, 12mmol) was dissolved was slowly added under ice bath, stirred at room temperature for 1 hour, and then reacted at 60 ℃ for 4 hours. Concentrated hydrochloric acid (2.8mL, 34mmol) was added at 35 deg.C, the temperature was maintained for 1 hour, and stirring was continued at room temperature for 1 hour. The resulting solid was suction filtered and washed three times with water. The solid was dried to give the product as a white solid (1.2g, 52% yield).
(3) Preparation of 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid
2- (6-hydroxybenzofuran-3-yl) acetic acid (1.2g, 6.3mmol) was added to HOAc (20mL), Pd/C (0.12g) was added, and hydrogen was passed through at 40 ℃ to react for 24 hours. The diatomaceous earth was filtered under reduced pressure, the filter cake was washed with methanol, and the solvent was removed by rotary evaporation of the filtrate to give the product as a white solid (1.1g, 90% yield).
(4) Preparation of methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate
2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetic acid (1.1g, 5.7mmol) was dissolved in methanol (20mL), and thionyl chloride (0.67g, 5.7mmol) was added dropwise over 10 minutes in an ice bath. Stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and additional toluene was added to remove excess thionyl chloride by rotary evaporation to give the product as a brown solid (1.1g, 93% yield).
(5) Preparation of tert-butyl (2- (4-bromo-3, 5-dimethylphenyloxy) ethyl) carbamate
N-Boc ethanolamine (2.1g,10.4mmol), p-bromodimethylphenol (2.08g, 10.4mmol), and azobisformyldipiperidine (3.9g, 15.5mmol) were added to THF (100mL), tri-N-butylphosphine (3.1g, 15.5mmol) was added while cooling on ice, the mixture was allowed to warm to room temperature after dropwise addition, and the reaction was continued for 4 hours, petroleum ether (100mL) was added, stirred for 20min, then suction filtered, the filtrate was spin-dried and column chromatographed, and eluent (PE/EA =20:1) gave an oily product (2.7g, 75% yield).
(6) Preparation of 2- (4-bromo-3, 5-dimethylphenoxy) ethylamine
Tert-butyl (2- (4-bromo-3, 5-dimethylphenyloxy) ethyl) carbamate (2.7g, 7.8mmol) was dissolved in DCM (15mL), TFA (10mL) was added, and stirring was carried out at room temperature for 2 hours. The solvent was removed by rotary evaporation, washed with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to give the product as an oil (1.8g, 94% yield).
(7) Preparation of N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) methanesulfonamide
2- (4-bromo-3, 5-dimethylphenoxy) ethylamine (1.8g, 7.4mmol) was dissolved in THF (40mL), triethylamine (1.5g) was added, methanesulfonyl chloride (1.0g, 8.9mmol) was added dropwise in an ice bath, and after completion of dropwise addition within 10 minutes, the reaction was allowed to warm to room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, spin-dried and separated by column chromatography to give an oily product (2.3g, 96% yield) as eluent (petroleum ether/ethyl acetate =5: 1).
(8) Preparation of N- (2- ((3'- (hydroxymethyl) -26-dimethyl- [11' -biphenyl ] -4-yl) oxy) ethyl) methanesulfonamide
N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) methanesulfonamide (1.2g,3.7mmol), m-hydroxymethylphenylboronic acid (0.57g, 3.8mmol), palladium acetate (25mg, 0.1mmol), triphenylphosphine (77mg, 0.3mmol), tetrabutylammonium bromide (120mg, 0.3mmol), potassium phosphate (3.0g, 11.3mmol) were added to THF (40mL) and the reaction was refluxed for 12h under nitrogen. Column chromatography was performed on the system by spin-drying, eluting with petroleum ether/ethyl acetate =3:1, to give the product as an oil (410mg, 32% yield).
(9) Preparation of methyl 2- (6- ((2',6' -dimethyl-4 '- (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
N- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) methanesulfonamide (410mg,1.2mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (245mg, 1.2mmol), and ADDP (454mg, 1.8mmol) were added to THF (40mL), tri-N-butylphosphine (364mg, 1.8mmol) was added while cooling on ice, and after dropwise addition, the mixture was allowed to warm to room temperature. The reaction was continued for 4h, petroleum ether (40mL) was added, stirring was carried out for 20min, then suction filtration was carried out, the filtrate was spin-dried and column chromatography was carried out, eluting (petroleum ether/ethyl acetate =2:1) to give the product as an oil (410mg, yield 63%).
(10) Preparation of 2- (6- ((2',6' -dimethyl-4 '- (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 1)
Methyl 2- (6- ((2',6' -dimethyl-4 '- (2- (methylsulfonylamino) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (410mg, 0.76mmol) was dissolved in THF/MeO H =1:1(10mL) and a solution of lithium hydroxide monohydrate (96mg, 2.3mmol) in water (5mL) was slowly added and stirred at 30 ℃ for 2 hours. The organic solvent was spin-dried, extracted with ethyl acetate, and aqueous hydrochloric acid was added to the aqueous phase to adjust pH = 3. Extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, spin drying of the solvent and column chromatography separation with eluent (petroleum ether/ethyl acetate =1:1) gave crude product (100mg) which was recrystallized from isopropanol to give compound 1(18mg) as a white solid product.
The molecular formula is as follows: c28H31NO7S molecular weight: 525.6 Mass Spectrometry (m/z): 526.2(M +1)
1H-NMR(400MHz,DMSO-d6):7.40-7.48(m,1H),7.34-7.39(m,1H),7.27(t,J=5.9Hz,1H),7.13(s,1H),7.06(dd,J=16.3,7.8Hz,2H),6.70(s,2H),6.40-6.49(m,2H),5.08(s,2H),4.66(t,J=9.0Hz,1H),4.17(dd,J=8.9,6.9Hz,1H),4.02(t,J=5.5Hz,2H),3.59-3.71(m,1H),2.95(s,3H),2.63-2.74(m,1H),2.41-2.46(m,1H),1.90(s,6H).
EXAMPLE 22 preparation of (6- ((4'- (2- (cyclopropylsulfonamido) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 2)
(1) Preparation of 2- (4-bromo-3, 5-dimethylphenoxy) ethylamine
Tert-butyl 2- (4-bromo-3, 5-dimethylphenoxy) ethylcarbamate (2.0g, 5.8mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (10mL) was added and stirred at room temperature for 2 h. The solvent was distilled off under reduced pressure, a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give an oily product (1.36g, yield 96%).
(2) Preparation of N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) cyclopropyl sulfonamide
2- (4-bromo-3, 5-dimethylphenoxy) ethylamine (1.36g, 5.6mmol) was dissolved in tetrahydrofuran (50mL), triethylamine (1.69g, 16.7mmol) was added, cyclopropylsulfonyl chloride (1.1g, 7.8mmol) was added dropwise in an ice bath, and after completion of the addition, the reaction was warmed to room temperature for 16 h. Water (100mL) was added, ethyl acetate extraction (100mL × 3) was performed, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to crude silica gel column chromatography (ethyl acetate/petroleum ether =0 to 1/5) to obtain a product (1.5g, yield 77%).
(3) Preparation of N- (2- (3'- ((hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) cyclopropylsulfonamide
N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) cyclopropylsulfonamide (1.5g, 4.3mmol), m-hydroxymethylphenylboronic acid (851mg, 5.6mmol) and tetrakis (triphenylphosphine) palladium (150mg, 0.13mmol) were added to dioxane (50mL), aqueous potassium carbonate (1.19g, 8.6mmol) was added (10mL), and the reaction was refluxed for 12h under nitrogen. Cooled to room temperature, concentrated, added with 100mL of water, extracted with ethyl acetate (100mL × 3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and the crude product isolated by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/3) to give the product (1.2g, 74% yield).
(4) Preparation of methyl 2- (6- ((4'- (2- (cyclopropylsulfonamido) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
Dissolving N- (2- (3'- ((hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) cyclopropyl sulfonamide (1.2g,3.2mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (874mg, 4.2mmol) and azodicarbonyl dipiperidine (1.21g, 4.8mmol) in tetrahydrofuran (100mL), adding tri-N-butyl phosphorus (970mg, 4.8mmol) in an ice bath, heating to room temperature after completion of dropwise addition, reacting for 16h, adding petroleum ether (50mL), suction-filtering, drying the filtrate, and separating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/2) to obtain a colorless oily product (1.3g, yield 72%).
(5) Preparation of 2- (6- ((4'- (2- (cyclopropylsulfonamido) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 2)
Methyl 2- (6- ((4'- (2- (cyclopropylsulfonamido) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.3g, 2.3mmol) was dissolved in tetrahydrofuran (30mL) and methanol (30mL), and an aqueous solution (30mL) of lithium hydroxide monohydrate (290mg, 6.9mmol) was added and reacted at room temperature for 4 h. Concentration to about 30mL, addition of water (100mL), pH =3 with 1mol/L dilute hydrochloric acid, extraction with ethyl acetate (150mL × 3), combination of organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, concentration, and isolation of the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/1) gave the product compound 2(1.0g, 26% yield).
The molecular formula is as follows: c30H33NO7S molecular weight: 551.6 Mass Spectrometry (m/z): 552.2(M +1)
1H-NMR(400MHz,CDCl3-d):7.36-7.47(m,2H),7.16(s,1H),7.02-7.09(m,2H),6.65(s,2H),6.44-6.53(m,2H),5.06(s,2H),4.82(m,1H),4.76(t,J=9.0Hz,1H),4.29(dd,J=9.2,6.1Hz,1H),4.14(t,J=5.0Hz,2H),3.75-3.86(m,1H),3.58(q,J=5.4Hz,2H),2.81(dd,J=16.9,5.4Hz,1H),2.62(dd,J=16.8,9.3Hz,1H),2.44-2.53(m,1H),2.00(s,6H),1.19-1.25(m,2H),1.00-1.07(m,2H).
EXAMPLE preparation of 32- (6- ((4'- (2- ((N, N-dimethylaminosulfonyl) amino) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 3)
(1) Preparation of tert-butyl 2- (4-bromo-3, 5-dimethylphenoxy) ethylcarbamate
Dissolving N-Boc ethanolamine (5.8g,36mmol), 4-bromo-3, 5-dimethylphenol (6.03g, 30mmol) and azodicarbonyl dipiperidine (11.34g, 45mmol) in tetrahydrofuran (300mL), adding tri-N-butylphosphine (9.1g, 45mmol) under ice bath, heating to room temperature after dropwise addition, reacting for 16h, adding petroleum ether (200mL), suction filtering, spin-drying the filtrate, and separating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/20) to obtain a colorless oily product (8.0g, 77% yield).
(2) Preparation of 2- (4-bromo-3, 5-dimethylphenoxy) ethylamine
Tert-butyl 2- (4-bromo-3, 5-dimethylphenoxy) ethylcarbamate (2.5g, 7.8mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (10mL) was added and stirred at room temperature for 2 h. The solvent was distilled off under reduced pressure, a saturated sodium bicarbonate solution was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give an oily product (1.7g, yield 89%).
(3) Preparation of N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) dimethylaminosulfonamide
2- (4-bromo-3, 5-dimethylphenoxy) ethylamine (1.7g, 7.0mmol) was dissolved in tetrahydrofuran (50mL), triethylamine (2.1g, 21mmol) was added, dimethylaminosulfonyl chloride (1.44g, 10mmol) was added dropwise in an ice bath, and after completion of addition, the mixture was warmed to room temperature for reaction for 16 hours. Water (100mL) was added, ethyl acetate was extracted (100mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was isolated by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/5) to give the product (1.6g, 65% yield).
(4) Preparation of N- (2- (3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-oxy) ethyl) dimethylamino sulfonamide
N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) dimethylaminosulfonamide (1.6g,4.5mmol), m-hydroxymethylphenylboronic acid (900mg, 5.9mmol), tetrakis (triphenylphosphine) palladium (160mg, 0.14mmol), and potassium carbonate (1.25g, 9.0mmol) were added to dioxane (40mL) and water (6mL) and reacted under reflux for 12h under nitrogen. Cooling to room temperature, concentrating, adding water (100mL), extracting with ethyl acetate (100mL × 3), combining the organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, concentrating, and isolating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/3) to give the product (1.2g, 70% yield).
(5) Preparation of methyl 2- (6- ((4'- (2- ((N, N-dimethylaminosulfonyl) amino) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
Dissolving N- (2- (3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-oxy) ethyl) dimethylaminosulfonamide (1.2g,3.2mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (858mg, 4.1mmol) and azodicarbonyl dipiperidine (1.29g, 5.1mmol) in tetrahydrofuran (80mL), adding tri-N-butylphosphine (1.0g, 5.1mmol) under ice bath, heating to room temperature after completion of dropwise addition, reacting for 16h, adding petroleum ether (50mL), suction-filtering, spin-drying the filtrate, and separating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/2) to obtain a colorless oily product (600mg, 33% yield).
(6) Preparation of 2- (6- ((4'- (2- ((N, N-dimethylaminosulfonyl) amino) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 3)
Methyl 2- (6- ((4'- (2- ((N, N-dimethylaminosulfonyl) amino) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (600mg, 1.05mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL), and an aqueous solution (10mL) of lithium hydroxide monohydrate (130mg, 3.1mmol) was added and reacted at room temperature for 4 h. Concentration to about 10mL, pH =3 with 1mol/L dilute hydrochloric acid, water (100mL), ethyl acetate extraction (100mL × 3), organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentration, and isolation of the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/1) gave the product compound 3(100mg, 17% yield).
The molecular formula is as follows: c29H34N2O7S molecular weight: 554.6 Mass Spectrometry (m/z): 555.2(M +1)
1H-NMR(400MHz,CDCl3-d):7.37-7.47(m,2H),7.16(s,1H),7.06(t,J=8.7Hz,2H),6.65(s,2H),6.42-6.54(m,2H),5.06(s,2H),4.76(t,J=9.0Hz,1H),4.69(br.s.,1H),4.23-4.39(m,1H),4.06-4.19(m,2H),3.69-3.87(m,1H),3.47(q,J=5.3Hz,2H),2.75-2.90(m,7H),2.61(dd,J=16.8,9.3Hz,1H),1.99(s,6H).
EXAMPLE 42 preparation of (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 4)
(1) Preparation of 2- (4-bromo-3, 5-dimethylphenoxy) ethylamine
Tert-butyl 2- (4-bromo-3, 5-dimethylphenoxy) ethylcarbamate (2.5g, 7.8mmol) was dissolved in dichloromethane (20mL), and trifluoroacetic acid (10mL) was added and stirred at room temperature for 2 h. The solvent was distilled off under reduced pressure, saturated sodium bicarbonate was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give an oily product (1.7g, yield 89%).
(2) Preparation of N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) -3-chloropropyl-1-sulfonamide
Dissolving 2- (4-bromo-3, 5-dimethylphenoxy) ethylamine (1.7g, 7.0mmol) in tetrahydrofuran (50mL), adding triethylamine (2.1g, 21mmol), dropwise adding 3-chloropropyl-1-sulfonyl chloride (1.77g, 10mmol) under ice bath, and after dropwise adding, heating to room temperature for reaction for 16 h. Water (100mL) was added, ethyl acetate extracted (100mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was isolated by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/5) to give the product (2.0g, 74% yield).
(3) Preparation of 2- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) isothiazolidine 1, 1-dioxide
N- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) -3-chloropropyl-1-sulfonamide (2.0g, 5.2mmol) was dissolved in DMF (100mL), and after the addition, sodium hydride (310mg, 7.8mmol) was added in ice bath, followed by reaction for 1h in ice bath and warming to room temperature for 2 h. Poured into ice water (500mL), extracted with ethyl acetate (200mL × 3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and the crude product isolated by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/4) to give the product (1.6g, 88% yield).
(4) Preparation of 2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide
2- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) isothiazoline 1, 1-dioxide (1.6g,4.6mmol), m-hydroxymethylphenylboronic acid (908mg, 6.0mmol) and tetrakis (triphenylphosphine) palladium (160mg, 0.14mmol) were added to dioxane (50mL), potassium carbonate (1.27g, 9.2mmol) in water (10mL) was added, and the reaction was refluxed for 12h under nitrogen. Cooling to room temperature, concentrating, adding water (100mL), extracting with ethyl acetate (100mL × 3), combining the organic phases, washing with saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, concentrating, and isolating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/3) to give the product (1.5g, 86% yield).
(5) Preparation of methyl 2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide (1.5g,4.0mmol), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (1.08g, 5.2mmol), and azobisdimethyldipiperidine (1.51g, 6.0mmol) were dissolved in tetrahydrofuran (100mL), adding tri-n-butylphosphine (1.21g, 6.0mmol) in an ice bath, heating to room temperature after dropwise addition, reacting for 16h, adding petroleum ether (50mL), performing suction filtration, performing spin-drying on the filtrate, and separating the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/2) to obtain a colorless oily product (1.6g, yield 71%).
6) Preparation of 2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid
Methyl 2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (1.6g, 2.8mmol) was dissolved in tetrahydrofuran (30mL) and methanol (30mL), and an aqueous solution (30mL) of lithium hydroxide monohydrate (353mg, 8.4mmol) was added to react at room temperature for 4 hours. Concentrate to about 30mL, add water (100mL), adjust pH =3 with 1mol/L dilute hydrochloric acid, extract with ethyl acetate (150mL × 3), combine the organic phases, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, concentrate, and isolate the crude product by silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/1) to give the product (1.2g, 78% yield).
The molecular formula is as follows: c30H33NO7S molecular weight: 551.6 Mass Spectrometry (m/z): 552.2(M +1)
1H-NMR(400MHz,CDCl3-d):7.37-7.41(m,2H),7.16(s,1H),7.07(t,J=8.4Hz,2H),6.66(s,2H),6.46-6.51(m,2H),5.06(s,2H),4.76(t,J=9.0Hz,1H),4.29(dd,J=9.3,6.0Hz,1H),4.20(t,J=5.1Hz,2H),3.77-3.87(m,1H),3.43-3.56(m,4H),3.16(t,J=7.7Hz,2H),2.81(dd,J=16.8,5.3Hz,1H),2.62(dd,J=16.8,9.3Hz,1H),2.38(quin,J=7.3Hz,2H),1.99(s,6H).
EXAMPLE 5 preparation of (S) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 5)
(1) Preparation of methyl (S) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
Dissolving 2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide (2.20g,5.87mmol), (S) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (1.34g, 6.45mmol), and azobisdimethyldipiperidine (2.37g, 9.39mmol) in tetrahydrofuran (150mL), adding tri-n-butylphosphine (1.90g, 9.39mmol) under ice bath, reacting at room temperature for 16h after completion of dropwise addition, adding petroleum ether (100mL), suction-filtering, concentrating the obtained filtrate under reduced pressure, subjecting the crude silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/2) to give the title compound (2.8g, yield 84%).
(2) Preparation of (S) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid
Mixing (S) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl)]-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester (2.8g, 4.9mmol) was dissolved in tetrahydrofuran (30mL) and methanol (30mL), LiOH. H.2O (617mg, 14.7mmol) in water (30mL), reacted at room temperature for 4h, concentrated to about 30mL, water (100mL), pH adjusted to 3 with 1mol/L dilute hydrochloric acid, extracted with ethyl acetate (150mL × 3), organic phases combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and crude silica gel column chromatography (methanol/dichloromethane = 0-1/15) afforded the title compound as a white solid (2.2g, 81% yield).
The molecular formula is as follows: c30H33NO7S molecular weight: 551.65 LC-MS (m/z): 552.3(M +1)
1H-NMR(400MHz,CDCl3-d):7.35-7.45(m,2H),7.16(s,1H),7.04-7.09(m,2H),6.66(s,2H),6.46-6.51(m,2H),5.06(s,2H),4.74-4.79(m,1H),4.27-4.31(m,1H),4.18-4.21(m,2H),3.79-3.84(m,1H),3.47-3.53(m,4H),3.14-3.18(m,2H),2.79-2.84(m,1H),2.59-2.65(m,1H),2.34-2.42(m,2H),1.99(s,6H).
EXAMPLE 6 preparation of (R) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 6)
(1) Preparation of methyl (R) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
Dissolving 2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) isothiazolidine 1, 1-dioxide (1.79g, 4.77mmol), (R) -methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (990mg, 4.76mmol), and azobisdimethyldipiperidine (1.92g, 7.62mmol) in tetrahydrofuran (150mL), adding tri-n-butylphosphine (1.54g, 7.62mmol) under ice bath, reacting at room temperature for 16h after completion of dropwise addition, adding petroleum ether (100mL), suction-filtering, concentrating the obtained filtrate under reduced pressure, subjecting the crude silica gel column chromatography (ethyl acetate/petroleum ether = 0-1/2) to give the title compound (2.4g, yield 89%).
(2) Preparation of (R) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid
Mixing (R) -2- (6- ((4'- (2- (1, 1-dioxoisothiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl)]-3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid methyl ester (2.4g, 4.2mmol) was dissolved in tetrahydrofuran (30mL) and methanol (30mL) and LiOH H.H. was added2O (529mg, 12.6mmol) in water (30mL), reacted at room temperature for 4h, concentrated to about 30mL, water (100mL), pH =3 adjusted with 1mol/L dilute hydrochloric acid, extracted with ethyl acetate (150mL × 3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product chromatographed over silica gel (methanol/dichloromethane = 0-1/15) to give the title compound as a white solid (1.9g, 81% yield).
The molecular formula is as follows: c30H33NO7S molecular weight: 551.65 LC-MS (m/z): 552.3(M +1)
1H-NMR(400MHz,CDCl3-d):7.37-7 .45(m,2H),7.16(s,1H),7.05-7.09(m,2H),6.66(s,2H),6.47-6.52(m,2H),5.07(s,2H),4.74-4.79(m,1H),4.27-4.31(m,1H),4.19-4.21(m,2H),3.79-3.84(m,1H),3.47-3.53(m,4H),3.14-3.18(m,2H),2.79-2.85(m,1H),2.59-2.66(m,1H),2.38-2.42(m,2H),1.99(s,6H).
EXAMPLE 72 preparation of (6- ((4'- (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 7)
(1) Preparation of methyl 2- (6- ((3-bromobenzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate
3-Bromobenzoyl alcohol (694mg,3.71mmol) was dissolved in tetrahydrofuran (6mL), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (772mg,3.71mmol), tributylphosphine (1.5g,7.42mmol) and azobisformyldipiperidine (1.87g,7.42mmol) were added, stirred at room temperature overnight, excess solvent was removed under reduced pressure, water (10mL) was added, ethyl acetate (10 mL. times.3) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated and isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate =5:1) to give the title compound (960mg, 68.5% yield).
(2) Preparation of methyl 2- (6- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate
Methyl 2- (6- ((3-bromobenzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (0.5g,1.33mmol) was dissolved in dimethyl sulfoxide (5mL), and 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolane) (0.41g,1.6mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (97mg,0.133mmol) and potassium acetate (0.39g,3.99mmol) were added, stirred overnight at 80 ℃ under nitrogen, cooled to room temperature, extracted with water (5mL), ethyl acetate (10mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.45g, 80% yield).
(3) Preparation of methyl 2- (6- ((4'- (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
2- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) -1,2, 5-thiadiazolidine 1, 1-dioxide (100mg,0.286mmol) was dissolved in dioxane/water (6mL,5:1), methyl 2- (6- ((3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl) acetate (146mg,0.344mmol), tetrakis (triphenylphosphine) palladium (33mg,0.0286mmol) and potassium carbonate (118mg,0.86mmol) were added, the mixture was stirred overnight under reflux, excess solvent was removed under reduced pressure, column chromatography (petroleum ether: ethyl acetate =2:1) was isolated and purified to give the title compound (102mg, yield 63%).
(4) Preparation of 2- (6- ((4'- (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid
Methyl 2- (6- ((4'- (2- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) -2',6 '-dimethyl- [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (100mg,0.17mmol) was dissolved in a mixed solvent of methanol (1mL), tetrahydrofuran (1mL) and water (1mL), and lithium hydroxide monohydrate (22mg,0.51mmol) was added and stirred at room temperature for 3 hours. The excess solvent was removed under reduced pressure, water (5mL) was added, diluted hydrochloric acid was adjusted to pH =3, ethyl acetate (5mL × 3) was extracted, dried over anhydrous sodium sulfate, filtered, and after concentration, the title compound was isolated and purified by silica gel column chromatography (dichloromethane: methanol =15:1) to obtain the title compound (32mg, yield 34%).
The molecular formula is as follows: c29H32N2O7S molecular weight: 552.6 LC-MS (m/z): 553.3(M +1)
1H-NMR(400MHz,MeOD-d4):7.36-7.44(m,2H),7.12(s,1H),7.02-7.07(m,2H),6.68(s,2H),6.47(m,1H),6.40(d,J=2Hz,1H),5.06(s,2H),4.68(m,1H),4.16-4.23(m,3H),3.71-3.75(m,1H),3.54-3.58(m,2H),3.31-3.43(m,4H),2.67-2.73(m,1H),2.47-2.53(m,1H),1.94(s,6H).
Example preparation of 82- (6- ((2',6' -dimethyl-4 '- (2- (5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid (Compound 8)
(1) Preparation of 2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) -5-methyl-1, 2, 5-thiadiazolidine 1, 1-dioxide
2- (2- (4-bromo-3, 5-dimethylphenoxy) ethyl) -5-methyl-1, 2, 5-thiadiazolidine 1, 1-dioxide (61mg,0.168mmol) was dissolved in dioxane/water (6mL,5:1), (3- (hydroxymethyl) phenyl) boronic acid (51mg,0.336mmol), tetrakis (triphenylphosphine) palladium (19mg,0.0168mmol) and potassium carbonate (58mg,0.42mmol) were added, stirring was performed at reflux overnight, excess solvent was removed under reduced pressure, and column chromatography (petroleum ether: ethyl acetate =1:1) was performed to isolate and purify the title compound (60mg, 91% yield).
(2) Preparation of methyl 2- (6- ((2',6' -dimethyl-4 '- (2- (5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate
2- (2- ((3'- (hydroxymethyl) -2, 6-dimethyl- [1,1' -biphenyl ] -4-yl) oxy) ethyl) -5-methyl-1, 2, 5-thiadiazolidin 1, 1-dioxide (60mg,0.154mmol) was dissolved in tetrahydrofuran (1mL), methyl 2- (6-hydroxy-2, 3-dihydrobenzofuran-3-yl) acetate (38mg,0.185mmol), tributylphosphine (62mg,0.308mmol) and azobisformyldipiperidine (78mg,0.308mmol) were added, the mixture was stirred at room temperature overnight, excess solvent was removed under reduced pressure, water (5mL) was added, ethyl acetate (10 mL. times.3) was extracted, anhydrous sodium sulfate was dried, filtered, and after concentration, column chromatography (petroleum ether: ethyl acetate =1:1) was separated and purified to give the title compound (62mg, yield 70%).
(3) Preparation of 2- (6- ((2',6' -dimethyl-4 '- (2- (5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetic acid
Methyl 2- (6- ((2',6' -dimethyl-4 '- (2- (5-methyl-1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) - [1,1' -biphenyl ] -3-yl) methoxy) -2, 3-dihydrobenzofuran-3-yl) acetate (60mg,0.1mmol) was dissolved in a mixed solvent of methanol (1mL), tetrahydrofuran (1mL) and water (1mL), and lithium hydroxide monohydrate (13mg,0.3mmol) was added and stirred at room temperature for 3 hours. The excess solvent was removed under reduced pressure, water (5mL) was added, diluted hydrochloric acid was adjusted to pH =3, ethyl acetate (5mL × 3) was extracted, dried over anhydrous sodium sulfate, filtered, and subjected to concentration column chromatography (dichloromethane: methanol =15:1) to isolate and purify the title compound (37mg, yield 65%).
The molecular formula is as follows: c30H34N2O7S molecular weight: 566.7 LC-MS (m/z): 567.3(M +1)
1H-NMR(400MHz,MeOD):7.37-7.42(m,2H),7.12(s,1H),7.02-7.08(m,2H),6.69(s,2H),6.47(m,1H),6.40(d,J=2Hz,1H),5.06(s,2H),4.69(m,1H),4.16-4.23(m,3H),3.71-3.75(m,1H),3.52(m,2H),3.41-3.44(m,2H),3.31-3.33(m,2H),2.68-2.73(m,4H),2.47-2.53(m,1H),1.94(s,6H).

Claims (7)

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
wherein,
R1is methylamino, dimethylamino, cyclobutyl, cyclopentyl or cyclohexyl;
x is-NH-, or R1And X and to which they are attached-S (O)2-forming a ren1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1-dioxo-1, 2, 3-thiadiazolidinyl or 1, 1-dioxo-1, 2, 4-thiadiazolidinyl optionally substituted by a substituent selected from fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl or methoxy;
R2、R3is methyl; r4、R5Is a hydrogen atom.
2. A compound shown in a general formula (I), pharmaceutically acceptable salt thereof or a stereoisomer thereof has a structure shown in a general formula (II):
wherein
R1Is methylamino, dimethylamino, cyclobutyl, cyclopentyl or cyclohexyl;
x is-NH-, or R1And X and to which they are attached-S (O)2-forming a1, 1-dioxo-1, 2, 5-thiadiazolidinyl, 1-dioxo-1, 2, 3-thiadiazolidinyl or 1, 1-dioxo-1, 2, 4-thiadiazolidinyl group optionally substituted by a substituent selected from a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group or a methoxy group;
R2、R3is methyl; r4、R5Is a hydrogen atom.
3. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, characterized in that it comprises one or more pharmaceutically acceptable carriers and/or diluents.
5. The pharmaceutical composition according to claim 4, further comprising one or more other drugs selected from the group consisting of a drug for treating diabetes, a drug for treating diabetic complications, a drug for treating hyperlipidemia, an antihypertensive drug, an antiobesity drug, a diuretic drug, a chemotherapeutic drug, an immunotherapeutic drug, an anti-inflammatory drug, an antithrombotic drug, a therapeutic drug for osteoporosis, a cellulose, an anti-dementia drug, a therapeutic drug for pollakiuria or urinary incontinence, or a therapeutic drug for dysuria.
6. The use of a pharmaceutical composition according to claim 4 for the preparation of a GPR40 receptor agonist for the prophylaxis and/or treatment of diabetes and diabetes-related diseases.
7. Use of a pharmaceutical formulation comprising a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus and conditions associated with diabetes mellitus.
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