CN109456274B - Benzimidazole derivatives, their preparation methods and their use as medicines - Google Patents
Benzimidazole derivatives, their preparation methods and their use as medicines Download PDFInfo
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- CN109456274B CN109456274B CN201811500134.4A CN201811500134A CN109456274B CN 109456274 B CN109456274 B CN 109456274B CN 201811500134 A CN201811500134 A CN 201811500134A CN 109456274 B CN109456274 B CN 109456274B
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- Prior art keywords
- methyl
- imidazol
- benzo
- alkyl
- ppar
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- 229940079593 drug Drugs 0.000 title description 11
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- 125000006413 ring segment Chemical group 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
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Abstract
本发明涉及一类通式(I)所示的新型苯并咪唑类PPARα/γ/δ泛激动剂、其制备方法及含有该衍生物的药物组合物作为制备预防或/和治疗葡萄糖代谢异常或/和脂质代谢异常疾病的药物用途。所述的PPARα/γ/δ泛激动剂具有优异的体内降血糖活性及调节血脂作用，可应用于制备预防或/和治疗糖尿病、肥胖症、高血脂、动脉粥样硬化及脂肪肝等代谢综合症相关疾病的药物，具有广阔的应用前景。 The present invention relates to a class of novel benzimidazole PPARα/γ/δ pan-agonists represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the derivatives as preparations for preventing or/and treating abnormal glucose metabolism or / and pharmaceutical use in disorders of lipid metabolism disorders. The PPARα/γ/δ pan-agonist has excellent hypoglycemic activity and blood lipid regulation in vivo, and can be used in the preparation of metabolic syndromes such as prevention or/and treatment of diabetes, obesity, hyperlipidemia, atherosclerosis and fatty liver. It has broad application prospects.
Description
Technical Field
The invention relates to the field of pharmacology related to glycolipid metabolic diseases, in particular to a novel benzimidazole derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating glycolipid metabolic diseases. The structure of the derivative involved in the invention has uniqueness and novelty in the field.
Background
The metabolic syndrome is a common disease characterized by abnormal glucose and lipid metabolism, which is accompanied by high-density lipoprotein increase and high-density lipoprotein cholesterol reduction, and the common diseases comprise obesity, diabetes, hyperlipidemia, atherosclerosis, fatty liver and the like, wherein the diabetes patients are also frequently complicated with diseases such as hyperlipidemia, cardiovascular diseases, diabetic nephropathy, diabetic neuropathy and the like.
According to the publication of the world health organization, more than 2.2 million people suffer from diabetes in the world at present, wherein China becomes the country with the most diabetes patients in the world, more than 9200 million diabetes patients exist, the current diabetes incidence rate in China is in the rise period, and the current diabetes mellitus early-stage patients in China are estimated to be about 1.5 million. The continuously expanding population of diabetics has brought enormous economic and medical burden to society. The world health organization indicates that heart disease, stroke, and diabetes alone are expected to cause economic losses of at least 5500 billion dollars in China within the next 10 years if no effective measures are taken to address the development of diabetes. Therefore, metabolic syndrome typified by diabetes has become a serious disease threatening human health. Metabolic syndrome can be treated by diet regulation and exercise, and when these fail to relieve symptoms, medication is required. In the aspect of drug treatment of metabolic syndrome, the currently clinically used hypoglycemic drugs or lipid-lowering drugs have single effects and have ideal effects of improving various pathological indexes of metabolic syndrome when the hypoglycemic drugs or lipid-lowering drugs have different effects, so that research on the drugs for improving metabolic syndrome in multiple fields is ongoing, and safer and more effective novel drugs are expected to be brought to patients with metabolic syndrome. Among them, peroxisome proliferator-activated receptor PPAR multiple agonists have become a recent research focus in this field.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor transcription factor superfamily which regulate the expression of target genes, and the PPARs can be divided into three types of alpha, beta (or delta) and gamma according to the difference of subtype structures, wherein the PPARs are mainly distributed in liver and brown fat and are closely related to the regulation of blood fat level and insulin resistance, namely inflammatory response; PPAR gamma is mainly expressed in adipose tissue and immune system, has close relation with adipocyte differentiation, body immunity and insulin resistance, and is a target molecule of action of Thiazolidinediones (TZDs) serving as insulin sensitizers; PPAR δ is mainly distributed in fat, skeletal muscle, heart and liver, and mainly regulates glycolipid metabolism, improves inflammatory response, and the like. Research has now confirmed that: the PPAR multiple agonist can activate and regulate the expression of related genes, plays an important role in adipogenesis and glycolipid metabolism, and can regulate and control various diseases including obesity, diabetes, hyperlipidemia and the like [ Azadeh Matin and the like, J.Med.chem.2009, 52, 6835-6850; shen et al, J.Nutr.2006, 899-905 ]. The PPAR alpha/delta dual agonist GFT505 is also in non-alcoholic fatty liver disease stage III clinical research and shows excellent pharmacological activity (Bertrand Cariou et al, Expert Opin investig. drugs.2014, 23, 1441-one 1448), therefore, screening of the compound with PPAR alpha/gamma/delta pan-agonist activity is very important for preventing or/and treating metabolic disorder diseases.
The invention relates to a PPAR alpha/gamma/delta pan-agonist with novel structure, which has excellent PPAR alpha/gamma/delta pan-agonist activity and in-vivo hypoglycemic and lipid-regulating activity. Therefore, the PPAR alpha/gamma/delta pan-agonist and the medicinal salt thereof can be potentially used for treating or preventing diabetes, hyperlipidemia, fatty liver and other related metabolic syndromes, and have wide development prospect.
Disclosure of Invention
In view of the above problems and unmet clinical needs in the prior art, the present invention aims to provide a PPAR α/γ/δ pan-agonist and its application, and to provide a new potential drug for preventing or/and treating metabolic disorders.
The benzimidazole PPAR alpha/gamma/delta pan-agonist provided by the invention contains an effective amount of a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1and R2Each independently selected from hydrogen, alkyl, wherein said alkyl is optionallyFurther substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl;
R3and R4Each independently selected from hydrogen, alkyl, alkoxy, halogen, cycloalkyl;
R5selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, wherein said alkyl, alkoxy, cycloalkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
more preferred compounds of formula (I) or a pharmaceutically acceptable salt thereof:
R1and R2Each independently selected from hydrogen, alkyl, wherein said alkyl is optionally further substituted with one or more groups selected from hydroxy, alkyl, alkoxy, cycloalkyl;
R3and R4Each independently selected from hydrogen, alkyl, halogen;
R5selected from the group consisting of hydrogen, alkyl, alkoxy, wherein said alkyl, alkoxy is optionally further substituted with one or more groups selected from the group consisting of hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
more preferred compounds of the invention include, but are not limited to:
2-methyl-2- (2-methyl-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid (I-1);
2-methyl-2- (2-methyl-4- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid (I-2);
2- (2-fluoro-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) -2-methylpropanoic acid (I-3);
2- (2-chloro-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) -2-methylpropanoic acid (I-4);
2- (4- (6-chloro-1H-benzo [ d ] imidazol-2-yl) -2-methylphenoxy) -2-methylpropanoic acid (I-5);
2- (4- (6-chloro-1H-benzo [ d ] imidazol-2-yl) -2-methylphenoxy) acetic acid (I-6);
sodium 2-methyl-2- (2-methyl-4- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) phenoxy) propionate (I-7).
The invention relates to the use of compounds or pharmaceutically acceptable salts thereof as PPAR alpha/gamma/delta pan-agonists.
Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective dose of said compound or a pharmaceutically acceptable salt thereof and a suitable carrier, diluent or excipient.
The invention also relates to application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for preventing or/and treating glucose metabolism disorder or/and lipid metabolism disorder diseases and application in preparing a medicament for preventing or/and treating at least one disease of metabolic syndrome related diseases such as diabetes, obesity, hyperlipidemia, atherosclerosis, fatty liver and the like.
Detailed description of the invention
Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, even more preferably an alkyl group having 1 to 3 carbon atoms, and most preferably a methyl group. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like, as well as various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered. Heteroaryl is preferably 5-or 6-membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in admixture with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the absorption of the active ingredients by organisms and to facilitate the active ingredients to exert biological activity in organisms.
The compound of the general formula (I) can be synthesized by the following steps:
the compound represented by the general formula (II) and the compound represented by the general formula (III) undergo a dehydration condensation reaction to give a compound represented by the general formula (IV), which is subjected to a hydrolysis reaction in the presence of a base to give a compound represented by the general formula (I).
Wherein: r1～R5The definition of (A) is described in the general formula (I).
As the base, inorganic bases and organic bases are included, and as the inorganic bases, there can be mentioned, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as potassium bicarbonate and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; as the organic base, there may be mentioned, for example, triethylamine, pyridine, lutidine, n-butyllithium, potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like.
The PPAR agonistic activity and the in vivo hypoglycemic lipid-modulating activity of the compounds of the present invention can be measured by using an assay system as described below.
The following description of the biological test example illustrates the present invention.
The experimental procedures for the specific conditions in the test examples of the present invention are generally carried out under conventional conditions or under conditions recommended by commercial manufacturers. Reagents with no specific source are indicated, and are commonly purchased in the market.
Test example 1 agonistic activity of the compound of the present invention on PPAR
The present invention uses the following method to determine the PPAR agonist activity of the compounds of the invention:
transfection: HEK293 cells at 5X 10 before transfection4The density of each well was inoculated into a 96-well plate and placed at 37 ℃ in 5% CO2One day (for PPAR γ and PPAR δ transfections); HepG2 cells at 6X 104The density of each well was inoculated into a 96-well plate and placed at 37 ℃ in 5% CO2One day (for PPAR α transfection); transfection was performed with FuGENE HD transfection reagent (purchased from Roche) separately: 25ng/well pBIND-PPAR α or PPAR δ or PPAR γ, 25ng/well pG5Luc, and 0.15 μ l/well FuGENE HD.
Agonist activity assay: after 24h transfection, the test compound was added to the transfected cell well plate, incubated for 18h, lysed by adding 20. mu.l of cell lysate and 30. mu.l of luciferase assay reagent II (purchased from Promega), mixed well, assayed for fluorescence, delayed for 2 seconds, and read for 10 seconds. Transfection efficiency was corrected using the internal reference Renilla luciferase activity. All transfection experiments were repeated at least three times independently, at least 2 replicates per experimental group. Relative fluorescence intensity ═ firefly fluorescence intensity/nephrotic fluorescence intensity. PPAR agonistic activity (%) [ (X-Min)/(Max-Min) ] × 100%, where X represents the relative fluorescence intensity of the compound group, Min represents the relative fluorescence intensity of the blank control group, and Max represents the relative fluorescence intensity of the positive control compound group at a concentration of 10 μ M. The agonist activities of the example compounds PPAR α, PPAR δ and PPAR γ (all at 10 μ M concentration) are shown in table 1.
Table 1: PPAR alpha, PPAR delta and PPAR gamma agonistic activities
And (4) conclusion: all the compounds of the invention have obvious agonistic activity on PPAR alpha, PPAR delta and PPAR gamma, wherein I-1, I-2 and I-5 have excellent agonistic activity.
Test example 2 the in vivo hypoglycemic lipid-regulating activity of the compounds of the present invention can be determined by using an assay system as described below:
8 weeks old ob/ob mice, male, were randomly divided into 5 groups, each group had 6 mice, a blank control group (blank vehicle: 0.5% sodium carboxymethylcellulose solution), a test compound group (10mg/kg) were gavaged twice daily with blank vehicle and test compound, administered for 15 days continuously, on day 15 of administration, oral glucose tolerance (OGTT) was determined, mice were fasted without water for 12 hours before the experiment, tail-broken blood was taken, and blood glucose values were determined (recorded as-30 min). Then, the blank solvent, the positive drug and the test compound are respectively administered by intragastric administration, the blood sugar value is measured and recorded as 0min after 30min of administration, 3g/kg of glucose aqueous solution is immediately administered by intragastric administration, and the blood sugar value is measured at 15 min, 30min, 60 min and 120 min. The OGTT results are shown in Table 2. On day 16, blood and plasma were collected from the mice, and the blood lipid levels of the mice were measured by a full-automatic biochemical analyzer, the results of which are shown in table 3.
Table 2: effect of preferred Compounds on oral glucose tolerance in ob/ob mice
Note: p ≦ 0.05 and P ≦ 0.01 for Student's t test results relative to the blank control.
The oral glucose tolerance test of ob/ob mice after long-term administration shows that: the compounds I-1, I-2 and I-5 and the medicinal sodium salt I-7 can obviously improve the oral glucose tolerance of ob/ob mice and show better hypoglycemic effect.
Table 3: effect of preferred Compounds on the blood lipid levels of ob/ob mice
Note: p ≦ 0.05 for Student's t test results relative to the blank control.
The results of the influence of the blood lipid level after long-term administration of ob/ob mice show that: the compounds I-1, I-2 and I-5 and the medicinal sodium salt I-7 can obviously improve the high blood lipid level of ob/ob mice and have the function of improving lipid metabolism.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of those skilled in the art in light of the teachings of this invention are intended to be within the scope of the claims appended hereto.
Example 1
2-methyl-2- (2-methyl-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid (I-1)
First step of
2- (4-formyl-2-methylphenoxy) -2-methylpropanoic acid methyl ester (2a)
3-methyl-4-hydroxybenzaldehyde 1a (1.0g, 7.35mmol) and methyl 2-bromoisobutyrate (4.0g, 22.1mmol) were dissolved in acetonitrile (20mL), potassium carbonate (3.0g, 22.1mmol) was added, reaction was carried out at 50 ℃ for 12h, after completion of the TLC detection reaction, the solid mixture in the reaction was dissolved by water, extracted with ethyl acetate (30 mL. times.4), and the combined organic phases were washed with water (20 mL. times.1), 1N HCl (20 mL. times.1), saturated NaCl solution (20 mL. times.2), dried, and concentrated, and the resulting product was used in the next reaction without purification.
Second step of
2-methyl-2- (2-methyl-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid methyl ester (3a)
2a (0.5g, 2.12mmol) and 3, 4-diaminotoluene (0.29g, 2.12mmol) were dissolved in DMF (15mL) containing 10% water, heated to 80 ℃ to complete the TLC reaction, cooled, diluted with 100mL of water, extracted with ethyl acetate (40 mL. times.3), the combined organic phases were washed successively with water (20 mL. times.1), saturated NaCl solution (20 mL. times.2), dried, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 85: 15, v/v) to give 0.56g of a white solid in 78% yield.
The third step
2-methyl-2- (2-methyl-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid (I-1)
Dissolve 3a (0.56g, 1.66mmol) in THF/CH3OH/H2And adding LiOH (0.05g) into the mixed solvent of O, reacting at normal temperature for 2 hours after the addition is finished, evaporating the solvent under reduced pressure, adding 1N HCl for acidification, separating out a solid, performing suction filtration to obtain a white solid, and recrystallizing with 80% ethanol to obtain 0.35g of the white solid with the yield of 62%.
1H NMR(300MHz，D2O)δ：10.53-10.29(m，2H)，9.87(d，J＝8.4Hz，1H)，9.77(s，1H)，9.56-9.47(m，1H)，9.10(d，J＝8.7Hz，1H)，5.38(s，1H)，4.70(s，3H)，4.49(s，3H)，3.85(s，6H).13C NMR(75MHz，DMSO-d6)δ：174.89，158.54，151.73，135.12，132.69，131.45，129.69，128.05，126.43，125.65，122.25，115.73，115.38，114.69，79.65，25.63，21.35，16.76.ESI-MS m/z：323.1[M-H]-.Anal.calcd.For C19H20N2O3：C，70.35；H，6.21；N，8.64；Found：C，70.46；H，6.33；N，8.72.
Example 2
2-methyl-2- (2-methyl-4- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid (I-2)
Referring to the production method of I-1, 1.5g of a white solid was obtained in a yield of 43%.
1H NMR(300MHz，D2O)δ：10.67-10.44(m，2H)，10.26(s，1H)，10.17(d，J＝8.5Hz，1H)，10.00(d，J＝8.5Hz，1H)，9.09(d，J＝8.7Hz，1H)，5.37(s，1H)，4.47(s，3H)，3.84(s，6H).13C NMR(75MHz，DMSO-d6)δ：174.87，158.57，151.79，135.46，132.90，131.31，129.53，128.01，126.47，126.05，125.62，122.27，115.79，115.35，111.67，79.69，25.60，16.82.ESI-MS m/z：377.1[M-H]-.Anal.calcd.For C19H17F3N2O3：C，60.32；H，4.53；N，7.40；Found：C，60.15；H，4.38；N，7.52.
Example 3
2- (2-fluoro-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) -2-methylpropanoic acid (I-3)
Referring to the production method of I-1, 0.29g of a white solid was obtained in a yield of 49%.
1H NMR(300MHz，D2O)δ：10.74-10.57(m，1H)，10.44(d，J＝8.7Hz，1H)，9.89(d，J＝8.4Hz，1H)，9.80(s，1H)，9.56(d，J＝8.4Hz，1H)，9.38(t，J＝8.6Hz，1H)，5.37(s，1H)，4.69(s，3H)，3.85(s，6H).13C NMR(75MHz，DMSO-d6)δ：174.23，147.62，147.38，136.27，132.54，130.41，127.75，125.41，119.85，116.52，113.90，113.69，81.16，25.43，21.64.ESI-MS m/z：327.1[M-H]-.Anal.calcd.For C18H17FN2O3：C，65.85；H，5.22；N，8.53；Found：C，65.67；H，5.35；N，8.58.
Example 4
2- (2-chloro-4- (6-methyl-1H-benzo [ d ] imidazol-2-yl) phenoxy) -2-methylpropanoic acid (I-4)
Referring to the production method of I-1, 0.56g of a white solid was obtained in a yield of 38%.
1H NMR(300MHz，DMSO-d6)δ：8.59(d，J＝2.1Hz，1H)，8.35(dd，J＝8.8，2.1Hz，1H)，7.64(d，J＝8.3Hz，1H)，7.54(s，1H)，7.28(d，J＝8.4Hz，1H)，7.08(d，J＝8.8Hz，1H)，2.45(s，3H)，1.65(s，6H).13C NMR(75MHz，DMSO-d6)δ：174.32，154.83，147.57，135.63，133.42，131.43，130.15，128.18，127.22，124.78，118.42，117.95，114.07，113.80，81.08，25.50，21.65.ESI-MS m/z：343.1[M-H]-.Anal.calcd.For C18H17ClN2O3：C，62.70；H，4.97；N，8.12；Found：C，62.56；H，4.85；N，8.23.
Example 5
2- (4- (6-chloro-1H-benzo [ d ] imidazol-2-yl) -2-methylphenoxy) -2-methylpropanoic acid (I-5)
Referring to the production method of I-1, 0.96g of a white solid was obtained in a yield of 46%.
1H NMR(300MHz，DMSO-d6)δ：8.26(d，J＝1.6Hz，1H)，8.19(dd，J＝8.7，2.1Hz，1H)，7.80-7.70(m，2H)，7.46，7.43(dd，J＝8.7，1.9Hz，1H)，6.86(d，J＝8.7Hz，1H)，2.26(s，3H)，1.62(s，6H).13C NMR(75MHz，DMSO-d6)δ：174.98，157.94，150.87，134.98，132.87，130.89，129.43，129.33，127.39，125.38，117.00，115.76，115.60，114.05，79.57，25.62，16.87.ESI-MS m/z：343.1[M-H]-.Anal.calcd.For C18H17ClN2O3：C，62.70；H，4.97；N，8.12；Found：C，62.79；H，4.89；N，8.07.
Example 6
2- (4- (6-chloro-1H-benzo [ d ] imidazol-2-yl) -2-methylphenoxy) acetic acid (I-6)
Referring to the production method of I-1, 0.37g of a white solid was obtained in a yield of 54%.
1H NMR(300MHz，DMSO-d6)δ：8.27(d，J＝1.8Hz，1H)，8.21(dd，J＝8.6，2.2Hz，1H)，7.82-7.74(m，2H)，7.45，7.42(dd，J＝8.8，1.8Hz，1H)，6.88(d，J＝8.8Hz，1H)，4.60(s，2H)，2.25(s，3H).13C NMR(75MHz，DMSO-d6)δ：174.87，157.96，150.85，134.96，132.85，130.87，129.46，129.37，127.35，125.39，117.03，115.78，115.62，114.03，65.77，16.81.ESI-MS m/z：315.1[M-H]-.Anal.calcd.For C16H13ClN2O3：C，60.67；H，4.14；N，8.84；Found：C，60.48；H，4.07；N，8.68.
Example 7
2-methyl-2- (2-methyl-4- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) phenoxy) propanoic acid sodium salt (I-7)
Compound I-2(0.6g) was added to a saturated aqueous sodium carbonate solution (8mL) in portions, stirred at room temperature for 24h, filtered, the filter cake was washed with a small amount of water, and the filter cake was dried to give 0.58g of a white solid.
Example 8
Tablets containing active agent I-2:
sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.
The composition also has excellent activity of reducing blood sugar and regulating lipid in vivo.
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