CN115504925B - PPAR agonist, preparation method thereof and application thereof as medicine - Google Patents
PPAR agonist, preparation method thereof and application thereof as medicine Download PDFInfo
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- CN115504925B CN115504925B CN202110694689.2A CN202110694689A CN115504925B CN 115504925 B CN115504925 B CN 115504925B CN 202110694689 A CN202110694689 A CN 202110694689A CN 115504925 B CN115504925 B CN 115504925B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention relates to a novel PPAR agonist, a preparation method thereof and a pharmaceutical composition containing the derivative as well as application of the novel PPAR agonist in preparing medicines for preventing or/and treating abnormal glucose metabolism or/and abnormal lipid metabolism.
Description
Technical Field
The invention relates to the field of pharmacology related to glycolipid metabolic diseases, in particular to a novel PPAR agonist, a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of medicines for treating the glycolipid metabolic diseases. The derivative structures referred to in the present invention are unique and novel in this field.
Background
Metabolic syndrome is a common disease characterized by abnormal glucose and lipid metabolism, accompanied by elevated low density lipoprotein and lowered high density lipoprotein cholesterol, and common diseases are obesity, diabetes, hyperlipidemia, atherosclerosis, fatty liver and the like, wherein diabetes patients are also frequently complicated with diseases such as hyperlipidemia, cardiovascular diseases, diabetic nephropathy, diabetic neuropathy and the like.
According to the world health organization publications, more than 2.2 hundred million people suffer from diabetes mellitus worldwide at present, wherein China becomes the most world of diabetes mellitus patients, more than 9200 ten thousand diabetes mellitus patients, and the current diabetes mellitus incidence rate of China is still in the rising period, and the current diabetes mellitus pre-patients in China are estimated to be about 1.5 hundred million. The continuously expanding diabetic population has brought great economic and medical burden to society. The world health organization indicates that if no effective measures are taken to cope with the development of diabetes, it is expected that in the next 10 years, only heart disease, stroke and diabetes will bring about economic losses of at least 5500 billion dollars to China. Thus, metabolic syndrome typified by diabetes has become a serious disease threatening the health of humans. Metabolic syndrome can be treated by dietary regulation and exercise, and when these fail to relieve symptoms, medication is required. In the aspect of the drug treatment of metabolic syndrome, the existing blood sugar-reducing drugs or lipid-lowering drugs used clinically have single action and have different ideal actions for improving various pathological indexes of metabolic syndrome, so that the research on drugs for improving metabolic syndrome in multiple fields is ongoing so as to bring safer and more effective novel drugs for metabolic syndrome patients. Among them, peroxisome proliferator-activated receptor PPAR multiple agonists have become a recent research focus in this field.
Peroxisome proliferator-activated receptors (peroxisome proliferator-activated receptor, PPARs) are members of the nuclear receptor transcription factor superfamily that regulate target gene expression, and PPARs can be classified into three types, α, β (or δ) and γ, depending on subtype structures, wherein pparα is mainly distributed in the liver and brown fat, and is closely related to regulation of blood lipid levels, insulin resistance, i.e., inflammatory response; PPARgamma is mainly expressed in adipose tissues and immune systems, has close relation with adipocyte differentiation, organism immunity and insulin resistance, and is a target molecule for the action of an insulin sensitizer Thiazolidinedione (TZDs); pparδ is mainly distributed in fat, skeletal muscle, heart and liver, and mainly regulates glycolipid metabolism, improves inflammatory response, and the like. The research has now confirmed that: PPAR multiple agonists are capable of activating and regulating the expression of related genes, playing an important role in adipogenesis, glycolipid metabolism, and regulating a variety of diseases including obesity, fatty liver, diabetes, hyperlipidemia, etc., [ Azadeh matrix, etc., j.med.chem.2009, 52, 6835-6850; shen et al, J.Nutr.2006, 899-905]. PPARα/δ dual agonist GFT505 are also in clinical studies of non-alcoholic fatty liver stage III, showing superior pharmacological activity (Bertrand Cariou et al, expert opin. In addition, PPAR alpha/gamma/delta pan-agonist index glitazar has obvious curative effect on diabetes and fatty liver animal models, but has shorter in vivo half-life of index glitazar, T in rats 1/2 Only 1.4h, greatly limiting the clinical application of this compound (Dean r. Artis et al, PNAS,2009, 106, 262-267). Therefore, screening for PPAR agonists that are more metabolically stable against metabolic defects in index azar is important for the prevention and/or treatment of metabolic disorders.
The invention relates to a PPAR (PPAR) agonist with a novel structure, which has excellent PPAR alpha/gamma/delta pan-agonistic activity and in-vivo hypoglycemic lipid-regulating activity, and has better metabolic stability than index glitazar. Therefore, the PPAR agonist and the pharmaceutically acceptable salt thereof can be potentially used for treating or preventing related metabolic syndromes such as diabetes, hyperlipidemia, fatty liver and the like, and have wide drug development prospect.
Disclosure of Invention
Aiming at the problems and unmet clinical needs in the prior art, the invention aims to provide a PPAR agonist with more stable metabolism and application thereof, and provides a new potential medicine for preventing or/and treating metabolic abnormality diseases.
The PPAR agonist disclosed by the invention contains an effective amount of a compound shown in the following formula or pharmaceutically acceptable salt or prodrug thereof, wherein the salt comprises pharmaceutically acceptable sodium salt, potassium salt, organic alkali salt and the like; prodrugs include pharmaceutically acceptable carboxylic acid esters, amides, and the like:
another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound, or a pharmaceutically acceptable salt or prodrug thereof, in combination with a suitable carrier, diluent or excipient.
The invention relates to the use of a compound or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutical composition in the preparation of a medicament for treating peroxisome proliferator-activated receptor-mediated diseases.
The invention also relates to application of the compound or pharmaceutically acceptable salt or prodrug thereof and a pharmaceutical composition thereof in preparing medicines for preventing or/and treating abnormal glucose metabolism or/and abnormal lipid metabolism diseases, and application in preparing medicines for preventing or/and treating at least one disease of diabetes, obesity, hyperlipidemia, inflammatory bowel disease, alzheimer disease, cholestatic liver disease, mitochondrial disease, liver graft versus host disease, chronic liver disease caused by viruses, alcoholic liver disease, pharmaceutical liver injury, diabetic complications, prediabetes, organ fibrosis, atherosclerosis and fatty liver.
Detailed Description
The invention is further illustrated below with reference to examples. It should be noted that the following examples are given by way of illustration only and are not intended to limit the present invention. Variations that occur to those skilled in the art in light of the teachings of the present invention are intended to be within the scope of the claims of the present application.
Example 1
3- (5-methoxy-1- (((4-methoxyphenyl) sulfonyl) -1H-indol-3-yl) -2,2-d 2-propionic acid (I-1)
Dissolving 5-methoxyindole-3-carbaldehyde (0.5 g,2.85 mmol) in 10ml anhydrous tetrahydrofuran at 0deg.C, cooling to about-5deg.C in ice bath, adding sodium hydride (0.075 g,3.14 mmol) in portions, controlling internal temperature below 0deg.C, stirring for 0.5 hr in ice bath, adding dropwise 10ml anhydrous tetrahydrofuran diluted p-methoxybenzenesulfonyl chloride (0.71 mg,3.42 mmol) in ice bath, keeping internal temperature below 0deg.C during the dropwise adding process, heating the obtained solution to room temperature for 4 hr, adding dropwise 10ml water for quenching reaction after TLC detection reaction, and collecting the final productEthyl acetate (20 ml. Times.3) was extracted, and the organic phases were combined, washed with 1N hydrochloric acid (15 ml. Times.2), saturated aqueous sodium bicarbonate (15 ml. Times.2), saturated brine (15 ml. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and purified by column chromatography (petroleum ether/ethyl acetate, 2:1, v/v) to give 0.88g of a white solid in 89.28% yield. The above product (0.5 g,1.45 mmol) was taken, isopropyl malonate (0.27 g,1.88 mmol) was dissolved in 10ml of tetrahydrofuran, a catalytic amount of DMAP was added, stirred at room temperature for 12h, after completion of tlc detection, the reaction solution was poured into 10ml of water, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with saturated brine (15 ml×2), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and 0.35g of yellow solid was obtained by recrystallization (absolute ethanol) in yield 51.28%, ESI-MS m/z:472.1[ M+H ]] + . The above product (0.35 g,0.74 mmol) was dissolved in 5ml of methanol, sodium borohydride (0.056 g,1.48 mmol) was added in portions, reacted at room temperature for 0.5h, after completion of TLC detection, 1ml of water was added dropwise to quench the reaction, 1N hydrochloric acid was added to acidify (pH: 5-6), extraction was performed with ethyl acetate (20 ml. Times.3), the organic phases were combined, each was washed with 1N hydrochloric acid (15 ml. Times.2), saturated sodium bicarbonate aqueous solution (15 ml. Times.2), saturated brine (15 ml. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 0.35g of a white solid, yield 99.57%, ESI-MS m/z:474.1[ M+H ]] + 。
Raw material 4 (0.35 g,0.74 mmol) was dissolved in 4.5mL DMF and D was added 2 O (0.5 ml), after stirring uniformly, heating to 100 ℃ for reaction 12h, after TLC detection reaction is completed, cooling to room temperature, pouring the reaction solution into 50ml of water, extracting with ethyl acetate (20 ml multiplied by 3), combining organic phases, washing with 1N hydrochloric acid (15 ml multiplied by 2) respectively, washing with saturated sodium bicarbonate aqueous solution (15 ml multiplied by 2), washing with saturated saline (15 ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, and evaporating the solvent from the filtrate under reduced pressure to obtain 0.30g of white liquid which is directly used for the next reaction. Dissolving the above product (0.3 g,0.74 mmol) in 5mL of methanol, slowly adding concentrated sulfuric acid (0.5 mL) dropwise, stirring, heating to 70deg.C for 3h, cooling to room temperature after TLC detection, evaporating solvent under reduced pressure, adding 10mL of water, extracting with ethyl acetate (20 ml×3), and mixing organic phasesThe mixture was washed with saturated aqueous sodium hydrogencarbonate (15 ml. Times.2), saturated brine (15 ml. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, followed by column chromatography (petroleum ether/ethyl acetate, 80:20, v/v) to give 0.18g of a white liquid. Dissolving the above product in 3mL tetrahydrofuran, 3mL methanol and 1mL water, adding LiOH H 2 O (0.1 g,2.4 mmol), for 4h at room temperature, evaporating tetrahydrofuran and methanol under reduced pressure, dropwise adding 1N diluted hydrochloric acid under ice water bath to adjust pH to 2-3, precipitating white solid, filtering, and drying to obtain white powdery solid 0.17g with yield of 97.83%.
1 H NMR(300MHz,DMSO-d 6 )δ7.87-7.77(m,3H),7.51(s,1H),7.10(d,J=2.5Hz,1H),7.05(d,J=8.9Hz,2H),6.95(dd,J=8.9,2.5Hz,1H),3.79(s,3H),3.77(s,3H),2.84(s,2H). 13 C NMR(75MHz,DMSO-d 6 )δ175.01,163.92,156.49,132.22,129.49,129.37,128.80,124.45,123.18,115.23,114.63,113.99,102.70,56.20,55.88,20.46.ESI-MS m/z:390.1[M-H] - .
Example 2
3- (1- (benzofuran-5-ylsulfonyl) -5-methoxy-1H-indol-3-yl) -2,2-d 2-propionic acid (I-2)
Referring to the preparation method of I-1, 0.25g of a white solid was obtained in 45% yield.
1 H NMR(300MHz,DMSO-d 6 )δ7.79(d,J=9.0Hz,1H),7.76(d,J=2.2Hz,1H),7.69(dd,J=8.5,2.2Hz,1H),7.49(s,1H),7.11(d,J=2.5Hz,1H),6.95(dd,J=9.0,2.5Hz,1H),6.88(d,J=8.5Hz,1H),4.60(t,J=8.8Hz,2H),3.79(s,3H),3.19(t,J=8.8Hz,2H),2.85(s,2H). 13 C NMR(75MHz,DMSO-d 6 )δ174.36,164.89,156.43,132.01,130.07,129.42,128.90,128.77,124.52,124.45,122.39,114.59,114.04,109.87,102.68,73.05,55.92,28.69,20.09.ESI-MS m/z:402.1[M-H] - .
Example 3
3- (5-methoxy-1- (((4- (trifluoromethoxy) phenyl) sulfonyl) -1H-indol-3-yl) -2,2-d 2-propionic acid (I-3)
Referring to the preparation method of I-1, 0.25g of a white solid was obtained in 43% yield.
1 H NMR(500MHz,DMSO-d 6 )δ8.05(d,J=8.9Hz,2H),7.81(d,J=9.0Hz,1H),7.59-7.53(m,3H),7.13(d,J=2.6Hz,1H),6.97(dd,J=9.0,2.6Hz,1H),3.79(s,3H),2.86(s,2H). 13 C NMR(126MHz,DMSO-d 6 )δ174.32,156.77,152.44,136.03,132.24,129.80,129.36,124.44,123.52,122.09,120.14(q,J=258.9Hz),114.61,114.33,102.99,55.92,20.09.ESI-MS m/z:444.1[M-H] - .
Example 4
3- (5-cyclopropyl-1- (((4-methoxyphenyl) sulfonyl) -1H-indol-3-yl) -2,2-d 2-propionic acid (I-4)
Referring to the preparation method of I-1, 0.51g of a white solid was obtained in 36% yield.
1 H NMR(500MHz,DMSO-d 6 )δ7.51(d,J=7.8Hz,1H),7.34(d,J=8.2Hz,1H),7.21(d,J=8.5Hz,2H),7.13-7.03(m,2H),7.02-6.93(m,1H),6.79(dd,J=8.2,1.8Hz,1H),3.46(s,3H),2.88(s,2H),1.97(tt,J=8.4,5.1Hz,1H),0.93-0.84(m,2H),0.71-0.58(m,2H). 13 C NMR(126MHz,DMSO-d 6 )δ174.78,136.67,135.23,133.32,127.49,127.38,122.83,122.67,121.34,119.76,115.19,113.33,111.59,59.68,20.65,15.82,9.20.ESI-MS m/z:400.1[M-H] - .
Example 5
3- (1- (((4-cyclopropylphenyl) sulfonyl) -5-methoxy-1H-indol-3-yl) -2,2-d 2-propanoic acid (I-5)
Referring to the preparation of I-1, 0.26g of a white solid was obtained in 35% yield.
1 H NMR(300MHz,DMSO-d 6 )δ7.78(d,J=9.0Hz,1H),7.73(d,J=8.5Hz,2H),7.48(s,1H),7.18(d,J=8.5Hz,2H),7.07(d,J=2.5Hz,1H),6.93(dd,J=9.0,2.5Hz,1H),3.77(s,3H),2.81(s,2H),1.90(tt,J=8.3,5.0Hz,1H),1.05-0.90(m,2H),0.75-0.60(m,2H). 13 C NMR(75MHz,DMSO-d 6 )δ175.78,156.49,151.99,134.00,132.40,129.48,127.04,126.58,124.25,124.01,114.59,113.94,102.73,55.86,21.04,15.66,11.34.ESI-MS m/z:400.1[M-H] - .
Example 6
3- (5- (methoxy-d 3) -1- ((4-methoxyphenyl) sulfonyl) -1H-indol-3-yl) propionic acid (I-6)
Referring to the preparation of I-1, 0.17g of a white solid was obtained in 24% yield.
1 H NMR(300MHz,DMSO-d 6 )δ7.89-7.78(m,3H),7.52(s,1H),7.13(d,J=2.5Hz,1H),7.07(d,J=8.8Hz,2H),6.96(dd,J=8.8,2.5Hz,1H),3.79(s,3H),2.96(t,J=7.6Hz,2H),2.74(t,J=7.6Hz,2H).ESI-MS m/z:391.1[M-H] - .
Example 7
3- (5-methoxy-1- ((4- (methoxy-d 3) phenyl) sulfonyl) -1H-indol-3-yl) propionic acid (I-7)
Referring to the preparation of I-1, 0.25g of a white solid was obtained in 29% yield.
1 H NMR(300MHz,DMSO-d 6 )δ7.87-7.75(m,3H),7.50(s,1H),7.15(d,J=2.5Hz,1H),7.08(d,J=8.8Hz,2H),6.95(dd,J=8.8,2.5Hz,1H),3.77(s,3H),2.95(t,J=7.6Hz,2H),2.74(t,J=7.6Hz,2H).ESI-MS m/z:391.1[M-H] - .
EXAMPLE 8 determination of agonist activity of the Compounds of the invention on PPAR
The following biological test examples illustrate the invention.
The experimental methods for the specific conditions in the test cases of the present invention are generally conventional or according to the conditions recommended by the commercial manufacturers. The reagents of specific origin are not noted and are commonly used reagents purchased in the market.
The invention uses the following methods to determine the PPAR agonistic activity of the compounds of the invention:
transfection: HEK293 cells were grown at 5X 10 prior to transfection 4 Density of wells/density of wells was seeded in 96-well plates at 37℃in 5% CO 2 One day (for pparγ and pparδ transfection) in cell culture; hepG2 cells at 6X 10 4 Density of wells/density of wells was seeded in 96-well plates at 37℃in 5% CO 2 One day (for pparα transfection); transfection was performed with FuGENE HD transfection reagent (available from Roche), respectively: 25ng/well pBIND-PPARα or PPARδ or PPARγ,25ng/well pG5Luc, and 0.15 μl/well FuGENE HD.
Agonist activity assay: after 24h of transfection, the test compound was added to the post-transfection cell well plate, incubated for 18h, lysed by addition of 20. Mu.l of cell lysate and 30. Mu.l of luciferase assay reagent II (from Promega), mixed well, fluorescence measured, 2 seconds delay, read for 10 seconds. Transfection efficiency was corrected using the reference Renilla luciferase activity. All transfection experiments were independently repeated at least three times, at least 2 duplicate wells per experimental group. Relative fluorescence intensity = firefly fluorescence intensity/renilla fluorescence intensity. PPAR agonistic activity (%) = [ (X-Min)/(Max-Min)]X100%, wherein X represents the relative fluorescence intensity of the compound group, min TableThe relative fluorescence intensity of the blank control group is shown, and Max represents the relative fluorescence intensity of the positive control compound group at a concentration of 10. Mu.M. Examples Compounds PPARα, PPARδ and PPARδ agonistic Activity EC 50 The values are shown in Table 1.
Table 1: PPARα, PPARδ and PPARγ agonistic activity
Conclusion: all the compounds of the invention have obvious agonistic activity on PPARα, PPARδ and PPARγ, and are PPAR multiple agonists.
EXAMPLE 9 determination of the metabolic stability of Compounds of the invention
Rat liver microsomes (0.25 mg/mL) were incubated with test compound (500 ng/mL) in 0.1M PBS buffer (pH 7.4) for 5 min at 37 ℃, then NADPH was added according to the metabolic stability kit instructions to catalyze the biological reaction, after incubation for different times (0, 15, 30 and 60 min) at 37 ℃, the reaction was stopped using an equal volume of glacial methanol with internal standard, then the supernatant drug concentration was detected by LC/MS and the half-life of the drug in rat liver microsomes was calculated, the experimental results are given in table 2.
TABLE 2 liver microsomal half-life of the compounds of the invention
Conclusion: the stability of the compounds I-1 to I-5 of the invention on liver microsomes is obviously better than that of the index glitazar, which shows that the metabolic stability of the compounds of the invention (deuteration is carried out on alpha-carboxylic acid) is greatly improved; while deuteration (I-6 and I-7) is carried out on the rest potential metabolic sites of the index azar, the stability of liver microsomes is hardly improved (even metabolism is promoted), which shows that not all deuterated compounds can improve the metabolic stability, namely, the compound of the invention has unexpected technical effects and is novel and creative.
EXAMPLE 10 in vivo hypoglycemic lipid-regulating Activity assay of the Compounds of the invention
8 week old ob/ob mice, males, randomized groups, 6 in each group, blank control group (blank vehicle: 0.5% sodium carboxymethylcellulose solution), test compound group (20 mg/kg) were administered by intragastric administration of blank vehicle and test compound, respectively, once daily for 15 days, oral glucose tolerance (OGTT) was measured on day 15, mice were fasted for 12 hours without water withdrawal, tail blood was taken, and blood glucose level was measured (recorded as-30 min) before the experiment. Then, the blank vehicle, the positive drug and the test compound were administered by gavage, respectively, and the blood glucose value was measured for 0min after 30min, immediately after which 3g/kg of glucose aqueous solution was administered by gavage, and the blood glucose value was measured at 15, 30, 60 min. OGTT results are shown in Table 3. And on day 16, the mice were sampled and plasma was taken, and the blood lipid levels of the mice were measured by a full-automatic biochemical analyzer, and the results are shown in table 4.
Table 3: influence of the compound of the invention on oral glucose tolerance of ob/ob micen=6)
Note that: * P.ltoreq.0.05 and p.ltoreq.0.01 are results of Student's t test against the blank.
The oral glucose tolerance test after long-term administration of ob/ob mice shows that: the compounds I-1, I-3 and I-5 can obviously improve the oral glucose tolerance of ob/ob mice, and show better blood sugar reducing effect.
Table 4: influence of the compound of the invention on ob/ob mouse blood lipid leveln=6)
Note that: * p.ltoreq.0.05 is the result of Student's t test against the blank.
The results show that: the compounds I-1, I-3 and I-5 can obviously improve the hyperlipidemia level of ob/ob mice and have the effect of improving lipid metabolism.
Example 11
Tablets containing active agent I-1:
sieving active ingredient, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the granule, and tabletting. The composition is proved to have excellent in-vivo hypoglycemic and lipid-regulating activity.
Claims (5)
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2. a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a suitable carrier or excipient.
3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment of peroxisome proliferator-activated receptor-mediated disorders.
4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention or/and treatment of abnormal glucose metabolism or/and abnormal lipid metabolism.
5. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention or/and treatment of at least one of diabetes, obesity, hyperlipidemia, inflammatory bowel disease, alzheimer's disease, cholestatic liver disease, mitochondrial disease, liver graft versus host disease, viral-induced chronic liver disease, alcoholic liver disease, pharmaceutical liver injury, diabetic complications, pre-diabetes, organ fibrosis, atherosclerosis and fatty liver.
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