CN116003403A - Deuterated indazole compound, pharmaceutical composition and application thereof - Google Patents
Deuterated indazole compound, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN116003403A CN116003403A CN202211451463.0A CN202211451463A CN116003403A CN 116003403 A CN116003403 A CN 116003403A CN 202211451463 A CN202211451463 A CN 202211451463A CN 116003403 A CN116003403 A CN 116003403A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- disease
- diabetes mellitus
- metabolite
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- -1 Deuterated indazole compound Chemical class 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
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- 239000002207 metabolite Substances 0.000 claims abstract description 21
- 239000000651 prodrug Substances 0.000 claims abstract description 18
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- 239000003814 drug Substances 0.000 claims description 11
- 230000001419 dependent effect Effects 0.000 claims description 10
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- 201000001421 hyperglycemia Diseases 0.000 claims description 9
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, a pharmaceutical composition and application thereof. The compound shown in the formula I provided by the invention has better therapeutic effects on non-insulin dependent diabetes mellitus (type 2 diabetes mellitus), obesity and the like.
Description
Technical Field
The invention belongs to the field of innovative pharmaceutical chemistry, and relates to a deuterated indazole compound, a pharmaceutical composition and application.
Background
Type 2 diabetes mellitus (T2 DM) is a chronic metabolic disease that manifests as an increase in blood glucose concentration, with a higher incidence and mortality rate. The prevalence of type 2 diabetes mellitus worldwide is rising at a striking rate. In 2019, more than 4.63 million people had diabetes mellitus, predominantly T2DM. Obesity is considered an important risk factor for T2DM, with about 85% of T2DM patients being overweight or obese. Furthermore, moderate weight loss in overweight/obese people can prevent the occurrence of T2DM and reduce the need for established T2DM patients to fight diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin secreted by small intestine L cells as nutrients pass through the gut, GLP-1 exerting a variety of physiological effects including glucose-dependent insulin secretion and biosynthesis by activating GLP-1 receptor, inhibiting glucagon release, survival of pancreatic beta cells, increasing insulin sensitivity, delaying gastric emptying. Although GLP-1 analogs have been used in clinical treatment of diabetes, GLP-1 analogs must be administered subcutaneously and patient compliance is poor. And development of non-polypeptide GLP-1 receptor small molecule agonists has important significance in improving patient compliance and becomes one of the research hotspots in the field of diabetes. Currently, GLP-1 receptor agonists have been used in the clinical treatment of T2DM. In addition, GLP-1 receptor agonists can induce satiety and reduce body weight in humans. However, in most obese patients, currently approved GLP-1 receptor agonists are limited by dose-dependent gastrointestinal side effects, and only moderate weight loss effects can be achieved. LY3502970 is a GLP-1 receptor agonist, currently in clinical II research.
Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Because the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction of the deuterated drug, and the half-life period of the deuterated drug is prolonged. Since 2000, deuteration strategies have been widely used in drug research.
Disclosure of Invention
The invention provides a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:
wherein R is 1 Is hydrogen or deuterium, and is preferably selected from the group consisting of,
R 2 、R 3 、R 4 、R 5 、R 6 or R is 7 Independently selected from CD 3 Or CH (CH) 3 ，
When R is 1 When hydrogen, R 2 、R 3 、R 4 、R 5 、R 6 Or R is 7 At least one of them is CD 3 。
In some embodiments, the R 1 Deuterium.
In some embodiments, the R 2 Is a CD 3 。
In some embodiments, the compound is represented by any one of the following structural formulas:
the invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing GLP-1 receptor agonists.
The invention provides an application of a compound shown in I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing medicaments for non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease or Alzheimer's disease.
In some embodiments, the non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance, and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease, or alzheimer's disease is non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance, and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease, or alzheimer's disease associated with aberrant GLP-1 receptor activity.
The invention provides a pharmaceutical composition, which contains a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.
In the pharmaceutical composition, the compound shown in the formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective in treatment.
The invention provides an application of a pharmaceutical composition in preparing GLP-1 receptor agonists.
The invention provides an application of a pharmaceutical composition in preparing medicines for non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson disease or Alzheimer disease.
In some embodiments, the non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance, and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease, or alzheimer's disease is non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance, and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease, or alzheimer's disease associated with aberrant GLP-1 receptor activity.
The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.
The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.
Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion product from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. Provided the metabolite products are not in other formsMeans cannot be found in vivo or they can be used in assays for the therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
The invention has the positive progress effects that:
(1) The compounds of the present invention have significant agonistic activity at the GLP-1 receptor.
(2) The compound of the invention has obviously improved pharmacokinetic property, prolonged half-life period, good oral bioavailability,
(3) The compound has good therapeutic effect on type 2 diabetes and obesity.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1: synthesis of Compound I-1
Step one: synthesis of Compound b
NaH (12 mmol,480mg, 60%) was added to a solution of compound a (2.13 g,10 mmol) in DMF (15 mL) at 0deg.C, stirred at room temperature for 10min, and then deuterated iodomethane (1.7 g,12 mmol) was added dropwise to the reaction solution. The reaction was stirred at room temperature for 2h. After the reaction is completed, saturated ammonium chloride is added to quench the reaction. The solvent was removed under reduced pressure, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound b (1.5 g, 63%). MS (ESI, M/z): 231 (M) + +1).
Step two: synthesis of Compound d
Compound c (552 mg,1 mmol) was dissolved in deuterated DMSO (2 mL) under nitrogen, potassium tert-butoxide (40 mol%,22 mg) was added to the above solution, and the mixture was heated to 35℃and stirred for 6h. After completion of the reaction, water was added, extraction was performed with ethyl acetate (5 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to give compound d (247 mg, 45%). MS (ESI, M/z): 548 (M) + +1).
Step three: synthesis of Compound 1
Compound d (268 mg,1 mmol) was dissolved in ethyl acetate (5 mL), EA/HCl (4M, 4mmol,1 mL) was added to the above solution, and the reaction was stirred at room temperature for 4h. After the reaction was completed, the mixture was suction-filtered, and the cake was collected and dried in vacuo to give compound 1 (295 mg, 85%). MS (ESI, M/z): 348 (M) + +1).
Step four: synthesis of Compound 3
To a solution of compound 1 (347 mg,1 mmol) and compound 2 (411 mg,1 mmol) in DMF (3 mL) were added HATU (575 mg,1.5 mmol) and DIPEA (0.53 mL,3 mmol) and the reaction was stirred at room temperature for 6h. After the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 3 (481mg, 65%). MS (ESI, M/z): 741 (M) + +1).
Step five: synthesis of Compound I-1
To a solution of compound b (13 mg,0.056 mmmol), compound 3 (21 mg,0.028 mmol), (1S, 2S) -1-N, 2-N-dimethylcyclohexane-1, 2-diamine (1.6 mg, 0.0111 mmol) and potassium carbonate (12 mg,0.085 mmol) in NMP (0.2 mL) was added cuprous iodide (1.1 mg,0.0056 mmol). The reaction solution is heated to 130 ℃ under the protection of nitrogen, and stirred for 3h. Cooled to room temperature and HPLC prepared compound I-5 (19 mg, 77%). 1 H NMR(500MHz,DMSO-d 6 )δ9.09(s,1H),7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):892(M + +1).
Example 2: synthesis of Compound I-2
Step one: synthesis of Compound e
To a solution of compound b (107 mg,0.47 mmol) in N, N-dimethylformamide (15 mL) were added potassium hydroxide (105.5 mg,1.88 mmol) and elemental iodine (239 mg,0.94 mmol), and the reaction was carried out at room temperature for 3 hours, and TLC was monitored to complete the reaction, and saturated sodium sulfite solution was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), washed with water (20 mL. Times.2), dried over anhydrous sodium sulfate with saturated salt (20 mL) and separated and purified by column chromatography to give compound e (67 mg, 40%). MS (ESI, M/z): 357 (M) + +1).
Step two: synthesis of Compound f
To a solution of compound e (127 mg,0.36 mmol) in deuterated acetic acid (8 mL) was added sodium acetate (97.9 mg,0.72 mmol), the reaction was completed for 2 hours, room temperature was reacted for 24 hours, TLC detection reaction was complete, concentrated under reduced pressure,the compound 3 (70 mg, 85%) was obtained by column chromatography separation and purification. MS (ESI, M/z): 232 (M) + +1).
Step three: synthesis of Compound I-2
Synthesis of Compound 4 reference example 1 Synthesis of Compound 3.
To a solution of compound f (13 mg,0.056 mmol), compound 4 (21 mg,0.028 mmol), (1S, 2S) -1-N, 2-N-dimethylcyclohexane-1, 2-diamine (1.6 mg, 0.0111 mmol) and potassium carbonate (12 mg,0.085 mmol) in NMP (0.2 mL) was added cuprous iodide (1.1 mg,0.0056 mmol). The reaction solution is heated to 130 ℃ under the protection of nitrogen, and stirred for 3h. Cooled to room temperature and HPLC prepared compound I-2 (17 mg, 67%). 1 H NMR(500MHz,DMSO-d 6 )δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),2.01(s,3H),1.99(s,3H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):887(M + +1).
Example 3: synthesis of Compound I-3
Synthesis of compound i: the synthesis was carried out as in example 2, except that the starting compound b was replaced by compound g.
Synthesis of Compound I-3: the synthesis is as in example 1, the starting materials are only required
Change to->
And (3) obtaining the product. 1 H NMR(500MHz,DMSO-d 6 )δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.77(s,3H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H)..MS(ESI,m/z):890(M + +1).
Example 4: synthesis of Compound I-4
The synthesis is as in example 2, only
Change to->
And (3) obtaining the product. 1 H NMR(500MHz,DMSO-d 6 )δ9.09(s,1H),7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),2.01(s,3H),1.99(s,3H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H).MS(ESI,m/z):886(M + +1).
Example 5: synthesis of Compound I-5
The synthesis is as in example 1, the starting materials are only required
Replaced by->
And (3) obtaining the product. 1 H NMR(500MHz,DMSO-d 6 )δ7.78(s,1H),7.76(dd,J＝8.4,4.9Hz,1H),7.55–7.46(m,2H),7.29(d,J＝5.0Hz,2H),7.21–7.12(m,2H),6.80(d,J＝7.0Hz,1H),6.62(d,J＝7.1Hz,1H),5.35(q,J＝7.0Hz,1H),3.68(ddd,J＝12.1,5.9,4.7Hz,1H),3.65–3.54(m,1H),3.56–3.47(m,2H),3.15(dddd,J＝7.5,6.4,5.1,4.2Hz,1H),2.93–2.82(m,2H),2.60(dd,J＝6.9,2.8Hz,1H),2.44(dp,J＝6.8,5.2Hz,2H),2.36(dd,J＝5.3,2.8Hz,2H),2.07–1.96(m,2H),1.93–1.83(m,2H),1.55(s,3H),1.25(s,3H),1.20(s,2H),1.01(d,J＝5.2Hz,3H)..MS(ESI,m/z):893(M + +1).
Example 7: detection of the extent of cAMP Signal activation by Compounds in cells
The experiment was performed in the cell line hGLP1R-HEK293, which stably expresses human GLP 1R. hGLP1R-HEK293 cells were subjected to a DMEM medium containing 10% fetal bovine serum, 100 units/mL penicillin G and 100. Mu.g/mL streptomycin sulfate and 500. Mu.g/mL geneticin under an included humid atmosphere. 5% CO 2 Culturing at 37 ℃. hGLP1R-HEK293 was inoculated into 96-well plates at 2.0X104 cells/well and cultured overnight. The next day, the medium from which the cells were cultured was changed to 50. Mu.L of Medium A (DMEM, 20mM HEPES,0.05%BSA,0.5mM 3-isobutyl-1-methylxanthine) and incubated at 37℃for 30 minutes. Then, 50. Mu.L of Medium B (DMEM, 20mM HEPES,0.05%BSA,0.5mM 3-isobutyl-1-methylxanthine) or a compound containing GLP-1 was added and incubated at 37℃for an additional 30 minutes. Then, 100. Mu.L of assay lysis buffer was added and incubated at 37℃for 30 minutes. cAMP concentration is quantified using the cAMP HiRange kit. By setting the cAMP concentration, the cAMP concentration of each well is converted to a reaction rate (%) when human GLP-1 (7-37) is put under the action at a concentration of 1nM to 100%. By applying a 4-parameter logistic regression analysis via xlfit, a dose-response curve of the test compound was created and the half maximal (50%) effective concentration (EC 50 )。
TABLE 1 test compounds activated the cAMP signaling in hGLP1R-HEK293 cells (EC 50 nM)
| Name of the name | cAMP signaling activation |
| I-1 | 1.85 |
| I-2 | 1.80 |
| I-3 | 1.90 |
| I-4 | 1.83 |
| I-5 | 1.84 |
| LY3502970 | 4.55 |
As shown in Table 1, compounds I-1 to I-6 significantly increased cAMP accumulation in hGLP1R-HEK293 cells and were better than the positive control LY3502970.
Example 8: test compound pharmacokinetic property detection
Male SD rats were selected for oral (10 mg/kg) or intravenous (2 mg/kg) administration, 5min,15min,30min,1h,2h,4h,8h,10h,24h after the administration, blood was continuously taken from the ocular fundus venous plexus and placed in an EP tube containing heparin, centrifuged, and upper plasma was taken for LC-MS/MS analysis, and pharmacokinetic parameters were calculated using WinNonlin software according to the blood concentration-time data obtained from the test, and oral bioavailability was calculated.
The study result shows that the oral bioavailability of LY3502970 in rats is 15%, and the half-life period is 1.2h; the oral bioavailability of compound I-1 was increased to 42% and the half-life was extended to 3.7h, indicating that the single dose of compound I-1 could be reduced.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (8)
1. A compound of formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, having the structure:
wherein R is 1 Is hydrogen or deuterium, and is preferably selected from the group consisting of,
R 2 、R 3 、R 4 、R 5 、R 6 or R is 7 Independently selected from CD 3 Or CH (CH) 3 ，
When R is 1 When hydrogen, R 2 、R 3 、R 4 、R 5 、R 6 Or R is 7 At least one of them is CD 3 。
2. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, wherein R 1 Deuterium.
3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, isomer, substitution thereofThe metabolite, prodrug, solvate or hydrate is characterized in that R 2 Is a CD 3 。
4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, wherein the compound is represented by any of the following structural formulas:
5. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claims 1-4, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or adjuvant.
6. Use of a compound of formula I as defined in claims 1-4, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 5, for the preparation of a GLP-1 receptor agonist.
7. Use of a compound of formula I according to claims 1-4, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance and insulin dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, nonalcoholic steatohepatitis, parkinson's disease or alzheimer's disease.
8. The use according to claim 7, wherein said non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease or alzheimer's disease is non-dependent diabetes mellitus, hyperglycemia, impaired glucose tolerance and insulin-dependent diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia, atherosclerosis, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, parkinson's disease or alzheimer's disease associated with abnormal GLP-1 receptor activity.
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