CN112608315B - Triazolodiazepine compound and preparation method and medical application thereof - Google Patents
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Abstract
The invention relates to triazolodiazepine compounds shown in a formula (I) and having glycogen phosphorylase inhibitory activity, a preparation method thereof and application thereof in preparing medicaments for treating and/or preventing diseases related to glycogen metabolism abnormality.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a triazolodiazepine compound serving as a glycogen phosphorylase inhibitor, and a preparation method and medical application thereof.
Background
In recent years, with the improvement of living standard and the change of life style of people, the number of people suffering from diabetes (MD) is rapidly increasing, the incidence rate is on the rise, and the disease gradually becomes the third disease which is harmful to human health. According to the statistics of 2017, 4.51 hundred million adults suffer from diabetes globally, 49.7 percent of diabetics are not diagnosed, the expenditure cost of the diabetes is huge, and the diabetes brings heavy burden to the country and the whole society. Related studies have shown that inhibition of glycogen phosphorylase activity significantly reduces fasting blood glucose levels. Glycogen phosphorylase is regarded as the key rate-limiting enzyme for hepatic glycogen degradation, and is highly regarded by new drug developers. The international famous pharmaceutical company Pfizer, Merck, Novo Nordisk, Abbott, OSI and the like have developed research and development work on the target of the potential hypoglycemic drugs.
Diazepine compounds have a heptadiazepine ring structure and have attracted considerable attention from workers and pharmacologists in organic synthesis since their discovery in the 19 th century, and mainly imidazodiazepine, benzodiazepine, pyrimidodiazepine and the like have been reported. Since being discovered as a central nervous system active drug, benzodiazepine drugs have obtained 1, 4-diazacyclo systems with different types of substituents, and biological activity evaluation is performed. These compounds exhibit a wide range of activities, including central nervous system disorders, MMP inhibitors, 5-HT3 receptor antagonists, antidiabetics, antimalarials, anti-HIV, etc., and can be used as biological tools [ Mini-rev. There are probably 35 benzodiazepine drug derivatives on the market today, 21 of which are globally approved.
The benzodiazepine micromolecules have stronger hydrophobicity, so the structure used by the invention is that the structure of the benzodiazepine is combined with 5-chloroindole-2-formic acid after a series of improvements, and the Glycogen Phosphorylase (GP) inhibitor based on the azaindoleamide derivatives is used as a potential novel antidiabetic medicament, and the antidiabetic medicament is characterized by having the glucose concentration dependent hypoglycemic effect and effectively avoiding the hypoglycemic adverse reaction. Therefore, the development of GP inhibitors is of great clinical significance. The invention discovers that the triazolodiazepine compound has an inhibitory effect on glycogen phosphorylase.
Disclosure of Invention
The invention provides a triazolodiazepine compound shown in a formula (I) and having glycogen phosphorylase inhibitory activity, and a preparation method and medical application thereof. The compounds of formula (I) of the present invention are useful for the prevention and/or treatment of diseases associated with abnormal glycogen metabolism because they inhibit glycogen phosphorylase.
According to one aspect of the invention, the invention relates to compounds of formula (I):
wherein:
r is H, halogen, hydroxy or C1-4An alkyl group.
Preferably, in the compounds of formula (I):
r is halogen.
In the present invention, "halogen" means fluorine, chlorine, bromine and iodine. "C1-4Alkyl "means a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
More preferably, the compound of formula (I) is a compound of formula (II) as follows:
according to a second aspect of the present invention, there is provided a process for the preparation of a compound as described above, comprising the steps of:
(1) will be provided with
Preference is given to
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(2) will be provided with
Adding into the solution obtained in step (1), and reacting at 0-45 deg.C, preferably room temperature for 1-48 hr to obtain compound
Preference is given to
(3) Dissolving the compound obtained in the step (2) in an organic solvent, dropwise adding an organic acid or an inorganic acid in an ice water bath, and reacting at 0-45 ℃, preferably room temperature for 1-48 hours to obtain the compound
Preference is given to
(4) Will be provided with
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(5) adding the compound obtained in the step (3) into the solution obtained in the step (4), and reacting for 1-48 hours at 0-45 ℃, preferably room temperature; obtaining:
preference is given to
Preferably, the organic solvent is an inert solvent; more preferably, the organic solvent is an aprotic solvent; further preferably, the organic solvent is selected from the group consisting of acetonitrile, chloroform, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, toluene, N-hexane, cyclohexane, tetrahydrofuran, t-butyl methyl ether and a mixture of two or more thereof; further preferably, the organic solvent is selected from the group consisting of 1, 2-dichloroethane, N-Dimethylformamide (DMF) and mixtures thereof.
Preferably, the condensation reagent is an amidation condensation reagent; further preferably, the condensation reagent is selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), N, N ' -Dicyclohexylcarbodiimide (DCC), 1-Hydroxybenzotriazole (HOBT), O-benzotriazol-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), 1-propylphosphonic acid tricyclo anhydride (T ™)3P) and mixtures of two or more thereof; further preferably, the condensation reagent is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/or 1-Hydroxybenzotriazole (HOBT).
Preferably, the organic amine is N, N-Diisopropylethylamine (DIEA), triethylamine or a mixture thereof.
Preferably, the inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and mixtures of two or more thereof.
Preferably, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, a mixture of two or more thereof, and the like, and further preferably hydrochloric acid; the organic acid is trifluoroacetic acid and the like.
According to the third aspect of the present invention, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or formula (II), and a pharmaceutically acceptable excipient.
Those skilled in the art will appreciate that various adjuvants commonly used in the art may be used in the present invention, including, but not limited to, fillers, diluents, disintegrants, lubricants, binders, dispersants, wetting agents, solvents, pH adjusters, flavoring agents, preservatives, antioxidants, and the like.
The dosage form of the pharmaceutical composition of the invention includes, but is not limited to, tablets, capsules, pills, suppositories, soft capsules, oral liquids, suspensions, injections and other pharmaceutically common dosage forms.
It will be appreciated by those skilled in the art that various dosage forms of the pharmaceutical compositions of the present invention may be prepared according to methods well known in the art.
According to a fourth aspect of the present invention, there is provided a method for the prevention and/or treatment of a disease associated with abnormal glycogen metabolism, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or formula (II) or a pharmaceutical composition of the invention.
It will be appreciated by those skilled in the art that the dosage of the compound of formula (I) or formula (II) will vary depending on the formulation. In general, amounts which have proven advantageous are from 0.01 to 800mg, preferably from 0.1 to 100mg/kg, of the compound of the formula (I) per kg of compound administered per 24 hours in order to achieve the desired result. If necessary in the form of several single doses. However, it is also possible to deviate from the above-mentioned amounts, if necessary, i.e. depending on the type and weight of the subject to be treated, the individual's behaviour towards the drug, the nature and severity of the disease, the type of preparation and administration, and the time and interval of administration.
According to a fifth aspect of the invention, there is provided the use of a compound of formula (I) or formula (II) according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment and/or prevention of a disease associated with abnormal glycogen metabolism.
According to the present invention, the disease associated with abnormal glycogen metabolism includes diabetes (including type 1 and type 2, particularly type 2 diabetes) or its complications (e.g., diabetic nephropathy, diabetic foot, diabetic neuropathy, diabetic cardiovascular and cerebrovascular diseases, etc.), hyperlipidemia, obesity, ischemic cardiovascular and cerebrovascular diseases (particularly myocardial infarction, angina pectoris, arrhythmia, coronary heart disease, cerebral ischemia, stroke, cerebral infarction, ischemic neurodegenerative diseases, etc.), hyperinsulinemia, insulin resistance, fasting hyperglycemia, hypertension or its complications, atherosclerosis, metabolic syndrome, or tumor.
According to a sixth aspect of the invention, there is provided the use of a compound of formula (I) or formula (II) according to the invention or a pharmaceutical composition according to the invention in the preparation of a glycogen phosphorylase inhibitor.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the description of the present invention, and such equivalents also fall within the scope of the invention.
Example 13- [ (5-chloro-1H-indole-2-carboxamido) methyl ] -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-a ] [1,4] diazepine-8 (9H) -carboxylic acid tert-butyl ester
Dissolving 5-chloroindole-2-carboxylic acid (145mg,0.74mmol) in DMF (6mL), adding EDCI (170mg,0.89mmol), HOBT (120mg,0.89mmol), DIEA (0.39mL,2.22mmol) under stirring, stirring at 0 deg.C for 30min under nitrogen protection, adding3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4]Triazole [4,3-a ]][1,4]Diazepine-8 (9H) -carboxylic acid tert-butyl ester (180mg,0.67mmol), followed by stirring at room temperature overnight, pouring the reaction solution into ice water, extracting with ethyl acetate (15 mL. times.3), washing the organic phase with saturated saline (15 mL. times.3), drying over anhydrous magnesium sulfate for 2-3H, and performing silica gel column Chromatography (CH)2Cl2/CH3OH 100/3, V/V) to yield a white solid (180mg, 60.6%).
HPLC analysis:100％.
ESI-MS m/z:445.0(M+H)+.
1H-NMR(400MHz,d6-DMSO):1.23(s,9H),1.80(br s,2H),3.64(br s,2H),4.22(br s,2H),4.63-4.67(m,4H),7.17-7.20(m,2H),7.43(d,J＝6.4Hz,1H),7.70(d,J＝3.8Hz,1H),9.19(s,1H),11.85(s,1H).
13C-NMR(100MHz,d6-DMSO):161.1,154.4,152.6,135.4,132.9,128.5,124.7,124.2,121.1,114.4,103.2,79.9,40.4,33.7,28.4,27.6.
Example 2N- [ (6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] [1,4] diazepin-3-yl) methyl ] -5-chloro-1H-indole-2-carboxamide
3- [ (5-chloro-1H-indole-2-carboxamido) methyl ] -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-a ] [1,4] diazepine-8 (9H) -carboxylic acid tert-butyl ester (180mg, 0.43mmol) was dissolved in 20mL of dichloromethane, 2mL of trifluoroacetic acid was added dropwise under an ice-water bath, after 30min the ice-water bath was removed, the reaction was stopped by stirring at room temperature for 4H, an appropriate amount of ice water was added to the reaction system, ethyl acetate was extracted (15 mL. times.3), the organic phase was washed with saturated brine (15 mL. times.3), dried over anhydrous magnesium sulfate for 2 to 3H, and concentrated to give a crude product (134.6mg, 90%). The mixture was directly used in the next step without further purification.
Example 3N- [ (8- (3-Hydroxypropionyl) -6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] [1,4] diazepin-3-yl) methyl ] -5-chloro-1H-indole-2-carboxamide
Dissolving 3-hydroxypropionic acid (90mg,1mmol) in DMF (6mL), adding EDCI (230mg,1.2mmol), HOBT (162mg,1.2mmol), DIEA (0.52mL,3mmol) under stirring, stirring at 0 deg.C for 30min under nitrogen protection, adding N- [ (6,7,8, 9-tetrahydro-5H- [1,2,4]]Triazole [4,3-a ]][1,4]Diazepin-3-yl) methyl]-5-chloro-1H-indole-2-carboxamide (180mg,0.52mmol), followed by stirring at room temperature overnight, pouring the reaction solution into ice water, extracting with ethyl acetate (15 mL. times.3), washing the organic phase with saturated brine (15 mL. times.3), drying over anhydrous magnesium sulfate for 2-3H, and performing silica gel column Chromatography (CH)2Cl2/CH3OH 100/3, V/V) to yield a white solid (108mg, 50%).
HPLC analysis:96.7％.
ESI-MS m/z:417.0(M+H)+.
1H-NMR(400MHz,d6-DMSO):1.80(br s,1H),1.98(br s,1H),2.55(t,J＝6.4Hz,2H),3.58-3.62(m,2H),3.77-3.83(m,2H),4.30-4.37(m,2H),4.74(dd,J＝15.2,5.4Hz,2H),4.85(d,J＝5.8Hz,2H),7.17-7.22(m,2H),7.44(dd,J＝8.7,2.0Hz,1H),7.72(dd,J＝3.8,1.7Hz,1H),9.25-9.31(m,1H),11.89(d,J＝3.6Hz,1H).
13C-NMR(100MHz,d6-DMSO):171.1(from isomer),170.9,161.5,161.3(from isomer),154.3,153.1(from isomer),152.9,135.4,132.7,132.6(from isomer),128.5,124.8,124.2,121.2,114.4,103.4,103.3(from isomer),57.7(from isomer),57.6,46.7,45.1,44.7(from isomer),43.5,36.6,36.1(from isomer),33.7,28.2(from isomer),27.6.
Example 4 in vitro glycogen phosphorylase inhibitory Activity assay
Preparation of a reagent: 1) preparing a color developing solution: weighing 5g of ammonium molybdate, dissolving the ammonium molybdate in 500ml of 1M HCl, stirring the ammonium molybdate with a stirrer until the ammonium molybdate is completely dissolved, adding 190mg of malachite green, continuing stirring the mixture until the ammonium molybdate is completely dissolved, and keeping the mixture away from light with tinfoil paper; 2) preparing a buffer solution: precisely weighing Hepes 0.5958g, dissolving in 5ml H2In O, adjusting the pH value to 7.2 by using 10M NaOH to prepare Hepes with the final concentration of 0.5M; ② KCl 0.3728g is precisely weighed and dissolved in 5ml H2In O, preparePreparing a KCl solution with the final concentration of 1M; ③ MgCl is precisely weighed20.0255g, dissolved in 1ml of H2In O, MgCl was prepared at a final concentration of 125mM2A solution; fourthly, precisely weighing EGTA0.0476g, dissolving the EGTA0.0476g in 5ml of H2In O, adjusting the pH value to 7.0 by using 10M NaOH to prepare an EGTA solution with the final concentration of 25 mM; accurately weighing 0.0152G of G-1-P, and dissolving in 10ml of H2In O, G-1-P with the final concentration of 5mM is prepared; sixthly, 10mg of glycogen is precisely weighed and dissolved in 1ml of H2O, preparing glycogen with the final concentration of 10 mg/ml; 3) preparing a positive drug caffeine solution: dissolving caffeine in 10ml of H2O preparing 0.5, 5, 50 and 500 mu M solutions; 4) preparing a GPa solution: adding 1 mul of GPa into a 100 mul reaction system, wherein the final concentration is 250ng/100 mul; 5) preparation of a solution of the compound to be tested: the compound to be tested is dissolved in DMSO to prepare a solution with the concentration of 10mM, and a proper amount of the compound solution is added into the reaction system to different final concentrations.
Dose-response curves for determination of rabbitmyoglycogen phosphorylase activity: the dose-response curve is determined by reading the OD value at 655nm after the GPa with different concentrations is added into the developing solution. From the dose-response curve, a GPa amount of 250ng can be chosen.
The experimental steps are as follows: 1) designing PC (positive control), Blank (Blank control) and positive drug (caffeine); 2) adding 52 mu l of reaction buffer; 3) adding the test compound to a final concentration; 4) adding enzyme 1 μ l to a final concentration of 250ng/100 μ l; 5) adding 150 mul of color development liquid; 6) reacting for 20 minutes at the temperature of 30 ℃; 7) colorimetric at 655nm wavelength; 8) data reading and suppression rate calculation: inhibition rate ═ positive control-test sample ]/[ positive control-blank control ].
Generally considered as IC50<10 μ M was effective and the results of activity of the compound of formula (II) of example 3 of the present invention are shown in Table 1 below. The pharmacological data show that the compounds of general formula (I) of the present invention have inhibitory effects on glycogen phosphorylase.
TABLE 1 inhibitory Activity of Compounds of formula (II) on rabbit muscle glycogen phosphorylase
a is the average of three determinations
As can be seen from the above experiments, the compounds of formula (I) of the present invention have glycogen phosphorylase inhibitory activity and show greatly increased activity as compared with the activity of the natural product. Therefore, can be used for treating or preventing various diseases related to glycogen metabolism abnormality.
Claims (25)
1. A compound of the formula (I):
wherein:
r is H, halogen, hydroxy or C1-4An alkyl group.
2. The compound of claim 1, wherein:
r is halogen.
3. A compound according to claim 1 or 2, wherein the compound of formula (I) is the following:
4. a process for the preparation of a compound according to claim 1 or 2, comprising the steps of:
(1) will be provided with
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(2) will be provided with
Adding into the solution obtained in the step (1), reacting for 1-48 hours at 0-45 DEG CThen, the compound is obtained
(3) Dissolving the compound obtained in the step (2) in an organic solvent, dropwise adding organic acid or inorganic acid in an ice water bath, and reacting at 0-45 ℃ for 1-48 hours to obtain the compound
(4) Will be provided with
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(5) adding the compound obtained in the step (3) into the solution obtained in the step (4), and reacting for 1-48 hours at the temperature of 0-45 ℃; to obtain
5. A process for the preparation of a compound according to claim 3, comprising the steps of:
(1) will be provided with
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(2) will be provided with
Adding the mixture into the solution obtained in the step (1), and reacting for 1-48 hours at the temperature of 0-45 ℃ to obtain a compound
(3) Dissolving the compound obtained in the step (2) in an organic solvent, dropwise adding organic acid or inorganic acid in an ice water bath, and reacting at 0-45 ℃ for 1-48 hoursTo obtain the compound
(4) Will be provided with
Dissolving in organic solvent, adding condensation reagent and organic amine or inorganic base;
(5) adding the compound obtained in the step (3) into the solution obtained in the step (4), and reacting for 1-48 hours at the temperature of 0-45 ℃; to obtain
6. The method according to claim 4 or 5, wherein the steps (2), (3) and (5) are carried out at room temperature.
7. The method according to claim 4 or 5, wherein the organic solvent is an inert solvent.
8. The method according to claim 7, wherein the organic solvent is an aprotic solvent.
9. The method of claim 8, wherein the organic solvent is selected from acetonitrile, chloroform, dichloromethane, 1, 2-dichloroethane, N-dimethylformamide, toluene, N-hexane, cyclohexane, tetrahydrofuran, t-butyl methyl ether, or a mixture of two or more thereof.
10. The method of claim 9, wherein the organic solvent is selected from the group consisting of 1, 2-dichloroethane, N-dimethylformamide, and mixtures thereof.
11. The method of claim 4 or 5, wherein the condensing agent is an amidation condensing agent.
12. The method of claim 11, wherein the condensation reagent is selected from the group consisting of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N ' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, O-benzotriazol-N, N ' -tetramethyluronium tetrafluoroborate, 2- (7-azobenzotriazol) -N, N ' -tetramethyluronium hexafluorophosphate, 1-propylphosphoric acid tricyclo anhydride, and mixtures of two or more thereof.
13. The method of claim 12, wherein the condensing agent is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and/or 1-hydroxybenzotriazole.
14. The method according to claim 4 or 5, wherein the organic amine is N, N-diisopropylethylamine, triethylamine, or a mixture thereof.
15. A process according to claim 4 or 5, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or a mixture of two or more thereof.
16. The method of claim 4 or 5, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or a mixture of two or more thereof.
17. The method of claim 16, wherein the inorganic acid is hydrochloric acid.
18. The method according to claim 4 or 5, wherein the organic acid is trifluoroacetic acid.
19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, together with a pharmaceutically acceptable adjuvant.
20. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 19 for the manufacture of a medicament for the treatment and/or prevention of a disease associated with abnormal glycogen metabolism.
21. The use of claim 20, wherein the disease associated with abnormal glycogen metabolism is selected from diabetes or its complications, hyperlipidemia, obesity, ischemic cardiovascular and cerebrovascular diseases, hyperinsulinemia, insulin resistance, fasting hyperglycemia, hypertension or its complications, atherosclerosis, metabolic syndrome, or tumors.
22. The use of claim 21, wherein the diabetes is type 2 diabetes.
23. The use according to claim 21, wherein the diabetic complication is diabetic nephropathy, diabetic foot, diabetic neuropathy, diabetic cardiovascular disease.
24. The use of claim 21, wherein the ischemic cardiovascular and cerebrovascular disease is myocardial infarction, angina pectoris, arrhythmia, coronary heart disease, cerebral ischemia, stroke, cerebral infarction, or ischemic neurodegenerative disease.
25. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 19 in the manufacture of a glycogen phosphorylase inhibitor.
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| CN1678372A (en) * | 2002-09-04 | 2005-10-05 | 百时美施贵宝公司 | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
| CN1787823A (en) * | 2003-05-14 | 2006-06-14 | 麦克公司 | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN101160290A (en) * | 2004-12-02 | 2008-04-09 | 阿斯比奥制药株式会社 | 7-membered ring compound, process for producing the same, and medicinal use thereof |
| CN103497181A (en) * | 2013-09-30 | 2014-01-08 | 承德医学院 | Benzoperhydroazepinone compounds as glycogen phosphorylase inhibitors as well as preparation method and medical application thereof |
| CN111533745A (en) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1678372A (en) * | 2002-09-04 | 2005-10-05 | 百时美施贵宝公司 | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
| CN1787823A (en) * | 2003-05-14 | 2006-06-14 | 麦克公司 | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN101160290A (en) * | 2004-12-02 | 2008-04-09 | 阿斯比奥制药株式会社 | 7-membered ring compound, process for producing the same, and medicinal use thereof |
| CN103497181A (en) * | 2013-09-30 | 2014-01-08 | 承德医学院 | Benzoperhydroazepinone compounds as glycogen phosphorylase inhibitors as well as preparation method and medical application thereof |
| CN111533745A (en) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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