APPLICATION OF HETEROCYCLIC COMPOUND

Abstract

An application of a heterocyclic compound. An application of a substance Y in the preparation of drugs for raising blood sugar. The compound can be used to raise blood sugar and treat hypoglycemia or congenital hyperinsulinism.

Claims

1. A method for one or more of raising blood glucose, treating hypoglycemia and treating congenital hyperinsulinism, comprising administering to a patient a therapeutically effective amount of a substance Y or a pharmaceutical composition thereof for the manufacture of a medicament; the pharmaceutical composition consists of the substance Y and at least one pharmaceutical excipient; the substance Y is a substance B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof; the substance B is ##STR00007##

2. The method as claimed in claim 1, wherein the method satisfies one or more of the following conditions: (1) the pharmaceutical composition consists of the following components in mass fractions: 0.5% of substance B, 20.0% of microcrystalline cellulose, 72.0% of mannitol, 4.0% of cross-linked sodium carboxymethylcellulose, 3.0% of hydroxypropyl methyl cellulose, 0.5% of magnesium stearate; (2) the medicament is presented in a tablet form; (3) the medicament is administered orally; (4) a single administration dose of the medicament is 0.1-1.4 mg; (5) an administration frequency of the medicament is 1 time/day, 2 times/day or 3 times/day; and/or (6) an administration dose of the medicament is 0.1-1.4 mg/day.

3. The method as claimed in claim 1, wherein the mass of the substance B is 0.1-1.4 mg.

4. A substance Y or a pharmaceutical composition thereof for use in one or more of raising blood glucose, treating hypoglycemia and treating congenital hyperinsulinism; the pharmaceutical composition consists of the substance Y and at least one pharmaceutical excipient; the substance Y is as defined in claim 1.

5. The substance Y or the pharmaceutical composition thereof for use in one or more of raising blood glucose, treating hypoglycemia and treating congenital hyperinsulinism as claimed in claim 4, wherein the pharmaceutical composition consists of the following components in mass fraction: 0.5% of substance B, 20.0% of microcrystalline cellulose, 72.0% of mannitol, 4.0% of cross-linked sodium carboxymethylcellulose, 3.0% of hydroxypropyl methyl cellulose, 0.5% of magnesium stearate; preferably, the mass of the substance B is 0.1-1.4 mg.

6. A method for one or more of raising blood glucose, treating hypoglycemia and treating congenital hyperinsulinism, comprising administering to a patient a therapeutically effective amount of a substance Y or a pharmaceutical composition thereof; the pharmaceutical composition consists of the substance Y and at least one pharmaceutical excipient; the substance Y is a substance B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof; the substance B is ##STR00008##

7. The method for one or more of raising blood glucose, treating hypoglycemia and treating congenital hyperinsulinism as claimed in claim 6, wherein the pharmaceutical composition consists of the following components in mass fraction: 0.5% of substance B, 20.0% of microcrystalline cellulose, 72.0% of mannitol, 4.0% of cross-linked sodium carboxymethylcellulose, 3.0% of hydroxypropyl methyl cellulose, 0.5% of magnesium stearate.

8. A pharmaceutical composition 1 or a pharmaceutical composition 2, wherein, the pharmaceutical composition 1 consists of the following components in mass fractions: 0.5% of substance Y, 20.0% of microcrystalline cellulose, 72.0% of mannitol, 4.0% of cross-linked sodium carboxymethylcellulose, 3.0% of hydroxypropyl methyl cellulose, 0.5% of magnesium stearate; the pharmaceutical composition 2 consists of a substance Y and at least one pharmaceutical excipient; in the pharmaceutical composition 1 and pharmaceutical composition 2, the substance Y is a substance B, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof; the substance B is ##STR00009## in the pharmaceutical composition 2, the mass of the substance B in the substance Y is 0.1 to 1.4 mg.

9. The pharmaceutical composition 1 or pharmaceutical composition 2 as claimed in claim 8, wherein the pharmaceutical composition 1 or pharmaceutical composition 2 is presented in a tablet form.

10. The pharmaceutical composition 1 or pharmaceutical composition 2 as claimed in claim 8, wherein the mass of the substance B in the pharmaceutical composition 1 is 0.1-1.4 mg.

11. The method as claimed in claim 2, wherein the method satisfies one or more of the following conditions: (a) the single administration dose of the medicament is 0.1 mg, 0.2 mg, 0.4 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1.1 mg or 1.4 mg; and/or (b) the administration dose of the medicament is 0.1 mg/day, 0.2 mg/day, 0.4 mg/day, 0.5 mg/day, 0.7 mg/day, 1.1 mg/day, or 1.4 mg/day.

12. The method as claimed in claim 7, wherein the mass of the substance B is 0.1-1.4 mg.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0042] The present disclosure will be further described below with reference to embodiments, but the present disclosure is not therefore limited to the scope of the embodiment. Experimental methods without specific conditions in the following embodiments are selected according to conventional methods and conditions, or according to the commercial specification.

[0043] The embodiments were all derived from a clinical trial study. The subjects were screened and eligible to enter groups according to the entry criteria specified in the clinical protocol. The test drug was administered orally on day 1, and adverse events and combined administration were observed and recorded after administration. After safety evaluation was conducted on day 7 of the single administration period, the subjects received continuous administration of the test drug until the subjects withdrew from the clinical trial. Safety assessments were conducted during the clinical trial according to the time specified in the clinical protocol.

[0044] Compound 11A in the following embodiments refers to

##STR00005##

supplied by Shanghai Jiatan Pharmatech Co., LTD., prepared according to CN 105461712A, embodiment 176.

Embodiment 1

[0045] In the present disclosure, the drugs can be presented in a tablet form, and the mass fractions of each component contained in the tablet are as shown in the following table 1:

TABLE-US-00001 TABLE 1 Percentage of raw auxiliary materials (w/w) % 11A 0.5 Microcrystalline cellulose 20.0 Mannitol 72.0 Cross-linked sodium 4.0 carboxymethylcellulose Hydroxypropyl methyl cellulose 3.0 Magnesium stearate 0.5 Total 100.0.

[0046] The preparation method of the tablets:

[0047] 1. The prescription amount of substance 11A was weighed, and 4 times the amount of mannitol was added, and the mixture was repeatedly passed through the 40-mesh sieve to mix evenly;

[0048] 2. an additional 4 times the amount of mannitol was added to the mixture from the step 1, and the mixture was mixed in a suitable mixing drum at 20 rpm for 15 minutes;

[0049] 3. the previous operation in step 2 was repeated until the amount of mixture reached 10% or more of the total mixture, and then the remaining materials other than magnesium stearate were added thereto to mix at 20 rpm for 15 minutes;

[0050] 4. the prescription amount of magnesium stearate was added to the mixture in step 3 to mix at 20 rpm for 3 minutes;

[0051] 5. the above mixture was sampled for mixing uniformity, and after qualification, the mixture was pressed and packaged according to the theoretical sheet weight, so as to obtain the product.

Embodiment 2

[0052] Case data: Subject 1, male, 56 years old, signed the informed consent on Oct. 25, 2018. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 5.64 mmol/L. The tablet containing 0.1 mg of compound 11A was administered for single administration on Nov. 2, 2018. One week later, the tablet containing 0.1 mg of compound 11A was administered for continuous administration once a day on Nov. 9, 2018. The case was followed up for blood routine, blood biochemical and other examinations on Mar. 14, 2019, and the fasting blood glucose increased to 6.19 mmol/L.

Embodiment 3

[0053] Case data: Subject 2, male, 64 years old, signed the informed consent on Jan. 4, 2019. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 5.81 mmol/L. The tablet containing 0.2 mg of compound 11A was administered for single administration on Jan. 9, 2019. One week later, the tablet containing 0.2 mg of compound 11A was administered for continuous administration once a day on Jan. 16, 2019. The case was followed up for blood routine, blood biochemical and other examinations on Jan. 23, 2019, and the fasting blood glucose increased to 6.45 mmol/L.

Embodiment 4

[0054] Case data: Subject 3, male, 37 years old, signed the informed consent on May 13, 2019. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 5.63 mmol/L. The tablet containing 0.4 mg of compound 11A was administered for single administration on May 23, 2019. One week later, the tablet containing 0.4 mg of compound 11A was administered for continuous administration once a day on May 30, 2019. The case was followed up for blood routine, blood biochemical and other examinations on Jun. 5, 2019, and the fasting blood glucose increased to 6.99 mmol/L.

Embodiment 5

[0055] Case data: Subject 5, male, 56 years old, signed the informed consent on Oct. 22, 2019. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 6.06 mmol/L. The tablet containing 0.7 mg of compound 11A was administered for single administration on Oct. 31, 2019. One week later, the tablet containing 0.7 mg of compound 11A was administered for continuous administration once a day on Nov. 7, 2019. The case was followed up for blood routine, blood biochemical and other examinations on Nov. 13, 2019, and the fasting blood glucose increased to 8.37 mmol/L. After continuous administration once a day, the case was followed up on Nov. 20, 2019, and fasting blood glucose increased to 9.44 mmol/L.

Embodiment 6

[0056] Case data: Subject 6, male, 52 years old, signed the informed consent on Nov. 5, 2019. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 5.87 mmol/L. The tablet containing 0.7 mg of compound 11A was administered for single administration on Nov. 14, 2019. One week later, the tablet containing 0.7 mg of compound 11A was administered for continuous administration once a day on Nov. 21, 2019. The case was followed up for blood routine, blood biochemical and other examinations on Nov. 27, 2019, and the fasting blood glucose increased to 11.4 mmol/L. After stopping administering tablets containing 0.7 mg of compound 11A on Nov. 27, 2019, the fasting blood glucose returned to normal on Nov. 29, 2019. The tablet containing 0.7 mg of compound 11A was administered continuously on Nov. 30, 2019. The case was followed up on Dec. 4, 2019, and the fasting blood glucose increased to 11.44 mmol/L.

Embodiment 7

[0057] Case data: subject 7, female, 50 years old, signed informed consent on Nov. 26, 2019. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, and the fasting blood glucose value was 5.92 mmol/L. The tablet containing 0.7 mg of compound 11A was administered for single administration on Dec. 3, 2019. One week later, the tablet containing 0.7 mg of compound 11A was administered for continuous administration once a day on Dec. 10, 2019. The case was followed up for blood routine, blood biochemical and other examinations on Jan. 20, 2020, and the fasting blood glucose increased to 9.13 mmol/L.

Embodiment 8

[0058] Case data: Subject 8, female, 48 years old, signed the informed consent on Dec. 3, 2020. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 6.87 mmol/L. The tablet containing 1.1 mg of compound 11A was administered for single administration on Dec. 10, 2020. One week later, the tablet containing 1.1 mg of compound 11A was administered for continuous administration once a day on Dec. 17, 2019. The fasting blood glucose increased to 12.66 mmol/L on Dec. 23, 2020.

Embodiment 9

[0059] Case data: Subject 9, female, 28 years old, signed the informed consent on Aug. 6, 2020. During the baseline period, vital signs, physical examination, blood routine, blood biochemical, coagulation function, urine routine and other examinations were performed, wherein the fasting blood glucose value was 5.94 mmol/L. The tablet containing 1.4 mg of compound 11A was administered for single administration on Aug. 20, 2020. One week later, the tablet containing 1.4 mg of compound 11A was administered for continuous administration once a day on Aug. 27, 2020. The fasting blood glucose increased to 10.77 mmol/L on Sep. 2, 2020.

[0060] Embodiments 2 to 9 were derived from an ongoing clinical trial study with dose groups of 0.1 mg, 0.2 mg, 0.4 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1.1 mg, and 1.4 mg. The incidence of hyperglycemia in these subjects was 80% during the administering period, which shows that compound 11A is very effective in raising blood glucose. In addition, there were no significant gastrointestinal side effects such as nausea, vomiting and diarrhea in these 8 subjects of above embodiments.

[0061] The clinical trial research method of any of the following compounds was the same as that of compound 11A as described above.

##STR00006##

Embodiment 10

[0062] Bioavailability Experiments

[0063] 1. Experimental Animals

[0064] The 12 non-naïve beagle dogs (6/sex) in this experiment were provided by Beijing Marshall Biotechnology Co., Ltd. Each animal had a tattoo number on its ear as an identification code. During the experimental period, animals were housed in single cages with animal identification codes marked on the cage tags. The 12 non-naïve beagle dogs (6/sex) were randomly divided into 2 groups (3/sex/group).

[0065] 2. Experimental Design

[0066] (1) Non-naïve beagle dogs were administered intravenously (solvent 50% PEG400+50% PBS) at a dose volume of 2 mL/kg per dog (dose of 0.1 mg/kg per dog), and then blood was collected to measure the plasma drug concentration of non-naïve beagle dogs at different time points of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours.

[0067] (2) Non-naïve beagle dogs were administered orally at a dose volume of 1 tablet per dog (dose of 0.5 mg per dog), and then blood was collected to measure the plasma drug concentration of non-naïve beagle dogs at different time points of 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours; the oral bioavailability of tablets was calculated.

[0068] 3. Pharmacokinetic Data Analysis

[0069] Plasma drug concentration data was processed in a non-compartment model using WinNonlin™ Version 6.2.1 (Pharsight, Mountain View, Calif.) pharmacokinetic software. The peak concentration (C.sub.max), peak time (T.sub.max) and quantifiable time were directly read out from the plasma drug concentration-time diagram.

[0070] The following pharmacokinetic parameters were calculated using the log-linear trapezoidal method: elimination phase half-life (T.sub.1/2), apparent volume of distribution (Vd.sub.ss) and clearance rate (CL), mean residence time of the drug from 0 to the end time point in vivo (MRT.sub.0-last), mean residence time of the drug from 0 to infinite time in vivo (MRT.sub.0-inf), the area under the time-plasma concentration curve from 0 to the end time point (AUC.sub.0-last), the area under the time-plasma concentration curve from 0 to infinite time (AUC.sub.0-inf), initial concentration (C.sub.0).

[0071] 4. Experimental Conclusion

[0072] After a single intravenous injection of 11A of 0.1 mg/kg, male and female beagle dogs showed a moderately high plasma clearance rate (CL) of 24.6±6.66 mL/min/kg, and the apparent volume of distribution (Vd.sub.ss) of 6.16±1.91 L/kg showed that the compound was widely distributed in vivo. The mean plasma elimination phase half-life Tin and area under the curve AUC.sub.0-last were 3.21±1.81 h and 114±27.6 nM*h, respectively.

[0073] After a single oral administration of tablets containing 0.5 mg of 11A prepared from the prescription of embodiment 1 in male and female beagle dogs, the bioavailability was 80.9% and the peak concentration (C.sub.max) was 11.1±2.08, and the peak times occurred at 1.00±0.00 h after administration, respectively.