Use of heterocyclic compound

Abstract

Disclosed is use of a heterocyclic compound. Provided is a method for treating chronic hepatitis B by using a substance A. The substance A has good safety and pharmacodynamics.

Description

Use of a heterocyclic compound

[0001] This application claims priority to Chinese patent application 2024104235847 with the filing date of 2024 / 4 / 9. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to the use of a heterocyclic compound. BACKGROUND

[0003] Hepatitis B is a viral hepatitis caused by hepatitis B virus, which can be divided into acute and chronic hepatitis B according to the speed of disease development. At present, there is still a lack of effective drugs for the treatment of chronic hepatitis B. SUMMARY

[0004] The technical problem to be solved by the present application is the lack of effective drugs for the treatment of chronic hepatitis B. To this end, the present application provides a method for treating chronic hepatitis B with substance A. The substance A has good safety and pharmacodynamics.

[0005] The present application provides a method for treating chronic hepatitis B, which comprises administering a therapeutically effective amount of substance A to a patient, wherein the substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0006] In a certain aspect, the dose of the substance A is 0.4 μg / time-1 μg / time, for example, 0.4 μg / time, 0.7 μg / time or 1 μg / time.

[0007] In a certain aspect, the administration of the substance A is oral.

[0008] In a certain aspect, the frequency of administration of the substance A is once a week.

[0009] In a certain aspect, the administration cycle of the substance A is 4 weeks.

[0010] In a certain aspect, the administration of the substance A is once a week for 4 weeks.

[0011] The present application provides a method for treating hepatitis B with negative hepatitis B e antigen (HBeAg), which comprises administering a therapeutically effective amount of substance A to a patient, wherein the substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the hepatitis B e antigen negative hepatitis B is chronic hepatitis B e antigen negative hepatitis B.

[0013] In one embodiment, the substance A is as described in any of the preceding embodiments.

[0014] The present application provides use of a substance A in the manufacture of a medicament for treating chronic hepatitis B, the substance A being a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof,

[0015] In one embodiment, the substance A is as described in any of the preceding embodiments.

[0016] The present application provides use of a substance A in the manufacture of a medicament for treating hepatitis B e antigen (HBeAg) negative hepatitis B, the substance A being a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof,

[0017] In one embodiment, the substance A is as described in any of the preceding embodiments.

[0018] The term "pharmaceutically acceptable salt" means a salt prepared from a compound of the present application with a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound of the present application contains relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired pharmaceutically acceptable base in a pure solution or in a suitable inert solvent. When a compound of the present application contains relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired pharmaceutically acceptable acid in a pure solution or in a suitable inert solvent. When a compound of the present application contains both relatively acidic and relatively basic functionalities, acid or base addition salts can be formed. Specific examples of pharmaceutically acceptable salts are provided in Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0019] The term "solvate" means a substance having a stoichiometric or non-stoichiometric amount of solvent molecules in combination with compounds of the application. The solvent molecules in solvates can be ordered or disordered but are typically not chemically bonded to the solvate entity.

[0020] The terms "pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" mean, as described above, a substance having a stoichiometric or non-stoichiometric amount of solvent molecules in combination with compounds of the application, prepared from a relatively non-toxic, pharmaceutically acceptable acid or base.

[0021] The term "treatment" refers to therapeutic treatment. With respect to a particular condition, treatment refers to: (1) relieving the disease or condition, or one or more of the biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more of the biological manifestations of the condition.

[0022] The term "therapeutically effective amount" means the amount of a compound that, when administered to a patient, is sufficient to effect treatment for a disease or condition as described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art according to the needs of the patient.

[0023] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, to which a compound is to be administered according to the embodiments of the application. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

[0024] The above-mentioned preferred conditions can be combined in any way, without departing from the scope of the present application, to give preferred embodiments of the present application.

[0025] The reagents and materials used in the present application are commercially available.

[0026] The above-mentioned preferred conditions can be combined in any way, without departing from the scope of the present application, to give preferred embodiments of the present application.

[0027] The reagents and materials used in the present application are commercially available.

[0028] The positive progress effect of the present application is that the substance A of the present application has good safety and pharmacodynamics. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is the percentage of subjects with HBsAg decline in subjects with baseline HBsAg > 2000 IU / mL.

[0030] Figure 2 is the HBsAg decline values by dose and time of testing. DETAILED DESCRIPTION

[0031] The application is further illustrated by the following examples without thereby limiting the application to the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are selected in accordance with the usual methods and conditions, or in accordance with the manufacturer's instructions.

[0032] Example 1: Clinical Phase I trial of the compound of Formula I

[0033] The clinical Phase I trial of the compound of Formula I evaluated the safety and pharmacodynamics of the compound of Formula I or placebo (PBO) in healthy volunteers, and the safety, antiviral activity, and pharmacodynamics of the compound of Formula I in virologically suppressed (VS) hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) patients.

[0034] Methods: The study included 3 CHB cohorts (8 subjects per cohort). The first cohort (0.4 μg of the compound of Formula I / PBO) and the second cohort (0.7 μg of the compound of Formula I / PBO); the third cohort (1 μg of the compound of Formula I / PBO).

[0035] The compound of Formula I or PBO (3: 1) was administered orally once weekly (QW) for 4 weeks (Days 1, 8, 15, and 22) while taking the previously prescribed nucleotide reverse transcriptase inhibitor (NtRTI). Subjects were followed up for 4 weeks after the last dose on Days 29, 36, 43, and 50. Of the 16 subjects randomized in the completed cohorts, 2 subjects from the 0.4 μg of the compound of Formula I / PBO cohort were excluded from the efficacy analysis due to protocol deviations prior to dosing.

[0036] Results: There were no serious adverse events, study discontinuations, grade 3-4 treatment-emergent adverse events (TEAEs), or clinically significant abnormalities in vital signs, electrocardiograms, or urinalysis. One subject (0.7 μg of the compound of Formula I / PBO) had a mild alanine aminotransferase elevation 1 week after the last dose of the compound of Formula I, but it was not related to the compound of Formula I. Two subjects were reported to have 3 TEAEs (taste disorder, malaise, and fatigue) that were possibly related to the compound of Formula I; all were grade 1 (mild) and resolved within 1-3 days without drug intervention.

[0037] Subjects with baseline hepatitis B surface antigen (HBsAg) greater than 2000 IU / mL (0.4 μg Compound of Formula I, N=3; 0.7 μg Compound of Formula I, N=4; 1 μg Compound of Formula I, N=2; PBO, N=1) observed a reduction in HBsAg of 33% and 75% for subjects receiving 0.4 μg and 0.7 μg of the Compound of Formula I, respectively, at Day 36. At Day 50, a reduction in HBsAg of 67% and 50% was observed for subjects receiving 0.4 μg and 0.7 μg of the Compound of Formula I, respectively. The magnitude of HBsAg reduction in subjects receiving the Compound of Formula I was approximately 0.02 log 10 IU / mL to 0.40 log 10 IU / mL at Day 36 and Day 50. A 100% reduction in HBsAg was also observed at Day 50 for the subject receiving 1 μg. No reduction in HBsAg was observed for the PBO subject at Day 36 and Day 50. Hepatitis B virus (HBV) DNA and HBV RNA were below the lower limit of quantitation for all subjects throughout the study.

[0038] Conclusion: The Compound of Formula I was safe and well tolerated following 4 weeks of PO QW dosing at 0.4 and 0.7 μg in HBeAg-negative subjects with chronic hepatitis B. In a subset of VS CHB subjects with baseline HBsAg > 2000 IU / mL, 4 weeks of PO QW dosing of the Compound of Formula I resulted in a reduction in HBsAg in some subjects. See Figure 1. These data support further evaluation of the Compound of Formula I in a clinical Phase II study.

Claims

1. A method for treating chronic hepatitis B, comprising administering to a patient a therapeutically effective amount of a substance A, wherein the substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; 2. The method of claim 1, which satisfies one or more of the following conditions: (1) The dosage of substance A is 0.1 μg / time-2 μg / time, such as 0.4 μg / time, 0.7 μg / time or 1 μg / time, 1.2 μg / time, 1.5 μg / time, 2 μg / time; (2) The dosage of substance A is 0.4 μg / time-1 μg / time, for example, 0.4 μg / time, 0.7 μg / time or 1 μg / time; (3) Substance A is administered orally; (4) The frequency of administration of substance A is once or twice a week; (5) The administration frequency of substance A is once a week; (6) The administration cycle of substance A is 4-52 weeks and (7) The administration cycle of substance A is 4 weeks.

3. A method for treating hepatitis B e antigen-negative hepatitis B, comprising administering to a patient a therapeutically effective amount of substance A, wherein substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; 4. The method of claim 3, which satisfies one or both of the following conditions: (1) The hepatitis B e antigen-negative hepatitis B is hepatitis B e antigen-negative chronic hepatitis B; and (2) The substance A is as described in claim 2.

5. Use of a substance A in the preparation of a medicament for treating chronic hepatitis B, wherein the substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, 6. The use according to claim 5, wherein the substance A is as described in claim 2.

7. Use of a substance A in the preparation of a medicament for treating hepatitis B e antigen-negative hepatitis B, wherein the substance A is a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, wherein the substance A or the hepatitis B e antigen-negative hepatitis B is as described in claim 4.

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