Drug combination containing TLR7 agonist

Patent metadata

Field	Value
Publication number	US-12336996-B2
Application number	US-202017754099-A
Country	US
Kind code	B2
Filing date	Sep 29, 2020
Priority date	Sep 29, 2019
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

A drug combination containing a TLR7 agonist. Specifically, a drug combination jointly using the compound of formula I acting as a TLR7 agonist and entecavir for the treatment of hepatitis B virus infection and a use thereof, the drug combination having a good anti-hepatitis B virus infection effect.

First claim

The invention claimed is:

1. A pharmaceutical combination, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and entecavir or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula I is shown as follows:

wherein,
L 1 is selected from —O—;
L 2 is selected from —CH 2 —, wherein the —CH 2 — is optionally substituted with R 4 ;
R 1 is selected from the group consisting of hydrogen and C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with R 5 ;
R 2 is selected from the group consisting of hydrogen, cyano, —COOH and —CONH 2 , wherein the —COOH and —CONH 2 are optionally substituted with R 6 ;
B is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl;
L 3 is selected from the group consisting of C 0-6 alkylene and imino, wherein the C 0-6 alkylene and imino are optionally substituted with R 7 ;
R 3 is selected from the group consisting of hydrogen, amino, C 1-10 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclohydrocarbyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the amino, C 1-10 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclohydrocarbyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted with R 8 , or
R 3 and L 3 , together with an ortho atom on ring B, form a saturated or unsaturated 5-8 membered ring, wherein the 5-8 membered ring is optionally substituted with R 9 ;
n is 0, 1, 2, 3, 4 or 5;
R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from halogen, cyano, hydroxy, sulfydryl, amino, —R, —OR, —O, —SR, —NHR and —NR 2 ; R is independently selected from the group consisting of C 1-8 alkyl, C 3-8 cyclohydrocarbyl, 3-8 membered heterocyclohydrocarbyl, 6-8 membered aryl and 5-8 membered heteroaryl.

2. The pharmaceutical combination according to claim 1 , wherein the compound of formula I or the pharmaceutically acceptable salt thereof is selected from the group consisting of:
2-butoxy-7-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(3-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
7-(3-(aminomethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(3-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((3,3-difluoropyrrolidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((3-fluoropyrrolidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)benzyl) pyrrolidin-3-ol;
2-butoxy-7-(4-(piperidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((dimethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((diethylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((dipropylamino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
7-(4-(azetidin-1-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((3-methoxylazetidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(4-methyl-1,4-diazepan-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((2,6-dimethylmorpholino)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
7-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)benzyl)-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((4-methoxypiperidin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-((4-isopropylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((6-(pyrrolidin-1-ylmethyl) pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(3-(2-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(1-(pyrrolidin-1-yl)ethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(1-methylpiperidin-4-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-(4-(1-methylpyrrolidin-2-yl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
1-(4-((4-amino-2-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;
7-benzyl-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-(2-methoxyethoxy)-7-((6-methylpyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
7-((5-chloropyridin-2-yl)methyl)-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-(2-methoxyethoxy)-7-((6-(pyrrolidin-1-ylmethyl) pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
1-(4-((4-amino-2-(2-methoxyethoxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)phenyl)-4-methylpiperazin-2-one;
2-butoxy-7-((5-(pyrrolidin-1-ylmethyl) pyridin-2-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
4-amino-2-butoxy-7-((6-(pyrrolidin-1-ylmethyl) pyridin-3-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carbonitrile;
4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carbonitrile;
4-amino-2-butoxy-7-(4-(morpholinomethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carbonitrile;
4-amino-2-butoxy-7-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carbonitrile;
4-amino-2-butoxy-7-(4-(pyrrolidin-1-ylmethyl)benzyl)-5H-pyrrolo[3,2-d]pyrimidin-6-carboxamide;
2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;
2-butoxy-7-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; and
2-butoxy-7-((2-(pyrrolidin-1-ylmethyl) thiazol-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical combination according to claim 1 , wherein the compound of formula I in the pharmaceutical combination is selected from a compound of formula A:

4. The pharmaceutical combination according to claim 1 , wherein entecavir or the pharmaceutically acceptable salt or solvate thereof is selected from the group consisting of entecavir maleate, entecavir monomaleate, entecavir hydrate, entecavir 0.5-2 hydrate, and entecavir monohydrate.

5. The pharmaceutical combination according to claim 4 , wherein entecavir or the pharmaceutically acceptable salt or solvate thereof is selected from entecavir monomaleate monohydrate.

6. The pharmaceutical combination according to claim 1 , wherein an average daily dose ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to entecavir or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical combination is selected from 10:1 to 1:10.

7. The pharmaceutical combination according to claim 6 , wherein the average daily dose ratio is selected from the group consisting of 1:1.5 to 1:4, 1:1.6 to 1:3.8, 1:1.8 to 1:3.8, 1:1.8 to 1:3.6 and 1:2 to 1:3.5.

8. The pharmaceutical combination acc

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Xu Hongjiang
• Lu Dandan
• Ge Xingfeng
• Song Wei
• Shi Wei
• Yang Ling
• Zhang Xiquan
• Yu Hao
• Xu Zhongnan

Classifications

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K9/2893

  Tablet coating processes (mechanical aspects A61J3/06) · CPC title

• A61P31/12 Primary

  Antivirals · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P31/20

  for DNA viruses · CPC title