Furaneone glycoside compound, pharmaceutical composition thereof, preparation method therefor, and application thereof

Patent metadata

Field	Value
Publication number	US-11673909-B2
Application number	US-202017786133-A
Country	US
Kind code	B2
Filing date	Dec 18, 2020
Priority date	Dec 20, 2019
Publication date	Jun 13, 2023
Grant date	Jun 13, 2023

Abstract

Disclosed are a furaneone glycoside compound, a pharmaceutical composition thereof, a preparation method therefor, and an application thereof. Specifically disclosed are a compound as represented by formula A-1, a pharmaceutically acceptable salt thereof or a crystal form thereof. Also disclosed is a pharmaceutical composition, which comprises the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant. Also disclosed is an application of the compound as represented by formula A-1, the pharmaceutically acceptable salt thereof, the crystal form thereof, or the pharmaceutical composition in the preparation of drugs. The drugs are drugs for treating inflammatory bowel diseases. The furaneone glycoside compound has a good effect of treating inflammatory bowel diseases, particularly ulcerative colitis.

First claim

What is claimed is:

1. A compound represented by formula A-1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystal form thereof,

wherein R 1 , R 2 , R 3 , and R 4 are independently hydrogen, C 1-4 alkyl, benzyl, —C(═O)R, or —C(═O)—O—R′, and R 1 , R 2 , R 3 , and R 4 are not simultaneously hydrogen;
each R′ is independently C 1-4 alkyl;
each R is independently C 1-4 alkyl or phenyl;
R 5 and R 6 are independently hydrogen, or R 5 and R 6 are taken together to form ═O;
R 8 and R 9 are independently C 1-4 alkyl;
alternatively, R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered cycloalkyl substituted with one or a plurality of R a , or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b ; in the 3- to 7-membered heterocycloalkyl and the 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b , the heteroatoms in the 3- to 7-membered heterocycloalkyl are independently selected from N, O, and S, and the number of heteroatoms is independently 1, 2, or 3;
R a and R b are independently C 1-4 alkyl, —C(═O)R″;
each R″ is independently C 1-4 alkyl;
carbon atoms marked with “*” indicate that when the carbon atoms are chiral, the carbon atoms are in the R-configuration, S-configuration, or a mixture of R-configuration and S-configuration.

2. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 1 , wherein the structure of the compound represented by formula A-1 is as follows:

wherein R 1 , R 2 , R 3 , and R 4 are independently hydrogen, C 1-4 alkyl, benzyl or —C(═O)R, and R 1 , R 2 , R 3 , and R 4 are not simultaneously hydrogen;
each R is independently C 1-4 alkyl or phenyl.

3. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 1 , wherein when R 1 , R 2 , R 3 , and R 4 are independently C 1-4 alkyl, then the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
or, each R′ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
or, when each R is independently C 1-4 alkyl, then the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
or, when R 8 and R 9 are independently C 1-4 alkyl, then the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
or, when R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl or 3- to 7-membered cycloalkyl substituted with one or a plurality of R a , then the 3- to 7-membered cycloalkyl is a 5- to 6-membered cycloalkyl;
or, when R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b , in the 3- to 7-membered heterocycloalkyl, the heteroatoms are independently selected from N and O, and the number of heteroatoms is independently 1;
or, when R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b , then the 3- to 7-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl;
or, when R a and R b are independently C 1-4 alkyl, then the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
or, each R″ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

4. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 3 , wherein when 10, R 2 , R 3 , and R 4 are independently C 1-4 alkyl, then the C 1-4 alkyl is methyl;
or, each R′ is independently ethyl;
or, when each R is independently C 1-4 alkyl, then the C 1-4 alkyl is methyl or tert-butyl;
or, when R 8 and R 9 are independently C 1-4 alkyl, then the C 1-4 alkyl is methyl;
or, when R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl, then

or, each R″ is independently methyl;
or, when R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b , then

5. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvent thereof, or the crystal form thereof as claimed in claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are independently hydrogen, C 1-4 alkyl, —C(═O)R, or —C(═O)—O—R′;
or, each R is independently C 1-4 alkyl;
or, R a and R b are independently —C(═O)R″;
or, R 8 and R 9 are independently C 1-4 alkyl, or, R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, or 3- to 7-membered heterocycloalkyl substituted with one or a plurality of R b ;
or,

6. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 5 ,
wherein R 1 is C 1 -4 alkyl, —C(═O)R, or —C(═O)—O—R′;
or, when R 5 and R 6 are independently hydrogen, then R 1 is —C(═O)R or —C(═O)—O—R′; when R 5 and R 6 are taken together to form ═O, then R 1 is C 1-4 alkyl;
or, R 2 and R 3 and R 4 are independently hydrogen or —C(═O)R;
or, each R is independently methyl or tert-butyl;
or, R a and R b are independently

or, R 8 and R 9 are independently C 1-4 alkyl, or, R 8 and R 9 are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl;
or,

7. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 5 , wherein R 1 is methyl,

or, R 2 , R 3 , and R 4 are independently hydrogen,

or, R 2 , R 3 , and R 4 are the same group;
or,

8. The compound represented by formula A-1, the pharmaceutically acceptable salt thereof, the solvate thereof, or the crystal form thereof as claimed in claim 2 , wherein R 1 , R 2

Assignees

• Univ Fudan

Inventors

• Chang Jun
• Jin Lin
• Zhang Heyanhao
• Niu Tong

Classifications

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title