Six-membered ring benzo derivatives as DPP-4 inhibitor and use thereof

Patent metadata

Field	Value
Publication number	US-10479798-B2
Application number	US-201515523058-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Oct 31, 2014
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

Abstract

The present invention relates to six-membered ring benzo derivatives as a DPP-4 inhibitor and a use thereof. In particular, the present invention relates to a compound as shown in formula I, a pharmaceutical composition containing the compound as shown in formula I and a use of the compound in the preparation of drugs for treating DPP-4 related diseases or inhibiting DPP-4.

First claim

The invention claimed is:

1. A compound having formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:

wherein:
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C 1-6 alkyl, a C 1-6 alkyl substituted by halogen, a C 1-6 alkoxy, or a C 1-6 alkoxy substituted by halogen;
A is a nitrogen-containing, or sulfur-containing five-membered or six-membered saturated or unsaturated heterocycle with 1 to 4 substituents, wherein each substituent is independently a halogen, a cyano, or a boronic acid group; or
A is a heterocycle selected from the following structures:

R is H, a halogen, a cyano, a hydroxy, a C 1-6 alkyl, C 1-6 alkyl with 1 to 5 F atoms, C 1-6 alkoxy, or C 1-6 alkoxy with 1 to 5 F atoms;
n is an integer of 1-2;
Ring B is an aromatic benzene ring, an aromatic heterocycle, a saturated or unsaturated 5-membered or 6-membered ring, a nitrogen-, oxygen-, or sulfur-containing five- or six-membered saturated or unsaturated heterocycle;
R 1 is independently selected from the group consisting of a halogen, a cyano, a hydroxy, a C 1-6 alkyl, a C 1-6 alkyl group containing 1 to 5 F atoms, a C 1-6 alkoxy, a C 1-10 alkylcarbonyloxy, a C 1-3 alkoxymethoxy, a disubstituted OCH 2 CH 2 O and OCH 2 O, COOH, a C 1-6 alkoxycarbonyl, a carbamoyl, a methylcarbamido, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, an amino, a NR 2 R 3 , a C 1-5 alkylcarboxamido, a C 3-5 alkyllactam group, a C 1-6 alkylsulfonamido, a C 3-5 alkylsultam group, a mercapto, a C 1-6 alkylthio, a C 1-6 alkylthio containing 1 to 5 F atoms, a C 1-6 alkylsulfinyl, a C 1-6 alkylsulfonyl, a C 3-5 cycloalkylsulfonyl, and a C 1-5 alkylsulfinyl, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, and a 3-pyrazolylamino;
m is an integer of 1 to 4; and
R 2 , R 3 are independently selected from a C 1-6 alkyl, or R 2 and R 3 together form a substituted or unsubstituted 5- or 6-membered heterocycloalkyl, or a substituted or unsubstituted 5-or 6-membered heterocycle group additionally containing N or O.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (II):

wherein,
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C 1-6 alkyl, a C 1-6 alkyl substituted by halogen, a C 1-6 alkoxy, or a C 1-6 alkoxy substituted by halogen;
R 4 is H, a hydroxyl, F, or a cyano;
R 5 is a halogen, a cyano, a hydroxyl, a mercapto, a C 1-6 alkyl group, a C 1-6 alkyl group containing 1 to 5 F atoms, a C 1-6 alkoxy, a C 1-10 alkylcarbonyloxy, a C 1-3 alkoxymethyloxy, COOH, a C 1-6 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a C 1-6 alkylthio, a C 1-6 alkylthio containing 1 to 5 F atoms, a C 1-6 alkylsulfinyl, a C 1-6 alkylsulfonyl, an amino, an acetylamino, a methanesulfonamido, a methylcarbamido, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, a 4-morpholinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
q is an integer of 1-4.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (II):

wherein,
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C 1-6 alkyl, a C 1-6 alkyl substituted by halogen, a C 1-6 alkoxy, or a C 1-6 alkoxy substituted by halogen;
R 4 is H, a hydroxyl, F, or a cyano;
R 5 is a halogen, a cyano, a hydroxyl, a mercapto, a C 1-6 alkyl group, a C 1-6 alkyl group containing 1 to 5 F atoms, a C 1-6 alkoxy, a C 1-3 alkoxymethyloxy, COOH, a C 1-6 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a C 1-6 alkylthio,-a C 1-6 alkylthio containing 1 to 5 F atoms, a C 1-6 alkylsulfinyl, a C 1-6 alkylsulfonyl, an amino, an acetylamino, a methanesulfonamido, a methylcarbamido, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, a 4-morpholinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
q is an integer of 1-4.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (III):

wherein
X is O
R 4 is H or a hydroxyl;
R 6 , R 7 are independently a hydrogen, a halogen, a cyano, a hydroxy, a mercapto, a C 1-2 alkoxy, a C 1-2 alkylcarbonyloxy, a C 1-3 alkoxymethoxy, COOH, a C 1-2 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a methylthio, a methylsulfinyl, a methanesulfonyl, an amino, acetamido, methanesulfonamido, a methylcarbamido, N-propanesulfonyllactam group, N-butanesulfonyllactam group, a 4-morphinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
R 8 , R 9 and R 10 are independently H, Cl, F, or a cyano.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (III):

wherein
X is O;
R 4 is H or a hydroxyl;
R 6 , R 7 are independently selected from a hydrogen, a halogen, a cyano, a hydroxy, a mercapto, a C 1-2 alkoxy, a C 1-3 alkoxymethoxy, COOH, a C 1-2 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a methylthio, a methylsulfinyl, a methanesulfonyl, an amino, acetamido, methanesulfonamido, a methylcarbamido, N-propanesulfonyllactam group, N-butanesulfonyllactam group, a 4-morphinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
R 8 , R 9 and R 10 are independently H, Cl, F, or a cyano.

6. The compound of claim 1 , or

Assignees

• Univ East China Science & Tech
• Shanghai Inst Materia Medica Cas

Inventors

• Li Honglin
• Jiang Hualiang
• Xu Yufang
• Li Jia
• Zhao Zhenjiang
• Li Jingya
• Xu Hongling
• Li Shiliang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

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