4-amino-imidazoquinoline compounds

Patent metadata

Field	Value
Publication number	US-9334268-B2
Application number	US-201514692968-A
Country	US
Kind code	B2
Filing date	Apr 22, 2015
Priority date	Apr 22, 2014
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

This invention relates to novel 4-amino-imidazoquinoline compounds of the formula

wherein R 1 to R 4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer or infectious diseases.

First claim

What is claimed is:

1. A compound of formula I

wherein
R 1 is C 1-7 -alkyl or C 1-7 -alkoxy-C 1-7 -alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy-C 1-7 -alkyl, alkoxy-C 1-7 -alkyl, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 2-7 -alkenyl, aminocarbonyl-C 1-7 -alkyl, aminocarbonyl-C 2-7 -alkenyl, C 1-7 -alkylamino-carbonyl-C 1-7 -alkyl, C 1-7 -alkylamino-carbonyl-C 2-7 -alkenyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 2-7 -alkenyl, C 1-7 -alkyl-sulfonyl-C 1-7 -alkyl, sulfamoyl-C 1-7 -alkyl, C 1-7 -alkyl-sulfamoyl-C 1-7 -alkyl,
phenyl, said phenyl being unsubstituted or substituted with one, two or three groups selected from the group consisting of C 1-7 -alkyl, C 1-7 -cycloalkyl, halogen, halogen-C 1-7 -alkyl, halogen-C 1-7 -alkoxy, hydroxy, hydroxy-C 1-7 -alkyl, C 1-7 -alkoxy, cyano, carboxyl, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, hydroxy-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-C 1-7 -alkylsulfonyl, carboxyl-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-carbonyl-C 1-7 -alkylsulfonyl, amino, C 1-7 -alkylamino, di-C 1-7 -alkylamino and nitro, and
phenoxy, said phenoxy group being unsubstituted or substituted with one, two or three groups selected from the group consisting of C 1-7 -alkyl, C 1-7 -cycloalkyl, halogen, halogen-C 1-7 -alkyl, halogen-C 1-7 -alkoxy, hydroxy, hydroxy-C 1-7 -alkyl, C 1-7 -alkoxy, cyano, carboxyl, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkyl-sulfonyl, hydroxy-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-C 1-7 -alkylsulfonyl, carboxyl-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-carbonyl-C 1-7 -alkylsulfonyl, amino, C 1-7 -alkylamino, di-C 1-7 -alkylamino and nitro;

R 3 is hydrogen or halogen;
R 4 is selected from the group consisting of
—O—(CH 2 ) m —NHR 5 , and
—O—(CO)—(CH 2 ) n —NHR 6 ,
wherein
m is selected from 1, 2 or 3,
n is selected from 1 or 2,
R 5 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl, and
R 6 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl,

or a pharmaceutically acceptable salt thereof.

2. A compound of formula I according to claim 1 , wherein R 1 is C 1-7 -alkoxy-C 1-7 -alkyl.

3. A compound of formula I according to claim 1 , wherein R 1 is ethoxyethyl.

4. A compound of formula I according to claim 1 , wherein R 3 is hydrogen.

5. A compound of formula I according to claim 1 , wherein R 4 is —O—(CH 2 ) m —NHR 5 and wherein m is selected from 1, 2 or 3 and wherein R 5 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl.

6. A compound of formula I according to claim 5 , wherein m is 2.

7. A compound of formula I according to claim 5 , wherein R 5 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, heteroarylcarbonyl and C 1-7 -alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl.

8. A compound of formula I according to claim 5 , wherein R 5 is hydrogen.

9. A compound of formula I according to claim 1 , wherein R 4 is —O—(CO)—(CH 2 ) n —NHR 6 and wherein n is selected from 1 or 2 and wherein R 6 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl.

10. A compound of formula I according to claim 9 , wherein n is 1.

11. A compound of formula I according to claim 9 , wherein R 6 is hydrogen.

12. A compound of formula I according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy-C 1-7 -alkyl, alkoxy-C 1-7 -alkyl, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 2-7 -alkenyl, aminocarbonyl-C 1-7 -alkyl, aminocarbonyl-C 2-7 -alkenyl, C 1-7 -alkylamino-carbonyl-C 1-7 -alkyl, C 1-7 -alkylamino-carbonyl-C 2-7 -alkenyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 2-7 -alkenyl, C 1-7 -alkyl-sulfonyl-C 1-7 -alkyl, sulfamoyl-C 1-7 -alkyl and C 1-7 -alkyl-sulfamoyl-C 1-7 -alkyl.

13. A compound of formula I according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, halogen, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 2-7 -alkenyl.

14. A compound of formula I according to claim 1 , wherein R 2 is hydrogen.

15. A compound of formula I according to claim 1 , selected from the group consisting of
1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,
1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl 2-aminoacetate,
N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)nicotinamide,
N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)acetamide,
3-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ol,
tert-butyl 6-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)-6-oxohexylcarbamate,
ethyl (E)-3-[4-amino-1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate,
ethyl 3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,
ethyl 3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,
1-(2-(2-aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine, and
1-(2-(2-aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, or a pharmaceutically acceptable salt thereof.

16. A compound of formula I according to claim 1 , which is 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, or a pharmaceutically acceptable salt thereof.

17. A compound of formula I which is 1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl 2-aminoacetate, or a pharmaceutically acceptable salt thereof.

18. A compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, for use as medicament.

19. A pharmaceutical composition comprising a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or adjuvant.

20. A pharmaceutical composition comprising a compound of formula I according to claim 16 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or adjuvant.

21. A pharmaceutical composition comprising a compound of formula I according to claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or adjuvant.

22. A compound of formula I which is ethyl 3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Hoves Sabine
• Kuhn Bernd
• Ricklin Fabienne
• Roever Stephan

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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