Antiviral activity of novel bicyclic heterocycles

Patent metadata

Field	Value
Publication number	US-9730944-B2
Application number	US-201514884997-A
Country	US
Kind code	B2
Filing date	Oct 16, 2015
Priority date	May 26, 2010
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The present invention relates to compound of Formula I, II, III, or IV, and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, and R12 are as defined in the claim 1 or as described in detail in the description of the invention, and to the use of said compounds to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with RNA-viruses belonging to the family of the Retroviridae, the family of the Flaviviridae and the family of the Picornaviridae and more preferably infections with Human Immunodeficiency Virus 1 (HIV1), Human Immunodeficiency Virus 2 (HIV2), Hepatitis C virus (HCV), Dengue virus, and enteroviruses like Coxsackievirus, Rhinovirus and Poliovirus. The present invention also relates to pharmaceutical compositions of said compounds and the use of said pharmaceutical compositions to treat or prevent viral infections. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of viral disorders and pathologic conditions such as, but not limited to, viral infections with Human Immunodeficiency Virus 1 (HIV1), Human Immunodeficiency Virus 2 (HIV2), Hepatitis C virus (HCV), Dengue virus, and enteroviruses like Coxsackievirus, Rhinovirus and Poliovints.

First claim

The invention claimed is:

1. A method of preventing or treating a viral infection in an animal, mammal, or human in need thereof, the method comprising administering to the animal, mammal, or human an effective amount of a composition comprising a compound having the general formula III or IV:

wherein
R 12 is represented by the general formula V:

 and wherein

 schematically represents a saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and optionally with one or more other heteroatoms in the said heterocyclic ring or attached to one or more carbon atoms of said heterocyclic ring, wherein one of said at least two nitrogen atoms in the heterocyclic ring is attached to a carbon atom 6 of the purine ring;
each substituent R 13 of the heterocyclic ring is a group independently selected from the group consisting of halogen, nitro, C 1-7 alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, C 1-7 alkoxy, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, C 1-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), C 3-7 alkenyl, C 2-7 alkynyl, halo C 1-7 alkyl, C 3-10 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, sulfhydryl, amino, C 1-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, C 1-7 alkoxy, C 3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, (thio)carboxylic acid or esters or thioesters or amides or thioamides thereof;
n is an integer from 0 to 6;
R 10 is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C 3-10 cycloalkyl-alkyl, C 3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, halo C 1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C 1-7 alkoxy, C 3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and
R 11 is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C 1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C 1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C 3-10 cycloalkylamino, (mono- or di) hydroxy C 1-7 alkylamino, (mono- or di) C 1-4 alkyl-arylamino, mercapto C 1-7 alkyl, and C 1-7 alkyloxy;
R 8 is selected from the group consisting of heteroaryl and aryl groups, halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, halo C 1-7 alkyl, carboxy C 1-7 alkyl, carboxyaryl, C 1-7 alkoxy, C 3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, hydroxylamino, acylamino, thio-acylamino, alkoxyamino, thioalkyl-amino, acetal, thio-acetal, carboxylic acid, carboxylic acid esters or thioesters or halides or anhydrides or amides or thioamides thereof, thiocarboxylic acid, thiocarboxylic acid esters or thioesters or halides or anhydrides or amides or thioamides thereof, hydroxyl, sulfhydryl, nitro, cyano, carbamoyl, thiocarbamoyl, ureido, thioureido, amino, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkyl-amino, heterocyclic amino, heterocyclic substituted arylamino, heterocyclic-substituted alkyl-amino, oximino, alkyloximino, hydrazino, alkylhydrazino, phenylhydrazino, esters, thioesters, halides, anhydrides, amides and thioamides thereof, and aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, halo C 1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C 1-7 alkoxy, C 3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C 1-7 alkyl, thio C 3-10 cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino,

Assignees

• De Jonghe Steven
• Gao Ling-Jie
• Herdewijn Piet
• Herman Jean
• Jang Miyeon
• Leyssen Pieter
• Louat Thierry
• Neyts Johan
• Pannecouque Christophe
• Vanderhoydonck Bart
• Univ Leuven Kath

Inventors

• De Jonghe Steven
• Gao Ling-Jie
• Herdewijn Piet
• Herman Jean
• Jang Miyeon
• Leyssen Pieter
• Louat Thierry
• Neyts Johan
• Pannecouque Christophe
• Vanderhoydonck Bart

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/551 Primary

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title