HIV replication inhibiting pyrimidines

Patent metadata

Field	Value
Publication number	US-9580392-B2
Application number	US-201414451761-A
Country	US
Kind code	B2
Filing date	Aug 5, 2014
Priority date	Aug 13, 2001
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

This invention concerns HIV replication inhibitors of formula

the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R 1 is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; substituted C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; R 2 is hydroxy, halo, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6 or a 5-membered heterocycle; X 1 is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- or —C 1-4 alkanediyl-X 2 —; R 3 is NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxyC 1-6 alkyl; substituted C 2-6 alkenyl; substituted C 2-6 alkynyl; C 1-6 alkyl substituted with hydroxy and a second substituent; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; or —X 3 —R 7 ; R 4 is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A combination containing (a) a compound of formula (I)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
-a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of formula:
—CH═CH—CH═CH—  (a-1);

-b 1 =b 2 -b 3 =b 4 - represents a bivalent radical of formula:
—CH═CH—CH═CH—  (b-1);

n is 0, 1, 2, 3, 4, or 5;
m is 1, 2, 3, or 4;
R l is selected from the group consisting of: hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with a member selected from the group consisting of: formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, and C 1-6 alkylcarbonyloxy; and C 1-6 alkyloxyC 1-6 alkylcarbonyl, wherein said C 1-6 alkyloxyC 1-6 alkylcarbonyl is substituted with C 1-6 alkyloxycarbonyl;
each R 2 independently is selected from the group consisting of: hydroxy, halo, C 1-6 alkyl optionally substituted with cyano or —C(═O)R 6 , C 3-7 cycloalkyl, C 2-6 alkenyl optionally substituted with one or more halogen atoms or cyano, C 2-6 alkynyl optionally substituted with one or more halogen atoms or cyano, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 ,—C(═NH)R 6 and a radical of formula

 wherein each A 1 independently is N, CH or CR 6 ; and
A 2 is NH, O, S or NR 6 ;

X 1 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- and —C 1-4 alkanediyl-X 2 —;
X 2 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, and —S(═O) p —;
R 3 is R 7 ;
X 3 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a —, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, and —C(═N—OR 8 )—C 1-4 alkanediyl-;
with X 2a being selected from the group consisting of: —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, and —S(═O) p —; and
with X 2b being selected from the group consisting of: —NH—NH—, —N═N—, —C(═O)—, —S—, and —S(═O) p —;

R 4 is selected from the group consisting of: halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino and R 7 ;
R 5 is selected from the group consisting of: hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with a member selected from the group consisting of: formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl and C 1-6 alkylcarbonyloxy; and C 1-6 alkyloxyC 1-6 alkylcarbonyl, wherein said C 1-6 alkyloxyC 1-6 alkylcarbonyl is substituted with C 1-6 alkyloxycarbonyl;
R 6 is C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino or polyhaloC 1-4 alkyl;
R 7 is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, —CH(═N—O—R 8 ), R 7a , —X 3 —R 7a and R 7a —C 1-4 alkyl;
R 7a is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein each of said carbocyclic or heterocyclic ring systems may optionally be substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, formyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, and —CH(═N—O—R 8 );
R 8 is selected from the group consisting of: hydrogen, C 1-4 alkyl, aryl and arylC 1-4 alkyl;
p is 1 or 2;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from the group consisting of: halo, hydroxy, mercapto, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono or di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, C 1-6 alkylthio, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, R 7 and —X 3 —R 7 ; and (b) another antiretroviral compound.

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
-a 1 =a 2 -a 3 =a 4 - represents a bivalent radical of a formula:
—CH═CH—CH═CH—  (a-1);

-b 1 =b 2 -b 3 =b 4 - represents a bivalent radical of a formula:
—CH═CH—CH═CH—(b-1);

n is 0, 1, 2, 3, or 5;
m is 1, 2, 3, or 4;
R 1 is selected from the group consisting of: hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl, wherein said C 1-6 alkyl is substituted with a member selected from the group consisting of: formyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, and C 1-6 alkylcarbonyloxy; and C 1-6 alkyloxyC 1-6 alkylcarbonyl wherein said C 1-6 alkyloxyC 1-6 alkylcarbonyl is substituted with C 1-6 alkyloxycarbonyl;
each R 2 independently is selected from the group consisting of: hydroxy, halo, C 1-6 alkyl optionally substituted with cyano or —C(═O)R 6 , C 3-7 cycloalkyl, C 2-6 alkenyl optionally substituted with one or more halogen atoms or cyano, C 2-6 alkynyl optionally substituted with one or more halogen atoms or cyano, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 ,—C(═NH)R 6 and a radical of formula

 wherein each A 1 independently is N, CH or CR 6 ; and
A 2 is NH, O, S or NR 6 ;

X 1 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- and —C 1-4 alkanediyl-X 2 —;
X 2 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, and —S(═O) p —;
R 3 is R 7 ;
X 3 is selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl-, —C 1-4 alkanediyl-X 2a —, —C 1-4 alkanediyl-X 2b —C 1-4 alkanediyl, and —C(═N—OR 8 )—C 1-4 alkanediyl-;
with X 2a being selected from the group consist

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Guillemont Jérôme Emile Georges
• Janssen Paul Adriaan Jan
• Palandjian Patrice
• De Jonge Marc René
• Koymans Lucien Maria Henricus
• Vinkers Hendrik Maarten
• Daeyaert Frederik Frans Desiré
• Heeres Jan
• Van Aken Koen Jeanne Alfons
• Lewi Paulus Joannes

Classifications

• A61P31/18

  for HIV · CPC title

• A61P43/00

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

• A61P31/00

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

• A61P31/14

  for RNA viruses · CPC title

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title