HIV replication inhibiting pyrimidines

Patent metadata

Field	Value
Publication number	US-9981919-B2
Application number	US-201715655570-A
Country	US
Kind code	B2
Filing date	Jul 20, 2017
Priority date	Aug 13, 2001
Publication date	May 29, 2018
Grant date	May 29, 2018

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 or 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 1 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl; C1-6alkyl substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl;
each R 2 is independently selected from: hydroxy; halo; C1-6alkyl 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; C1-6alkyloxycarbonyl; 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 is independently selected from the group consisting of: N, CH and CR 6 ; and
A 2 is selected from the group consisting of: NH, O, S and 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 —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O) p —;
R 3 is C1-6alkyl substituted with R 7 ;
R 4 is selected from the group consisting of: halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino and R 7 ;
R 5 is hydrogen;
R 6 is selected from the group consisting of: C 1-4 alkyl; amino; mono- or di(C 1-4 alkyl)amino; and polyhaloC 1-4 alkyl;
R 7 is selected from the group consisting of: 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, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, 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, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, 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;
X 3 is —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, —C(═N—OR 8 )—C 1-4 alkanediyl-;
with X 2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O) p —; and
with X 2b being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O) p —;

p is 1 or 2; and
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, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl, C 3-7 cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, 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 or 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, or 4;
m is 1, 2, 3, or 4;
R 1 is selected from the group consisting of: hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl; C1-6alkyl substituted with a member selected from the group consisting of: formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, and C1-6alkylcarbonyloxy; and C1-6alkyloxyC1-6alkylcarbonyl substituted with C1-6alkyloxycarbonyl;
each R 2 is independently selected from: hydroxy; halo; C1-6alkyl 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; C1-6alkyloxycarbonyl; 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 is independently selected from the group consisting of: N, CH and CR 6 ; and
A 2 is selected from the group consisting of: NH, O, S and 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 —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O) p —;
R 3 is C1-6alkyl substituted with R 7 ;
R 4 is selected from the group consisting of: halo, hydroxy, C1-6alkyl, C 3-7 cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino and R 7 ;
R 5 is hydrogen;
R 6 is selected from the group consisting of: C 1-4 alkyl; amino; mono- or di(C 1-4 alkyl)amino; and polyhaloC 1-4 alkyl;
R 7 is selected from the group consisting of: 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

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Guillemont Jérôme Emile Georges
• 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
• Janssen Paul Adriaan Jan

Classifications

• A61P31/18

  for HIV · CPC title

• A61P31/00

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

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

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

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title