HIV replication inhibiting pyrimidines

Patent metadata

Field	Value
Publication number	US-10611732-B2
Application number	US-201916460898-A
Country	US
Kind code	B2
Filing date	Jul 2, 2019
Priority date	Aug 13, 2001
Publication date	Apr 7, 2020
Grant date	Apr 7, 2020

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; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl; C 1-6 alkyl 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 substituted with C 1-6 alkyloxycarbonyl;
each R 2 is independently 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; 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 selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S— and —S(═O) p —;
R 3 is C1-6alkyl substituted with R 7 ;
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 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 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;
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, 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) one or more immunomodulating agents.

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; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkyl; C 1-6 alkyl 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 substituted with C 1-6 alkyloxycarbonyl;
each R 2 is independently selected from: 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 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 selected from the group consisting of: —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S— and —S(═O) p —;
R 3 is C 1-6 alkyl substituted with R 7 ;
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 -4alkyl)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 a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle; or a monocyclic, bicyclic or tricyclic satura

Assignees

• 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

• A61K31/505

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

• A61P31/14

  for RNA viruses · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C257/12

  having carbon atoms of amidino groups bound to hydrogen atoms · CPC title