US 2017/0320835 A1 · HIV REPLICATION INHIBITING PYRIMIDINES

Hiv replication inhibiting pyrimidines

AssigneeJanssen Pharmaceutica NV

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

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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 -a1=a2-a3=a4- and -b1=b2-b3=b4- represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl; C1-6alkyloxycarbonyl; substituted C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy; substituted C1-6alkyloxyC1-6alkylcarbonyl; R2 is hydroxy, halo, optionally substituted C1-6alkyl, C3-7cycloalkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR6, —NH—S(═O)pR6, —C(═O)R6, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R6, —C(═NH)R6 or a 5-membered heterocycle; X1 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- or —C1-4alkanediyl-X2—; R3 is NHR13; NR13R14; —C(═O)—NHR13; —C(═O)—NR13R14; —C(═O)—R15; —CH═N—NH—C(═O)—R16; substituted C1-6alkyl; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkenyl; substituted C2-6alkynyl; C1-6alkyl substituted with hydroxy and a second substituent; —C(═N—O—R8)—C1-4alkyl; R7; or —X3—R7; R4 is halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

Claims8

Dependent claims

-15. (canceled)

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
-a1=a2-a3=a4- represents a bivalent radical of formula
—CH═CH—CH═CH— (a-1);
-b1=b2-b3=b4- 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;
R1 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 R2 is independently selected from:
hydroxy;
halo;
C1-6alkyl optionally substituted with cyano or —C(═O)R6;
C3-7cycloalkyl;
C2-6alkenyl optionally substituted with one or more halogen atoms or cyano;
C2-6alkynyl optionally substituted with one or more halogen atoms or cyano;
C1-6alkyloxycarbonyl;
carboxyl;
cyano;
nitro;
amino;
mono- or di(C1-6alkyl)amino;
polyhalomethyl;
polyhalomethylthio;
—S(═O)pR6;
—NH—S(═O)pR6;
—C(═O)R6;
—NHC(═O)H;
—C(═O)NHNH2;
—NHC(═O)R6;
—C(═NH)R6 and a radical of formula
wherein each A1 is independently selected from the group consisting of:
N, CH and CR6;
and
A2 is selected from the group consisting of:
NH, O, S and NR6;
X1 is selected from the group consisting of:
—NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- and —C1-4alkanediyl-X2—;
X2 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)p—;
R3 is C1-6alkyl substituted with R7;
R4 is selected from the group consisting of:
halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino and R7;
R5 is hydrogen;
R6 is selected from the group consisting of:
C1-4alkyl;
amino;
mono- or di(C1-4alkyl)amino;
and polyhaloC1-4alkyl;
R7 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3-R7a and R7a—C1-4alkyl;
R7a 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8);
R8 is selected from the group consisting of:
hydrogen, C1-4alkyl, aryl and arylC1-4alkyl;
X3 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, —C(═N—OR8)—C1-4alkanediyl-;
with X2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—;
and
with X2b 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7 and —X3—R7;
and (b) another antiretroviral compound.

74 more elements

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
-a1=a2-a3=a4- represents a bivalent radical of formula
—CH═CH—CH═CH— (a-1);
-b1=b2-b3=b4- represents a bivalent radical of formula
—CH═CH—CH═CH— (b-1);
n is 0, i, 2, 3, or 4;
m is 1, 2, 3, or 4;
R1 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 R2 is independently selected from:
hydroxy;
halo;
C1-6alkyl optionally substituted with cyano or —C(═O)R6;
C3-7cycloalkyl;
C2-6alkenyl optionally substituted with one or more halogen atoms or cyano;
C2-6alkynyl optionally substituted with one or more halogen atoms or cyano;
C1-6alkyloxycarbonyl;
carboxyl;
cyano;
nitro;
amino;
mono- or di(C1-6alkyl)amino;
polyhalomethyl;
polyhalomethylthio;
—S(═O)pR6;
—NH—S(═O)pR6;
—C(═O)R6;
—NHC(═O)H;
—C(═O)NHNH2;
—NHC(═O)R6;
—C(═NH)R6 and a radical of formula
wherein each A1 is independently selected from the group consisting of:
N, CH and CR6;
and
A2 is selected from the group consisting of:
NH, O, S and NR6;
X1 is selected from the group consisting of:
—NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, C1-4alkanediyl, —CHOH—, —S—, —S(═O)p—, —X2—C1-4alkanediyl- and —C1-4alkanediyl-X2—;
X2 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)p—;
R3 is C1-6alkyl substituted with R7;
R4 is selected from the group consisting of:
halo, hydroxy, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyl, formyl, amino, mono- or di(C1-4alkyl)amino and R7;
R5 is hydrogen;
R6 is selected from the group consisting of:
C1-4alkyl;
amino;
mono- or di(C1-4alkyl)amino;
and polyhaloC1-4alkyl;
R7 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, —CH(═N—O—R8), R7a, —X3-R7a and R7a—C1-4alkyl;
R7a 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, and —CH(═N—O—R8);
R8 is selected from the group consisting of:
hydrogen, C1-4alkyl, aryl and arylC1-4alkyl;
X3 is —NR5—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—, —X2—C1-4alkanediyl-, —C1-4alkanediyl-X2a—, —C1-4alkanediyl-X2b—C1-4alkanediyl, —C(═N—OR8)—C1-4alkanediyl-;
with X2a being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)p—;
and
with X2b 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, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, R7 and —X3—R7;
and (b) another antiretroviral compound.

74 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/655,570Filed 20 Jul 2017

Priority

EP 01203090.413 Aug 2001

Published

9 Nov 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 239/48
Two or more oxygen, sulphur or nitrogen atoms: two nitrogen atoms
A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol

Family

Application10/485,636Continuation · filed 3 Feb 2004

Application11/474,855Continuation · filed 26 Jun 2006

Application13/249,796Division · filed 30 Sep 2011

Application14/451,761Continuation · filed 5 Aug 2014

Application15/406,918Continuation · filed 16 Jan 2017

Application15/655,570Continuation

Application14/451,761Division

Application13/249,796Continuation

US 2004/0198739 A1Published application

US 2006/0252764 A1Published application

US 2012/0076835 A1Published application