Title of Invention

"HIV INHIBITING 5-HETEROCYCLYL PYRIMIDINES"

Abstract HIV replication inhibitors of formula (I), N-oxides, pharmaceutically acceptable addition salts, quaternary amines or stereoisomeric forms (I) thereof, wherein -a=a-a=a- is -CH=CH-CH=CH, -N=CH-CH=CH-, -N=CH-N=CH-, -N=CH-CH=N-, -N=N-CH=CH-; -b1=b2-b3=b4- is -CH=CH-CH=CH-, -N=CH-CH=CH-, -N=CH-N=CH-, -N=CH-CH=N-, -N=N-CH=CH-; R1 is hydrogen; aryl; formyl; C1-6a]kylcarbonyl; optionally substituted C1-6alky!; C1-6alkyloxycarbony]; R2 is OH; halo; optionally substituted Chalky!, C2.6alkenyl or C2.6alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; -S(=O)PR6 ; C(=NH)R6 ; R2a is CN; arru'no; substituted amino; optionally substituted Cl-6alkyl; halo; optionally substituted C1-6alkyloxy; substituted carbonyl; -CH=N-NH-C(O)-R ; optionally substituted C1-6alkyloxyC1-6alkyl; substituted C2-6alkcnyl or C 2-6 alkynyl; -C(=N-O-R8)-C1-4alkyl; R7 or -X3-R7; Xt is -NR1-, -O-, -C(=O)-, -CH2, -CHOH-, -S-, -S(=O)P- R3 is CN; amino; C1-6alkyl; halo; optionally substituted C1-6alkyloxy; substituted carbonyl; -CH=N-NH-C(O)-R16 ; substituted C1-6alkyl; optionally substituted C1-6aIkyloxyC1-6alkyl; substituted C2-6alkenyl or C2-6,alkynyl; -C(=N-O-R8)-C1(alkyl; R7; -X3-R7 ; R4 is halo; OH; optionally substituted C1-6alkyl, C2-6alkenyl or C2-6alkynyl; C3-7cycloalkyl; C1-6alkyloxy; CN; nitro; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C1-4alkyl)amino or R7 ; R5 is a 5- or 6-membered completely unsaturated ring system wherein 1-4 ring members are nitrogen, oxygen or sulfur; which ring may optionally be substituted and may optionally be annelated with a benzene ring; methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of these compounds for the prevention or the treatment of HIV infection.
Full Text HIV INHIBITING 5-HETEROCYCLYL PYRIMIDINES
The present invention is concerned with pyrimidine derivatives having HIV (Human
Immunodeficiency Virus) replication inhibiting properties. The invention further relates
to methods for their preparation and pharmaceutical compositions comprising them.
The invention also relates to the use of said compounds in the prevention or the
treatment of HIV infection.
Resistance of the HIV virus against currently available HIV drugs continues to be a
major cause of therapy failure. This has led to the introduction of combination therapy
of two or more anti-HIV agents usually having a different activity profile. Significant
progress was made by the introduction of HAART therapy (Highly Active Anti-
Retroviral Therapy), which has resulted in a significant reduction of morbidity and
mortality in HIV patient populations treated therewith. HAART involves various
combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside
reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis). Current
guidelines for antiretroviral therapy recommend such triple combination therapy
regimen for initial treatment. However, these multidrug therapies do not completely
eliminate HIV and long-term treatment usually results in multidrug resistance. In
particular, half of the patients receiving anti-HIV combination therapy do not respond
fully to the treatment, mainly because of resistance of the virus to one or more drugs
used. It also has been shown that resistant virus is carried over to newly infected
individuals, resulting in severely limited therapy options for these drug-naive patients.
Therefore there is a continued need for new combinations of active ingredients that are
effective against HIV. New types of anti-HIV effective active ingredients, differing in
chemical structure and activity profile are useful in new types of combination therapy
Finding such active ingredients therefore is a highly desirable goal to achieve.
The present invention is aimed at providing particular novel series of pyrimidine
derivatives having HIV replication inhibiting properties. WO 99/50250, WO 00/27825
and WO 01/85700 disclose certain substituted aminopyrimidines and WO 99/50256
and EP-834 507 disclose aminotriazines having HIV replication inhibiting properties.
The compounds of the invention differ from prior art compounds in structure,
pharmacological activity and/or pharmacological potency. It has been found that the
introduction of a heterocyclyl group in the 5-position of specifically substituted
pyrimidines results in compounds the compounds not only acting favorably in terms of
their capability to inhibit the replication of Human Immunodeficiency Virus (HIV), but
also by their improved ability to inhibit the replication of mutant strains, in particular
strains which have become resistant to one or more known NNRTI drugs (Non
Nucleoside Reverse Transcriptase Inhibitor drugs), which strains are referred to as drug
or multidrug resistant HIV strains.
Thus in one aspect, the present invention concerns compounds of formula
the JV-oxides, pharmaceutically acceptable addition salts, quaternary amines or
stereochemically isomeric forms thereof, wherein
n is 0, 1, 2, 3 and in case -a'=a2-a3=a4- is (a-1), then n may also be 4;
m is 0, 1, 2, 3 and in case -b1=b2-b3=b4- is (b-1), then m may also be 4;
each R1 independently is hydrogen; aryl; formyl; C1-6alkylcarbonyl; Chalky!;
C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl,
C1-6alkyloxycarbonyl, or with C1-6alkylcarbonyloxy;
each R2 independently is hydroxy; halo; C1-6alkyl optionally substituted with one, two
or three substituents each independently selected from halo, cyano or -C(=O)R6;
C1-6cycloalkyl; C1-6alkenyl optionally substituted with one, two or three substituents
each independently selected from halo, cyano or -C(=O)R6; C1-6alkynyl optionally
substituted with one, two or three substituents each independently selected from
halo, cyano or -C(=O)R6; 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;
R2a is cyano; aminocarbonyl; amino; Chalky!; halo; Ci^alkyloxy wherein Ci^alkyl
may optionally be substituted with cyano; NHR13; NR13R14; -C(=O)-NHR13;
-C(=0)-NR13RH; -C(=O)-R15; -CH=N-NH-C(=O)-R16; Ci^alkyl substituted with one,
two or three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; Chalky! substituted with hydroxy and a
second substituent selected from halo, cyano, NRV, -C(=O)-NR9R10,
-C(=O)-Ci-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C2-6alkenyl substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C].6alkyl or R7; C2-6alkynyl substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R!0,
-C(=O)-NR9R10, -C(=O)-C,_6alkyl or R7; -C(=N-O-R8)-CMalkyl; R7 or -X3-R7;
X, is -NR'-, -0-, -C(=0)-, -CH2-, -CHOH-, -S-, -S(=O)P-,;
R3 is cyano; aminocarbonyl; amino; Ci^alkyl; halo; C1-6alkyloxy wherein C1-6alkyl
may optionally be substituted with cyano; NHR13; NR13R14; -C(=O)-NHR13;
-C(=0)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C^alkyl substituted with
one, two or three substituents each independently selected from halo, cyano,
NR9R10, -C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; Chalky! substituted with
hydroxy and a second substituent selected from halo, cyano, NR1-6
0,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; Ci-ealkyloxyC1-6alkyl optionally
substituted with one, two or three substituents each independently selected from
halo, cyano, NR9R10, -C(=O)-NR9R10, -C(O)-C1-6alkyl or R7; C^alkenyl
substituted with one, two or three substituents each independently selected from
halo, cyano, 0, -C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C1-6alkynyl
substituted with one, two or three substituents each independently selected from
halo, cyano, NR9^0, -C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7;
-C(=N-0-R8)-CMalkyl; R7 or -X3-R7;
X3 is -NR1 -, -0-, -C(=0)-, -S-, -S(=0)p-,;
R4 is halo; hydroxy; C1-6alkyl optionally substituted with one, two or three substituents
each independently selected from halo, cyano or -C(=O)R6; C1-6alkenyl
optionally substituted with one, two or three substituents each independently
selected from halo, cyano or -C(=O)R6; C2-ealkynyl optionally substituted with
one, two or three substituents each independently selected from halo, cyano or
-C(=O)R6; Cs-ycycloalkyl; C1-6alkyloxy; cyano; nitro; polyhaloC1-6alkyl;
polyhaloC1-6alkyloxy; aminocarbonyl; mono- or di(C1-6alkyl)aminocarbonyl;
C1-6alkyloxycarbonyl; C1-6alkylcarbonyl; formyl; amino; mono- or
di(C1-6alkyl)amino or R7;
R5 is a 5- or 6-membered completely unsaturated ring system wherein one, two, three
or four ring members are hetero atoms each independently selected from the group
consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are
carbon atoms; and, where possible, any nitrogen ring member may optionally be
substituted with C1-6alkyl; which ring system may optionally be annelated with a
benzene ring; and wherein any ring carbon atom, including any carbon of an optionally
annelated benzene ring, may, each independently, optionally be substituted with a
substituent selected from halo, hydroxy, mercapto, cyano, Cuealkyl, hydroxyCwalkyl,
carboxyCMalkyl, CualkyloxyC1-6alkyl, cyanoCMalkyl, di(C1-6alkyl)aminoCMalkyl,
Het-C1-6alkyl, arylCMalkyl, polyhaloCMalkyl, Cs-vcycloalkyl, ,
arylC2-4alkenyl, alkyloxy, -OCONH2, polyhaloCi^alkyloxy, aryloxy, amino, monoand
di-Ci^alkylamino, Cmalkylcarbonylamino, formyl, Ci^alkylcarbonyl,
CMalkyloxycarbonyl, aminocarbonyl, mono- and diCi_4alkylaminocarbonyl, aryl, Het;
wherein Het is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,
thiazolyl, thiadiazolyl, oxadiazolyl, quinolinyl, benzothienyl, benzofuranyl; which each
may optionally be substituted with one or two Chalky! radicals;
Q is hydrogen, Ci^alkyl, halo, polyhaloC1-6alkyl, or -NRV°;
R6 is CMalkyl, amino, mono- or di(CMalkyl)amino or polyhaloCMalkyl;
R7 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 halo, hydroxy, mercapto, C1-6alkyl, hydroxyC1-6alkyl,
aminoCi^alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
Cs-ycycloalkyl, Ci^alkyloxy, C1-6alkyloxycarbonyl, C1-6lkylthio, cyano, nhro,
polyhaloCi-ealkyl, polyhaloC1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8), R7a,
-X3-R7aorR7a-CMalkyl;
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 halo, hydroxy, mercapto, C1-6alkyl, hydroxy C1-6alkyl,
aminoCi^alkyl, mono or di(C1-66alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
-5-
l, C1-6alkyloxy, C1-6alkyloxycarbonyl, Cj^alkylthio, cyano, nitro,
polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8);
R8 is hydrogen, CMalkyl, aryl or arylCMalkyl;
R9 and R10 each independently are hydrogen; Ci-ealkyi; Ci^alkylcarbonyl;
C1-6alkyloxycarbonyl; amino; mono- or di(Ci^alkyl)aminocarbonyl; -CH(=NRn) or
R7, wherein each of the aforementioned CMalkyl groups may optionally and each
individually be substituted with one or two substituents each independently selected
from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, Ci^alkyloxycarbonyl,
cyano, amino, imino, 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, R7; or
R9 and R10 may be taken together to form a bivalent or bivalent radical of formula
R1' is cyano; Chalky! optionally substituted with Ci^alkyloxy, cyano, amino, monoor
di(C1-6alkyl)amino or aminocarbonyl; Ci_4alkylcarbonyl; Ci^alkyloxycarbonyl;
aminocarbonyl; mono- or di(C1-6alkyl)aminocarbonyl;
R12 is hydrogen or C1-6alkyl;
R13 and R14 each independently are Chalky! optionally substituted with cyano or
aminocarbonyl, C2-«alkenyl optionally substituted with cyano or aminocarbonyl,
alkynyl optionally substituted with cyano or aminocarbonyl;
R15 is Chalky! substituted with cyano or aminocarbonyl;
R16 is CMalkyl optionally substituted with cyano or aminocarbonyl, or R7;
each p is 1 or 2;
each aryl is phenyl or phenyl substituted with one, two, three, four or five substituents
each independently selected from halo, hydroxy, mercapto, Ci-6alkyl, hydroxy-
Ci-6alkyl, aminoCi-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylcarbonyl,
Cs-ycycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio,cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, Het or
The present invention also relates to the use of a compound for the manufacture of a
medicament for the treatment or prevention of HIV infection, wherein the compound
has the formula (I) as specified herein.
As used hereinbefore or hereinafter C1-6alkyl as a group or part of a group defines
straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon
atoms such as methyl, ethyl, propyl, 1 -methylethyl, butyl; C1-6alkyl as a group or part
of a group defines straight or branched chain saturated hydrocarbon radicals having
from 1 to 6 carbon atoms such as the group defined for Chalky! and pentyl, hexyl,
2-methylbutyl and the like; C1-6alkyl as a group or part of a group defines straight or
branched chain saturated hydrocarbon radicals having from 2 to 6 carbon atoms such as
ethyl, propyl, 1 -methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like;
C1-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl; alkenyl defines straight and branched chain hydrocarbon radicals
having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl,
butenyl, pentenyl, hexenyl and the like; C2-6alkynyl defines straight and branched chain
hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as
ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Preferred amongst
C1-6alkenyl and C1-6a]kynyl are the unsaturated analogs having from 2 to 4 carbon
atoms, i.e. C1-6alkenyl and C1-6alkynyl respectively.
In a number of instances the radicals C1-6alkyl, C2-6alkenyl, C2-ealkynyl or
oxyd-6alkyl may be substituted with one, two or three substituents. Preferably, said
radicals are substituted with up to 2 substituents, more preferably with one substituent.
A monocyclic, bicyclic or tricyclic saturated carbocycle represents a ring system
consisting of I, 2 or 3 rings, said ring system being composed of only carbon atoms and
said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic
partially saturated carbocycle represents a ring system consisting of 1, 2 or 3 rings, said
ring system being composed of only carbon atoms and comprising at least one double
bond provided that the ring system is not an aromatic ring system; a monocyclic,
bicyclic or tricyclic aromatic carbocycle represents an aromatic ring system consisting
of 1, 2 or 3 rings, said ring system being composed of only carbon atoms; the term
aromatic is well known to a person skilled in the art and designates cyclically
conjugated systems of 4n + 2 electrons, that is with 6, 10, 14 etc. 70-electrons (rule of
Hiickel); a monocyclic, bicyclic or tricyclic saturated heterocycle represents a ring
system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected
from O, N or S, said ring system containing only single bonds; a monocyclic, bicyclic
or tricyclic partially saturated heterocycle represents a ring system consisting of 1, 2 or
3 rings and comprising at least one heteroatom selected from O, N or S, and at least one
double bond provided that the ring system is not an aromatic ring system; a
monocyclic, bicyclic or tricyclic aromatic heterocycle represents an aromatic ring
system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected
from O, N or S.
Particular examples of monocyclic, bicyclic or tricyclic saturated carbocycles are
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
bicyclo[4,2,0]octanyl, cyclononanyl, cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl
and the like. Preferred are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl; more preferred are cyclopentyl, cyclohexyl, cycloheptyl.
Particular examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles
are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
bicyclo[4,2,0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl,
1,2,3,4-tetrahydronaphthalenyl, l,2,3,4,4a,9,9a,10-octahydro-anthracenyl and the like.
Particular examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are
phenyl, naphthalenyl, anthracenyl. Preferred is phenyl.
Particular examples of monocyclic, bicyclic or tricyclic saturated heterocycles are
tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl,
dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,
thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl,
dioxanyl, morpholinyl, dithianyl, thiomprpholinyl, piperazinyl, trithianyl, decahydroquinolinyl,
octahydroindolyl and the like. Preferred are tetrahydrofuranyl, pyrrolidinyl,
dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl, piperidinyl,
dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl. Particularly preferred are
tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, piperidinyl, dioxanyl, morpholinyl,
thiomorpholinyl, piperazinyl.
Particular examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles
are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,
2,3-dihydro-l,4-benzodioxinyl, indolinyl and the like. Preferred are pyrrolinyl,
imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, indolinyl.
Particular examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are
azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl,
benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl,
benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl,
benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,
pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl,
thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl,
pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,
isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl,
pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl,
thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,
imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl,
isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl,
pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,
triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl,
oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl,
thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,
imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl,
oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,
triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,
phenoxazinyl and the like.
Preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles.
Interesting monocyclic, bicyclic or tricyclic aromatic heterocycles are pyrrolyl, furyl,
thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl,
thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, pyranyl, benzoturyl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl,
isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl,
benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl,
pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl,
isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl,
thienopyrazinyl, iuropyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl,
oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl,
thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,
isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl,
oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl,
thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,
triazolopyrimidinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and the like.
Particularly interesting aromatic heterocycles are pyrrolyl, furyl, thienyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl,
benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl,
benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl,
benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,
quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, and the like.
As used herein before, the term (=O) forms a carbonyl moiety when attached to a
carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety
when two of said terms are attached to a sulfur atom.
The terms carboxyl, carboxy or hydroxycarbonyl refer to a group -COOH.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing
and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or
polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for
example, difluoromethyl or trifluoromethyl; polyhalod-4alkyl or polyhaloCi^alkyl as a
group or part of a group is defined as mono- or polyhalosubstituted Ci^aBcyl or
Ci-galkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the
like. In case more than one halogen atoms are attached to an alkyl group within the
definition of polyhalomethyl, polyhaloCi_4alkyl or polyhaloCi-ealkyl, they may be the
same or different.
R5 is a 5- or 6-membered completely unsaturated ring system as specified herein. The
term completely unsaturated as used in this definition means that the ring contains the
maximum number of double bonds. In many instances the 5- or 6-membered ring
system will be aromatic. Particular subgroups of compounds in accordance with the
present invention therefore are those groups or subgroups as defined herein wherein R5
is a 5- or 6-membered aromatic ring system as specified herein. The radical Het in
particular may be any of the heterocycles mentioned in the groups of monocyclic,
bicyclic or tricycles specified above, that are covered by the general definition of Het,
e.g. pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl,
isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl,
benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,
benzotriazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl,
quinazolinyl, naphthiridinyl, benzopyranyl.
Whenever it occurs in the definition of the compounds of formula (I) or in any of the
subgroups specified herein, each aryl independently is as defined above in the
-10-
definition of the compounds of formulas (I) or each aryl can have any of the meanings
specified hereinafter.
The term heterocycle in the definition of R7 or R7a is meant to include all the possible
isomeric forms of the heterocycles, for instance, pyrrolyl comprises IH-pyrrolyl and
The carbocycle or heterocycle in the definition of R7 or R7a may be attached to the
remainder of the molecule of formula (I) through any ring carbon or heteroatom as
appropriate, if not otherwise specified. Thus, for example, when the heterocycle is
imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when
the carbocycle is naphthalenyl, it may be l-naphthalenyl, 2-naphthalenyl and the like.
When any variable (e.g. R7, X2) occurs more than one time in any constituent, each
definition of such variable is independent.
Any of the restrictions in the definitions of the radicals herein are meant to be
applicable to the group of compounds of formula (I) as well as to any subgroup defined
or mentioned herein.
Lines drawn from substituents into ring systems indicate mat the bond may be attached
to any of the suitable ring atoms.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counter
ion is pharmaceutically acceptable. However, salts of acids and bases which are nonpharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically
acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to
comprise the therapeutically active non-toxic acid addition salt forms which the
compounds of formula (I) are able to form. The latter can conveniently be obtained by
treating the base form with such appropriate acids as inorganic acids, for example,
hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;
phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic,
2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic,
fumaric, malic, tartaric, 2-hydroxy-l,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,
2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt
form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their
therapeutically active non-toxic metal or amine addition salt forms by treatment with
appropriate organic and inorganic bases. Appropriate base salt forms comprise, for
example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium,
sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
primary, secondary and tertiary aliphatic and aromatic amines such as methylamine,
ethylamine, propylamine, isopropylamine, the four butylamine isomers,
dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine,
di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylarnine, triethylamine,
tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,
A'-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine
salts, and salts with ammo acids such as, for example, arginine, lysine and the like.
Conversely the salt form can be converted by treatment with acid into the free acid
form. The term addition salt also comprises the hydrates and solvent addition forms
which the compounds of formula (I) are able to form. Examples of such forms are e.g.
hydrates, alcoholates and the like.
The term "quaternary amine" as used hereinbefore defines the quaternary ammonium
salts which the compounds of formula (I) are able to form by reaction between a basic
nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as,
for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g.
methyliodide or benzyliodide. Other reactants with good leaving groups may also be
used, such as alkyl trifJuoromethanesulfonates, alkyl methanesulfonates, and alkyi
p-toluenesulfonates. A quaternary amine has a positively charged nitrogen.
Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate
and acetate. The counterion of choice can be introduced using ion exchange resins.
The Af-oxide forms of the present compounds are meant to comprise the compounds of
formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called
Af-oxide.
It will be appreciated that some of the compounds of formula (I) and their A'-oxides,
addition salts, quaternary amines and stereochemically isomeric forms may contain one
or more centers of chirality and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinbefore defines all the
possible stereoisomeric forms which the compounds of formula (I), and their A'-oxides,
addition salts, quaternary amines or physiologically functional derivatives may possess.
Unless otherwise mentioned or indicated, the chemical designation of compounds
denotes the mixture of all possible stereochemically isomeric forms, said mixtures
containing all diastereomers and enantiomers of the basic molecular structure as well as
each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates
or quaternary amines substantially free, i.e. associated with less than 10%, preferably
less than 5%, in particular less than 2% and most preferably less than 1% of the other
isomers. Thus, when a compound of formula (I) is for instance specified as (E), this
means that the compound is substantially free of the (Z) isomer. In particular,
stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or tarns-configuration.
Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen)
-stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well
known to a person skilled in the art. Stereochemically isomeric forms of the
compounds of formula (I) are intended to be embraced within the scope of this
invention.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such
forms although not explicitly indicated in the above formula are intended to be included
within the scope of the present invention.
Whenever used hereinafter, the term "compounds of formula (I)" is meant to also
include their AT-oxide forms, their salts, their quaternary amines and their
stereochemically isomeric forms. Of special interest are those compounds of formula
(I), which are stereochemically pure.
Particular subgroups of compounds of formula (I) or any of the subgroups of
compounds of formula (I) specified herein which are the non-salt-forms, the salts, the
N-oxide forms and stereochemically isomeric forms. Of interest amongst these are the
non-salt-forms, the salts and stereochemically isomeric forms. As used herein, the term
'non-salt-form' refers to the form of a compound which is not a salt, which in most
cases will be the free base form.
Whenever mention is made hereinbefore or hereinafter, that substituents can be
selected each independently out of a list of numerous definitions, such as for example
for R9 and R10, all possible combinations are intended which are chemically possible or
which lead to chemically stable molecules.
It is to be understood that any of the subgroups of compounds of formulae (I) as
defined herein, are meant to also comprise any prodrugs, N-oxides, addition salts,
quaternary amines, metal complexes and stereochemically isomeric forms of such
compounds.
Particular subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein
-aW-aW4- is -CH=CH-CH=CH- (a-1).
Further subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein -b1=b2-b3=b4- is
-CH=CH-CH=CH- (b-1).
Further subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein (a) n is 0, 1,2,
3; or wherein (b) n is 0,1 or 2; or (c) n is 0.
Other subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein (a)m is 0, 1, 2,
3; or wherein (b) m is 0, 1 or 2; or (c) m is 2.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R1 is hydrogen; formyl; Ci^alkylcarbonyl; Ci-ealkyl; Ci^alkyloxycarbonyl; or
(b) R1 is hydrogen; Ci^alkyl; or
(c) R1 is hydrogen.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R2 is hydroxy; halo; Chalky] optionally substituted with one substituent selected
from halo, cyano or -C(=O)R6; Cs-vcycloalkyl; Ca-ealkenyl optionally substituted
with one substituent selected from halo, cyano or -C(=O)R6; C2^alkynyl
optionally substituted with one substituent selected from halo, cyano or
-C(=O)R6; Ci-ealkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or
di(Ci-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;
(b) R2 is hydroxy; halo; Chalky! optionally substituted with one substituent selected
from halo, cyano or -C(=O)R6; Ca-ealkenyl optionally substituted with one
substituent selected from halo, cyano or -C(=O)R6; Ca-eaBcynyl optionally
substituted with one substituent selected from halo, cyano or -C(=O)R6;
Cj.galkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or
amino; trifluoromethyl;
(c) R2 is halo, d-galkyl optionally substituted with cyano, C2-ealkenyl optionally
substituted with cyano, C2-ealkynyl optionally substituted with cyano,
Ci-fialkyloxycarbonyl, carboxyl, cyano, amino, mono(Ci^alkyl)amino,
di(Ci ^alkyl)amino;
(d) R2 is halo, cyano, aminocarbonyl, Chalkyloxy, Chalky!, Ci-ealkyl substituted
with cyano or Ca-^alkenyl substituted with cyano;
(e) R2 is halo, cyano, aminocarbonyl, Chalky] substituted with cyano or C24alkenyl
substituted with cyano;
(f) R2 is cyano, aminocarbonyl; or (g) R2 is cyano.
Still farther subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R2a is cyano; aminocarbonyl; amino; Ci^alkyl; halo; Ci^alkyloxy wherein
Ci-ealkyl may optionally be substituted with cyano; NHR13; NR13R14;
-C(=0)-NHR13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; Chalky!
substituted with one substituent selected from halo, cyano, NR^R10,
-C(=O)-NR9R10, -C(=O)-Ci_6alkyl or R7; C^alkyl substituted with hydroxy and a
second substituent selected from halo, cyano, NRV°, -C(=O)-NR9R10,
-C(=O)-Ci_6alkyl or R7; C^alkyloxyC^alkyl optionally substituted with one
substituent selected from halo, cyano, NR9R10, -C(=O)-NR9R10, -C(=O)-Ci^alkyl
or R7; C2-«alkenyl substituted with one substituent selected from halo, cyano,
NR9R10, -C(=0)-NR9R10, -C(=O)-Ci^alkyl or R7; C^alkynyl substituted with
one substituent selected from halo, cyano, NR'R10, -C(=O)-NR9R10,
-C(=0)-Ci-6alkyl or R7; -C(=N-O-R8)-CMalkyl; R7 or -X3-R7;
(b) R2a is cyano; aminocarbonyl; amino; Ci^alkyl; halo; Ci^alkyloxy wherein
Ci^alkyl may optionally be substituted with cyano; NHR13; NR13R14;
-C(=O)-NHR13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C^aDcyl
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
Ci-ealkyl substituted with hydroxy and a second substituent selected from halo,
cyano, -C(=O)-NR9R10; C^alkyloxyC^alkyl optionally substituted with one
substituent selected from halo, cyano, -C(=O)-NR9R10; C2-6alkenyl substituted
with one substituent selected from halo, cyano, -C(=O)-NR9R10; C2-6alkynyl
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
(c) R2a is halo, cyano, aminocarbonyl, Ci-ealkyi optionally substituted with cyano or
aminocarbonyl, C2-6alkenyl optionally substituted with cyano or aminocarbonyl;
(d) R2" is halo, cyano, aminocarbonyl, Chalky! substituted with cyano or
aminocarbonyl, or C2^alkenyl substituted with cyano or aminocarbonyl;
(e) R2a is cyano, aminocarbonyl, Ci^alkyl substituted with cyano or C2-ealkenyl
substituted with cyano;
(f) R2a is cyano, aminocarbonyl, Ci^alkyl substituted with cyano or C2^alkenyl
substituted with cyano;
(g) R2a is cyano, Chalky! substituted with cyano or C2^alkenyl substituted with
cyano; or (h) R2a is cyano.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) Xi is -NR1-, -0-, -S-, -S(=O)P-;
(b) Xi is -NH--N(CMalkyl)-, -O-,-S-, -S(=O)P-;
(c) X, is -NH-, -N(CH3)-, -O-, -S-; (d) XT is -NH-, -O-, -S-;
(d) X, is -NH-, -O-; or (i) X, is -NH-.
Still other subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R3 is cyano; aminocarbonyl; amino; Ci^alkyl; halo; Ci^alkyloxy wherein
Ci-ealkyl may optionally be substituted with cyano; NHR13; NR13R14;
-C(=0)-NHR13; -C(=0)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C^alkyl
substituted with one substituent selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-Ci-6aIkyl or R7; Chalky! substituted with hydroxy and a
-C(=O)-NHR13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; Ci-ealkyl
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
Chalky! substituted with hydroxy and a second substituent selected from halo,
cyano, -C(=O)-NR9R10alkyl optionally substituted with one
substituent selected from halo, cyano, -C(=O)-NR9R10; C2-6alkenyl substituted
with one substituent selected from halo, cyano, -C(=O)-NR9R10; C2-ealkynyl
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
(c) R3 is halo, cyano, aminocarbonyl, Ci .galley 1 optionally substituted with cyano or
aminocarbonyl, Ca^alkenyl optionally substituted with cyano or aminocarbonyl;
(d) R3 is halo, cyano, aminocarbonyl, Chalky! substituted with cyano or aminocarbonyl,
or C2-6alkenyl substituted with cyano or aminocarbonyl;
(e) R3 is cyano, Ci^alkyl substituted with cyano or Ca^alkenyl substituted with
cyano;
(f) R3 is Chalky! substituted with cyano or Cz^alkenyl substituted with cyano;
(g) R3 is C2~4alkyl substituted with cyano or Cz^alkenyl substituted with cyano;
(h) R3 is C2-4alkenyl substituted with cyano;
(i) R3 is ethenyl substituted with cyano;
(j) R3 is (E)-2-cyanoethenyl
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R4 is halo; hydroxy; Chalky! optionally substituted with one substituent selected
from halo, cyano or -C(=O)R6; C2-6alkenyl optionally substituted with one
, amino;
(e) R4 is halo, hydroxy, Chalky!, CMalkyloxy, cyano; or (f) R4 is halo, Chalky!,
Ci4alkyloxy.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R5 is a 5- or 6-membered completely unsaturated ring system wherein one, two,
three or four ring members are hetero atoms each independently selected from the
group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring
members are carbon atoms; and, where possible, any nitrogen ring member may
5 optionally be substituted with Ci-ealkyl; which ring system may optionally be
annelated with a benzene ring; and wherein any ring carbon atom, including any
carbon of an optionally annelated benzene ring, may, each independently,
optionally be substituted with a substituent selected from halo, hydroxy,
mercapto, cyano, hydroxyCMalkyl, , Cualkyloxy-
10, cyanoCMalkyl, di(CMalkyl)aminoCMalkyl, Het-Ci_4alkyl, aryl-
Ciuialkyl, polyhaloCi_4alkyl, Cs.ycycloalkyl, arylC2-4alkenyl,Cualkyloxy,
-OCONHa, polyhaloCi^alkyloxy, aryloxy, amino, mono- and di-Ci_4alkylamino,
CMaDcylcarbonylamino, formyl, Ci-4alkylcarbonyl, aryl, Het;
(b) R5 is a heterocycle selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,
15 oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl,
thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
benzoftiranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzolhiazolyl,
benzotriazolyl, indolyl, benzothiadiazolyl, benzofiorazanyl, benzoxadiazolyl,
indazolyl, quinolinyl, said heterocycle optionally being substituted on its carbon
20 atoms with one, two or three substituents each independently selected from halo,
hydroxy, mercapto, cyano, Ci-ealkyl, hydroxyCptalkyl, carboxyCwalkyl,
alkyl, cyanoCMalkyl, di(CMalkyl)aminoCMalkyl, Het-Ci^alkyl,
olyhaloCMalkyl, Cs-ycycloalkyl, arylC2-*alkenyl, Ci-4alkyloxy,
-OCONHa, polyhaloCMalkyloxy, aryloxy, amino, mono- and di-Ci_4alkylamino,
25 Q^alkylcarbonylamino, formyl, Cualkylcarbonyl, Ci-4alkyloxycarbonyl,
aminocarbonyl, mono- and diCMalkylaminocarbonyl, aryl, Het;
(c) R5 is a heterocycle selected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl,
thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
30 benzofuranyl, indolyl, benzothiadiazolyl, quinolinyl, said heterocycle optionally
being substituted on its carbon atoms with one, two or three substituents each
independently selected from halo, hydroxy, cyano, Ci-6alkyl,amino, mono- and di-
Ci^alkylamino, CMalkylcarbonylamino, aminocarbonyl, mono- and diCi^alkylaminocarbonyl,
35 (d) R5 is a heterocycle selected from pyrrolyl, ruranyl, thienyl, isothiazolyl,
thiatriazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzofuranyl,
quinolinyl, said heterocycle optionally being substituted on its carbon atoms with
one, two or three substituents each independently selected from halo, hydroxy,
cyano, Chalky!, amino, mono- and di-Cualkylamino, Ci-4alkylcarbonylamino,
aminocarbonyl, aryl (the latter in particular being phenyl), Het;
(e) R5 is a heterocycle selected from pyrrolyl, furanyl, thienyl, isothiazolyl,
thiatriazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, benzofuranyl,
quinolinyl, said heterocycle optionally being substituted on its carbon atoms with
one, two or three substituents each independently selected from halo, hydroxy,
cyano, Ci-galkyl, amino, mono- and di-CMalkylamino, Ci-4alkylcarbonylamino,
aryl (the latter in particular being phenyl), Het;
(f) R5 is a heterocycle selected from pyrrolyl, furanyl, thienyl, oxadiazolyl pyridyl,
said heterocycle optionally being substituted on its carbon atoms with one, two or
three substituents each independently selected from halo, hydroxy, Ci-ealkyl, aryl
(the latter in particular being phenyl), Het;
(g) R5 is a heterocycle selected from pyrrolyl, furanyl, thienyl, thiazolyl, oxadiazolyl,
pyridyl, benzofuranyl, quinolinyl, said heterocycle optionally being substituted on
its carbon atoms with one, two or three substituents each independently selected
from Q-ealkyl, amino, aminocarbonyl, phenyl, Het.
Still farther subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) Het is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,
thiazolyl, thiadiazolyl, oxadiazolyl; which each may optionally be substituted
with one or two Chalky! radicals;
(b) Het is pyridyl, thienyl, faranyl; which each may optionally be substituted with
one or two Chalky! radicals; or
(c) Het is pyridyl, thienyl, furanyl;
(d) Het is pyridyl.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) Q is hydrogen, Chalky! or -NR9R10; (b) Q is hydrogen or -NRV°;
(c) Q is hydrogen, amino, mono- or di-Ci-4alkylamino; or (d) Q is hydrogen.
Other subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein
(a) R6 is CMalkyl, amino, mono- or di^^alkyljamino; in particular
(b) R6 is CMalkyl or amino; or (c) R6 is CMalkyl.
Still further subgroups of the compounds of formula (I) are those compounds of
formula (I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R7 is a monocyclic or bicyclic, partially saturated or aromatic carbocycle or a
monocyclic or bicyclic, partially saturated or aromatic heterocycle, wherein each
of said carbocyclic or heterocyclic ring systems may optionally be substituted
with one, two or three substituents each independently selected from halo,
hydroxy, mercapto, Ci^alkyl, hydroxyCi^alkyl, aminoCi^alkyl, Ci^alkylcarbonyl,
Ci^alkyloxy, Ci^alkyloxycarbonyl, Chalky fthio, cyano, nitro,
polyhaloCi^alkyl, polyhaloCi^alkyloxy or aminocarbonyl; in particular
(b) R7 is any of the specific monocyclic or bicyclic, partially saturated or aromatic
carbocycles or monocyclic or bicyclic, partially saturated or aromatic heterocycles
specifically mentioned in this specification, wherein each of said
carbocyclic or heterocyclic ring systems may optionally be substituted with one,
two or three substituents each independently selected from halo, hydroxy,
mercapto, Chalky!, hydroxyCi^alkyl, aminoCi^alkyl, Ci-ealkylcarbonyl,
Ci-ealkyloxy, Ci-ealkyloxycarbonyl, Ci^alkylthio, cyano, nitro, polyhalo-
Ci-ealkyl, polyhaloCi^alkyloxy or aminocarbonyl;
(c) R7a is a monocyclic or bicyclic, partially saturated or aromatic carbocycle or a
monocyclic or bicyclic, partially saturated or aromatic heterocycle, wherein each
of said carbocyclic or heterocyclic ring systems may optionally be substituted
with one, two or three substituents each independently selected from halo,
hydroxy, mercapto, Chalky!, hydroxyCi^alkyl, aminoCi-ealkyl, Ci-eaBcylcarbonyl,
Ci-ealkyloxy, Chalkyloxycarbonyl, Ci^alkylthio, cyano, nitro,
polyhaloCi-galkyl, polyhaloCi^alkyloxy or aminocarbonyl; in particular
(d) R7a is any of the specific monocyclic or bicyclic, partially saturated or aromatic
carbocycles or monocyclic or bicyclic, partially saturated or aromatic
heterocycles specifically mentioned in this specification, wherein each of said
carbocyclic or heterocyclic ring systems may optionally be substituted with one,
two or three substituents each independently selected from halo, hydroxy,
mercapto, Ci^alkyl, hydroxyCi^alkyl, aminoCi-ealkyl, Ci^alkylcarbonyl,
Ci-ealkyloxy, Ci^alkyloxycarbonyl, Ci-ealkylthio, cyano, nitro, polyhaloCi^alkyl,
polyhaloCi-ealkyloxy or aminocarbonyl.
Further subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein
Other subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein (a)R8 is
hydrogen, CMalkyl or arylCMalkyl; or (b) R8 is hydrogen or CMalkyl.
Other subgroups of the compounds of formula (I) are those compounds of formula (I),
or any subgroup of compounds of formula (I) specified herein, wherein
(a) R9 and R10 each independently are hydrogen; Ci-ealkyi; Ci^alkylcarbonyl;
Ci-galkyloxycarbonyl; mono- or di(C]^alkyl)aminocarbonyl; -CH(=NRn),
wherein each of the aforementioned Ci-ealkyl groups may optionally be
substituted with one or two substituents each independently selected from
hydroxy, Chalky loxy, hydroxyCi^alkyloxy, carboxyl, Ci^alkyloxycarbonyl,
cyano, amino, mono- or di(C] -4alkyl)amino, polyhalomethyl, polyhalomethyloxy;
(b) R9 and R10 each independently are hydrogen; Ci^alkyl; Ci^alkylcarbonyl or
(c) R9 and R10 each independently are hydrogen or Ci-ealkyl;
(d) R9 and R10 are hydrogen.
Still other subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R13 and R14 each independently are Ci^alkyl optionally substituted with cyano,
C2-ealkenyl optionally substituted with cyano, Cz-ealkynyl optionally substituted
with cyano;
(b) R13 and R14 each independently are hydrogen or Chalky!;
(c) R13 and R14 are hydrogen.
Still other subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein R15 is
optionally substituted with cyano.
Still other subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) R16 is Ci-ealkyl optionally substituted with cyano or aminocarbonyl; or wherein
(b) R16 is Ci^alkyl optionally substituted with cyano.
Still other subgroups of the compounds of formula (I) are those compounds of formula
(I), or any subgroup of compounds of formula (I) specified herein, wherein
(a) aryl is phenyl or phenyl substituted with one, two or three substituents each
independently selected from halo, hydroxy, mercapto, alkyl, hydroxy-
Ci-ealkyl, aminoCi-ealkyl, mono or di(Ci-6alkyl) alkyl, Chalky 1-
(b) aryl is phenyl or phenyl substituted with one, two or three substituents each
independently selected from halo, hydroxy, mercapto, Ci^alkyl, hydroxy-
Ci-ealkyl, aminoCi-ealkyl, mono or di(C]^alkyl)amino Ci-galkyl, Ci^alkylcarbonyl,
Ci^alkyloxy, Ci-ealkyloxycarbonyl, Ci-ealkylthio, cyano, nitro,
trifluoromethyl, trifluoromethoxy, aminocarbonyl, phenyl;
(c) aryl is phenyl or phenyl substituted with one, two or three substituents each
independently selected from halo, hydroxy, Chalky!, hydroxyCi-ealkyl, amino
Ci^alkyl, mono or di(Ci^alkyl)amino Ci^alkyl, Ci^alkylcarbonyl, Ci^alkyloxy,
Chalkyloxycarbonyl, cyano, nitro, trifluoromethyl;
(d) aryl is phenyl or phenyl substituted with one, two or three substituents each
independently selected from halo, hydroxy, Ci-ealkyl, Ci-ealkyloxy, cyano, nitro,
trifluoromethyl.
One embodiment comprises a subgroup of compounds of formula (I) having the
the JV-oxides, the pharmaceutically acceptable addition salts, the quaternary amines or
the stereochemically isomeric forms thereof, wherein -b'=b2-b3=b4-, R1, R2, R2s, R3, R4,
R5, m, n and Xi are as defined hereinabove in the general definitions of the compounds
of formula (I) or in the various subgroups thereof.
Yet another embodiment concerns a subgroup of compounds of formula (I) having the
the .TV-oxides, the pharmaceutically acceptable addition salts, the quaternary amines or
the stereochemically isomeric forms thereof, wherein -a1=a2-a3=a4-, R1, R2, R2a, R3, R4,
R5, m, n and X] are as defined hereinabove in the general definitions of the compounds
of formula (I) or in the various subgroups thereof.
Another embodiment concerns a subgroup of compounds of formula (I) having the
formula:
the N-oxidss, the pharmaceutically acceptable addition salts, the quaternary amines or
the stereochemically isomeric forms thereof, wherein R1, R2, R2*, R3, R4, R5, m, n and
X] are as defined hereinabove in the general definitions of the compounds of formula
(I) or in the various subgroups thereof.
A further embodiment encompasses a subgroup of compounds of formula (I) having
the Af-oxides, the pharmaceutically acceptable addition salts, the quaternary amines or
the stereochemically isomeric forms thereof, wherein R1, R2", R3, R4, R5 and Xj are as
defined hereinabove in the general definition of the compounds of formula (I) or in the
various subgroups thereof.
Also an interesting embodiment encompasses a subgroup of compounds of formula (I)
having the formula:
the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines or
the stereochemically isomeric forms thereof, wherein R1, R2, R2", R3, R5 and X] are as
defined hereinabove in the general definition of the compounds of formula (I) or in the
The compounds of formula (I) can be prepared by reacting an intermediate of formula
(II) wherein Wi represents a suitable leaving group, such as for example halogen, e.g.
chloro and the like, with an intermediate of formula (in).
The reaction of the pyrimidine derivative (II) with the amine (III) is typically conducted
in the presence of a suitable solvent. Suitable solvents are for example an alcohol, such
as for example ethanol, 2-propanol; a dipolar aprotic solvent such as acetonitrile,
-dimethylformamide; .TV-dirnethylacetamide, l-methyl-2-pyrrolidinone; an ether
such as tetrahydrofuran, 1,4-dioxane, propylene glycol monomethylether. The reaction
may be done under acid conditions which may be obtained by adding amounts of a
suitable acid, e.g. camphor sulfonic acid, and a suitable solvent, such as for example
tetrahydrofuran or an alcohol, e.g. 2-propanol, or by using acidified solvents, e.g.
hydrochloric acid dissolved in an alkanol such as 1- or 2-propanol.
The compounds of formula (I) can also be prepared by forming the X1 linkage by either
reacting (IV-a) with (V-a) or (FV-b) with (V-b) as outlined in the following scheme.
In this reaction scheme W2 represents an appropriate functional group, which combined
with the -XiH group can be transformed into an Xi link. This procedure is most
convenient for the preparation of compounds of formula (I) wherein Xi is a heteroatom
In particular, compounds of formula (I) wherein Xi represents NR1, said compounds
being represented by formula (I-a), can be prepared by reacting an intermediate of
formula (IV-c), wherein Wi is an appropriate leaving group, e.g. chloro or bromo, with
an intermediate of formula (V-c). The leaving group Wi may also be introduced in situ,
e.g. by converting the corresponding hydroxy function into a leaving group for example
by POCls. The reaction of (IV-c) with (V-c) preferably is conducted in a suitable
solvent in the presence of a base, e.g. triethylamine. Suitable solvents are for example
acetonitrile, alcohols, such as for example ethanol, 2-propanol, ethylene glycol,
propylene glycol, polar aprotic solvents such as A^-dimethyl-formamide;
dimethylacetamide, dimethylsufoxide, l-methyl-2-pyrrolidinone, [bmim]PFs;
ethers such as 1,4-dioxane, propylene glycol monomethylether.
This conversion is also suited in the instance where Xi is -O- or -S-. In particular,
compounds of formula (I) wherein Xi represents O, said compounds being represented
15 by formula (I-b), can be prepared by reacting an intermediate of formula (VI) wherein
Wi represents a suitable leaving group, such as for example halo, e.g. chloro and the
like, with an intermediate of formula (VII) in the presence of a suitable base, such as
for example KzCOs or potassium f-butoxide (K.O f-Bu), and a suitable solvent, such as
for example acetone or tetrahydrofuran. In a particular execution, intermediate (VII) is
20 first reacted under stirring at room temperature with a suitable metal hydride in an
organic solvent. Subsequently, an intermediate (VI), wherein -Wi is a suitable leaving
group, is added.
Compounds of formula (I-b) can also be prepared by reacting an intermediate of
formula (IV-b) wherein -X!H is -OH, said intermediates being represented by (FV-d),
with an intermediate of formula (VII) in the presence of POCls, a suitable base, such as
for example K2COa or potassium f-butoxide (KO f-Bu), and a suitable solvent, such as
for example acetone or tetrahydroiuran.
The thio-compounds (Xi is -S-) can be obtained in a similar manner and can
conveniently be transferred to the corresponding sulfoxide or sulfone using art-known
oxidation procedures.
Compounds of formula (I) wherein Xj is other than a heteroatom can be prepared by
reacting (IV-a) with (V-a) or (IV-b) with (V-b), as outlined in the above scheme, by
selecting the appropriate functional groups -XiH and -W2.
In particular, where X] is -C(=O)- a starting material (V-a) or (IV-b) wherein the group
-X]H is a Grignard type of group (-Mg-halo) or lithium is reacted with a starting
material (IV-a) or (V-b) wherein W2 is an ester (-COOalkyl). The latter ester may also
be reduced to an alcohol with e.g. LiAlH4 and subsequently oxidized with a mild
oxidant such as MnC>2 to the corresponding aldehyde which subsequently is reacted
with the appropriate starting material wherein the group -X]H is a Grignard type of
group (-Mg-halo) or lithium. The compounds wherein -Xi. is -C(=O)- can be
converted to the -CHOH- analogs by a suitable reduction reaction e.g. with
Where Xi is -CH2- this linkage can be introduced by a Grignard reaction, e.g. by
reacting a starting material (V-a) or (FV-b) wherein the -X]H group is - CHa-Mg-halo
with an intermediate (TV-a) or (V-b) wherein W2 is a halo group. The methylene group
can be oxidized to a -C(=O)- group (Xi is -C(=O)-) e.g. with selenium dioxide. The
-C(=O)- group in turn can be reduced with a suitable hydride such as LiAlF^ to a
-CHOH- group.
The compounds of formula (I) can also be prepared by reacting an intermediate (VIII)
wherein Wi represents a suitable leaving group, such as for example halogen, e.g.
chloro, bromo, with a heterocycle with special groups such as boronic acid (i.e.
-B(OH)2) or borate esters (i.e. -B(OR)2 wherein R is alkyl or alkylene, e.g. R is methyl,
ethyl or ethylene),. This type of reaction can be typically conducted in the presence of a
copper salt, in particular copper(II) acetate, and a suitable quencher like pyridine may
be added to the reaction mixture. The introduction of a heterocyclyl group can also be
done by other boron derivatives such as bis(pinacolato)diboron. The diboron ester
bis(pinacolato)diboron reacts with heterocyclyl halides in the presence of palladium
catalysts to give heterocyclylboronic esters, which are readily converted to heterocyclyl
boronic acids which react with (VTfl). This reaction can be done as a one-pot
procedure; it can be conducted under mild reaction conditions, e.g. in a dipolar aprotic
solvent such as DMF, or any other of such solvents mentioned above.
The intermediates (VTII) can be prepared by halogenating a starting material (X) e.g.
with JV-chloro or JV-bromo succinimide or with other iodine chlorides. Other leaving
groups can be introduced by replacing the halo group using suitable reagents.
The compounds of formula (I) wherein R is pyrrolyl can also be prepared by reacting
an intermediate (IX) with a suitable 1,2-ethanedial derivative, e.g. an acetal derivative
thereof such as 2,5-dimethoxytetrahydrofuran.
The compounds of formula (I) may further be prepared by converting compounds of
formula (I) into each other according to art-known group transformation reactions.
The compounds of formula (I) maybe converted to the corresponding AT-oxide forms
following art-known procedures for converting a tertiary nitrogen into its W-oxide
form. Said .TV-oxidation reaction may generally be carried out by reacting the starting
material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate
inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth
alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate
organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic
acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic
acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.
tert.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols,
e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,
halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Compounds of formula (I) wherein R2, R2a, R3 or R4 is C2-ealkenyl substituted with
aminocarbonyl, can be converted into a compound of formula (I) wherein R2, R2a, R3 or
R4 is C2.«alkenyl substituted with cyano by reaction with
Compounds of formula (I) wherein m is zero, can be converted into a compound of
formula (I) wherein m is other than zero and R4 represents halo, by reaction with a
suitable halo-introducing agent, such as for example Af-chlorosuccinimide or AT-borosuccinimide,
or a combination thereof, in the presence of a suitable solvent, such as for
example acetic acid.
Compounds of formula (I) wherein R3 represents halo, may be converted into a
compound of formula (I) wherein R3 represents Ca-ealkenyl substituted with one or
more substituents each independently selected from halo, cyano, NR9R10,
, by reaction with the corresponding C2-6alkene
substituted with one or more substituents each independently selected from halo, cyano,
NR9R10, -C(=O)-NR9R10, -C(=O)-Ci^alkyl or R7 in the presence of a suitable base,
such as for example A^-diethyl-ethanamine, a suitable catalyst, such as for example
palladium acetate in the presence of triphenylphosphine, and a suitable solvent, such as
for example -dimethylformamide.
Compounds of formula (I) wherein R2a represents halo, may be converted into a
compound of formula (I) wherein R2a represents Cj-ealkenyl substituted with one or
more substituents each independently selected from halo, cyano, NR9R10,
-CCO^NR^10, -C(=O)-Ci^aDcyl or R7, by reaction with the corresponding Ca-ealkene
substituted with one or more substituents each independently selected from halo, cyano,
NR9R10, -C(=O)-NR9R10, -C(=O)-Ci-6alkyl or R7 in the presence of a suitable base,
such as for example A^JV-diethyl-ethanamine, a suitable catalyst, such as for example
palladium acetate in the presence of triphenylphosphine, and a suitable solvent, such as
for example A^A^-dimethylformamide.
Compounds of formula (I) wherein R1 represents Ci^alkyloxycarbonyl, can be
converted into a compound of formula (I) wherein R1 represents hydrogen, by reaction
with a suitable base, such as for example sodium hydroxide or methoxide. Where R1 is
t.butyloxycarbonyl, the corresponding compounds wherein R1 is hydrogen can be made
by treatment with trifluoroacetic acid.
Some of the compounds of formula (I) and some of the intermediates in the present invention
may contain an asymmetric carbon atom. Pure stereochemically isomeric
forms of said compounds and said intermediates can be obtained by the application of
art-knowr) procedures. For example, diastereoisomers can be separated by physical
methods such as selective crystallization or chromatographic techniques, e.g. counter
current distribution, liquid chromatography and the like methods. Enantiomers can be
obtained from racemic mixtures by first converting said racemic mixtures with suitable
resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts
or compounds; then physically separating said mixtures of diastereomeric salts or
compounds by, for example, selective crystallization or chromatographic techniques,
e.g. liquid chromatography and the like methods; and finally converting said separated
diastereomeric salts or compounds into the corresponding enantiomers. Pure
stereochemically isomeric forms may also be obtained from the pure stereochemically
isomeric forms of the appropriate intermediates and starting materials, provided that the
intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of
formula (I) and intermediates involves liquid chromatography, in particular liquid
chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be
commercially available or may be prepared according to art-known procedures.
Intermediates of formula (II) can be prepared by reacting an intermediate of formula
(XI) wherein Wi is defined as hereinabove, with an intermediate of formula (XII) in the
presence of a suitable solvent, such as for example tetrahydrofuran, and optionally in
the presence of a suitable base, such as for example Na2CC>3.
represented by formula (ni-a), or intermediates (V-a-1), which are intermediates (V-a)
wherein -X]H is -NH2, can be prepared by reacting an intermediate of formula (XIII)
or (XIV) with a suitable reducing agent, such as Fe, in the presence of NH4C1 and a
suitable solvent, such as for example tetrahydroftiran, F^O and an alcohol, e.g.
methanol and the like.of formula (Ill-a) or (V-a-1) wherein R2a respectively R3 represents
C2-6alkyl substituted with cyano, said intermediates being represented by formula
(III-a-1) and (V-a-2), can be prepared by reacting an intermediate of formula (Xni-a)
respectively (XlV-a) with Pd/C in the presence of a suitable solvent, such as for
example an alcohol, e.g. ethanol and the like.
arxC2.6alkenyl-CN reductionIntermediates of formula (III), (V-a) or (VTI) wherein R " respectively R is halo, said
intermediates being represented by formula (Ill-b), (V-V) and (Vll-a), may be
converted into an intermediate of formula (III) respectively (V) or (VII) wherein R2a
respectively R3 is C2-6alkenyl substituted with C(=O)NR9R10, said intermediates being
represented by formula (ITI-c), (V-c) and (VTI-b) by reaction with an intermediate of
formula (XIII) in the presence of Pd(OAc)2, P(o-Tol)3, a suitable base, such as for
example A^V-diethylethanamine, and a suitable solvent, such as for example CHa-CN.
Intermediates of formula (III-c), (V-c) and (Vll-b) can also be prepared by reacting an
intermediate of formula (Hl-f), (V-f) and (VH-c) with H-NR9R10 in the presence of
oxalyl chloride and in the presence of a suitable solvent, such as for example
Intermediates of formula (Ill-d), (V-d) and (VH-c) can be prepared by reacting an
intermediate of formula (HI-b), (V-b) and (VH-a), with H-C2-6alkenyl-C(=O)-OH in the
presence of Pd(OAc)2, P(o-Tol)3, a suitable base, such as for example A^-diethylethanamine,
and a suitable solvent, such as for example CHa-CN.
Intermediates of formula (XV) can be prepared by reacting an intermediate of formula
(XVI) wherein Wa represents a suitable leaving group, such as for example halogen,
e.g. chloro, with H-NR9!?.10 in the presence of a suitable solvent, such as for example
diethylether and tetrahydroniran.
H-C2^alkenyl-C(=0)-W3 + H-NR>R'° - ^ H-C2.6alkenyl-C(=O)-NR9R10
(XVI)
Intermediates of formula (XIII) or (XIV) wherein R a respectively R represents
cyanovinyl, said intermediates being represented by formula (Xlll-b) and (XTV-b), can
be prepared by reacting an intermediate of formula (XVIII) respectively (XIX) with
diethylcyanomethylphosphonate in the presence of a suitable base, such as for example
NaOCHa, and a suitable solvent, such as for example tetrahydrofuran.
Intermediates of formula (XHI) or (XIV) wherein R2a respectively R3 represents
-C(CH3)=CH-CN, said intermediates being represented by formula (XIII-c) and (XIIIc),
can be prepared by reacting an intermediate of formula (XX) respectively (XXI)
with diethylcyanomethylphosphonate in the presence of a suitable base, such as for
example NaOCHs, and a suitable solvent, such as for example tetrahydrofuran.
Intermediates of formula (XVIII) and (XEX) can be prepared by reacting an
intermediate of formula (XXII) respectively (XXIII) with a suitable oxidizing agent,
such as for example MnO2, in the presence of a suitable solvent, such as for example
acetone.
Intermediates of formula (XXII) and (XXEI) can be prepared by reacting an
intermediate of formula (XXIV) respectively (XXV) with NaBFU in the presence of
ethylchloroformate, a suitable base, such as for example AyV-diethylethanamine, and a
suitable solvent, such as for example tetrahydrofuran.
Intermediates of formula (XIII) and (XIV) wherein R respectively R represent
hydroxy, said intermediates being represented by formula (Xlll-d) respectively
(XlV-d), can be converted into an intermediate of formula (XIII) respectively (XIV)
wherein R2a respectively R3 represent Ci^alkyloxy wherein the Ci-ealkyl may
optionally be substituted with cyano, said R2a respectively R3 being represented by P
and said intermediates being represented by formula (Xlll-e) respectively (XIV-e), by
reaction with an intermediate of formula (XXV) wherein W4 represents a suitable
leaving group, such as for example halogen, e.g. chloro and the like, in the presence of
Nal, a suitable base, such as for example K^COa, and a suitable solvent, such as for
example acetone.
Intermediates of formula (XIII) and (XIV) can be prepared by reacting an intermediate
of formula (XXVI) respectively (XXVII) with NaNO3 in the presence of CH3SO3H.
The intermediates of formula (IV-d) can be prepared as follows :
Intermediates of formula (XXX) can be converted into intermediates of formula (IV-e)
which are intermediates of formula (IV-d) wherein R5 represents bromo by reaction
with Brz in the presence of a suitable base, such as for example ^V-diethylethanamine,
and a suitable solvent, such as for example dimethylsulfoxide.
Intermediates of formula (IV-e) can be converted into intermediates of formula (VI)
wherein R5 and Wa represent chloro, said intermediate being represented by formula
The compounds of formula (I) have antiretroviral properties (reverse transcriptase
inhibiting properties), in particular against Human Immunodeficiency Virus (HIV),
which is the aetio logical agent of Acquired Immune Deficiency Syndrome (AIDS) in
humans. The HIV virus preferentially infects human T-4 cells and destroys them or
changes their normal function, particularly the coordination of the immune system. As
a result, an infected patient has an ever decreasing number of T-4 cells, which
moreover behave abnormally. Hence, the immuno logical defense system is unable to
combat infections and neoplasms and the HTV infected subject usually dies by
opportunistic infections such as pneumonia, or by cancers. Other conditions associated
with HTV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the
central nervous system characterized by progressive demyelination, resulting in
dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HTV
infection further has also been associated with peripheral neuropathy, progressive
generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
The present compounds also show activity against (multi) drug resistant HTV strains, in
particular (multi) drug resistant HIV-1 strains, more in particular the present
compounds show activity against HTV strains, especially HTV-1 strains that have
acquired resistance to one or more art-known non-nucleoside reverse transcriptase
inhibitors. Art-known non-nucleoside reverse transcriptase inhibitors are those
non-nucleoside reverse transcriptase inhibitors other than the present compounds and
known to the person skilled in the art, in particular commercial non-nucleoside reverse
transcriptase inhibitors. The present compounds also have little or no binding affinity
to human a-1 acid glycoprotein; human oc-1 acid glycoprotein does not or only weakly
affect the anti HIV activity of the present compounds.
Due to their antiretroviral properties, particularly their anti-HTV properties, especially
their anti-HTV-1-activity, the compounds of formula (I), their JV-oxides,
pharmaceutically acceptable addition salts, quaternary amines and stereochemically
isomeric forms thereof, are useful in the treatment of individuals infected by HIV and
for the prophylaxis of these infections. In general, the compounds of the present
invention may be useful in the treatment of warm-blooded animals infected with
viruses whose existence is mediated by, or depends upon, the enzyme reverse
transcriptase. Conditions which may be prevented or treated with the compounds of the
present invention, especially conditions associated with HIV and other pathogenic
retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized
lymphadenopathy (PGL), as well as chronic Central Nervous System diseases caused
by retroviruses, such as, for example HTV mediated dementia and multiple sclerosis.
The compounds of the present invention or any subgroup thereof may therefore be used
as medicines against above-mentioned conditions. Said use as a medicine or method of
treatment comprises the administration to HIV-infected subjects of an amount effective
to combat the conditions associated with HIV and other pathogenic retroviruses,
especially HIV-1. In particular, the compounds of formula (I) may be used in the
manufacture of a medicament for the treatment or the prevention of HIV infections.
In view of the utility of the compounds of formula (I), there is provided a method of
treating warm-blooded animals, including humans, suffering from or a method of
preventing warm-blooded animals, including humans, to suffer from viral infections,
especially HIV infections. Said method comprises the administration, preferably oral
administration, of an effective amount of a compound of formula (I), a A'-oxide form, a
pharmaceutically acceptable addition salt, a quaternary amine or a possible
stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating viral infections
comprising a therapeutically effective amount of a compound of formula (I) and a
pharmaceutically acceptable carrier or diluent
The compounds of the present invention or any subgroup thereof may be formulated
into various pharmaceutical forms for administration purposes. As appropriate
compositions there may be cited all compositions usually employed for systemically
administering drugs. To prepare the pharmaceutical compositions of this invention, an
effective amount of the particular compound, optionally in addition salt form, as the
active ingredient is combined in intimate admixture with a pharmaceutically acceptable
carrier, which carrier may take a wide variety of forms depending on the form of
preparation desired for administration. These pharmaceutical compositions are
desirable in unitary dosage form suitable, particularly, for administration orally,
rectally, percutaneously, or by parenteral injection. For example, in preparing the
compositions in oral dosage form, any of the usual pharmaceutical media may be
employed such as, for example, water, glycols, oils, alcohols and the like in the case of
oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or
solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders,
disintegrating agents and the like in the case of powders, pills, capsules, and tablets.
Because of their ease in administration, tablets and capsules represent the most
advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are
obviously employed. For parenteral compositions, the carrier will usually comprise
sterile water, at least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may be prepared in
which the carrier comprises saline solution, glucose solution or a mixture of saline and
glucose solution. Injectable suspensions may also be prepared in which case
appropriate liquid carriers, suspending agents and the like may be employed. Also
included are solid form preparations which are intended to be converted, shortly before
use, to liquid form preparations. In the compositions suitable for percutaneous
administration, the carrier optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives of any nature in
minor proportions, which additives do not introduce a significant deleterious effect on
the skin. Said additives may facilitate the administration to the skin and/or may be
helpful for preparing the desired compositions. These compositions may be
administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
The compounds of the present invention may also be administered via inhalation or
insufflation by means of methods and formulations employed in the art for
administration via this way. Thus, in general the compounds of the present invention
may be administered to the lungs in the form of a solution, a suspension or a dry
powder. Any system developed for the delivery of solutions, suspensions or dry
powders via oral or nasal inhalation or insufflation are suitable for the administration of
the present compounds.
To aid solubility of the compounds of formula (I), suitable ingredients, e.g. cyclodextrins,
may be included in the compositions. Appropriate cyclodextrins are a-, p-,
y-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy
groups of the anhydroglucose units of the cyclodextrin are substituted with Ci^alkyl,
particularly methyl, ethyl or isopropyl, e.g. randomly methylated P-CD; hydroxy-
, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxy-
particularly carboxymethyl or carboxy-ethyl; ealkylcarbonyl, particularly
acetyl. Especially noteworthy as complexants and/or solubilizers are P-CD, randomly
methylated P-CD, 2,6-dimethyl-p-CD, 2-hydroxyethyl-p-CD, 2-hydroxyethyl-p-CD,
2-hydroxypropyl-p-CD and (2-carboxymethoxy)propyl-p-CD, and in particular
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin
hydroxy groups are etherified with different groups such as, for example,
hydroxy-propyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of
moles of alkoxy units per mole of anhydroglucose. The average substitution degree
(D.S1.) refers to the average number of substituted hydroxyls per anhydroglucose unit.
The M.S. and D.5. value can be determined by various analytical techniques such as
nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared
spectroscopy (IR). Depending on the technique used, slightly different values may be
obtained for one given cyclodextrin derivative. Preferably, as measured by mass
spectrometry, the M.S. ranges from 0.125 to 10 and the D.5. ranges from 0.125 to 3.
Other suitable compositions for oral or rectal administration comprise particles
consisting of a solid dispersion comprising a compound of formula (I) and one or more
appropriate pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" used hereinafter defines a system in a solid state (as
opposed to a liquid or gaseous state) comprising at least two components, in casu the
compound of formula (I) and the water-soluble polymer, wherein one component is
dispersed more or less evenly throughout the other component or components (in case
additional pharmaceutically acceptable formulating agents, generally known in the art,
are included, such as plasticizers, preservatives and the like). When said dispersion of
the components is such that the system is chemically and physically uniform or
homogenous throughout or consists of one phase as defined in thermo-dynamics, such a
solid dispersion will be called "a solid solution". Solid solutions are preferred physical
systems because the components therein are usually readily bioavailable to the
organisms to which they are administered. This advantage can probably be explained
by the ease with which said solid solutions can form liquid solutions when contacted
with a liquid medium such as the gastro-intestinal juices. The ease of dissolution may
be attributed at least in part to the fact that the energy required for dissolution of the
components from a solid solution is less than that required for the dissolution of
components from a crystalline or microcrystalline solid phase.
The term "a solid dispersion" also comprises dispersions, which are less homogenous
throughout than solid solutions. Such dispersions are not chemically and physically
uniform throughout or comprise more than one phase. For example, the term "a solid
dispersion" also relates to a system having domains or small regions wherein
amorphous, microcrystalline or crystalline compound of formula (I), or amorphous,
-41-
microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or
less evenly in another phase comprising water-soluble polymer, or compound of
formula (I), or a solid solution comprising compound of formula (I) and water-soluble
polymer. Said domains are regions within the solid dispersion distinctively marked by
some physical feature, small in size, and evenly and randomly distributed throughout
the solid dispersion.
Various techniques exist for preparing solid dispersions including melt-extrusion,
spray-drying and solution-evaporation.
The solution-evaporation process comprises the following steps :
a) dissolving the compound of formula (I) and the water-soluble polymer in an
appropriate solvent, optionally at elevated temperatures;
b) heating the solution resulting under point a), optionally under vacuum, until the
solvent is evaporated. The solution may also be poured onto a large surface so as to
form a thin film, and evaporating the solvent therefrom.
In the spray-drying technique, the two components are also dissolved in an appropriate
solvent and the resulting solution is then sprayed through the nozzle of a spray dryer
followed by evaporating the solvent from the resulting droplets at elevated
temperatures.
The preferred technique for preparing solid dispersions is the melt-extrusion process
comprising the following steps :
a) mixing a compound of formula (I) and an appropriate water-soluble polymer,
b) optionally blending additives with the thus obtained mixture,
c) heating and compounding the thus obtained blend until one obtains a
homogenous melt,
d) forcing the thus obtained melt through one or more nozzles; and
e) cooling the melt until it solidifies.
The terms "melt" and "melting" should be interpreted broadly. These terms not only
mean the alteration from a solid state to a liquid state, but can also refer to a transition
to a glassy state or a rubbery state, and in which it is possible for one component of the
mixture to get embedded more or less homogeneously into the other. In particular
cases, one component will melt and the other components) will dissolve in the melt
thus forming a solution, which upon cooling may form a solid solution having
advantageous dissolution properties.
-42-
After preparing the solid dispersions as described hereinabove, the obtained products
can be optionally milled and sieved.
The solid dispersion product may be milled or ground to particles having a particle size
of less than 600 urn, preferably less than 400 join and most preferably less than 125 um.
The particles prepared as described hereinabove can then be formulated by
conventional techniques into pharmaceutical dosage forms such as tablets and capsules.
It will be appreciated that a person of skill in the art will be able to optimize the
parameters of the solid dispersion preparation techniques described above, such as the
most appropriate solvent, the working temperature, the kind of apparatus being used,
the rate of spray-drying, the throughput rate in the melt-extruder.
The water-soluble polymers in the particles are polymers that have an apparent
viscosity, when dissolved at 20°C in an aqueous solution at 2 % (w/v), of 1 to
5000 mPa.s more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s.
For example, suitable water-soluble polymers include aDcylcelluloses, hydroxyalkylcelluloses,
hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of
carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters,
starches, pectines, chitin derivates, di-, oligo- and polysaccharides such as trehalose,
alginic acid or alkali metal and ammonium salts thereof, carrageenans, galactomannans,
tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic
acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate
copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone
with vinyl acetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,
polyalkylene oxides and copolymers of ethylene oxide and propylene
oxide. Preferred water-soluble polymers are hydroxypropyl methylcelluloses.
Also one or more cyclodextrins can be used as water-soluble polymer in the preparation
of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins
include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins
known in the art, more particularly a, |5 or 7 cyclodextrins or the pharmaceutically
acceptable derivatives thereof.
Substituted cyclodextrins which can be used to prepare the above described particles
include polyethers described in U.S. Patent 3,459,731. Further substituted cyclodextrins
are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is
replaced by Chalky!, hydroxy Ci^alkyl, carboxy-Ci^alkyl or Ci^aDcyloxycarbonylor
mixed ethers thereof. In particular such substituted cyclodextrins are ethers
-43-
wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by
Ci^alkyl, hydroxyC2-4alkyl or carboxyCi-jalkyl or more in particular by methyl, ethyl,
hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.
Of particular utility are the (3-cyclodextrin ethers, e.g. dimethyl-p-cyclodextrin as
described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 by M. Nogradi (1984) and
polyethers, e.g. hydroxypropyl P-cyclodextrin and hydroxyethyl P-cyclodextrin, being
examples. Such an alkyl ether may be a methyl ether with a degree of substitution of
about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for
example be formed from the reaction between P-cyclodextrin an propylene oxide and
may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.
Another type of substituted cyclodextrins is sulfobutylcyclodextrines.
The ratio of the compound of formula (I) over the water soluble polymer may vary
widely. For example ratios of 1/100 to 100/1 may be applied Interesting ratios of the
compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More
interesting ratios range from about 1/5 to 5/1.
It may further be convenient to formulate the compounds of formula (I) in the form of
nanoparticles which have a surface modifier adsorbed on the surface thereof in an
amount sufficient to maintain an effective average particle size of less than 1000 nm.
Useful surface modifiers are believed to include those which physically adhere to the
surface of the compound of formula (I) but do not chemically bond to said compound.
Suitable surface modifiers can preferably be selected from known organic and inorganic
pharmaceutical excipients. Such excipients include various polymers, low molecular
weight oligomers, natural products and surfactants. Preferred surface modifiers include
nonionic and anionic surfactants.
Yet another interesting way of formulating the compounds of formula (I) involves a
pharmaceutical composition whereby the compounds of formula (I) are incorporated in
hydrophilic polymers and applying this mixture as a coat film over many small beads,
thus yielding a composition which can conveniently be manufactured and which is
suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads comprise a central, rounded or spherical core, a coating film of a
hydrophilic polymer and a compound of formula (I) and optionally a seal-coating layer.
.44-
Materials suitable for use as cores in the beads are manifold, provided that said
materials are pharmaceutically acceptable and have appropriate dimensions and
firmness. Examples of such materials are polymers, inorganic substances, organic
substances, and saccharides and derivatives thereof.
It is especially advantageous to formulate the aforementioned pharmaceutical
compositions in unit dosage form for ease of administration and uniformity of dosage.
Unit dosage form as used herein refers to physically discrete units suitable as unitary
dosages, each unit containing a predetermined quantity of active ingredient calculated
to produce the desired therapeutic effect in association with the required
pharmaceutical carrier. Examples of such unit dosage forms are tablets (including
scored or coated tablets), capsules, pills, powder packets, wafers, suppositories,
injectable solutions or suspensions and the tike, and segregated multiples thereof.
Those of skill in the treatment of HIV-infection could determine the effective daily
amount from the test results presented here. In general it is contemplated that an
effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more
preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to
administer the required dose as two, three, four or more sub-doses at appropriate
intervals throughout the day. Said sub-doses may be formulated as unit dosage forms,
for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active
ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound
of formula (I) used, the particular condition being treated, the severity of the condition
being treated, the age, weight and general physical condition of the particular patient as
well as other medication the individual may be taking, as is well known to those skilled
in the art. Furthermore, it is evident that said effective daily amount may be lowered or
increased depending on the response of the treated subject and/or depending on the
evaluation of the physician prescribing the compounds of the instant invention. The
effective daily amount ranges mentioned hereinabove are therefore only guidelines and
are not intended to limit the scope or use of the invention to any extent.
The present compounds of formula (I) can be used alone or hi combination with other
therapeutic agents, such as anti-virals, antibiotics, immunomodulators or vaccines for
the treatment of viral infections. They may also be used alone or in combination with
other prophylactic agents for the prevention of viral infections. The present compounds
may be used in vaccines and methods for protecting individuals against viral infections
over an extended period of time. The compounds may be employed in such vaccines
either alone or together with other compounds of this invention or together with other
anti-viral agents in a manner consistent with the conventional utilization of reverse
transcriptase inhibitors in vaccines. Thus, the present compounds may be combined
with pharmaceutically acceptable adjuvants conventionally employed in vaccines and
administered in prophylactically effective amounts to protect individuals over an
extended period of time against HIV infection.
Also, the combination of one or more additional antiretroviral compounds and a
compound of formula (I) can be used as a medicine. Thus, the present invention also
relates to a product containing (a) a compound of formula (I), and (b) one or more
additional antiretroviral compounds, as a combined preparation for simultaneous,
separate or sequential use in anti-HTV treatment. The different drugs may be combined
in a single preparation together with pharmaceutically acceptable carriers. Said other
antiretroviral compounds may be known antiretroviral compounds such as suramine,
pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnetsodium
(trisodium phosphono formate); nucleoside reverse transcriptase inhibitors, e.g.
zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (2',3'-dideoxyinosine;
ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (2I-3'-dideoxy-3'-thiacytidine,
3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir and the like; nonnucleoside
reverse transcriptase inhibitors such as nevirapine (1 l-cyclopropyl-5,11-dihydro-
4-methyl-6/T-dipyrido-[3,2-b: 2',3'-e][l,4]diazepin-6-one), efavirenz,
delavirdine, TMC-120, TMC-125 and the like; phosphonate reverse transcriptase
inhibitors, e.g. tenofovir and the like; compounds of the TIBO (tetrahydroimidazo-
[4,5,l-jk][l,4]-benzodiazepine-2(l/f)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-
tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,l-jk][l,4]benzodiazepine-
2(l//)-thione; compounds of the a-APA (a-anilino phenyl acetamide) type e.g.
a-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like; inhibitors of
trans-activating proteins, such as TAT-inhibitors, e.g. RO-5-3335, or REV inhibitors,
and the like; protease inhibitors e.g. indinavir, ritonavir, saquinavir, lopinavir (ABT-
378), nelfinavir, amprenavir, TMC-126, BMS-232632, VX-175 and the like; fusion
inhibitors, e.g. T-20, T-1249 and the like; CXCR4 receptor antagonists, e.g.
AMD-3100 and the like; inhibitors of the viral integrase; nucleotide-like reverse
transcriptase inhibitors, e.g. tenofovir and the like; ribonucleotide reductase inhibitors,
e.g. hydroxyurea and the like.
By administering the compounds of the present invention with other anti-viral agents
which target different events in the viral life cycle, the therapeutic effect of these
compounds can be potentiated. Combination therapies as described above exert a
synergistic effect in inhibiting HIV replication because each component of the
combination acts on a different site of HIV replication. The use of such combinations
may reduce the dosage of a given conventional anti-retroviral agent which would be
required for a desired therapeutic or prophylactic effect as compared to when that agent
is administered as a monotherapy. These combinations may reduce or eliminate the
side effects of conventional single anti-retroviral therapy while not interfering with the
anti-viral activity of the agents. These combinations reduce potential of resistance to
single agent therapies, while minimizing any associated toxicity. These combinations
may also increase the efficacy of the conventional agent without increasing the
associated toxicity.
The compounds of the present invention may also be administered in combination with
immunomodulating agents, e.g. levamisole, bropirimine, anti-human alpha interferon
antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate,
tumor necrosis iactor, naltrexone and the like; antibiotics, e.g. pentamidine
isethiorate and the like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil,
galantamine and the like; NMDA channel blockers, e.g. memantine to prevent or
combat infection and diseases or symptoms of diseases associated with HIV infections,
such as AIDS and ARC, e.g. dementia. A compound of formula (I) can also be
combined with another compound of formula (I).
Although the present invention focuses on the use of the present compounds for
preventing or treating HIV infections, the present compounds may also be used as
inhibitory agents for other viruses which depend on similar reverse transcriptases for
obligatory events in their life cycle.
The following examples are intended to illustrate the present invention.
Examples
N-bromosuccinimide (0.0393 mol) was added portion wise at room temperature to
Intermediate 1 (0.0327 mol), the preparation of which has been described in
WO-03/016306, in CH3CN (100 ml). The mixture was stirred at room temperature for
4 hours. The precipitate was filtered off, washed with CHsCN and dried yielding
10.08 g of the desired end product. The filtrate was evaporated and purified by column
chromatography (eluent: CHjCb 100; 35-70 urn). The pure fractions were collected, the
solvent was evaporated and the residue was crystallized from CHsCN. Yielding : 2.4 g
of Intermediate 2. The two fractions were collected. Total yield: 12.48 g of
Intermediate 2 (86 %, melting point: > 250°C).
Example A2: Preparation of intermediate 3
N-chlorosuccinimide (0.000327 mol) was added portion wise at room temperature to
Intermediate 1 (0.000273 mol) in CH3CN (5 ml). The mixture was stirred at room
temperature for 4 hours. The precipitate was filtered, washed with CfTjCN and dried.
Yield: 0.065 g of intermediate 3 (59 %, melting point: > 250°C).
Example A3: Preparation of intermediate 4
The same procedure as in example Alwas used, starting from the 2-fluoro-6-chloro
analog of Intermediate I (0.000128 mol) and N-bromosuccinimide (0.000154 mol) in
CH3CN (5 ml); yield: 0.037 g of Intermediate 4 (62 %, melting point: 236°C)
Example A4: Preparation of intermediate 5
A suspension of (1.64g) in water (30ml) was added to a suspension of
intermediate I (0.0273 mol) in EtOH (180ml). Iodine chloride (IC1) in CH2C12 (IN)
(22.5ml) was added dropwise. The mixture was stirred at room temperature for 24 hours,
then cooled to 0°C and filtered. The filtrate was dried under vacuo, then taken up in
EtOH (180ml), filtered, washed with EtOH and CH3CN and dried. Yield: 8.5g . Part of
the filtrate was evaporated. The residue was crystallized from hot CTbCN. The
precipitate was filtered off and dried. Yielding: 1.54g of intermediate 5 (total yield
A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0516 mol) and 4-(2-cyanoethenyl)-2,6-
dimethylphenylamine (0.0516 mol) were stirred at 140°C in an oil bath for 45 minutes,
then poured in a mixture of water and KjCQa 10 %. The precipitate was filtered off and
the filtrate extracted with CTkCk. The organic layer was dried over magnesium sulfate,
filtered and the solvent evaporated. The residue was purified by column chromatography
over silica gel (eluent: CHjCklOO; 35-70 um). The pure fractions were
collected and the solvent evaporated, yielding 6.0 g of Intermediate 6 (35 %, melting
point: >250 °C).
Preparation of intermediate 7
A mixture of Intermediate 6 (0.0182 mol) and 4-cyanoaniline (0.0182 mol) were heated
at fusion for 5 minutes, then poured into a mixture of water and 10 %. CHaClz
and a small quantity of MeOH were added and the precipitate was filtered and dried.
Yield : 7.4 g of Intermediate 7 (95 %, melting point: > 250°C)
Preparation of intermediate 8
A mixture of Intermediate 7 (0.0180 mol) and tin (II) chloride dihydrate (0.125 mol) in
ethanol (100 ml) were stirred at 70°C overnight, then poured in a mixture of water and
K2CO3 10 %. The precipitate was filtered over celite. The filtrate was removed and the
precipitate was washed with CH2C12 and THF. The solvent was evaporated. Yield:
6.0 g of Intermediate 8 (87 %, melting point: > 250°C).
Example A6
Preparation of the 2-fluoro-6-chloro-phenyl analogs of Intermediates 6, 7 and 8.
A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0153 mol) and 4-(2-cyanoethenyl)-2-
fluoro-6-chloro-phenylamine (0.0153 mol) were heated at fusion for 5 minutes, then
poured into a mixture of water and K^COs 10 % and extracted with CHaCk. The
organic layer was dried over magnesium sulfate, filtered and the solvent evaporated.
The residue was purified by column chromatography over silica gel (eluent:
CH2Cl2lOO; 35-70 um). The pure fractions were collected and the solvent evaporated.
Yield: 1.9 g of 2-chloro-4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-
nitro-pyrimidine, Intermediate 9 (35 %, melting point: 217°C).
A mixture of Intermediate 9 (0.000424 mol) and 4-cyanoaniline (0.000424 mol) were
heated at fusion for 5 minutes, then poured in a mixture of water and KjCOs 10 %.
CH2Cl2 and a small quantity of MeOH were added and the precipitate was filtered and
dried. Yield : 1.34 g of 4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-
nitro-pyrimidine]amino]benzonitrilej Intermediate H) (73 %, melting point: > 250°C)
A mixture of Intermediate 10 (0.00306 mol) and tin (II) chloride dihydrate (0.0214
mol) in ethanol (20 ml) were stirred at 70°C overnight, then poured into a mixture of
water and K^COs 10 %. The precipitate was filtered over celite. The filtrate was
removed and the precipitate was washed with CHaCb and THF. The solvent was
evaporated. Yield: 1.1 gof4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-
5-aminopyrimidine]amino]benzbnitrile, Intermediate H (89 %, melting point:
A mixture of intermediate 2 (0.0247 mol), dichlorobis(triphenylphosphine)-
palladium(n) (0.00494 mol) and triethylamine (0.107 mol) in ethanol (100 ml) were
stirred at 100°C for 72 hours under 15 bars pressure of carbon monoxide. The mixture
was poured into water. The precipitate was filtered off, yielding 6 g of intermediate 12.
The filtrate was extracted with CHfeCb. The organic layer was dried over magnesium
sulfate, filtered and the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: CHaCfe/MeOH 99.5/0.5; 15-40 um). The pure
fractions were collected and the solvent evaporated, yielding 1.9 g of intermediate 12.
The two portions of intermediate 12 were combined giving a total yield of 7.9g (73 %,
2,5-dimethoxytetrahydroiuran (0.00157 mol) was added at room temperature to
Intermediate 8 (0.00524 mol) in acetic acid (5 ml). The mixture was stirred at 90°C for
50 minutes. After cooling, the mixture was poured into water, K2CO3 10 % was added
and the mixture was extracted with CHaCh . The organic layer was dried over
magnesium sulfate, filtered and the solvent evaporated. The residue was purified by
column chromatography over silica gel (eluent: CHaCfelOO; 35-70 um). The pure
fractions were collected and the solvent evaporated, yielding 0.145 g (64 %, melting
point: 163°C) of Compound!.
Intermediate 2 (0.449 mmol) was added to a solution of tetrakis(triphenylphosphme)-
palladium(O) (0.0449 mmol) in 1,2-dimethoxyethane at room temperature. A solution
of pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.135 mmol) in methanol
(3 ml) was added at room temperature. The mixture was stirred at 95°C for 20h and
was then poured in water, extracted with ethyl acetate. The organic layer was washed
with a brine solution and dried over magnesium sulfate, filtered and evaporated. The
residue was purified by column chromatography over silica gel (eluent: ClfcCVMeOI-
98/2; 10 um). The pure fractions were collected and the solvent evaporated, yielding
0.130 g (65 %, melting point: 238 °C) of Compound 2.
Example B3: Compound 3 and 22
10 % Palladium on charcoal (0.069 mmol) was added under argon to a solution of
Compound 3 (0.347 mmol) in THF (50 ml) and methanol (30 ml). Compound 3 was
prepared following the procedures of example B2 starting from furan-2-yl boronic acid
1,3-propanediol cyclic ester. This mixture was introduced into a hydrogenation
apparatus under pressure of hydrogen (3 bars) and stirred at room temperature for 1.5 h.
The mixture was then filtered over celite, rinsed with THF and the solvent was
evaporated. The residue was taken up in ethyl acetate and washed with water and with
a saturated solution of brine. It was then dried over magnesium sulfate, filtered,
evaporated and the residue was purified by column chromatography over silica gel
(eluent: CH2Cl2/AcOEt 90/10; 35-70 urn). The pure fractions were collected and the
solvent evaporated. Yield: 0.149 g (98 %, melting point: 211-212°C) of Compound 22.
2,5-dimethoxytetrahydrofuran (0.000739 mol) was added at room temperature to
Intermediate JJ. (0.000246 mol) in acetic acid (3 ml). The mixture was stirred at 90°C
for 50 minutes. After cooling, the mixture was poured in water, KaCOs 10 % was added
and the mixture was extracted with CFfeC^ . The organic layer was dried over
magnesium sulfate, filtered and the solvent evaporated. The residue was purified by
column chromatography over silica gel (eluent: CH2cyMeOH 99/1; 35-70 urn). The
pure fractions were collected and the solvent evaporated. Yield: 0.050 g (45% ,
melting point: 211°C) of compound 4.
A mixture of intermediate 12 (0.00057 mol), 2-pyridylamidoxime (0.00171 mol)
sodium hydride 60% (0.00285 mol) in DMF (15 ml) was stirred at 0°C for 15 min.
Then the mixture was introduced in a micro-wave (MW) apparatus and irradiated at
-54-
300 W during 15 min (T=142°C). The mixture was poured in water and extracted with
ethyl acetate. The organic layer was washed with a saturated solution of NaCl, then
dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was
purified by column chromatography over silica gel (eluent: CH2Cl2/MeOH 99/1;
10 um, then eluent: MeOH/NH4HCO3 0,5%/THF: 45/35/20; Hyperprep HS-C18 Sum).
The pure fractions were collected and the solvent evaporated. Yield : 0.021 g. (7 %,
melting point: > 250°C) of Compound 5.
Example B6
A mixture of intermediate 5 (0.002 mol), PdCl2(dppf) (0.0004 mol), Bis(pinacolato)-
diboron (0.0024mol) and AcOK (0.006mol) in DMF (10ml) was stirred at 85°C for
18 hours under N2 flow. A mixture of 4-amino-3-bromopyridine (0.004 mol),
PdCl2(dppf) (0.0004 mol) and K2CO3 2N (0.01 mol) in DMF (10ml) was added. The
mixture was stirred at 85°C for 3 days. H2O was added The mixture was extracted
twice with CFfeCt/THF. The organic layer was washed with saturated NaCl, dried
(MgSC^X filtered and the solvent was evaporated. The residue was purified by column
chromatography over kromasil (eluent: CH2C12/CH3OH/ NH4OH 98/2/0.2 to 90/10/0.1;
Sum). The pure fractions were collected and the solvent was evaporated. Yield :
0.075g (8%) (melting point: 188°C) of compound 6_(structure: see table).
A compound of formula (I) is dissolved in organic solvent such as ethanol, methanol or
methylene chloride, preferably, a mixture of ethanol and methylene chloride. Polymers
such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or
hydroxypropyhnethylcellulose (HPMC), typically 5 mPa.s, are dissolved in organic
solvents such as ethanol, methanol methylene chloride. Suitably the polymer is
dissolved in ethanol. The polymer and compound solutions are mixed and subsequently
spray dried. The ratio of compound/polymer is selected from 1/1 to 1/6. Intermediate
ranges can be 1/1.5 and 1/3. A suitable ratio can be 1/6. The spray-dried powder, a
solid dispersion, is subsequently filled in capsules for administration. The drug load in
one capsule ranges between 50 and 100 mg depending on the capsule size used.
Film-coated Tablets
Preparation of Tablet Core
A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 g starch is
mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and
10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved,
dried and sieved again. Then there is added 100 g microcrystalline cellulose and 15 g
hydrogenated vegetable oil. The whole is mixed well and compressed into tablets,
giving 10.000 tablets, each comprising 10 mg of the active ingredient.
Coating
To a solution of 10 g methylcellulose in 75 ml of denaturated ethanol there is added a
solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then there is added
75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol is
molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the
former and then there is added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone
and 30 ml of concentrated color suspension and the whole is homogenized.
The tablet cores are coated with the thus obtained mixture in a coating apparatus.
Antiviral spectrum:
Because of the increasing emergence of drug resistant HIV strains, the present
compounds were tested for their potency against clinically isolated HIV strains
harboring several mutations. These mutations are associated with resistance to reverse
transcriptase inhibitors and result in viruses that show various degrees of phenotypic
cross-resistance to the currently commercially available drugs such as for instance AZT
and delavirdine.
The antiviral activity of the compound of the present invention has been evaluated in
the presence of wild type HIV and HIV mutants bearing mutations at the reverse
transcriptase gene. The activity of the compounds is evaluated using a cellular assay
and the residual activity is expressed in pECso values. The acnodlu Am-nGs inI ItIhBe
table list the pEC5o values against various strains IIIB, A- G.
Strain IIIB is wild type HIV-LAI strain
Strain A contains mutation Yl 81C in HIV reverse transcriptase,
Strain B contains mutation Kl 03N in HIV reverse transcriptase,
Strain C contains mutation LI001 in HIV reverse transcriptase,
Strain D contains mutation Y188L in HIV reverse transcriptase,
Strain E contains mutations L1001 and K103N in HIV reverse transcriptase,
Strain F contains mutations K103N and Y181C in HIV reverse transcriptase, and
Strain G contains mutations LIOOI, K103N, Y181C, V179I, Y181C, E138G, V179I,



Claims
1. A compound of formula
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
-b1'=b2-b3=b4- represents a bivalent radical of n is 0, 1, 2, 3 and in case -a1=a2-a3=a4- is (a-1), then n may also be 4;
m is 0, 1, 2, 3 and in case -b1==b2-b3=b4- is (b-1), then m may also be 4;
each R1 independently is hydrogen; aryl; formyl; C1-6alkylcarbonyl; C1-6alkyl;
C1-6alkyloxycarbonyl; C1-6alkyl substituted with formyl, C1-6alkylcarbonyl,
C1-6alkyloxycarbonyl, or with C1-6alkylcarbonyloxy;
each R2 independently is hydroxy; halo; C1-6alkyl optionally substituted with one, two
or three substituents each independently selected from halo, cyano or -C(=O)R6;
Ca-vcycloalkyl; C2-ealkenyl optionally substituted with one, two or three substituents
each independently selected from halo, cyano or -C(=O)R6; C2-6alkynyl optionally
substituted with one, two or three substituents each independently selected from
halo, cyano or -C(=O)R6; 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;
-60-
R2a is cyano; aminocarbonyl; amino; C1-6alkyl; halo; C1-6alkyloxy wherein
may optionally be substituted with cyano; NHR13; NR13R14; -C(=O)-NHR13;
-C(=0)-NR13R14; -C(=0)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl substituted with one,
two or three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C1-6alkyi substituted with hydroxy and a
second substituent selected from halo, cyano, NRV0, -C(=O)-NR9R10,
-C(=O)-C1-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C2-6alkenyl substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R10,
-C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C2-6alkynyl substituted with one, two or
three substituents each independently selected from halo, cyano, NR9R10,
-C(=0)-NR9R10, -C(=0)-C1-6alkyl or R7; -C(=N-O-R8)-CMalkyl; R7 or -X3-R7;
X, is -NR1-, -0-, -C(=0)-, -CH2-, -CHOH-, -S-, -S(=O)P-,;
R3 is cyano; aminocarbonyl; amino; C1-6alkyl; halo; C1-6alkyloxy wherein C1-6alkyl
may optionally be substituted with cyano; NHR13; NR13R14; -C(=O)-NHR13;
-C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16; C1-6alkyl substituted with
one, two or three substituents each independently selected from halo, cyano,
NR9R10, -C(=0)-NR9R10, -C(=O)-C1-6alkyl or R7; C1-6alkyl substituted with
hydroxy and a second substituent selected from halo, cyano, NR^10,
-CXOJ-NR9, -C(=0)-C1-6alkyl or R7; C1-6alkyloxyC1-6alkyl optionally
substituted with one, two or three substituents each independently selected from
halo, cyano, NR'R10, -C1-6CO-NRV, -C(=O)-C1-6alkyl or R7; C2-6alkenyl
substituted with one, two or three substituents each independently selected from
halo, cyano, NR1 - 6 , -C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7; C1-6alkynyl
substituted with one, two or three substituents each independently selected from
halo, cyano, NR1-6
0, -C(=O)-NR9R10, -C(=O)-C1-6alkyl or R7;
-C(=N-O-R8)-alkyl; R7 or-X3-R7;
X3 is -NR1-, -0-, -C(=0)-, -S-, -S(=0)p-,;
R4 is halo; hydroxy; C1-6alkyl optionally substituted with one, two or three substituents
each independently selected from halo, cyano or -C(=O)R6; C1-6alkenyl
optionally substituted with one, two or three substituents each independently
selected from halo, cyano or -C(=O)R6; C1-6alkynyl optionally substituted with
one, two or three substituents each independently selected from halo, cyano or
-C(=O)R6; Ca-ycycloalkyl; C1-6alkyloxy; cyano; nitro; polyhaloCi^alkyl;
polyhaloC1-6alkyloxy; aminocarbonyl; mono- or di(CMaDcyl)aminocarbonyl;
C1-6alkyloxycarbonyl; 1-6alkylcarbonyl; formyl; amino; mono- or
di(CMalkyl)amino or R7;
-61-
R5 is a 5- or 6-membered completely unsaturated ring system wherein one, two, three
or four ring members are hetero atoms each independently selected from the group
consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are
carbon atoms; and, where possible, any nitrogen ring member may optionally be
substituted with C1-6alkyl; which ring system may optionally be annelated with a
benzene ring; and wherein any ring carbon atom, including any carbon of an optionally
annelated benzene ring, may, each independently, optionally be substituted with a
substituent selected from halo, hydroxy, mercapto, cyano, C1-6alkyl, hydroxyC1-6alknyl,
Ci^alkyloxycarbonyl, aminocarbonyl, mono- and diC1-6alkylaminocarbonyl, aryl, Het;
wherein Het is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,
thiazolyl, thiadiazolyl, oxadiazolyl, quinolinyl, benzothienyl, benzofuranyl; which each
may optionally be substituted with one or two C1-6alkyl radicals;
Q is hydrogen, Chalky!, halo, polyhaloC1-6alkyl, or -NR9R10;
R6 is CMalkyl, amino, mono- or di(CMalkyl)amino or polyhaloClu,alkyl;
R7 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 halo, hydroxy, mercapto, C1-6alkyl, hydroxyCi^alkyl,
aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
Cs-ycycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro,
polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, amuiocarbonyl, -CH(=N-O-R8), R7',
-X3-R7aorR78-CMalkyl;
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 halo, hydroxy, mercapto, Chalky!, hydroxy Chalky!,
aminoC1-6alkyl, mono or di(C1-6alkyl)aminoC1-6alkyl, formyl, C1-6alkylcarbonyl,
C1-6cycloalkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, C1-6alkylthio, cyano, nitro,
polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, -CH(=N-O-R8);
R8 is hydrogen, CMalkyl, aryl or arylClJ(alkyl;

R9 and R10 each independently are hydrogen; Chalky!; C1-6alkylcarbonyl;
C1-6alkyloxycarbonyl; amino; mono- or di(C1-6alkyl)aminocarbonyl; -CH(=NRn) or
R7, wherein each of the aforementioned Chalky! groups may optionally and each
individually be substituted with one or two substituents each independently selected
from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl,
cyano, amino, imino, mono- or di(C1-6alkyl)amino, polyhalomethyl,
polyhalomethyloxy, polyhalomethylthio, -S(=O)PR6, -NH-S(=O)PR6, -C(=O)R6,
-NHC(=0)H, -C(=0)NHNH2, -NHC(=O)R6,-C(=NH)R6,
R9 and R10 may be taken together to form a bivalent or trivalent radical of formula
Rn is cyano; Chalky! optionally substituted with C1-6alkyloxy, cyano, amino, monoor
di(Ci.4alkyl)amino or aminocarbonyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl;
aminocarbonyl; mono- or di(C1-4alkyljamuiocarbonyl;
R12 is hydrogen or C1-4alkyl;
R13 and R14 each independently are C1-6alkyl optionally substituted with cyano or
aminocarbonyl, C1-4alkenyl optionally substituted with cyano or aminocarbonyl,
C2-6alkynyl optionally substituted with cyano or aminocarbonyl;
R15 is C1-6alkyl substituted with cyano or aminocarbonyl;
R16 is C1-6alkyl optionally substituted with cyano or aminocarbonyl, or R7;
each p is 1 or 2;
each aryl is phenyl or phenyl substituted with one, two, three, four or five substituents
each independently selected from halo, hydroxy, mercapto, C1-6alkyl, hydroxy-
C1-4alkyl, aminoC1-4alkyl, mono or di(C1-6alkyl)aminoC1-4alkyl, C1-6-fialkylcarbonyl,
Cs.vcycloalkyi, C1-6alkyloxy, Cl-6alkyloxycarbonyl, Cl-6alkylthio,
cyano, nitro, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, aminocarbonyl, Het or
-X3-Het.
2. A compound according to claim 1 wherein R5 is a heterocycle selected from
pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl, thiadiazolyl, oxadiazolyl, pyridyl,
pyrunidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, benzothiadiazolyl,

benzofurazanyl, benzoxadiazolyl, indazolyl, quinolinyl, said heterocycle
optionally being substituted on its carbon atoms with one, two or three
substituents each independently selected from halo, hydroxy, mercapto, cyano,
l, hydroxyCi1-4alkyl, carboxyCualkyl, CMalkyloxyCi
lkyl, di(CMalkyl)aminoC1-4alkyl, Het-CMalkyl,
polyhaloC1-4alkyl, C3-7cycloalkyl, arylC2-4alkenyl, C1-4alkyloxy, -
polyhaloCMalkyloxy, aryloxy, amino, mono- and di-C1-4alkylamino,
C1-4alkylcarbonylamino, formyl, C1-4alkylcarbonyl, Cwalkyloxycarbonyl,
aminocarbonyl, mono- and dC1-4alkylaminocarbonyl, aryl, Het.
3. A compound according to claim 1 wherein R5 is a heterocycle selected from
pyrrolyl, furanyl, thienyl, isothiazolyl, thiatriazolyl, thiadiazolyl, oxadiazolyl,
pyridyl, pyrimidinyl, benzofuranyl, quinolinyl, said heterocycle optionally being
substituted on its carbon atoms with one, two or three substituents each
independently selected from halo, hydroxy, cyano, C1-6alkyl, amino, mono- and
di-Cwalkylamino, CMalkylcarbonylamino, aminocarbonyl, aryl, Het.
4. A compound according to claim 1 wherein R5 is a heterocycle selected from
pyrrolyl, furanyl, thienyl, thiazolyl, oxadiazolyl, pyridyl, benzofuranyl,
\quinolinyl, said heterocycle optionally being substituted on its carbon atoms with
one, two or three substituents each independently selected from C1-6alkyl, amino,
aminocarbonyl, aryl, Het.
5. A compound according to claims 1 - 4 wherein
-a'=a2-a3=a4- is -CH=CH-CH=CH- (a-1);
-b'=b2-b3=b4- is -CH=CH-CH=CH- (b-1);
n is 0, 1 or 2; or preferably n is 0;
m is 0, 1 or 2; or preferably m is 2;
R1 is hydrogen; Chalky!; or preferably R1 is hydrogen;
Xi is -NR1-, -O-, -S-, -S(=O)p-;wherein in -NR1- R1 preferably is hydrogen.
6. A compound according to claims 1 -5 wherein
R2 is hydroxy; halo; Chalky! optionally substituted with one substituent selected
from halo, cyano or -C(=O)R6; C2-6alkenyl optionally substituted with one
substituent selected from halo, cyano or -C(=O)R6; C2-6alkynyl optionally
substituted with one substituent selected from halo, cyano or -C(=O)R6;
C1-6alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or di(
amino; trifluoromethyl;
R2a is cyano; aminocarbonyl; amino; C1-6alkyl; halo; C1-6alkyloxy wherein
C1-6alky! may optionally be substituted with cyano; NHR13; NR13R14;
-C(=O)-NHR13; -C(=0)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16;
C1-6alkyl substituted with one substituent selected from halo, cyano,
-C(=O)-NR9R10; C1-6alkyl substituted with hydroxy and a second substituent
selected from halo, cyano, -C(=O)-NR9R10; C1-6alkyloxyC alkyl optionally
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
C2-6alkenyl substituted with one substituent selected from halo, cyano,
-C(=O)-NR9R10; C2-ealkynyl substituted with one substituent selected from
halo, cyano, -C(=O)-NR9R10;
R3 is cyano; aminocarbonyl; amino; C1-6alkyl; halo; C1-6alkyloxy wherein
C1-6alkyl may optionally be substituted with cyano; NHR13; NR13R14;
-C(=O)-NHR13; -C(=O)-NR13R14; -C(=O)-R15; -CH=N-NH-C(=O)-R16;
Ci-galkyl substituted with one substituent selected from halo, cyano,
-C(=O)-NR9R10; C1-6alkyl substituted with hydroxy and a second substituent
selected from halo, cyano, -C(=O)-NR9R10; C1-6alkyloxyC1-6alkyl optionally
substituted with one substituent selected from halo, cyano, -C(=O)-NR9R10;
Ca-ealkenyl substituted with one substituent selected from halo, cyano,
-C(=O)-NR9R10; C2-6alkynyl substituted with one substituent selected from
halo, cyano, -C(=O)-NR9R10;
R4 is halo; hydroxy; C1-6alkyl optionally substituted with one substituent selected
from cyano; C2-6alkenyl optionally substituted with cyano; C2-6alkynyl
optionally substituted with cyano; C3-7ycycloalkyl; C1-6alkyloxy; cyano; nitro;
trifluoromethyl; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl;
C1-6alkyloxycarbonyl; C1-6alkylcarbonyl; formyl; amino; mono- or
di(C1-4alkyl)amino or R7;
Q is hydrogen or -NR9R10.
7. A compound according to claims 1-5 wherein
R2 is halo, C1-6alkyl optionally substituted with cyano, C2-6alkenyl optionally
substituted with cyano, C2-ealkynyl optionally substituted with cyano,
C1-6alkyloxycarbonyl, carboxyl, cyano, amino, mono(C1-6alkylamino,
di(C1-6alkyl)amino;
R2a is halo, cyano, aminocarbonyl, C1-6alkyl optionally substituted with cyano
or aminocarbonyl, C2-6alkenyl optionally substituted with cyano or aminocarbonyl;

R3 is halo, cyano, aminocarbonyl, Chalky! optionally substituted with cyano
or aminocarbonyl, C2-ealkenyl optionally substituted with cyano or
aminocarbonyl;
R4 is halo, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyloxy, cyano,
nitro, amino;
R4 is halo, hydroxy, C1-4alkyl, C1-4alkyloxy, cyano;
Q is hydrogen, amino, mono- or di-C 4alkylamino.
8. A compound according to claims 1 -7 wherein the compound has the formula

9. A compound according to claims 1 - 7 wherein the compound has the formula


10. A compound according to claims 1 - 7 wherein the compound has the formula

11. A compound according to claims 1-7 wherein the compound has the formula
(I"")
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier
and as active ingredient a therapeutically effective amount of a compound as claimed in
any one of claims 1 to 8.
5 13. A compound according to claims 1-10 for use as a medicine.

Documents:

1593-delnp-2007-Abstract-(30-09-2013).pdf

1593-delnp-2007-abstract.pdf

1593-delnp-2007-Assignment-(13-02-2014).pdf

1593-delnp-2007-Claims-(30-09-2013).pdf

1593-delnp-2007-claims.pdf

1593-delnp-2007-Correspondence Others-(03-10-2013).pdf

1593-delnp-2007-Correspondence Others-(13-02-2014).pdf

1593-delnp-2007-Correspondence Others-(18-11-2013).pdf

1593-delnp-2007-Correspondence Others-(30-09-2013).pdf

1593-DELNP-2007-Correspondence-Others.pdf

1593-delnp-2007-description (complete).pdf

1593-delnp-2007-form-1.pdf

1593-delnp-2007-Form-18 (29-09-2008).pdf

1593-delnp-2007-Form-2-(30-09-2013).pdf

1593-delnp-2007-form-2.pdf

1593-delnp-2007-Form-3-(18-11-2013).pdf

1593-delnp-2007-Form-3-(30-09-2013).pdf

1593-delnp-2007-form-3.pdf

1593-delnp-2007-form-5.pdf

1593-delnp-2007-GPA-(30-09-2013).pdf

1593-delnp-2007-gpa.pdf

1593-delnp-2007-pct-210.pdf

1593-delnp-2007-pct-220.pdf

1593-delnp-2007-pct-237.pdf

1593-delnp-2007-pct-304.pdf

1593-delnp-2007-pct-306.pdf

1593-delnp-2007-Petition-137-(13-02-2014).pdf

1593-delnp-2007-Petition-137-(30-09-2013).pdf

abstract.jpg


Patent Number 260172
Indian Patent Application Number 1593/DELNP/2007
PG Journal Number 14/2014
Publication Date 04-Apr-2014
Grant Date 03-Apr-2014
Date of Filing 28-Feb-2007
Name of Patentee TIBOTEC PHARMACEUTICALS LTD.,
Applicant Address EASTGATE VILLAGE, EASTGATE, LITTLE ISLAND, CO CORK, IRELAND
Inventors:
# Inventor's Name Inventor's Address
1 JEROME EMILE GEORGES GUILLEMONT 51BIS, ROUTE DE MUIDS, 27430 ANDE, FRANCE
2 JAN HEERES LEEMSKUILEN 18, 2350 VOSSELAAR, BELGIUM
3 PAULUS JOANNES LEWI PATER VAN MIERLOSTRAAT 18, 2300 TURNHOUT, BELGIUM,
PCT International Classification Number C07D 401/04
PCT International Application Number PCT/EP2005/054930
PCT International Filing date 2005-09-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04104812.5 2004-09-30 EUROPEAN UNION