U.S. patent application number 13/606468 was filed with the patent office on 2013-01-03 for inhibitors of the interaction between mdm2 and p53.
Invention is credited to Imre Christian Francis Csoka, Philipp Ermert, Arnaud Marcel Pierre Piettre, Virginie Sophie Poncelet, Bruno Schoentjes, Pierre Henri Storck.
Application Number | 20130005769 13/606468 |
Document ID | / |
Family ID | 39047055 |
Filed Date | 2013-01-03 |
United States Patent
Application |
20130005769 |
Kind Code |
A1 |
Storck; Pierre Henri ; et
al. |
January 3, 2013 |
INHIBITORS OF THE INTERACTION BETWEEN MDM2 AND P53
Abstract
The present invention provides compounds of formula (I), their
use as an inhibitor of a p53-MDM2 interaction as well as
pharmaceutical compositions comprising said compounds: ##STR00001##
wherein n, s, t, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, Y,
Q, Z, G, E and D have defined meanings.
Inventors: |
Storck; Pierre Henri;
(Ramsgate, GB) ; Schoentjes; Bruno;
(Bois-Guillaume, FR) ; Piettre; Arnaud Marcel Pierre;
(Sierentz, FR) ; Ermert; Philipp; (Allschwil,
CH) ; Poncelet; Virginie Sophie; (Le Manoir sur
Seine, FR) ; Csoka; Imre Christian Francis;
(Louviers, FR) |
Family ID: |
39047055 |
Appl. No.: |
13/606468 |
Filed: |
September 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12678680 |
Mar 17, 2010 |
8288377 |
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PCT/EP2008/062551 |
Sep 19, 2008 |
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13606468 |
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Current U.S.
Class: |
514/314 ;
546/165 |
Current CPC
Class: |
A61P 21/02 20180101;
A61P 37/06 20180101; A61P 19/02 20180101; A61P 27/02 20180101; A61P
3/06 20180101; C07D 413/14 20130101; A61P 7/00 20180101; A61P 3/10
20180101; A61P 7/06 20180101; A61P 25/00 20180101; A61P 27/12
20180101; A61P 35/02 20180101; A61P 37/08 20180101; A61P 25/28
20180101; A61P 13/12 20180101; A61P 17/00 20180101; A61P 29/00
20180101; A61P 37/02 20180101; A61P 43/00 20180101; A61P 21/04
20180101; A61P 35/00 20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/314 ;
546/165 |
International
Class: |
C07D 401/14 20060101
C07D401/14; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02; A61K 31/4709 20060101 A61K031/4709 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 21, 2007 |
EP |
07116897.5 |
Claims
1. A compound of formula (I): ##STR00226## including any
stereochemically isomeric form thereof, wherein n is 0, 1, 2, 3 or
4 and when n is 0 then a direct bond is intended, and wherein
R.sup.1 on each carbon of the --(CHR.sup.1).sub.n-- group is each
independently selected from hydrogen, halo, hydroxy, amino, mono-
or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl, heteroaryl,
C.sub.3-7cycloalkyl, heteroarylC.sub.1-6alkyl, and
C.sub.3-7cycloalkyl-C.sub.1-6alkyl, any of said mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl, heteroaryl,
C.sub.3-7cycloalkyl, heteroarylC.sub.1-6alkyl or
C.sub.3-7cycloalkylC.sub.1-6alkyl being optionally and
independently substituted with one or more, substituents selected
from hydroxy, amino, aryl and heteroaryl; s is 0 or 1 and when s is
0 then a direct bond is intended; t is 0 or 1 and when t is 0 then
a direct bond is intended; R.sup.2 is selected from hydrogen, halo,
cyano, amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.2-6alkenyl, aryl, heteroaryl,
heteroaryl-C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-6alkyl,
morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C.sub.1-6alkyloxy, aryloxy, heteroaryloxy, C.sub.1-6alkylthio,
arylthio, heteroarylthio, C.sub.1-6alkylcarbonyl,
C.sub.3-7cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
substituents selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl,
aryl, heteroaryl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; R.sup.3 is
hydrogen; C.sub.1-6alkyl; aryl; heteroaryl; C.sub.3-7cycloalkyl;
C.sub.1-6alkyl substituted with a substituent selected from
hydroxy, amino, aryl and heteroaryl; or C.sub.3-7cycloalkyl
substituted with a substituent selected from hydroxy, amino, aryl
and heteroaryl; X is NR.sup.6, S or O; ##STR00227## is
--CR.sup.7.dbd.R.sup.8-- and then the dotted line is a bond,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
wherein R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each
independently selected from: hydrogen, halo, hydroxy, cyano;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.2-6alkenyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-6alkyl,
morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkyloxy, aryloxy, heteroaryloxy,
C.sub.1-6alkylthio, arylthio, heteroarylthio,
C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.3-7cycloalkyloxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
substituents selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl,
aryl, heteroaryl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; or wherein
any of R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10
together form a bivalent radical selected from
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2- and
--(CH.sub.2).sub.2--NR.sup.21--(CH.sub.2).sub.2- wherein R.sup.21
is hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxyalkyl; or wherein
any of R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10
together form a bivalent radical --(CH.sub.2).sub.m--, wherein m is
2, 3, 4, 5 or 6; -D- is CHR.sup.20--, wherein R.sup.20 is selected
from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl and
C.sub.1-6alkyloxycarbonyl; ##STR00228## is --CR.sup.19.dbd.C<
and then the dotted line is a bond, --C(.dbd.O)--CH<,
--C(.dbd.O)--N<, --CHR.sup.19--CH<, or --CHR.sup.19--N<,
wherein each R.sup.19 is independently hydrogen or C.sub.1-6alkyl;
R.sup.4 and R.sup.5 are each independently hydrogen, halo,
C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl,
cyano, cyanoC.sub.1-6alkyl, hydroxy, amino, C.sub.2-6alkenyl or
C.sub.1-6alkyloxy, or R.sup.4 and R.sup.5 together form a bivalent
radical selected from methylenedioxy or ethylenedioxy; R.sup.6 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl or
C.sub.1-6alkyloxycarbonyl; Z is a radical selected from
##STR00229## wherein R.sup.11 or R.sup.12 are each independently
selected from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl,
nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl,
tetrazolo-C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, aryl(hydroxy)-C.sub.1-6alkyl,
heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkylcarbonyl,
arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkylcarbonyl,
C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl,
arylC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.2-6alkenyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl
and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CHR.sup.18).sub.u--NR.sup.14R.sup-
.15, wherein v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a
direct bond is intended; r is 0 or 1 and when r is 0 then a direct
bond is intended; u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then
a direct bond is intended; R.sup.18 is hydrogen or C.sub.1-6alkyl;
R.sup.14 and R.sup.15 are each independently selected from
hydrogen; C.sub.1-12alkyl; C.sub.1-6alkylcarbonyl;
C.sub.1-6alkylsulfonyl; arylC.sub.1-6alkylcarbonyl;
C.sub.3-7cycloalkyl; C.sub.3-7cycloalkylcarbonyl;
--(CH.sub.2).sub.k--NR.sup.16R.sup.17; C.sub.1-12alkyl substituted
with a substituent selected from hydroxy, hydroxycarbonyl, cyano,
C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyloxy, aryl or heteroaryl;
or C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, amino, arylC.sub.1-6alkyl,
heteroaryl or heteroarylC.sub.1-6alkyl, or R.sup.14 and R.sup.15
together with the nitrogen to which they are attached form
morpholinyl; piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl
substituted with a substituent selected from C.sub.1-6alkyl,
arylC.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl and
C.sub.3-7cycloalkylC.sub.1-6alkyl; wherein k is 0, 1, 2, 3, 4, 5,
or 6 and when k is 0 then a direct bond is intended; R.sup.16 and
R.sup.17 are each independently selected from hydrogen;
C.sub.1-12alkyl; arylC.sub.1-6alkyloxycarbonyl;
C.sub.3-7cycloalkyl; C.sub.1-12alkyl substituted with a substituent
selected from hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and
C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl,
and heteroarylC.sub.1-6alkyl; or R.sup.16 and R.sup.17 together
with the nitrogen to which they are attached form morpholinyl,
piperazinyl, or piperazinyl substituted with
C.sub.1-6alkyloxycarbonyl; R.sup.13 is hydrogen; C.sub.1-6alkyl;
C.sub.3-7cycloalkyl; C.sub.1-6alkyl substituted with a substituent
selected from hydroxy, amino, C.sub.1-6alkyloxy and aryl; or
C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, amino, aryl and C.sub.1-6alkyloxy; aryl is phenyl or
naphthalenyl; each phenyl or naphthalenyl can optionally be
substituted with one, two or three substituents each independently
selected from halo, hydroxy, C.sub.1-6alkyl, amino,
polyhaloC.sub.1-6alkyl and C.sub.1-6alkyloxy; and each phenyl or
naphthalenyl can optionally be substituted with a bivalent radical
selected from methylenedioxy and ethylenedioxy; heteroaryl is
pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,
oxadiazolyl, tetrazolyl, benzofuranyl or tetrahydrofuranyl; each
pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,
oxadiazolyl, tetrazolyl, benzofuranyl, or tetrahydrofuranyl can
optionally be substituted with one, two or three substituents each
independently selected from halo, hydroxy, C.sub.1-6alkyl, amino,
polyhaloC.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl or
C.sub.1-6alkyloxy; and each pyridinyl, indolyl, quinolinyl,
imidazolyl, furanyl, thienyl, benzofuranyl, or tetrahydrofuranyl
can optionally be substituted with a bivalent radical selected from
methylenedioxy or ethylenedioxy; an N-oxide form thereof, an
addition salt thereof or a solvate thereof.
2. The compound according to claim 1 wherein R.sup.1 on each carbon
of the --(CHR.sup.1).sub.n-- group is each independently selected
from hydrogen, halo, hydroxy, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl, heteroaryl,
C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
and C.sub.3-7cycloalkyl-C.sub.1-6alkyl, any of said mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, heteroaryl,
C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl
or C.sub.3-7cycloalkylC.sub.1-6alkyl being optionally and
independently substituted with one or more, substituents selected
from hydroxy, amino, aryl and heteroaryl; R.sup.2 is selected from
hydrogen, halo, cyano, amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, C.sub.2-6alkenyl, aryl,
heteroaryl, arylC.sub.1-6alkyl, heteroaryl-C.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, morpholinyl, piperidinyl,
pyrrolidinyl, piperazinyl, C.sub.1-6alkyloxy, aryloxy,
heteroaryloxy, C.sub.1-6alkylthio, arylthio, heteroarylthio,
C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.3-7cycloalkyloxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
substituents selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl,
aryl, heteroaryl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; X is
NR.sup.6; ##STR00230## is --CR.sup.7.dbd.R.sup.8-- and then the
dotted line is a bond, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
wherein R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each
independently selected from: hydrogen, halo, hydroxy, cyano;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.2-6alkenyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-6alkyl,
morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkyloxy, aryloxy, heteroaryloxy,
C.sub.1-6alkylthio, arylthio, heteroarylthio,
C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.3-7cycloalkyloxycarbonyl, aryloxycarbonyl,
heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
substituents selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl,
aryl, heteroaryl, C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; or wherein
any of R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10
together form a bivalent radical selected from
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2-- and
--(CH.sub.2).sub.2--NR.sup.21--(CH.sub.2).sub.2- wherein R.sup.21
is hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxyalkyl; or wherein
any of R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10
together form a bivalent radical selected from
--(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or 6; R.sup.4 and
R.sup.5 are each independently hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, hydroxy, amino,
or C.sub.1-6alkyloxy, or R.sup.4 and R.sup.5 together form a
bivalent radical selected from methylenedioxy or ethylenedioxy;
R.sup.6 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl or
C.sub.1-6alkyloxycarbonyl; Z is a radical selected from
##STR00231## wherein R.sup.11 or R.sup.12 are each independently
selected from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl,
nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl,
tetrazolo-C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, aryl(hydroxy)-C.sub.1-6alkyl,
heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkylcarbonyl,
arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkylcarbonyl,
C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl,
arylC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.2-6alkenyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl
and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CHR.sup.18).sub.u--NR.sup.14R.sup-
.15, wherein v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0 then a
direct bond is intended; r is 0 or 1 and when r is 0 then a direct
bond is intended; u is 0, 1, 2, 3, 4, 5, or 6 and when u is 0 then
a direct bond is intended; R.sup.18 is hydrogen or C.sub.1-6alkyl;
R.sup.14 and R.sup.15 are each independently selected from
hydrogen; C.sub.1-12alkyl; C.sub.1-6alkylcarbonyl;
C.sub.1-6alkylsulfonyl; arylC.sub.1-6alkylcarbonyl;
C.sub.3-7cycloalkyl; C.sub.3-7cycloalkylcarbonyl;
--(CH.sub.2).sub.k--NR.sup.16R.sup.17; C.sub.1-12alkyl substituted
with a substituent selected from hydroxy, hydroxycarbonyl, cyano,
C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkyloxy, aryl or heteroaryl;
or C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, amino, arylC.sub.1-6alkyl,
heteroaryl or heteroarylC.sub.1-6alkyl, or R.sup.14 and R.sup.15
together with the nitrogen to which they are attached form
morpholinyl; piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl
substituted with a substituent selected from C.sub.1-6alkyl,
arylC.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl and
C.sub.3-7cycloalkylC.sub.1-6alkyl; wherein k is 0, 1, 2, 3, 4, 5,
or 6 and when k is 0 then a direct bond is intended; R.sup.16 and
R.sup.17 are each independently selected from hydrogen;
C.sub.1-6alkyl; arylC.sub.1-6alkyloxycarbonyl; C.sub.3-7cycloalkyl;
C.sub.1-12alkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and
C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl,
and heteroarylC.sub.1-6alkyl; or R.sup.16 and R.sup.17 together
with the nitrogen to which they are attached form morpholinyl,
piperazinyl, or piperazinyl substituted with
C.sub.1-6alkyloxycarbonyl.
3. The compound according to claim 1, wherein R.sup.1 on each
carbon of the --(CHR.sup.1).sub.n-- group is each independently
selected from hydrogen, hydroxy, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, arylC.sub.1-6alkyl and
heteroarylC.sub.1-6alkyl; when any one R.sup.1 substituent in the
--(CHR.sup.1).sub.n-- group is different from hydrogen, the other
R.sup.1 substituents in the --(CHR.sup.1).sub.n-- group are each
hydrogen; s is 0; t is 0 or 1; R.sup.2 is selected from hydrogen,
halo, cyano, amino, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylthio, arylthio,
C.sub.1-6alkylcarbonyl, hydroxyC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylcarbonylamino, morpholinyl, piperidinyl, pyrrolidinyl
and piperazinyl; R.sup.3 is hydrogen or C.sub.1-6alkyl; R.sup.20 is
selected from hydrogen and C.sub.1-6alkyl; ##STR00232## is
--CR.sup.19.dbd.C< wherein R.sup.19 is hydrogen or
C.sub.1-6alkyl; R.sup.4 and R.sup.5 are each independently
hydrogen, halo, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, cyano,
cyanoC.sub.1-6alkyl, hydroxy, amino, or C.sub.1-6alkyloxy; Z is a
radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
R.sup.11 or R.sup.12 are each independently selected from hydrogen,
hydroxy, amino, C.sub.1-6alkyl, nitro, polyhaloC.sub.1-6alkyl,
cyano, aryl, arylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl,
arylcarbonyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonyl, aminocarbonyl, hydroxyl-C.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CH.sub.2).sub.u--NR.sup.14R.sup.1-
5; v is 0 or 1; r is 0 or 1; u is 0; R.sup.14 and R.sup.15 are each
independently selected from hydrogen, C.sub.1-6alkyl,
--(CH.sub.2).sub.k--NR.sup.16R.sup.17 and C.sub.1-12alkyl
substituted with hydroxy; R.sup.14 and R.sup.15 together with the
nitrogen to which they are attached form pyrrolidinyl; k is 2;
R.sup.16 and R.sup.17 are each independently C.sub.1-6alkyl;
R.sup.13 is hydrogen or C.sub.1-6alkyl; aryl is phenyl or phenyl
substituted with halo; and heteroaryl is pyridinyl, indolyl,
oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl, oxadiazolyl
or tetrazolyl can optionally be substituted with one substituent
selected from C.sub.1-6alkyl, aryl and arylC.sub.1-6alkyl.
4. The compound according to claim 1, wherein n is 2; each R.sup.1
is hydrogen; s is 0; t is 0; R.sup.2 is selected from hydrogen
halo, cyano, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonylamino and morpholinyl; R.sup.3 is hydrogen;
##STR00233## is --CH.dbd.C<; R.sup.4 and R.sup.5 are each
independently hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy;
R.sup.6 is hydrogen; Z is a radical selected from (a-1), (a-2) and
(a-4), and R.sup.11 or R.sup.12 are each independently selected
from hydrogen, hydroxy and hydroxyl-C.sub.1-6alkyl.
5. The compound according to claim 1 wherein X is NR.sup.6.
6. The compound according to claim 1 wherein t is 0; s is 0; n is
2; X is NR.sup.6, S or O; R.sup.1 is hydrogen; R.sup.2 is hydrogen
or halo; R.sup.3 is hydrogen; R.sup.4 and R.sup.5 are each
independently hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy;
R.sup.6 is hydrogen; ##STR00234## is --CR.sup.19.dbd.C< and then
the dotted line is a bond, wherein R.sup.19 is hydrogen;
--CH.sub.2-- wherein R.sup.20 is hydrogen or C.sub.1-6alkyl; Z is a
radical of formula (a-2) or (a-4); R.sup.11 and R.sup.12 are each
independently selected from hydrogen, hydroxyl and
hydroxyC.sub.1-6alkyl.
7. (canceled)
8. The compound according to claim 1 wherein ##STR00235## is
--CR.sup.19.dbd.C< and then the dotted line is a bond, wherein
R.sup.19 is hydrogen.
9. The compound according to claim 1, wherein ##STR00236## is
--CR.sup.7.dbd.CR.sup.8--, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
and R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each independently
selected from hydrogen, halo, hydroxy; perhaloC.sub.1-6alkyl;
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, C.sub.1-6alkyloxy,
aryl-C.sub.1-6alkyloxy, heteroarylC.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonyl, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino and morpholinyl, any of said groups
optionally substituted with one or more, substituents selected from
halo, hydroxy, amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, aryl,
heteroaryl and C.sub.1-6alkyloxy; or wherein any of R.sup.7 and
R.sup.9 together, or R.sup.8 and R.sup.10 together form a bivalent
radical --(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or 6.
10. The compound according to claim 1, wherein ##STR00237## is
--CR.sup.7.dbd.CR.sup.8--, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
and R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each independently
selected from hydrogen, halo, C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, or wherein any of R.sup.7 and R.sup.9
together, or R.sup.8 and R.sup.10 together form a bivalent radical
--(CH.sub.2).sub.m-- wherein m is 2, 3, 4, 5 or 6.
11. The compound according to claim 1 wherein ##STR00238## is
--CH.sub.2--CH.sub.2--; --CH.sub.2--CH(CH.sub.3)--;
--CH.sub.2--C(CH.sub.3).sub.2--; --CH.sub.2--CH(CH.sub.2OH)--;
--CH.sub.2--C(CH.sub.3)(CH.sub.2CH.sub.3)--;
--C(.dbd.O)--CH.sub.2--; --C(.dbd.O)--CH(CH.sub.3)--;
--C(.dbd.O)--C(CH.sub.3).sub.2--; --C(.dbd.O)--CF.sub.2--;
##STR00239##
12. The compound according to claim 1, wherein the compound is
##STR00240## including any stereochemically isomeric form thereof;
an N-oxide form thereof, an addition salt thereof or a solvate
thereof.
13. A compound according to claim 1 for use as a medicine.
14. A pharmaceutical composition comprising pharmaceutically
acceptable carriers and as an active ingredient a therapeutically
effective amount of a compound as claimed in claim 1.
15. A method for the manufacture of a medicament for the treatment
of a disorder mediated by a p53-MDM2 interaction with a compound
according to claim 1.
16. A method for the manufacture of a medicament for the treatment
of cancer by administering an effective amount compound according
to claim 1.
17. The method according to claim 16 wherein the cancer is breast
cancer, colorectal cancer, non-small cell lung cancer or acute
myelogenous leukaemia.
18. A combination of an anti-cancer agent and a compound according
to claim 1.
19. A process for preparing a compound as claimed in claim 1,
characterized by a) reacting an intermediate of formula (II) with
an intermediate of formula (III) or an appropriate acid addition
salt thereof, wherein W is an appropriate leaving group
##STR00241## with the variables as defined in claim 1; b) reacting
an intermediate of formula (XIX) wherein P represents a suitable
protective group, with an intermediate of formula (III) or an
appropriate acid addition salt thereof, wherein W is an appropriate
leaving group ##STR00242## with the variables as defined in claim
1; c) reacting an intermediate of formula (XX) with an intermediate
of formula (III) or an appropriate acid addition salt thereof,
wherein W is an appropriate leaving group ##STR00243## with the
variables as defined in claim 1; d) reacting an intermediate of
formula (XXI) with a suitable deprotection agent for the alcohol
function in the presence of a suitable solvent ##STR00244## with
the variables as defined in claim 1; e) reacting an intermediate of
formula (IV), wherein A is an appropriate leaving group, with an
intermediate of formula (V ##STR00245## with the variables as
defined in claim 1; f) reducing an intermediate of formula (VI)
with lithium aluminium hydride in a suitable solvent ##STR00246##
with the variables as defined in claim 1; g) reacting an
appropriate carboxaldehyde of formula (VII), with an intermediate
of formula (V), in the presence of an appropriate reducing reagent
and a suitable solvent, ##STR00247## with the variables as defined
in claim 1; h) reacting an intermediate of formula (II) with an
appropriate carboxaldehyde of formula HC(.dbd.O)Z to obtain
compounds of formula (I) wherein t is 1, herein referred to as
compounds of formula (I-b); g) reducing an intermediate of formula
(VIII) with lithium aluminium hydride in a suitable solvent
##STR00248## with the variables as defined in claim 1; h)
converting a compound of formula (I) wherein ##STR00249## is
--C(.dbd.O)--CR.sup.8R.sup.10--, with R.sup.8 and R.sup.10
representing hydrogen, herein referred to as compounds of formula
(I-f), into a compound of formula (I) wherein ##STR00250## is
--CH.sub.2--CH.sub.2--, herein referred to as compounds of formula
(I-g), by reaction with a suitable reducing agent, ##STR00251##
with the variables as defined in claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds and compositions
containing said compounds acting as inhibitors of the interaction
between MDM2 and p53, in particular modulators of the
MDM2-proteasome interaction. The invention also provides processes
for the preparation of the disclosed compounds and compositions and
methods of using them, for instance as a medicine.
[0002] p53 is a tumour suppressor protein which plays a pivotal
role in the regulation of the balance between cell proliferation
and cell growth arrest/apoptosis. Under normal conditions the half
life of p53 is very short and consequently the level of p53 in
cells is low. However, in response to cellular DNA damage or
cellular stress (e.g. oncogene activation, telomere erosion,
hypoxia), levels of p53 increase. This increase in p53 levels leads
to the activation of the transcription of a number of genes which
drives the cell into either growth arrest or into the processes of
apoptosis. Thus, an important function of p53 is to prevent the
uncontrolled proliferation of damaged cells and thus protect the
organism from the development of cancer.
[0003] MDM2 is a key negative regulator of p53 function. It forms a
negative autoregulatory loop by binding to the amino terminal
transactivation domain of p53 and thus MDM2 both inhibits the
ability of p53 to activate transcription and targets p53 for
proteolytic degradation. Under normal conditions this regulatory
loop is responsible for maintaining the low levels of p53. However,
in tumours with wild-type p53, the equilibrium concentration of
active p53 can be increased by antagonising the interaction between
MDM2 and p53. Other activities of MDM2 are also required for p53
degradation, as evidenced by the accumulation of ubiquitylated p53
when phosphorylation in the central domain of HDM2 is abrogated
(Blattner et al., Hypophosphorylation of Mdm2 augments p53
stability. (2002) Mol. Cell. Biol., 22, 6170-6182). The association
of HDM2 with different subunits of the 26S proteasome such as S4,
S5a, S6a and S6b (3.sup.rd Mdm2 workshop, September 2005 in
Constance, Germany) might play a key role in this process. Thus,
p53 concentrations can also be increased by modulating the
MDM2-proteasome interaction. This will result in restoration of the
p53-mediated pro-apoptotic and anti-proliferative effects in such
tumour cells. MDM2 antagonists might even exhibit
anti-proliferative effects in tumour cells that are devoid of
functional p53.
[0004] This positions the HDM2 protein as an attractive target for
the development of anti-cancer therapy.
[0005] MDM2 is a cellular proto-oncogene. Over-expression of MDM2
has been observed in a range of cancers. MDM2 is over-expressed in
a variety of tumours due to gene amplification or increased
transcription or translation. The mechanism by which MDM2
amplification promotes tumourigenesis is at least in part related
to its interaction with p53. In cells over-expressing MDM2 the
protective function of p53 is blocked and thus cells are unable to
respond to DNA damage or cellular stress by increasing p53 levels,
leading to cell growth arrest and/or apoptosis. Thus after DNA
damage and/or cellular stress, cells over-expressing MDM2 are free
to continue to proliferate and assume a tumorigenic phenotype.
Under these conditions disruption of the interaction of p53 and
MDM2 would release the p53 and thus allow normal signals of growth
arrest and/or apoptosis to function.
[0006] MDM2 may also have separate functions in addition to
inhibition of p53. The number of MDM2 substrates is rapidly
expanding. For example, it has been shown that MDM2 interacts
directly with the pRb-regulated transcription factor E2F1/DP1. This
interaction could be crucial for the p53-independent oncogenic
activities of MDM2. A domain of E2F1 shows striking similarity to
the MDM2-binding domain of p53. Since the interactions of MDM2 with
both p53 and E2F1 locate to the same binding site on MDM2, it can
be expected that MDM2/p53 antagonists will not only activate
cellular p53 but also modulate E2F1 activities, which are commonly
deregulated in tumour cells. Other key examples of MDM2 substrates
include p63, p73, p21.sup.waf1,cip1.
[0007] Also the therapeutic effectiveness of DNA damaging agents
currently used (chemotherapy and radiotherapy), may be limited
through the negative regulation of p53 by MDM2. Thus if the MDM2
feed-back inhibition of p53 is interrupted, an increase in
functional p53 levels will increase the therapeutic effectiveness
of such agents by restoring the wild-type p53 function that leads
to apoptosis and/or reversing of p53-associated drug resistance. It
was demonstrated that combining MDM2 inhibition and DNA-damaging
treatments in vivo led to synergistic anti-tumour effects (Vousden
K. H., Cell, Vol. 103, 691-694, 2000).
[0008] Thus disruption of the interaction of MDM2 and p53 offers an
approach for therapeutic intervention in tumours with wild-type or
mutant p53, might even exhibit anti-proliferative effects in tumour
cells that are devoid of functional p53 and furthermore can
sensitise tumorigenic cells for chemotherapy and radiotherapy.
BACKGROUND OF THE INVENTION
[0009] WO 2006/032631, WO 2007/107545 and WO 2007/107543 disclose
inhibitors of the interaction between MDM2 and p53, useful inter
alia in treating tumours and enhancing the effectiveness of
chemotherapy and radiotherapy.
[0010] The compounds of the instant invention differ structurally
from the compounds of WO 2006/032631, WO 2007/107545 and WO
2007/107543 by comprising an N-containing ring fused to the central
phenyl ring and wherein the N is linked to a bicycle.
[0011] Unexpectedly, this substantial structural modification
yields novel compounds which retain or may even show improved
inhibitory activity or useful properties. Hence, the invention
provides a further useful series of effective and potent small
molecules that inhibit the interactions between MDM2 and p53.
DESCRIPTION OF THE INVENTION
[0012] The present invention provides compounds and compositions
for, and methods of, inhibiting the interactions between MDM2 and
p53 for treating proliferative disease, including tumours and
cancer. Furthermore, the compounds and compositions of the
invention are useful in enhancing the effectiveness of chemotherapy
and radiotherapy.
[0013] Accordingly, in an aspect the invention provides a compound
of formula (I):
##STR00002##
including any stereochemically isomeric form thereof, wherein n is
0, 1, 2, 3 or 4 and when n is 0 then a direct bond is intended, and
wherein [0014] R.sup.1 on each carbon of the --(CHR.sup.1).sub.n--
group is each independently selected from hydrogen, halo, hydroxy,
amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl,
heteroaryl, C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, and C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
[0015] any of said mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, aryl, heteroaryl, C.sub.3-7cycloalkyl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl or
C.sub.3-7cycloalkylC.sub.1-6alkyl being optionally and
independently substituted with one or more, preferably one or two,
substituents selected from hydroxy, amino, aryl and heteroaryl; s
is 0 or 1 and when s is 0 then a direct bond is intended; t is 0 or
1 and when t is 0 then a direct bond is intended; R.sup.2 is
selected from [0016] hydrogen, halo, cyano, amino; [0017]
polyhaloC.sub.1-6alkyl; [0018] C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.2-6alkenyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroaryl-C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-6alkyl,
morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C.sub.1-6alkyloxy, aryloxy, heteroaryloxy, C.sub.1-6alkylthio,
arylthio, heteroarylthio, C.sub.1-6alkylcarbonyl, [0019]
C.sub.3-7cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
preferably one or two, substituents selected from halo, hydroxy,
cyano, amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, aryl, heteroaryl, C.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl and
C.sub.1-6alkylcarbonyloxy; R.sup.3 is hydrogen; C.sub.1-6alkyl;
aryl; heteroaryl; C.sub.3-7cycloalkyl; C.sub.1-6alkyl substituted
with a substituent selected from hydroxy, amino, aryl and
heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent
selected from hydroxy, amino, aryl and heteroaryl;
X is NR.sup.6, S or O;
##STR00003##
[0020] is --CR.sup.7.dbd.CR.sup.8-- and then the dotted line is a
bond, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
wherein [0021] R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each
independently selected from: [0022] hydrogen, halo, hydroxy, cyano;
[0023] polyhaloC.sub.1-6alkyl; [0024] C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.2-6alkenyl, aryl, heteroaryl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, morpholinyl, piperidinyl,
pyrrolidinyl, piperazinyl, C.sub.1-6alkyloxy,
C.sub.3-7cycloalkyloxy, aryloxy, heteroaryloxy, C.sub.1-6alkylthio,
arylthio, heteroarylthio, C.sub.1-6alkylcarbonyl,
C.sub.3-7cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or [0025]
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
preferably one or two, substituents selected from halo, hydroxy,
cyano, amino, mono- or [0026] di(C.sub.1-6alkyl)amino, [0027]
C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, aryl, heteroaryl,
C.sub.1-6alkyloxy, [0028] C.sub.1-6alkylcarbonyl, [0029]
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; [0030] or
wherein any of R.sup.7 and R.sup.9 together, or R.sup.8 and
R.sup.10 together form a bivalent radical selected from
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.2- and
--(CH.sub.2).sub.2--NR.sup.21--(CH.sub.2).sub.2- wherein R.sup.21
is hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxyalkyl; [0031] or
wherein any of R.sup.7 and R.sup.9 together, or R.sup.8 and
R.sup.10 together form a bivalent radical --(CH.sub.2).sub.m--,
wherein m is 2, 3, 4, 5 or 6; -D- is --O--, --CHR.sup.20-- or
--NR.sup.20--, wherein R.sup.20 is selected from hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl and
C.sub.1-6alkyloxycarbonyl;
##STR00004##
[0031] is --CR.sup.19.dbd.C< and then the dotted line is a bond,
--C(.dbd.O)--CH<, --C(.dbd.O)--N<, --CHR.sup.19--CH<, or
--CHR.sup.19--N<, wherein each R.sup.19 is independently
hydrogen or C.sub.1-6alkyl; R.sup.4 and R.sup.5 are each
independently hydrogen, halo, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, cyano,
cyanoC.sub.1-6alkyl, hydroxy, amino, C.sub.2-6alkenyl or
C.sub.1-6alkyloxy, or R.sup.4 and R.sup.5 together form a bivalent
radical selected from methylenedioxy or ethylenedioxy; R.sup.6 is
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl or
C.sub.1-6alkyloxycarbonyl; Z is a radical selected from
##STR00005##
wherein [0032] R.sup.11 or R.sup.12 are each independently selected
from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl, nitro,
polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl,
tetrazolo-C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, aryl(hydroxy)-C.sub.1-6alkyl,
heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkylcarbonyl,
arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkylcarbonyl,
C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl,
arylC.sub.1-6alkyloxyC.sub.1-6alkyl, [0033]
C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.2-6alkenyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl
and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CHR.sup.18).sub.u--NR.sup.14R.sup-
.15, wherein [0034] v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0
then a direct bond is intended; [0035] r is 0 or 1 and when r is 0
then a direct bond is intended; [0036] u is 0, 1, 2, 3, 4, 5, or 6
and when u is 0 then a direct bond is intended; [0037] R.sup.18 is
hydrogen or C.sub.1-6alkyl; [0038] R.sup.14 and R.sup.15 are each
independently selected from hydrogen; C.sub.1-12alkyl;
C.sub.1-6alkylcarbonyl; C.sub.1-6alkylsulfonyl;
arylC.sub.1-6alkylcarbonyl; C.sub.3-7cycloalkyl;
C.sub.3-7cycloalkylcarbonyl; --(CH.sub.2).sub.k--NR.sup.16R.sup.17;
C.sub.1-12alkyl substituted with a substituent selected from
hydroxy, hydroxycarbonyl, cyano, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkyloxy, aryl or heteroaryl; or C.sub.3-7cycloalkyl
substituted with a substituent selected from hydroxy,
C.sub.1-6alkyloxy, aryl, amino, arylC.sub.1-6alkyl, heteroaryl or
heteroarylC.sub.1-6alkyl, or [0039] R.sup.14 and R.sup.15 together
with the nitrogen to which they are attached form morpholinyl;
piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl substituted
with a substituent selected from C.sub.1-6alkyl,
arylC.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl and
C.sub.3-7cycloalkylC.sub.1-6alkyl; wherein [0040] k is 0, 1, 2, 3,
4, 5, or 6 and when k is 0 then a direct bond is intended; [0041]
R.sup.16 and R.sup.17 are each independently selected from
hydrogen; C.sub.1-12alkyl; arylC.sub.1-6alkyloxycarbonyl;
C.sub.3-7cycloalkyl; substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and
C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl,
and heteroarylC.sub.1-6alkyl; or [0042] R.sup.16 and R.sup.17
together with the nitrogen to which they are attached form
morpholinyl, piperazinyl, or piperazinyl substituted with
C.sub.1-6alkyloxycarbonyl; [0043] R.sup.13 is hydrogen;
C.sub.1-6alkyl; C.sub.3-7cycloalkyl; C.sub.1-6alkyl substituted
with a substituent selected from hydroxy, amino, C.sub.1-6alkyloxy
and aryl; or C.sub.3-7cycloalkyl substituted with a substituent
selected from hydroxy, amino, aryl and C.sub.1-6alkyloxy; aryl is
phenyl or naphthalenyl; [0044] each phenyl or naphthalenyl can
optionally be substituted with one, two or three substituents each
independently selected from halo, hydroxy, C.sub.1-6alkyl, amino,
polyhaloC.sub.1-6alkyl and C.sub.1-6alkyloxy; and [0045] each
phenyl or naphthalenyl can optionally be substituted with a
bivalent radical selected from methylenedioxy and ethylenedioxy;
heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,
thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or
tetrahydrofuranyl; [0046] each pyridinyl, indolyl, quinolinyl,
imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl,
benzofuranyl, or tetrahydrofuranyl can optionally be substituted
with one, two or three substituents each independently selected
from halo, hydroxy, C.sub.1-6alkyl, amino, polyhaloC.sub.1-6alkyl,
aryl, arylC.sub.1-6alkyl or C.sub.1-6alkyloxy; and [0047] each
pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,
benzofuranyl, or tetrahydrofuranyl can optionally be substituted
with a bivalent radical selected from methylenedioxy or
ethylenedioxy; an N-oxide form thereof, an addition salt thereof or
a solvate thereof.
[0048] The compounds of formula (I) may also exist in their
tautomeric forms. Such forms although not explicitly indicated in
the above formula are intended to be included within the scope of
the present invention.
[0049] A number of terms used in the foregoing definitions and
hereinafter are explained hereunder. These terms may be used as
such or in composite terms.
[0050] As used herein, halo is generic to fluoro, chloro, bromo and
iodo. C.sub.1-6alkyl defines straight- and branched-chain saturated
hydrocarbon radicals having from 1 to 6 carbon atoms such as, e.g.,
methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl,
2-methylpropyl, 2-methyl-butyl, 2-methylpentyl and the like.
C.sub.1-12 alkyl includes C.sub.1-6alkyl and the higher straight-
and branched-chain homologues thereof having 7 to 12 carbon atoms
such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl
and the like. HydroxyC.sub.1-6alkyl refers to a C.sub.1-6alkyl as
defined herein, wherein one or more (e.g., one, two, three or more)
hydrogens of said
C.sub.1-6alkyl are replaced with a hydroxyl substituent.
PolyhaloC.sub.1-6alkyl refers to a C.sub.1-6alkyl as defined
herein, wherein one or more hydrogens of said C.sub.1-6alkyl are
replaced with identical or different halogen substituents; the term
also encompasses perhaloC.sub.1-6alkyls, i.e., C.sub.1-6alkyl as
defined herein, wherein all hydrogens of said C.sub.1-6alkyl are
replaced with identical or different halogen substituents--for
example, trihalomethyl defines methyl containing three identical or
different halo substituents, such as, e.g., trifluoromethyl.
C.sub.2-6alkenyl defines straight- and branched-chain hydrocarbon
radicals containing one or more double bonds, preferably one double
bond, and having from 2 to 6 carbon atoms such as, for example,
ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,
3-methyl-2-butenyl, and the like. C.sub.3-7cycloalkyl includes
alicyclic saturated and unsaturated hydrocarbon groups having from
3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like.
Preferably C.sub.3-7cycloalkyl includes alicyclic saturated
hydrocarbon groups having from 3 to 7 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
the like.
[0051] The term "addition salt" comprises the salts which the
compounds of formula (I) are able to form with organic or inorganic
bases such as amines, alkali metal bases and earth alkaline metal
bases, or quaternary ammonium bases, or with organic or inorganic
acids, such as mineral acids, sulfonic acids, carboxylic acids or
phosphorus containing acids.
[0052] The term "addition salt" further comprises pharmaceutically
acceptable salts, metal complexes and the salts thereof, that the
compounds of formula (I) are able to form.
[0053] The term "pharmaceutically acceptable salts" means
pharmaceutically acceptable acid or base addition salts. The
pharmaceutically acceptable acid or base addition salts as
mentioned hereinabove are meant to comprise the therapeutically
active non-toxic acid and non-toxic base addition salt forms which
the compounds of formula (I) are able to form. The compounds of
formula (I) which have basic properties can be converted in their
pharmaceutically acceptable acid addition salts by treating said
base form with an appropriate acid. Appropriate acids comprise, for
example, inorganic acids such as hydrohalic acids, e.g.,
hydrochloric or hydrobromic acid, sulphuric, nitric, phosphoric and
the like acids; or organic acids such as, for example, acetic,
propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic,
succinic (i.e., butanedioic acid), maleic, fumaric, malic,
tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic
and the like acids.
[0054] The compounds of formula (I) which have acidic properties
may be converted in their pharmaceutically acceptable base addition
salts by treating said acid form with a suitable organic or
inorganic base. 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., the benzathine,
N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids
such as, for example, arginine, lysine and the like.
[0055] Preferably, the term addition salt means a pharmaceutically
acceptable acid or base addition salt.
[0056] The term "metal complexes" means a complex formed between a
compound of formula (I) and one or more organic or inorganic metal
salt or salts. Examples of said organic or inorganic salts comprise
the halogenides, nitrates, sulfates, phosphates, acetates,
trifluoroacetates, trichloroacetates, propionates, tartrates,
sulfonates, e.g., methylsulfonates, 4-methylphenylsulfonates,
salicylates, benzoates and the like of the metals of the second
main group of the periodical system, e.g., the magnesium or calcium
salts, of the third or fourth main group, e.g., aluminium, tin,
lead, as well as the first to the eighth transition groups of the
periodical system such as, for example, chromium, manganese, iron,
cobalt, nickel, copper, zinc and the like.
[0057] The term "stereochemically isomeric forms of compounds of
formula (I)", as used herein, defines all possible compounds made
up of the same atoms bonded by the same sequence of bonds but
having different three-dimensional structures which are not
interchangeable, which the compounds of formula (I) may possess.
Unless otherwise mentioned or indicated, the chemical designation
of a compound encompasses the mixture of all possible
stereochemically isomeric forms which said compound may possess.
Said mixture may contain all diastereomers and/or enantiomers of
the basic molecular structure of said compound. All
stereochemically isomeric forms of the compounds of formula (I)
both in pure form or in admixture with each other are intended to
be embraced within the scope of the present invention.
[0058] Of special interest are those compounds of formula (I) which
are stereochemically pure.
[0059] Pure stereoisomeric forms of the compounds and intermediates
as mentioned herein are defined as isomers substantially free of
other enantiomeric or diastereomeric forms of the same basic
molecular structure of said compounds or intermediates. In
particular, the term "stereoisomerically pure" concerns compounds
or intermediates having a stereoisomeric excess of at least 80%
(i.e., minimum 90% of one isomer and maximum 10% of the other
possible isomers) up to a stereoisomeric excess of 100% (i.e., 100%
of one isomer and none of the other), more preferably, compounds or
intermediates having a stereoisomeric excess of 90% up to 100%,
even more preferably having a stereoisomeric excess of 94% up to
100% and most preferably having a stereoisomeric excess of 97% up
to 100%. The terms "enantiomerically pure" and "diastereomerically
pure" should be understood in a similar way, but then having regard
to the enantiomeric excess respectively diastereomeric excess of
the mixture in question.
[0060] The N-oxide forms of the compounds of formula (I) are meant
to comprise those compounds of formula (I) wherein one or several
tertiary nitrogen atoms are oxidized to the so-called N-oxide,
particularly those N-oxides wherein one or more of the piperidine-,
piperazine- or pyridazinyl-nitrogens are N-oxidized.
[0061] The compounds of formula (I) may be converted to the
corresponding N-oxide forms following art-known procedures for
converting a trivalent nitrogen into its N-oxide form. Said
N-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 inter alia 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., t-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.
[0062] The compounds of formula (I) may form solvates, for example,
with water (i.e., hydrates) or common organic solvents e.g.
alcohols. As used herein, the term "solvate" means a physical
association of the compounds of formula (I) with one or more
solvent molecules, as well as the salts thereof. This physical
association involves varying degrees of ionic and other bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example, when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. The term "solvate" is intended to encompass both
solution-phase and isolatable solvates. Non-limiting examples of
suitable solvates include hydrates, ethanolates, methanolates, and
the like.
[0063] Furthermore, the compounds of the present invention may be
amorphous or may have one or more crystalline polymorph forms, as
such forms are intended to be included in the scope of the
invention.
[0064] The invention encompasses any isotopes of atoms present in
the compounds of the invention. For example, isotopes of hydrogen
include tritium and deuterium and isotopes of carbon include
.sup.13C and .sup.14C.
[0065] Whenever used hereinafter, the term "compounds of formula
(I)" is meant to include also the N-oxide forms, the acid or base
addition salts particularly the pharmaceutically acceptable acid or
base addition salts, the solvates and all stereoisomeric forms of
said compounds of formula (I).
[0066] A first group of interesting compounds (herein referred to
as group "G1") consists of those compounds of formula (I) wherein
any one or more or all of the following restrictions apply: [0067]
a) n is 1, 2 or 3; [0068] b) R.sup.1 on each carbon of the
--(CHR.sup.1).sub.n-- group is each independently selected from
hydrogen, hydroxy, amino, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, arylC.sub.1-6alkyl and heteroarylC.sub.1-6alkyl,
[0069] any of said mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, arylC.sub.1-6alkyl or heteroaryl-C.sub.1-6alkyl
being optionally and independently substituted with one or more,
preferably one or two, substituents selected from hydroxy, amino,
aryl and heteroaryl; [0070] c) when any one or any two R.sup.1
substituents in the --(CHR.sup.1).sub.n-- group are different from
hydrogen, the other R.sup.1 substituents in the
--(CHR.sup.1).sub.n-- group are each hydrogen; [0071] d) R.sup.2 is
selected from hydrogen, halo, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl, heteroaryl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylthio, arylthio
preferably phenylthio, C.sub.1-6alkylcarbonyl,
hydroxyC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylamino,
morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl, [0072] any
of said mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl,
heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhalo-C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylthio, arylthio
preferably phenylthio, C.sub.1-6alkylcarbonyl,
hydroxyC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylamino,
morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl being
optionally and independently substituted with one or more,
preferably one or two, substituents selected from halo, hydroxy,
cyano, amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, aryl, heteroaryl and C.sub.1-6alkyloxy;
[0073] e) R.sup.3 is hydrogen; C.sub.1-6alkyl; C.sub.3-7cycloalkyl;
C.sub.1-6alkyl substituted with a substituent selected from
hydroxy, amino, aryl and heteroaryl; or C.sub.3-7cycloalkyl
substituted with a substituent selected from hydroxy, amino, aryl
and heteroaryl; [0074] f) -D- is --O--, --CH.sub.2-- or
--NR.sup.20--, wherein R.sup.20 is selected from hydrogen and
C.sub.1-6alkyl; preferably -D- is --O-- or --NR.sup.20--; [0075]
g)
##STR00006##
[0075] is --CR.sup.19.dbd.C< wherein R.sup.19 is hydrogen or
C.sub.1-6alkyl; [0076] h) R.sup.4 and R.sup.5 are each
independently hydrogen, halo, C.sub.1-6alkyl,
hydroxyl-C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, cyano,
cyanoC.sub.1-6alkyl, hydroxy, amino, C.sub.2-6alkenyl, or
C.sub.1-6alkyloxy; more preferably hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, hydroxy, amino,
or C.sub.1-6alkyloxy; even more preferably R.sup.4 and R.sup.5 are
each independently hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, hydroxy, amino or C.sub.1-6alkyloxy; [0077]
i) Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and
(a-5); [0078] j) R.sup.11 or R.sup.12 are each independently
selected from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl,
nitro, polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl,
tetrazoloC.sub.1-6alkyl, aryl, heteroaryl,
heteroarylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl,
arylcarbonyl, C.sub.1-6alkylcarbonyl, C.sub.3-7cycloalkylcarbonyl,
C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl,
arylC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.2-6alkenyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
aminocarbonyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl,
hydroxycarbonyl, hydroxycarbonyl-C.sub.1-6alkyl and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CHR.sup.18).sub.u--NR.sup.14R.sup-
.15; [0079] v is 0 or 1; [0080] r is 0 or 1; [0081] u is 0 or 1;
[0082] R.sup.14 and R.sup.15 are each independently selected from
hydrogen; C.sub.1-12alkyl; C.sub.1-6alkylcarbonyl;
C.sub.1-6alkylsulfonyl; arylC.sub.1-6alkylcarbonyl;
C.sub.3-7cycloalkylcarbonyl; --(CH.sub.2).sub.k--NR.sup.16R.sup.17;
C.sub.1-12alkyl substituted with a substituent selected from
hydroxy, hydroxycarbonyl, cyano, C.sub.1-6alkyloxycarbonyl or aryl;
or R.sup.14 and R.sup.15 together with the nitrogen to which they
are attached form morpholinyl, pyrrolidinyl, piperazinyl or
piperazinyl substituted with a substituent selected from
C.sub.1-6alkyl or arylC.sub.1-6alkyloxycarbonyl; [0083] k is 2;
[0084] R.sup.16 and R.sup.17 are each independently selected from
hydrogen, C.sub.1-6alkyl or arylC.sub.1-6alkyloxycarbonyl; or
[0085] R.sup.16 and R.sup.17 together with the nitrogen to which
they are attached form morpholinyl or piperazinyl, or piperazinyl
substituted with C.sub.1-6alkyloxycarbonyl; [0086] k) R.sup.13 is
hydrogen or C.sub.1-6alkyl; [0087] l) X is NR.sup.6.
[0088] A second group of interesting compounds (herein referred to
as group "G2") consists of those compounds of formula (I) wherein
any one or more or all of the following restrictions apply: [0089]
a) n is 1, 2 or 3, preferably n is 2; [0090] b) R.sup.1 on each
carbon of the --(CHR.sup.1).sub.n-- group is each independently
selected from hydrogen, hydroxy, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, arylC.sub.1-6alkyl and
heteroarylC.sub.1-6alkyl, [0091] c) when any one R.sup.1
substituent in the --(CHR.sup.1).sub.n-- group is different from
hydrogen, the other R.sup.1 substituents in the
--(CHR.sup.1).sub.n-- group are each hydrogen; [0092] d) s is 0;
[0093] e) t is 0 or 1, preferably t is 0; [0094] f) R.sup.2 is
selected from hydrogen, halo, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl, heteroaryl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylthio, arylthio
preferably phenylthio, C.sub.1-6alkylcarbonyl,
hydroxyC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylamino,
morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl; [0095] g)
R.sup.3 is hydrogen or C.sub.1-6alkyl; [0096] h) -D- is --O--,
--CH.sub.2-- or --NR.sup.20--, wherein R.sup.20 is hydrogen or
C.sub.1-6alkyl; preferably -D- is --O-- or --NR.sup.20--; [0097]
i)
##STR00007##
[0097] is --CR.sup.19.dbd.C< wherein R.sup.19 is hydrogen or
C.sub.1-6alkyl; [0098] j) R.sup.4 and R.sup.5 are each
independently hydrogen, halo, C.sub.1-6alkyl, hydroxy or
C.sub.1-6alkyloxy; [0099] k) R.sup.6 is hydrogen or C.sub.1-6alkyl;
[0100] l) Z is a radical selected from (a-1), (a-2), (a-3), (a-4)
and (a-5); [0101] m) R.sup.11 or R.sup.12 are each independently
selected from hydrogen, hydroxy, amino, C.sub.1-6alkyl, nitro,
polyhaloC.sub.1-6alkyl, cyano, aryl, arylC.sub.1-6alkyl,
aryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl, C.sub.1-6alkyloxy,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
aminocarbonyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl,
hydroxycarbonyl and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CH.sub.2).sub.u--NR.sup.14R.sup.1-
5; [0102] v is 0 or 1; [0103] r is 0 or 1; [0104] u is 0; [0105]
R.sup.14 and R.sup.15 are each independently selected from
hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.k--NR.sup.16R.sup.17 and
C.sub.1-12alkyl substituted with hydroxy; or [0106] R.sup.14 and
R.sup.15 together with the nitrogen to which they are attached form
pyrrolidinyl; [0107] k is 2; [0108] R.sup.16 and R.sup.17 are each
independently hydrogen or C.sub.1-6alkyl; [0109] n) R.sup.13 is
hydrogen or C.sub.1-6alkyl; [0110] o) aryl is phenyl or phenyl
substituted with halo; and [0111] p) heteroaryl is pyridinyl,
indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl, indolyl,
oxadiazolyl or tetrazolyl can optionally be substituted with one
substituent selected from C.sub.1-6alkyl, aryl and
arylC.sub.1-6alkyl; [0112] q) X is NR.sup.6.
[0113] A third group of interesting compounds (herein referred to
as group "G3") consists of those compounds of formula (I) wherein
any one or more or all of the following restrictions apply: [0114]
a) n is 1, 2 or 3, preferably n is 2; [0115] b) R.sup.1 on each
carbon of the --(CHR.sup.1).sub.n-- group is each independently
selected from hydrogen, arylC.sub.1-6alkyl, hydroxy or
heteroarylC.sub.1-6alkyl; [0116] c) when any one R.sup.1
substituent in the --(CHR.sup.1).sub.n-- group is different from
hydrogen, the other R.sup.1 substituents in the
--(CHR.sup.1).sub.n-- group are each hydrogen; [0117] d) s is 0;
[0118] e) t is 0; [0119] f) R.sup.2 is selected from hydrogen,
halo, cyano, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl preferably perhaloC.sub.1-6alkyl,
C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonylamino and morpholinyl;
[0120] g) R.sup.3 is hydrogen or C.sub.1-6alkyl, preferably
hydrogen; [0121] h) -D- is --O--, --CH.sub.2-- or --NH--;
preferably -D- is --O-- or --NH--; more preferably -D- is --O--;
[0122] i)
##STR00008##
[0122] is --CH.dbd.C<;
[0123] j) R.sup.4 and R.sup.5 are each independently hydrogen,
C.sub.1-6alkyl or C.sub.1-6alkyloxy; [0124] k) R.sup.6 is hydrogen
or C.sub.1-6alkyl, preferably hydrogen; [0125] l) Z is a radical
selected from (a-1), (a-2), (a-3), (a-4) and (a-5), preferably Z is
a radical selected from (a-1), (a-2) and (a-4); [0126] m) R.sup.11
or R.sup.12 are each independently selected from hydrogen, hydroxy
and hydroxyC.sub.1-6alkyl; [0127] n) R.sup.13 is hydrogen or
C.sub.1-6alkyl, preferably hydrogen; [0128] o) aryl is phenyl or
phenyl substituted with halo; and [0129] p) heteroaryl is pyridinyl
or indolyl; [0130] q) X is NR.sup.6.
[0131] A fourth group of interesting compounds (herein referred to
as group "G4") consists of those compounds of formula (I) wherein
any one or more or all of the following restrictions apply: [0132]
a) n is 2; [0133] b) each R.sup.1 is hydrogen; [0134] c) s is 0;
[0135] d) t is 0; [0136] e) R.sup.2 is selected from hydrogen,
halo, cyano, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl preferably perhaloC.sub.1-6alkyl,
C.sub.1-6alkyloxy, C.sub.1-6alkylcarbonylamino and morpholinyl,
more preferably R.sup.2 is selected from hydrogen, halo,
C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, and C.sub.1-6alkyloxy; [0137] f) R.sup.3 is
hydrogen; [0138] g) -D- is --O--, --CH.sub.2-- or --NH--; -D- is
--O-- or --NH--; more preferably -D- is --O--; [0139] h)
##STR00009##
[0139] is --CH.dbd.C<;
[0140] i) R.sup.4 and R.sup.5 are each independently hydrogen,
C.sub.1-6alkyl or C.sub.1-6alkyloxy; [0141] j) R.sup.6 is hydrogen;
[0142] k) Z is a radical selected from (a-1), (a-2) and (a-4),
preferably Z is (a-2) or (a-4); [0143] l) R.sup.11 or R.sup.12 are
each independently selected from hydrogen, hydroxy and
hydroxyC.sub.1-6alkyl; [0144] m) R.sup.13 is hydrogen; [0145] n)
aryl is phenyl or phenyl substituted with halo; and [0146] o)
heteroaryl is pyridinyl or indolyl; [0147] p) X is NR.sup.6, S or
O, preferably X is NR.sup.6.
[0148] A fifth group of interesting compounds (herein referred to
as group "G5") consists of those compounds of formula (I) wherein
any one or more or all of the following restrictions apply: [0149]
a) n is 2; [0150] b) each R.sup.1 is hydrogen; [0151] c) s is 0;
[0152] d) t is 0; [0153] e) R.sup.2 is selected from hydrogen,
fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, trihalomethyl
preferably trifluoromethyl, methyloxy, methylcarbonylamino and
morpholinyl, more preferably R.sup.2 is selected from hydrogen,
fluoro, chloro, methyl, trifluoromethyl and methyloxy; [0154] f)
R.sup.3 is hydrogen; [0155] g) -D- is --O--, --CH.sub.2-- or
--NH--; preferably -D- is --O-- or --NH--, more preferably -D- is
--O--; [0156] h)
##STR00010##
[0156] is --CH.dbd.C<;
[0157] i) R.sup.4 and R.sup.5 are each independently hydrogen,
methyl or methyloxy; [0158] j) R.sup.6 is hydrogen; [0159] k) Z is
a radical selected from (a-1), (a-2) and (a-4), preferably Z is
(a-2) or (a-4), even more preferably Z is (a-4); [0160] l) R.sup.11
or R.sup.12 are each independently selected from hydrogen, hydroxy
and hydroxymethyl; [0161] m) R.sup.13 is hydrogen; [0162] n) aryl
is phenyl or phenyl substituted with halo; and [0163] o) heteroaryl
is pyridinyl or indolyl; [0164] p) X is NR.sup.6, S or O,
preferably X is NR.sup.6.
[0165] A sixth group of interesting compounds (herein referred to
as group "G6") consists of those compounds of formula (I) or any
subgroup thereof, wherein:
n is 1, 2 or 3, preferably n is 2; R.sup.1 on each carbon of the
--(CHR.sup.1).sub.n-- group is each independently selected from
hydrogen, hydroxy, amino, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, arylC.sub.1-6alkyl and heteroarylC.sub.1-6alkyl;
when any one R.sup.1 substituent in the --(CHR.sup.1).sub.n-- group
is different from hydrogen, the other R.sup.1 substituents in the
--(CHR.sup.1).sub.n-- group are each hydrogen; s is 0; t is 0 or 1,
preferably t is 0; R.sup.2 is selected from hydrogen, halo, cyano,
amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl,
heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylthio, arylthio
preferably phenylthio, C.sub.1-6alkylcarbonyl,
hydroxyC.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylamino,
morpholinyl, piperidinyl, pyrrolidinyl and piperazinyl; R.sup.3 is
hydrogen or C.sub.1-6alkyl; -D- is --O--, --CHR.sup.20--, or
--NR.sup.20--, wherein R.sup.20 is selected from hydrogen and
C.sub.1-6alkyl;
##STR00011##
is --CR.sup.19.dbd.C< wherein R.sup.19 is hydrogen or
C.sub.1-6alkyl; R.sup.4 and R.sup.5 are each independently
hydrogen, halo, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, cyano,
cyanoC.sub.1-6alkyl, hydroxy, amino, or C.sub.1-6alkyloxy; Z is a
radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
R.sup.11 or R.sup.12 are each independently selected from hydrogen,
hydroxy, amino, C.sub.1-6alkyl, nitro, polyhaloC.sub.1-6alkyl,
cyano, aryl, arylC.sub.1-6alkyl, aryl(hydroxy)C.sub.1-6alkyl,
arylcarbonyl, C.sub.1-6alkyloxy, C.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonyl, aminocarbonyl, hydroxyl-C.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CH.sub.2).sub.u--NR.sup.14R.sup.1-
5; [0166] v is 0 or 1; [0167] r is 0 or 1; [0168] u is 0; [0169]
R.sup.14 and R.sup.15 are each independently selected from
hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.k--NR.sup.16R.sup.17 and
C.sub.1-12alkyl substituted with hydroxy; or [0170] R.sup.14 and
R.sup.15 together with the nitrogen to which they are attached form
pyrrolidinyl; [0171] k is 2; [0172] R.sup.16 and R.sup.17 are each
independently C.sub.1-6alkyl; R.sup.13 is hydrogen or
C.sub.1-6alkyl; X is NR.sup.6, S or N; preferably X is NR.sup.6;
aryl is phenyl or phenyl substituted with halo; and heteroaryl is
pyridinyl, indolyl, oxadiazolyl or tetrazolyl; and each pyridinyl,
indolyl, oxadiazolyl or tetrazolyl can optionally be substituted
with one substituent selected from C.sub.1-6alkyl, aryl and
arylC.sub.1-6alkyl.
[0173] A seventh group of interesting compounds (herein referred to
as group "G7") consists of those compounds of formula (I) or any
subgroup thereof, wherein:
n is 2; each R.sup.1 is hydrogen; s is 0; t is 0; R.sup.2 is
selected from hydrogen halo, cyano, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonylamino and morpholinyl; more preferably
R.sup.2 is selected from hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl preferably perhaloC.sub.1-6alkyl, and
C.sub.1-6alkyloxy; R.sup.3 is hydrogen; -D- is --O--,
--CHR.sup.20--, or --NR.sup.20--, wherein R.sup.20 is selected from
hydrogen and C.sub.1-6alkyl;
##STR00012##
is --CH.dbd.C<;
[0174] R.sup.4 and R.sup.5 are each independently hydrogen,
C.sub.1-6alkyl or C.sub.1-6alkyloxy; R.sup.6 is hydrogen; Z is a
radical selected from (a-1), (a-2) and (a-4), preferably Z is (a-2)
or (a-4), even more preferably Z is (a-4); and R.sup.11 or R.sup.12
are each independently selected from hydrogen, hydroxy and
hydroxyC.sub.1-6alkyl; X is NR.sup.6, S or N; preferably X is
NR.sup.6.
[0175] Another embodiment consists of compounds of formula (I)
##STR00013##
including any stereochemically isomeric form thereof, wherein n is
0, 1, 2, 3 or 4 and when n is 0 then a direct bond is intended, and
wherein [0176] R.sup.1 on each carbon of the --(CHR.sup.1).sub.n--
group is each independently selected from hydrogen, halo, hydroxy,
amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, aryl,
heteroaryl, C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, and C.sub.3-7cycloalkyl-C.sub.1-6alkyl,
[0177] any of said mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkyl, heteroaryl, C.sub.3-7cycloalkyl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl or
C.sub.3-7cycloalkylC.sub.1-6alkyl being optionally and
independently substituted with one or more, preferably one or two,
substituents selected from hydroxy, amino, aryl and heteroaryl; s
is 0 or 1 and when s is 0 then a direct bond is intended; t is 0 or
1 and when t is 0 then a direct bond is intended; R.sup.2 is
selected from [0178] hydrogen, halo, cyano, amino; [0179]
polyhaloC.sub.1-6alkyl; [0180] C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
C.sub.2-6alkenyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroaryl-C.sub.1-6alkyl, C.sub.3-7cycloalkylC.sub.1-6alkyl,
morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl,
C.sub.1-6alkyloxy, aryloxy, heteroaryloxy, C.sub.1-6alkylthio,
arylthio, heteroarylthio, C.sub.1-6alkylcarbonyl, [0181]
C.sub.3-7cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
preferably one or two, substituents selected from halo, hydroxy,
cyano, amino, mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, aryl, heteroaryl, C.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxycarbonyl and
C.sub.1-6alkylcarbonyloxy; R.sup.3 is hydrogen; C.sub.1-6alkyl;
aryl; heteroaryl; C.sub.3-7cycloalkyl; C.sub.1-6alkyl substituted
with a substituent selected from hydroxy, amino, aryl and
heteroaryl; or C.sub.3-7cycloalkyl substituted with a substituent
selected from hydroxy, amino, aryl and heteroaryl;
##STR00014##
[0181] is --CR.sup.7.dbd.CR.sup.8-- and then the dotted line is a
bond, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
wherein [0182] R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each
independently selected from: [0183] hydrogen, halo, hydroxy, cyano;
[0184] polyhaloC.sub.1-6alkyl; [0185] C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, C.sub.2-6alkenyl, aryl, heteroaryl,
arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, morpholinyl, piperidinyl,
pyrrolidinyl, piperazinyl, C.sub.1-6alkyloxy,
C.sub.3-7cycloalkyloxy, aryloxy, heteroaryloxy, C.sub.1-6alkylthio,
arylthio, heteroarylthio, C.sub.1-6alkylcarbonyl,
C.sub.3-7cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.3-7cycloalkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, C.sub.1-6alkylcarbonyloxy,
[0186] C.sub.3-7cycloalkylcarbonyloxy, arylcarbonyloxy,
heteroarylcarbonyloxy, mono- or di(C.sub.1-6alkyl)amino,
C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkylcarbonylaminoC.sub.1-6alkyl, mono- or
di(C.sub.1-6alkyl)aminocarbonyl and mono- or [0187]
di(C.sub.1-6alkyl)aminocarbonylC.sub.1-6alkyl, any of said groups
being optionally and independently substituted with one or more,
preferably one or two, substituents selected from halo, hydroxy,
cyano, amino, mono- or [0188] di(C.sub.1-6alkyl)amino, [0189]
C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, aryl, heteroaryl,
C.sub.1-6alkyloxy, [0190] C.sub.1-6alkylcarbonyl, [0191]
C.sub.1-6alkyloxycarbonyl and C.sub.1-6alkylcarbonyloxy; [0192] or
wherein any of R.sup.7 and R.sup.9 together, or R.sup.8 and
R.sup.10 together form a bivalent radical selected from
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2-- and
--(CH.sub.2).sub.2--NR.sup.21--(CH.sub.2).sub.2-- wherein R.sup.21
is hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxyalkyl; [0193] or
wherein any of R.sup.7 and R.sup.9 together, or R.sup.8 and
R.sup.10 together form a bivalent radical --(CH.sub.2).sub.m--,
wherein m is 2, 3, 4, 5 or 6; -D- is --O-- or --NR.sup.20--,
wherein R.sup.20 is selected from hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkylcarbonyl and C.sub.1-6alkyloxycarbonyl;
##STR00015##
[0193] is --CR.sup.19.dbd.C< and then the dotted line is a bond,
--C(.dbd.O)--CH<, --C(.dbd.O)--N<, --CHR.sup.19--CH<, or
--CHR.sup.19--N<, wherein each R.sup.19 is independently
hydrogen or C.sub.1-6alkyl; R.sup.4 and R.sup.5 are each
independently hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl, hydroxy, amino,
or C.sub.1-6alkyloxy, or R.sup.4 and R.sup.5 together form a
bivalent radical selected from methylenedioxy or ethylenedioxy;
R.sup.6 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl or
C.sub.1-6alkyloxycarbonyl; Z is a radical selected from
##STR00016##
wherein [0194] R.sup.11 or R.sup.12 are each independently selected
from hydrogen, halo, hydroxy, amino, C.sub.1-6alkyl, nitro,
polyhaloC.sub.1-6alkyl, cyano, cyanoC.sub.1-6alkyl,
tetrazolo-C.sub.1-6alkyl, aryl, heteroaryl, arylC.sub.1-6alkyl,
heteroarylC.sub.1-6alkyl, aryl(hydroxy)-C.sub.1-6alkyl,
heteroaryl(hydroxy)C.sub.1-6alkyl, arylcarbonyl,
heteroarylcarbonyl, C.sub.1-6alkylcarbonyl,
arylC.sub.1-6alkylcarbonyl, heteroarylC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxy, C.sub.3-7cycloalkylcarbonyl,
C.sub.3-7cycloalkyl(hydroxy)C.sub.1-6alkyl,
arylC.sub.1-6alkyloxyC.sub.1-6alkyl, [0195]
C.sub.1-6alkyloxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.1-6alkyloxyC.sub.1-6alkyl,
hydroxyC.sub.1-6alkyloxyC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonylC.sub.2-6alkenyl,
C.sub.1-6alkyloxyC.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkylcarbonyloxy, aminocarbonyl, hydroxyC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxycarbonyl, hydroxycarbonylC.sub.1-6alkyl
and
--(CH.sub.2).sub.v--(C(.dbd.O)).sub.r--(CHR.sup.18).sub.u--NR.sup.14R.sup-
.15, wherein [0196] v is 0, 1, 2, 3, 4, 5, or 6 and when v is 0
then a direct bond is intended; [0197] r is 0 or 1 and when r is 0
then a direct bond is intended; [0198] u is 0, 1, 2, 3, 4, 5, or 6
and when u is 0 then a direct bond is intended; [0199] R.sup.18 is
hydrogen or C.sub.1-6alkyl; [0200] R.sup.14 and R.sup.15 are each
independently selected from hydrogen; C.sub.1-12alkyl;
C.sub.1-6alkylcarbonyl; C.sub.1-6alkylsulfonyl;
arylC.sub.1-6alkylcarbonyl; C.sub.3-7cycloalkyl;
C.sub.3-7cycloalkylcarbonyl; --(CH.sub.2).sub.k--NR.sup.16R.sup.17;
C.sub.1-12alkyl substituted with a substituent selected from
hydroxy, hydroxycarbonyl, cyano, C.sub.1-6alkyloxycarbonyl,
C.sub.1-6alkyloxy, aryl or heteroaryl; or C.sub.3-7cycloalkyl
substituted with a substituent selected from hydroxy,
C.sub.1-6alkyloxy, aryl, amino, arylC.sub.1-6alkyl, heteroaryl or
heteroarylC.sub.1-6alkyl, or [0201] R.sup.14 and R.sup.15 together
with the nitrogen to which they are attached form morpholinyl;
piperidinyl; pyrrolidinyl; piperazinyl; or piperazinyl substituted
with a substituent selected from C.sub.1-6alkyl,
arylC.sub.1-6alkyl, arylC.sub.1-6alkyloxycarbonyl,
heteroarylC.sub.1-6alkyl, C.sub.3-7cycloalkyl and
C.sub.3-7cycloalkylC.sub.1-6alkyl; wherein [0202] k is 0, 1, 2, 3,
4, 5, or 6 and when k is 0 then a direct bond is intended; [0203]
R.sup.16 and R.sup.17 are each independently selected from
hydrogen; C.sub.1-6alkyl; arylC.sub.1-6alkyloxycarbonyl;
C.sub.3-7cycloalkyl; C.sub.1-12alkyl substituted with a substituent
selected from hydroxy, C.sub.1-6alkyloxy, aryl, and heteroaryl; and
C.sub.3-7cycloalkyl substituted with a substituent selected from
hydroxy, C.sub.1-6alkyloxy, aryl, arylC.sub.1-6alkyl, heteroaryl,
and heteroarylC.sub.1-6alkyl; or [0204] R.sup.16 and R.sup.17
together with the nitrogen to which they are attached form
morpholinyl, piperazinyl, or piperazinyl substituted with
C.sub.1-6alkyloxycarbonyl; [0205] R.sup.13 is hydrogen;
C.sub.1-6alkyl; C.sub.3-7cycloalkyl; C.sub.1-6alkyl substituted
with a substituent selected from hydroxy, amino, C.sub.1-6alkyloxy
and aryl; or C.sub.3-7cycloalkyl substituted with a substituent
selected from hydroxy, amino, aryl and C.sub.1-6alkyloxy; aryl is
phenyl or naphthalenyl; [0206] each phenyl or naphthalenyl can
optionally be substituted with one, two or three substituents each
independently selected from halo, hydroxy, C.sub.1-6alkyl, amino,
polyhaloC.sub.1-6alkyl and C.sub.1-6alkyloxy; and [0207] each
phenyl or naphthalenyl can optionally be substituted with a
bivalent radical selected from methylenedioxy and ethylenedioxy;
heteroaryl is pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl,
thienyl, oxadiazolyl, tetrazolyl, benzofuranyl or
tetrahydrofuranyl; [0208] each pyridinyl, indolyl, quinolinyl,
imidazolyl, furanyl, thienyl, oxadiazolyl, tetrazolyl,
benzofuranyl, or tetrahydrofuranyl can optionally be substituted
with one, two or three substituents each independently selected
from halo, hydroxy, C.sub.1-6alkyl, amino, polyhaloC.sub.1-6alkyl,
aryl, arylC.sub.1-6alkyl or C.sub.1-6alkyloxy; and [0209] each
pyridinyl, indolyl, quinolinyl, imidazolyl, furanyl, thienyl,
benzofuranyl, or tetrahydrofuranyl can optionally be substituted
with a bivalent radical selected from methylenedioxy or
ethylenedioxy; an N-oxide form thereof, an addition salt thereof or
a solvate thereof.
[0210] Another embodiment of particularly preferred compounds
(herein referred to as group "G8") consists of those compounds of
formula (I) wherein t is 0; s is 0; n is 2; X is NR.sup.6, S or O,
in particular O; R.sup.1 is hydrogen; R.sup.2 is hydrogen or halo,
in particular hydrogen or fluoro; R.sup.3 is hydrogen; R.sup.4 and
R.sup.5 are each independently hydrogen, C.sub.1-6alkyl or
C.sub.1-6alkyloxy; R.sup.6 is hydrogen;
##STR00017##
is --CR.sup.19.dbd.C< and then the dotted line is a bond,
wherein R.sup.19 is hydrogen; D is --O--, --CH.sub.2-- or
--NR.sup.20-- wherein R.sup.20 is hydrogen or C.sub.1-6alkyl, in
particular D is O; Z is a radical of formula (a-2) or (a-4);
R.sup.11 and R.sup.12 are each independently selected from
hydrogen, hydroxyl and hydroxyC.sub.1-6alkyl.
[0211] Another embodiment of particularly preferred compounds
(herein referred to as group "G9") consists of those compounds of
formula (I) wherein X is NR.sup.6.
[0212] Another embodiment of particularly preferred compounds
(herein referred to as group "G10") consists of those compounds of
formula (I) wherein D is O.
[0213] Another embodiment of particularly preferred compounds
(herein referred to as group "G11") consists of those compounds of
formula (I) wherein
##STR00018##
is --CR.sup.19.dbd.C< and then the dotted line is a bond,
wherein R.sup.19 is hydrogen.
[0214] Preferably, in compounds of formula (I), and in particular
in compounds of any one of the above groups "G1" to "G11" (the
recitation "any one of the groups `G1` to `G11`" as used throughout
this specification encompasses a specific reference to any one or
each of the compound groups "G1", "G2", "G3", "G4", "G5", "G6",
"G7", "G8", "G9", "G10", or "G11" as defined herein), the
substituent --(CH.sub.2).sub.s--NR.sup.3--(CH.sub.2).sub.t--Z may
be bound on the central phenyl ring in the para (p-) position
relative to the position on the central phenyl ring whereto the N
atom of the substituent
##STR00019##
is bound.
[0215] In a preferred embodiment, in compounds of formula (I), and
in particular in compounds of any one of the above groups "G1" to
"G11",
##STR00020##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00021##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from [0216] hydrogen,
halo, hydroxy, cyano; [0217] polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl; [0218] C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
aryl, heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.3-7cycloalkylC.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyl, hydroxyl-C.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy, mono- or
di(C.sub.1-6alkyl)amino, [0219] C.sub.1-6alkylcarbonylamino, mono-
or di(C.sub.1-6alkyl)aminocarbonyl, morpholinyl, piperidinyl,
pyrrolidinyl and piperazinyl, any of said groups optionally
substituted with one or more, preferably one or two, substituents
selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhalo-C.sub.1-6alkyl,
aryl, heteroaryl and C.sub.1-6alkyloxy; [0220] or wherein any of
R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10 together form
a bivalent radical --(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or
6;
[0221] In another preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00022##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00023##
--CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from [0222] hydrogen,
halo, hydroxy; [0223] perhaloC.sub.1-6alkyl; [0224] C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.1-6alkyloxy, aryl-C.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, mono- or
di(C.sub.1-6alkyl)amino, [0225] C.sub.1-6alkylcarbonylamino and
morpholinyl, any of said groups optionally substituted with one or
more, preferably one or two, substituents selected from halo,
hydroxy, amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, aryl,
heteroaryl and C.sub.1-6alkyloxy; [0226] or wherein any of R.sup.7
and R.sup.9 together, or R.sup.8 and R.sup.10 together form a
bivalent radical --(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or
6;
[0227] In a further preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00024##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00025##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from hydrogen, halo,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyloxy,
mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkylcarbonylamino and
morpholinyl, or wherein any of R.sup.7 and R.sup.9 together, or
R.sup.8 and R.sup.10 together form a bivalent radical
--(CH.sub.2).sub.m-- wherein m is 2, 3, 4, 5 or 6.
[0228] In a further preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00026##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00027##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from hydrogen, halo,
C.sub.1-6alkyl, perhaloC.sub.1-6alkyl, or wherein any of R.sup.7
and R.sup.9 together, or R.sup.8 and R.sup.10 together form a
bivalent radical --(CH.sub.2).sub.m-- wherein m is 2, 3, 4, 5 or
6;
[0229] In a further preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00028##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00029##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each hydrogen.
[0230] In a preferred embodiment, in compounds of formula (I), and
in particular in compounds of any one of the above groups "G1" to
"G11",
##STR00030##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 are as defined above.
[0231] In another preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00031##
is --C(.dbd.O)--CR.sup.8R.sup.10-- or
--CR.sup.7R.sup.9--C(.dbd.O)--, more preferably
##STR00032##
is --C(.dbd.O)--CR.sup.8R.sup.10, wherein R.sup.7, R.sup.8, R.sup.9
and R.sup.10 are as defined above.
[0232] In another preferred embodiment, in compounds of formula
(I), and in particular in compounds of any one of the above groups
"G1" to "G11",
##STR00033##
is --CH.sub.2--CH.sub.2--; --CH.sub.2--CH(CH.sub.3)--;
--CH.sub.2--C(CH.sub.3).sub.2--; --CH.sub.2--CH(CH.sub.2OH)--;
--CH.sub.2--C(CH.sub.3)(CH.sub.2CH.sub.3)--;
--C(.dbd.O)--CH.sub.2--; --C(.dbd.O)--CH(CH.sub.3)--;
--C(.dbd.O)--C(CH.sub.3).sub.2--; --C(.dbd.O)--CF.sub.2--;
##STR00034##
[0233] Further, in some embodiments, when
##STR00035##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10--, either one of the
following restrictions may preferably apply: a) when any one or
both of R.sup.7 and R.sup.9 is different from hydrogen, then at
least one and preferably both of R.sup.8 and R.sup.10 are hydrogen;
or b) when any one or both of R.sup.8 and R.sup.10 is different
from hydrogen, then at least one and preferably both of R.sup.7 and
R.sup.9 are hydrogen; or c) when two substituents of R.sup.7,
R.sup.8, R.sup.9 and R.sup.10 are different from hydrogen, then
R.sup.7 or R.sup.9 is one of said two substituents, and R.sup.8 or
R.sup.10 is the other one of said two substituents; or d)
preferably, when one or two substituents of R.sup.7, R.sup.8,
R.sup.9 and R.sup.10 are different from hydrogen, then said one or
two substituents are selected from R.sup.8 and R.sup.10.
[0234] Further, in some embodiments, when
##STR00036##
is --CR.sup.7.dbd.CR.sup.8--, either one of the following
restrictions may preferably apply: a) when R.sup.7 is different
from hydrogen, then R.sup.8 is hydrogen; or b) when R.sup.8 is
different from hydrogen, then R.sup.7 is hydrogen.
[0235] In a further embodiment, when
##STR00037##
is --C(.dbd.O)--CR.sup.8R.sup.10, at least one of R.sup.8 and
R.sup.10 is hydrogen.
[0236] In a further embodiment, when
##STR00038##
is --CR.sup.7R.sup.9--C(.dbd.O)--, at least one of R.sup.7 and
R.sup.9 is hydrogen.
[0237] Table 1 lists several non-limiting examples of
##STR00039##
groups suitable herein:
TABLE-US-00001 Ex. G E R.sup.7 R.sup.9 R.sup.8 R.sup.10 1
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --H --H 2
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CH.sub.3 --H 3
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CH.sub.3
--CH.sub.3 4 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H
--CH.sub.2CH.sub.3 --H 5 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10--
--H --H --CH.sub.2CH.sub.3 --CH.sub.3 6 --CR.sup.7R.sup.9--
--CR.sup.8R.sup.10-- --H --H --CH.sub.2CH.sub.3 --CH.sub.2CH.sub.3
7 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --CH.sub.3 --H --H --H 8
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --CH.sub.2CH.sub.3 --H --H
--H 9 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CF.sub.3
--H 10 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CF.sub.3
--CF.sub.3 11 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --CF.sub.3
--H --H --H 12 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --CF.sub.3
--CF.sub.3 --H --H 13 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H
--H --F --H 14 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --F
--F 15 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --Cl --H 16
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --Cl --Cl 17
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --F --H --H --H 18
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --Cl --H --H --H 19
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CH.sub.2OH --H
20 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --CH.sub.2OH
--CH.sub.3 21 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H
--CH.sub.2OH --CH.sub.2OH 22 --CR.sup.7R.sup.9--
--CR.sup.8R.sup.10-- --CH.sub.2OH --H --H --H 23
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --OCH.sub.3 --H 24
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H --OCH.sub.3
--CH.sub.3 25 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H
--OCH.sub.3 --OCH.sub.3 26 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10--
--OCH.sub.3 --H --H --H 27 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10--
--H --H ##STR00040## --H 28 --CR.sup.7R.sup.9--
--CR.sup.8R.sup.10-- ##STR00041## --H --H --H 29
--CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- --H --H R.sup.8 and
R.sup.10 together form: --(CH.sub.2).sub.m--, wherein m is 2, 3, 4,
5 or 6 30 --CR.sup.7R.sup.9-- --CR.sup.8R.sup.10-- R.sup.7 and
R.sup.9 together form: --H --H --(CH.sub.2).sub.m--, wherein m is
2, 3, 4, 5, or 6 31 --C(.dbd.O)-- --CR.sup.8R.sup.10-- --H --H 32
--C(.dbd.O)-- --CR.sup.8R.sup.10-- --CH.sub.3 --H 33 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.3 --CH.sub.3 34 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2CH.sub.3 --H 35 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2CH.sub.3 --CH.sub.3 36 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2CH.sub.3 --CH.sub.2CH.sub.3 37
--C(.dbd.O)-- --CR.sup.8R.sup.10-- --CF.sub.3 --H 38 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CF.sub.3 --CF.sub.3 39 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --F --H 40 --C(.dbd.O)-- --CR.sup.8R.sup.10--
--F --H 41 --C(.dbd.O)-- --CR.sup.8R.sup.10-- --Cl --H 42
--C(.dbd.O)-- --CR.sup.8R.sup.10-- --Cl --Cl 43 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2OH --H 44 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2OH --CH.sub.3 45 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --CH.sub.2OH --CH.sub.2OH 46 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --OCH.sub.3 --H 47 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --OCH.sub.3 --CH.sub.3 48 --C(.dbd.O)--
--CR.sup.8R.sup.10-- --OCH.sub.3 --OCH.sub.3 49 --C(.dbd.O)--
--CR.sup.8R.sup.10-- ##STR00042## --H 50 --C(.dbd.O)--
--CR.sup.8R.sup.10-- R.sup.8 and R.sup.10 together form:
--(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5, or 6 51
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --H --H 52 --CR.sup.7R.sup.9--
--C(.dbd.O)-- --CH.sub.3 --H 53 --CR.sup.7R.sup.9-- --C(.dbd.O)--
--CH.sub.3 --CH.sub.3 54 --CR.sup.7R.sup.9-- --C(.dbd.O)--
--CH.sub.2CH.sub.3 --H 55 --CR.sup.7R.sup.9-- --C(.dbd.O)--
--CH.sub.2CH.sub.3 --CH.sub.3 56 --CR.sup.7R.sup.9-- --C(.dbd.O)--
--CH.sub.2CH.sub.3 --CH.sub.2CH.sub.3 57 --CR.sup.7R.sup.9--
--C(.dbd.O)-- --CF.sub.3 --H 58 --CR.sup.7R.sup.9-- --C(.dbd.O)--
--CF.sub.3 --CF.sub.3 59 --CR.sup.7R.sup.9-- --C(.dbd.O)-- --F --H
60 --CR.sup.7R.sup.9-- --C(.dbd.O)-- --F --F 61 --CR.sup.7R.sup.9--
--C(.dbd.O)-- --Cl --H 62 --CR.sup.7R.sup.9-- --C(.dbd.O)-- --Cl
--F 63 --CR.sup.7R.sup.9-- --C(.dbd.O)-- --Cl --Cl 64
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --CH.sub.2OH --H 65
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --CH.sub.2OH --CH.sub.3 66
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --CH.sub.2OH --CH.sub.2OH 67
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --OCH.sub.3 --H 68
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --OCH.sub.3 --CH.sub.3 69
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --OCH.sub.3 --OCH.sub.3 70
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --NC(.dbd.O) CH.sub.3 --H 71
--CR.sup.7R.sup.9-- --C(.dbd.O)-- --NC(.dbd.O) CH.sub.3 --CH.sub.3
72 --CR.sup.7R.sup.9-- --C(.dbd.O)-- ##STR00043## --H 73
--CR.sup.7R.sup.9-- --C(.dbd.O)-- R.sup.7 and Rtogether form:
--(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5, or 6
[0238] With any one option listed in Table 1, -D- may be --O--,
--CHR.sup.20--, or --NR.sup.20-- wherein R.sup.20 is selected from
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl and
C.sub.1-6alkyloxycarbonyl, preferably R.sup.20 is selected from
hydrogen and C.sub.1-6alkyl, more preferably R.sup.20 is hydrogen;
and even more preferably -D- is --O--.
[0239] Thus, exemplary preferred groups of compounds consists of
those compounds of formula (I) or any subgroup thereof,
wherein:
n is 2; each R.sup.1 is hydrogen; s is 0; t is 0; R.sup.2 is
selected from hydrogen, halo, cyano, C.sub.1-6alkyl,
hydroxyC.sub.1-6alkyl, polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.1-6alkylcarbonylamino and morpholinyl; R.sup.3 is hydrogen;
-D- is --O-- or --NR.sup.20-- wherein R.sup.20 is hydrogen or
C.sub.1-6alkyl;
##STR00044##
is --CR.sup.19.dbd.C< wherein R.sup.19 is hydrogen or
C.sub.1-6alkyl; R.sup.4 and R.sup.5 are each independently
hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy; R.sup.6 is hydrogen;
Z is a radical selected from (a-1), (a-2), (a-3), (a-4) and (a-5);
R.sup.11 or R.sup.12 are each independently selected from hydrogen,
hydroxy and hydroxyC.sub.1-6alkyl; R.sup.13 is hydrogen; and
##STR00045##
is --CR.sup.7.dbd.CR.sup.8--,
--CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00046##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from [0240] hydrogen,
halo, hydroxy, cyano; [0241] polyhaloC.sub.1-6alkyl preferably
perhaloC.sub.1-6alkyl; [0242] C.sub.1-6alkyl, C.sub.3-7cycloalkyl,
aryl, heteroaryl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.3-7cycloalkylC.sub.1-6alkyloxy, arylC.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkylcarbonyl, hydroxyC.sub.1-6alkylcarbonyl,
C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylcarbonyloxy, mono- or
di(C.sub.1-6alkyl)amino, [0243] C.sub.1-6alkylcarbonylamino, mono-
or di(C.sub.1-6alkyl)aminocarbonyl, morpholinyl, piperidinyl,
pyrrolidinyl and piperazinyl, any of said groups optionally
substituted with one or more, preferably one or two, substituents
selected from halo, hydroxy, cyano, amino, mono- or
di(C.sub.1-6alkyl)amino, C.sub.1-6alkyl, polyhalo-C.sub.1-6alkyl,
aryl, heteroaryl and C.sub.1-6alkyloxy; [0244] or wherein any of
R.sup.7 and R.sup.9 together, or R.sup.8 and R.sup.10 together form
a bivalent radical --(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or
6; more preferably wherein R.sup.7, R.sup.8, R.sup.9 or R.sup.10
are each independently selected from [0245] hydrogen, halo,
hydroxy; [0246] perhaloC.sub.1-6alkyl; [0247] C.sub.1-6alkyl,
C.sub.3-7cycloalkyl, arylC.sub.1-6alkyl, heteroarylC.sub.1-6alkyl,
C.sub.1-6alkyloxy, aryl-C.sub.1-6alkyloxy,
heteroarylC.sub.1-6alkyloxy, C.sub.1-6alkylcarbonyl, mono- or
di(C.sub.1-6alkyl)amino, [0248] C.sub.1-6alkylcarbonylamino and
morpholinyl, any of said groups optionally substituted with one or
more, preferably one or two, substituents selected from halo,
hydroxy, amino, C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl, aryl,
heteroaryl and C.sub.1-6alkyloxy; [0249] or wherein any of R.sup.7
and R.sup.9 together, or R.sup.8 and R.sup.10 together form a
bivalent radical --(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or
6.
[0250] Further exemplary preferred groups of compounds consists of
those compounds of formula (I) or any subgroup thereof,
wherein:
n is 2; each R.sup.1 is hydrogen; s is 0; t is 0; R.sup.2 is
selected from hydrogen, halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl preferably perhaloC.sub.1-6alkyl, and
C.sub.1-6alkyloxy; R.sup.3 is hydrogen; -D- is --O-- or --NH--,
preferably -D- is --O--;
##STR00047##
is --CH.dbd.C<; R.sup.4 and R.sup.5 are each independently
hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyloxy; R.sup.6 is hydrogen;
Z is a radical selected from (a-1), (a-2) and (a-4), preferably Z
is (a-2) or (a-4), even more preferably Z is (a-4); R.sup.11 or
R.sup.12 are each independently selected from hydrogen, hydroxy and
hydroxyC.sub.1-6alkyl; and
##STR00048##
is --CR.sup.7.dbd.R.sup.8--, --CR.sup.7R.sup.9--CR.sup.8R.sup.10--,
--C(.dbd.O)--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--C(.dbd.O)--,
more preferably
##STR00049##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10-- or
--C(.dbd.O)--CR.sup.8R.sup.10--, wherein R.sup.7, R.sup.8, R.sup.9
or R.sup.10 are each independently selected from hydrogen, halo,
C.sub.1-6alkyl, C.sub.3-7cycloalkyl, haloC.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyloxy,
mono- or di(C.sub.1-6alkyl)amino, C.sub.1-6alkylcarbonylamino and
morpholinyl, or wherein any of R.sup.7 and R.sup.9 together, or
R.sup.8 and R.sup.10 together form a bivalent radical
--(CH.sub.2).sub.m-- wherein m is 2, 3, 4, 5 or 6; more preferably
wherein R.sup.7, R.sup.8, R.sup.9 or R.sup.10 are each
independently selected from hydrogen, halo, C.sub.1-6alkyl,
perhaloC.sub.1-6alkyl, or wherein any of R.sup.7 and R.sup.9
together, or R.sup.8 and R.sup.10 together form a bivalent radical
--(CH.sub.2).sub.m--, wherein m is 2, 3, 4, 5 or 6; also preferably
wherein each R.sup.7, R.sup.8, R.sup.9 or R.sup.10 is hydrogen.
[0251] Table 2 lists preferred albeit non-limiting examples of
compounds of formula (I) that were prepared in the present
invention.
TABLE-US-00002 TABLE 2 ##STR00050## Comp. No. 1 ##STR00051## Comp.
No. 2 ##STR00052## Comp. No. 3 ##STR00053## Comp. No. 4
[0252] Particularly preferred are compounds No. 1 and 2, more
preferably compound No. 1, which may achieve especially pronounced
desired biological effects.
[0253] Further preferred compounds are compounds No. 22, 13, 25,
34, 27, 5, 12, 11, which may achieve especially pronounced desired
biological effects. Thus, preferred compounds are selected
from:
##STR00054## ##STR00055##
including any stereochemically isomeric form thereof; an N-oxide
form thereof, an addition salt thereof or a solvate thereof.
[0254] The compounds of formula (I), their N-oxides,
pharmaceutically acceptable salts, solvates, and stereochemically
isomeric forms thereof may be prepared in conventional manner. The
starting materials and some of the intermediates are known
compounds and are commercially available or may be prepared
according to conventional reaction procedures as generally known in
the art.
[0255] A number of such preparation methods will be described
hereinafter in more detail. Other methods for obtaining final
compounds of formula (I) are described in the examples.
[0256] The compounds of formula (I) can be prepared by reacting an
intermediate of formula (II) with an intermediate of formula (III)
or an appropriate acid addition salt thereof, wherein W is an
appropriate leaving group such as, for example, halo, e.g., fluoro,
chloro, bromo or iodo, or a sulfonyloxy radical such as
methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like. The
reaction can be performed in a reaction-inert solvent such as, for
example, an alcohol, e.g., methanol, ethanol, 2-methoxy-ethanol,
propanol, butanol and the like; an ether, e.g., 1,4-dioxane
optionally in mixture with hydrochloric acid, 1,1'-oxybispropane
and the like; a ketone, e.g., 4-methyl-2-pentanone; or
N,N-dimethylformamide, nitrobenzene, acetonitrile, acetic acid and
the like. The addition of an appropriate base such as, for example,
an alkali or earth alkaline metal carbonate or organic base, e.g.,
triethylamine, N,N-diisopropylethanamine or sodium carbonate, may
be utilized to neutralise the acid which is liberated during the
course of the reaction. A small amount of an appropriate metal
iodide, e.g., sodium or potassium iodide may be added to promote
the reaction. Stirring may enhance the rate of the reaction. The
reaction may conveniently be carried out at a temperature ranging
between room temperature and the reflux temperature of the reaction
mixture and, if desired, the reaction may be carried out at an
increased pressure.
##STR00056##
[0257] The above reaction can also be used to prepare compounds of
formula (I) wherein
##STR00057##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10--, wherein R.sup.8 and
R.sup.10 together form a bivalent radical
--(CH.sub.2).sub.2--NR.sup.21--(CH.sub.2).sub.2- wherein R.sup.21
represents hydrogen and R.sup.7 and R.sup.9 represent hydrogen,
herein referred to as compounds of formula (I-d), starting from the
corresponding intermediate of formula (XIX) wherein P represents a
suitable protective group, e.g. C.sub.1-6alkyloxycarbonyl
##STR00058##
[0258] The above reaction can also be used to prepare compounds of
formula (I) wherein
##STR00059##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10--, wherein R.sup.8
represents hydroxyC.sub.1-6alkyl and R.sup.7, R.sup.9 and R.sup.10
represent hydrogen, herein referred to as compounds of formula
(I-e), starting from the corresponding intermediate of formula
(XX).
##STR00060##
[0259] The compounds of formula (I-e) can also be prepared reacting
the corresponding intermediate of formula (XXI) with a suitable
deprotection agent for the alcohol function, e.g.
tetrabutylammonium fluoride, in the presence of a suitable solvent,
e.g. tetrahydrofuran.
##STR00061##
[0260] The compounds of formula (I) can be prepared by reacting an
intermediate of formula (IV), wherein A is an appropriate leaving
group such as, for example, halo, e.g., fluoro, chloro, bromo or
iodo, or a sulfonyloxy radical such as methylsulfonyloxy,
4-methylphenylsulfonyloxy and the like, with an intermediate of
formula (V). The addition of an appropriate base such as, for
example, an alkali or earth alkaline metal carbonate or organic
base, e.g., cesium carbonate, may be utilised to neutralise the
acid which is liberated during the course of the reaction. The
reaction can be performed in a reaction-inert solvent such as, for
example, N,N-dimethylformamide, tetrahydrofuran, and the like.
##STR00062##
[0261] The compounds of formula (I), wherein --(CHR.sup.1).sub.n--
is (CHR.sup.1).sub.n-1CH.sub.2--, herein referred to as compounds
of formula (I-a), can be prepared by reducing an intermediate of
formula (VI) with lithium aluminium hydride in a suitable solvent
such as tetrahydrofuran.
##STR00063##
[0262] The compounds of formula (I-a) can also be prepared by
reacting an appropriate carboxaldehyde of formula (VII), with an
intermediate of formula (V), in the presence of an appropriate
reducing reagent, such as a sodium borohydride, e.g., sodium
tetrahydroborate or polymer supported cyanotrihydroborate, in a
suitable solvent, such as an alcohol, e.g., methanol, and an acid,
e.g. acetic acid.
##STR00064##
[0263] In an identical way the compounds of formula (I) wherein t
is 1, herein referred to as compounds of formula (I-b), may be
prepared by reacting an intermediate of formula (II) with an
appropriate carboxaldehyde of formula HC(.dbd.O)Z.
[0264] The compounds of formula (I), wherein s is 1, herein
referred to as compounds of formula (I-c), can be prepared by
reducing an intermediate of formula (VIII) with lithium aluminium
hydride in a suitable solvent such as tetrahydrofuran.
##STR00065##
[0265] The compounds of formula (I) wherein
##STR00066##
is --C(.dbd.O)--CR.sup.8R.sup.10--, with R.sup.8 and R.sup.10
representing hydrogen, herein referred to as compounds of formula
(I-f), can be converted into a compound of formula (I) wherein
##STR00067##
is --CH.sub.2--CH.sub.2--, herein referred to as compounds of
formula (I-g), by reaction with a suitable reducing agent, e.g.
tetrahydrofuran-trihydroborane complex.
##STR00068##
[0266] The compounds of formula (I) and their intermediates may
also be converted into each other via art-known reactions or
functional group transformations. A number of such transformations
are already described hereinabove. Other examples are hydrolysis of
carboxylic esters to the corresponding carboxylic acid or alcohol;
hydrolysis of amides to the corresponding carboxylic acids or
amines; hydrolysis of nitriles to the corresponding amides; amino
groups on imidazole or phenyl may be replaced by a hydrogen by
art-known diazotation reactions and subsequent replacement of the
diazo-group by hydrogen; alcohols may be converted into esters and
ethers; primary amines may be converted into secondary or tertiary
amines; double bonds may be hydrogenated to the corresponding
single bond; an iodo radical on a phenyl group may be converted in
to an ester group by carbon monoxide insertion in the presence of a
suitable palladium catalyst; etc.
[0267] Intermediates of formula (II), wherein s is 0 and R.sup.3 is
hydrogen, herein referred to as intermediates of formula (II-a),
can be prepared by a nitro to amine reduction reaction starting
with an intermediate of formula (IX), in the presence of a metal
catalyst such as Raney Nickel or palladium on carbon (Pd/C), and an
appropriate reductant such as hydrogen, in a suitable solvent such
as methanol or ethanol or tetrahydrofuran.
##STR00069##
[0268] Intermediates of formula (II-a) wherein
--(CHR.sup.1).sub.n-- is (CHR.sup.1).sub.n-1CH.sub.2--, herein
referred to as intermediates of formula (II-a-1), can also be
prepared by deprotecting an intermediate of formula (XXVII) wherein
P represents a suitable protective group, e.g.
C.sub.1-6alkyloxycarbonyl, in the presence of a suitable acid, e.g.
hydrochloric acid, and a suitable solvent, e.g. dioxane.
Intermediate of formula (XXVII) can be prepared by reacting an
intermediate of formula (VII) with an intermediate of formula
(XXVIII) in the presence of a suitable reducing agent, e.g. sodium
cyanotrihydroborate.
##STR00070##
[0269] Intermediates of formula (VI) can be prepared by reacting an
intermediate of formula (VII) with an intermediate of formula (V)
in the presence of appropriate dehydrating reagents such as
N'-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine
monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT). The
reaction may be performed in the presence of a base such as
triethylamine, in a suitable solvent, such as, a mixture of
dichloromethane and tetrahydrofuran.
##STR00071##
[0270] The intermediates of formula (VII) can be prepared by
reacting intermediates of formula (XI) with lithium aluminium
hydride in a suitable solvent such as tetrahydrofuran.
##STR00072##
[0271] The intermediates of formula (VIII) can be prepared by
reacting an intermediate of formula (XII) with an intermediate of
formula (XIII) in the presence of a suitable dehydrating agent such
as 2-chloro-1-methylpyridinium iodide and triethylamine in a
suitable solvent such as acetonitrile.
##STR00073##
[0272] The intermediates of formula (IX) can be prepared by
reacting an intermediate of formula (IV) wherein A is an
appropriate leaving group as above, with an intermediate of formula
(XIV) in an appropriate solvent such as for example,
N,N-dimethylformamide, tetrahydrofuran, and the like, preferably in
the presence of a suitable base, e.g. Cs.sub.2CO.sub.3.
[0273] Intermediates of formula (IX) wherein
##STR00074##
is --C(.dbd.O)--CR.sup.8R.sup.10-- or
--CR.sup.7R.sup.9--C(.dbd.O)--, can be converted into an
intermediate of formula (IX) wherein
##STR00075##
is --CH.sub.2--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--CH.sub.2--,
by reaction with a suitable reducing agent, e.g.
tetrahydrofuran-trihydroborane complex.
##STR00076##
[0274] The intermediates of formula (IX) wherein D is O and
##STR00077##
is --CR.sup.7R.sup.9--CR.sup.8R.sup.10--, herein referred to as
intermediates of formula (IX-a), can also be prepared by
cyclization of an intermediate of formula (XXII) wherein W is as
defined above, in the presence of a suitable base, e.g. sodium
hydride or potassium hydroxide, and a suitable solvent, e.g.
tetrahydrofuran or N,N-dimethylsulfoxide.
##STR00078##
[0275] The intermediates of formula (XXII) can be prepared by
reacting an intermediate of formula (XXIII) with an intermediate of
formula (XXIV) with W as defined above, in the presence of a
suitable solvent, e.g. N,N-dimethylsulfoxide. The addition of a
suitable base, e.g. sodium bicarbonate, may be utilized to
neutralise the acid which is liberated during the course of the
reaction.
##STR00079##
[0276] The intermediates of formula (XXIII) can be prepared by
reacting an intermediate of formula (XXV) with an intermediate of
formula (XXVI) in the presence of a suitable solvent, e.g. an
alcohol, e.g. ethanol.
##STR00080##
[0277] The intermediates of formula (XXVI) wherein R.sup.7 and
R.sup.9 are hydrogen, can be prepared by reacting
##STR00081##
with trimethylsulphoxonium iodide in the presence of a suitable
base, e.g. potassium hydroxide or sodium hydride, and a suitable
solvent, e.g. acetonitrile, N,N-dimethylsulfoxide.
[0278] The intermediates of formula (IX-a) can also be prepared by
reacting an intermediate of formula (XVII) wherein W is as defined
above, with an intermediate of formula (XXV) in the presence of a
suitable solvent, e.g. N,N-dimethylsulfoxide, then by addition of
an intermediate of formula (XXIV) and a suitable base, e.g. sodium
bicarbonate or potassium hydroxide.
##STR00082##
[0279] The intermediates of formula (XII) can be prepared by
converting an intermediate of formula (XV) in the presence of
sodium hydroxide and water, in a suitable solvent, such as
ethanol.
##STR00083##
[0280] The intermediates of formula (XV) can be prepared by
reacting an intermediate of formula (IV) wherein A is an
appropriate leaving group as above, with an intermediate of formula
(XVI) in an appropriate solvent, such as for example,
N,N-dimethylformamide, tetrahydrofuran, and the like.
##STR00084##
[0281] The intermediates of any of formulas (V), (XIV) or (XVI) may
be prepared inter alia by cyclo-condensation of an intermediate of
formula (XVII) wherein T is any of
--(CH.sub.2).sub.s--NR.sup.3--(CH.sub.2).sub.t--Z,
--NO.sub.2 or --CN, respectively, and -DH is --OH or --NH.sub.2,
with any intermediate of formula (XVIII-a), (XVIII-b), (XVIII-c) or
(XVIII-d) wherein L.sup.1 to L.sup.8 are each independently a
suitable leaving group, such as for example halo, e.g., fluoro,
chloro, bromo, iodo or C.sub.1-6alkyloxy, e.g. methyloxy, more
preferably chloro or bromo, preferably in the presence of a base,
e.g. K.sub.2CO.sub.3, to neutralise the acid formed during the
reaction, in an appropriate inert solvent, e.g.
N,N-dimethylformamide.
##STR00085##
[0282] The intermediates of any of formulas (V), (XIV) or (XVI)
wherein
##STR00086##
is --CH.sub.2--CR.sup.8R.sup.10-- or --CR.sup.7R.sup.9--CH.sub.2--
can be prepared from the corresponding intermediates of any of
formulas (V), (XIV) or (XVI) wherein
##STR00087##
is --C(.dbd.O)--CR.sup.8R.sup.10-- or
--CR.sup.7R.sup.9--C(.dbd.O)--, respectively, in the presence of an
appropriate reducing reagent, such as borohydride, in a suitable
solvent, such as an alcohol, e.g., methanol.
##STR00088##
wherein T is any of
--(CH.sub.2).sub.s--NR.sup.3--(CH.sub.2).sub.t--Z, --NO.sub.2 or
--CN.
[0283] Intermediates of formula (V) wherein D is N--C.sub.1-6alkyl
and R.sup.3 is hydrogen and s is 0, herein referred to as
intermediates of formula (V-a), can also be prepared according to
the following reaction scheme wherein in step (a) an intermediate
of formula (XXIX) is protected with a suitable protective group,
e.g. C.sub.1-6alkyloxycarbonyl, by reaction with e.g.
di-tert-butyl-dicarbonate, in a suitable solvent, e.g.
dichloromethane, and a suitable base, e.g. triethylamine or
4-dimethylaminopyridine, resulting in an intermediate of formula
(XXX) which is alkylated in a next step (b) to an intermediate of
formula (XXXI) by reaction with a suitable alkylating agent, e.g.
C.sub.1-6alkyl iodide, in the presence of a suitable base, e.g. di
potassium carbonate, and a suitable solvent, e.g. acetonitrile. In
step (c), the intermediate of formula (XXXI) is hydrogenated to the
corresponding amine of formula (XXXII) in the presence of a
suitable catalyst, e.g. Raney nickel, and a suitable solvent, e.g.
an alcohol, e.g. methanol. In step (d), the intermediate of formula
(XXXII) is reacted with an intermediate of formula (III) according
to the reaction procedure described above for compounds of formula
(II) starting from intermediates of formula (II) and (III)
resulting in an intermediate of formula (V-a).
##STR00089##
[0284] Intermediates of formula (XXI) can be prepared according to
the synthesis protocol described above for compounds of formula (I)
but starting from the appropriate Si derivative of intermediate
(II). This appropriate Si derivative of formula (II) can be
prepared according to the protocols above described for
intermediate (II).
[0285] Some compounds of formula (I) and some of the intermediates
may have at least one stereogenic centre in their structure. Any
such stereogenic centre may be independently present in an R or an
S configuration.
[0286] Some of the compounds of formula (I) and some of the
intermediates in the present invention may contain an asymmetric
carbon atom. Such compounds as prepared in the hereinabove
described processes may generally be racemic mixtures of
enantiomers or diastereoisomers, which can be separated from one
another following art-known resolution 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, supercritical fluid chromatography 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.
[0287] The compounds of formula (I), pharmaceutically acceptable
acid or base addition salts, solvates, N-oxides and stereoisomeric
forms thereof have valuable pharmacological properties in that they
inhibit the interaction between p53 and MDM2.
[0288] The term "MDM2" (Murine Double Minute2) is used herein to
mean a protein obtained as a result of expression of the mdm2 gene.
Within the meaning of this term, MDM2 encompass all proteins
encoded by mdm2, mutants thereof, alternative slice proteins
thereof, and phosphorylated proteins thereof. Additionally, as used
herein, the term "MDM2" includes MDM2 analogues, e.g. MDMX, also
known as MDM4, and MDM2 homologues and analogues of other animals,
e.g. the human homologue HDM2 or the human analogue HDMX.
[0289] The term "inhibiting the interaction" or "inhibitor of the
interaction" is used herein to mean preventing or reducing the
direct or indirect association of one or more molecules, peptides,
proteins, enzymes or receptors; or preventing or reducing the
normal activity of one or more molecules, peptides, proteins,
enzymes, or receptors.
[0290] The term "inhibitor of the interaction of p53 with MDM2" or
"p53-MDM2 inhibitor" is used herein to describe an agent which
increases the expression of p53 in the assay described in C.1. This
increase may be caused by, but is not limited to, one or more of
the following mechanisms of action: [0291] inhibiting the
interaction between p53 and MDM2, [0292] direct association with
either the MDM2 or the p53 protein, [0293] interactions with
upstream or downstream targets, e.g. kinases, or enzyme activities
involved in ubiquitination or SUMO modification, [0294]
sequestering or transportation of MDM2 and p53 into different
cellular compartments, [0295] modulation of proteins associating
with MDM2, for example (but not limited to), p63, p73, E2F-1, Rb,
p21waf1 or cip1, HIF1alpha, Foxo3A, p14ARF, [0296] downregulating
or interference with MDM2 expression and/or MDM2 activity, for
example (but not limited to), impacting on its cellular
localisation, post-translational modification, nuclear export,
ubiquitin ligase activity or interference with binding of MDM2 with
the proteasome, modulating the MDM2-proteasome interaction, [0297]
direct or indirect stabilization of the p53 protein, e.g. by
keeping it in its functional structural form, or by preventing
misfolding, [0298] enhancing p53 expression or expression of p53
family members, e.g. p63 and p73. [0299] increasing p53 activity,
for example by (but not limited to), enhancing its transcriptional
activity and/or [0300] increasing expression of genes and proteins
of the p53-signalling pathway, for example (but not limited to)
p21waf1, cip1, MIC-1 (GDF-15), PIG-3, Bax, Puma, Noxa, and
ATF-3.
[0301] Hence, the present invention discloses the compounds of
formula (I) for use as a medicine, in particular for the treatment
of cancer or related diseases, for inhibiting tumour growth, for
inhibiting the interaction between MDM2 and p53, for modulating the
MDM2-proteasome interaction.
[0302] Furthermore, the invention also concerns the use of a
compound for the manufacture of a medicament for the treatment of a
disorder mediated through a p53-MDM2 interaction, wherein said
compound is a compound of formula (I)
[0303] The term "treating" or "treatment" as used herein covers any
treatment of a disease and/or condition in an animal, particularly
a human, and includes: (i) preventing a disease and/or condition
from occurring in a subject which may be predisposed to the disease
and/or condition but has not yet been diagnosed as having it; (ii)
inhibiting the disease and/or condition, i.e., arresting its
development; (iii) relieving the disease and/or condition, i.e.,
causing regression of the disease and/or condition.
[0304] With the term "a disorder mediated through a p53-MDM2
interaction" is meant any undesired or detrimental condition that
results from the interaction between the MDM2 protein and p53 or
other cellular proteins that induce apoptosis, induce cellular
death, or regulate the cell cycle.
[0305] This invention also provides a method for treating a
disorder mediated through a p53-MDM2 interaction by administering
an effective amount of a compound of the present invention, to a
subject, e.g. a mammal (and more particularly a human) in need of
such treatment.
[0306] The compounds of the invention can have antiproliferative
effects in tumour cells, even if such cells are devoid of
functional p53. More in particular, the compounds of the invention
can have antiproliferative effects in tumours with wild-type or
mutant p53 and/or in tumours overexpressing MDM2.
[0307] Thus, this invention also provides a method for inhibiting
tumour growth by administering an effective amount of a compound of
the present invention, to a subject, e.g. a mammal (and more
particularly a human) in need of such treatment.
[0308] Examples of tumours including adult and pediatric
malignancies, which may be inhibited by the compounds of the
present invention include, but are not limited to, lung cancer
including small cell lung cancer and non-small cell lung cancer
(e.g. adenocarcinoma), pancreatic cancers, colon cancers (e.g.
colorectal carcinomas, such as, for example, colon adenocarcinoma
and colon adenoma), oesophageal cancer, oral squamous carcinoma,
tongue carcinoma, gastric carcinoma, liver cancer, nasopharyngeal
cancer, hematopoietic tumours of lymphoid lineage (e.g. acute
lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma),
non-Hodgkin's lymphoma (e.g. mantle cell lymphoma), Hodgkin's
disease, myeloid leukemias (for example, acute myelogenous leukemia
(AML) or chronic myelogenous leukemia (CML)), acute lymphoblastic
leukemia, chronic lymphocytic leukemia (CLL), thyroid follicular
cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal
origin, soft tissue sarcomas, liposarcomas, gastrointestinal
stromal sarcomas, malignant peripheral nerve sheath tumours
(MPNST), Ewing sarcomas, leiomyosarcomas, mesenchymal
chondrosarcomas, lymphosarcomas, fibrosarcomas, rhabdomyosarcomas,
melanomas, teratocarcinomas, neuroblastomas, brain tumours,
gliomas, benign tumour of the skin (e.g. keratoacanthomas), breast
carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary
carcinoma, cervical carcinoma, endometrial carcinoma, bladder
carcinoma, prostate cancer including the advanced disease and
hormone refractory prostate cancer, testicular cancers,
osteosarcoma, head and neck cancer, epidermal carcinoma, multiple
myeloma (e.g. refractory multiple myeloma), mesothelioma.
Particular cancers that can be treated with the compounds of the
present invention are breast cancer, colorectal cancer, non-small
cell lung cancer, acute myelogenous leukemia (AML).
[0309] The compounds of the present invention can also be used for
the treatment and prevention of inflammatory conditions.
[0310] Thus, this invention also provides a method for the
treatment and prevention of inflammatory conditions by
administering an effective amount of a compound of the present
invention, to a subject, e.g. a mammal (and more particularly a
human) in need of such treatment.
[0311] The compounds of the present invention can also be used for
the treatment of autoimmune diseases and conditions. With the term
"autoimmune diseases" is meant any disease in which an animal's
immune system reacts adversely to a self-antigen. With the term
"self-antigen" is meant any antigen that is normally found in the
animal's body. Representative autoimmune diseases include but are
not limited to: Hashimoto's thyroiditis, Grave's disease, multiple
sclerosis, pernicious anemia, Addison's disease, insulin-dependent
diabetes mellitus, rheumatoid arthritis, systemic lupus
erythematosus (SLE or lupus), dermatomyositis, Crohn's disease,
Wegener's granulomatosis, Anti Glomerular Basement Membrane
Disease, Antiphospholipid Syndrome, 25 Dermatitis Herpetiformis,
Allergic Encephalomyelitis, Glomerulonephritis, Membranous
Glomerulonephritis, Goodpasture Syndrome, Lambert-Eaton, Myasthenic
Syndrome, Myasthenia Gravis, Bullous Pemphigoid,
Polyendocrinopathies, Reiter's Disease, and Stiff-Man Syndrome.
[0312] Thus, this invention also provides a method for the
treatment of autoimmune diseases and conditions by administering an
effective amount of a compound of the present invention, to a
subject, e.g. a mammal (and more particularly a human) in need of
such treatment.
[0313] The compounds of the present invention can also be useful
for the treatment of diseases associated with conformational
unstable or misfolded proteins.
[0314] Examples of diseases associated with conformational unstable
or misfolded proteins include but are not limited to: cystic
fibrosis (CFTR), Marfan syndrom (fibrillin), Amyotrophic lateral
sclerosis (superoxide dismutase), scurvy (collagen), maple syrup
urine disease (alpha-ketoacid dehydrogenase complex), osteogenesis
imperfecta (type) procollagen pro-alpha), Creutzfeldt-Jakob disease
(prion), Alzheimer's disease (beta-amyloid), familial amyloidosis
(lysozyme), cataracts (crystallins), familial hypercholesterolemia
(LDL receptor), a 1-antitrypsin deficiency, Tay-Sachs disease
(beta-hexosaminidase), retinitis pigmentosa (rhodopsin), and
leprechaunism (insulin receptor).
[0315] Thus, this invention also provides a method for the
treatment of diseases associated with conformational unstable or
misfolded proteins by administering an effective amount of a
compound of the present invention, to a subject, e.g. a mammal (and
more particularly a human) in need of such treatment.
[0316] In view of their useful pharmacological properties, the
subject compounds may be formulated into various pharmaceutical
forms for administration purposes.
[0317] To prepare the pharmaceutical compositions of this
invention, an effective amount of a compound of the present
invention, 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 desirably in unitary dosage form suitable,
preferably, 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 and solutions; or solid carriers such
as starches, sugars, kaolin, lubricants, binders, disintegrating
agents and the like in the case of powders, pills, capsules and
tablets.
[0318] Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit form, 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, to
aid solubility for example, 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. 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 cause a significant deleterious
effect to 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. It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in dosage unit form for
ease of administration and uniformity of dosage. Dosage unit form
as used in the specification and claims 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 dosage unit forms are
tablets (including scored or coated tablets), capsules, pills,
powder packets, wafers, injectable solutions or suspensions,
teaspoonfuls, tablespoonfuls and the like, and segregated multiples
thereof.
[0319] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in dosage unit form for
ease of administration and uniformity of dosage. Dosage unit form
as used in the specification and claims 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 dosage unit forms are
tablets (including scored or coated tablets), capsules, pills,
powder packets, wafers, injectable solutions or suspensions,
teaspoonfuls, tablespoonfuls and the like, and segregated multiples
thereof.
[0320] The compound of the invention is administered in an amount
sufficient to inhibit the interaction between MDM2 and p53 or other
cellular proteins that induce apoptosis, induce cellular death,
regulate the cell cycle, regulate tumor cell migration or invasion
or metastasis, in particular an amount sufficient to modulate the
MDM2-proteasome interaction.
[0321] The oncogenic potential of MDM2 is not only determined by
its ability to suppress p53, but also by its ability to regulate
other tumour suppressor proteins, e.g. the retinoblastoma protein
pRb and the closely associated E2F1 transcription factor, p63,
p73.
[0322] Thus, the compound of the invention is administered in an
amount sufficient to modulate the interaction between MDM2 and the
E2F1 transcription factors.
[0323] Those skilled in the art could easily determine the
effective amount from the test results presented hereinafter. In
general it is contemplated that a therapeutically effective amount
would be from 0.005 mg/kg to 100 mg/kg body weight, and in
particular from 0.005 mg/kg to 10 mg/kg body weight. It may be
appropriate to administer the required dose as single, 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 0.5 to 500 mg, in particular 1 mg to 500 mg, more in
particular 10 mg to 500 mg of active ingredient per unit dosage
form.
[0324] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% by weight,
more preferably from 0.1 to 70% by weight, even more preferably
from 0.1 to 50% by weight of the compound of the present invention,
and, from 1 to 99.95% by weight, more preferably from 30 to 99.9%
by weight, even more preferably from 50 to 99.9% by weight of a
pharmaceutically acceptable carrier, all percentages being based on
the total weight of the composition.
[0325] As another aspect of the present invention, a combination of
a p53-MDM2 inhibitor with another anticancer agent is envisaged,
especially for use as a medicine, more specifically in the
treatment of cancer or related diseases.
[0326] For the treatment of the above conditions, the compounds of
the invention may be advantageously employed in combination with
one or more other medicinal agents, more particularly, with other
anti-cancer agents or adjuvants in cancer therapy.
[0327] Examples of anti-cancer agents or adjuvants (supporting
agents in the therapy) include but are not limited to: [0328]
platinum coordination compounds for example cisplatin optionally
combined with amifostine, carboplatin or oxaliplatin; [0329] taxane
compounds for example paclitaxel, paclitaxel protein bound
particles (Abraxane.TM.) or docetaxel; [0330] topoisomerase I
inhibitors such as camptothecin compounds for example irinotecan,
SN-38, topotecan, topotecan hcl; [0331] topoisomerase II inhibitors
such as anti-tumour epipodophyllotoxins or podophyllotoxin
derivatives for example etoposide, etoposide phosphate or
teniposide; [0332] anti-tumour vinca alkaloids for example
vinblastine, vincristine or vinorelbine; [0333] anti-tumour
nucleoside derivatives for example 5-fluorouracil, leucovorin,
gemcitabine, gemcitabine hcl, capecitabine, cladribine,
fludarabine, nelarabine; [0334] alkylating agents such as nitrogen
mustard or nitrosourea for example cyclophosphamide, chlorambucil,
carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine,
busulfan, dacarbazine, estramustine, ifosfamide optionally in
combination with mesna, pipobroman, procarbazine, streptozocin,
telozolomide, uracil; [0335] anti-tumour anthracycline derivatives
for example daunorubicin, doxorubicin optionally in combination
with dexrazoxane, doxil, idarubicin, mitoxantrone, epirubicin,
epirubicin hcl, valrubicin; [0336] molecules that target the IGF-1
receptor for example picropodophilin; [0337] tetracarcin
derivatives for example tetrocarcin A; [0338] glucocorticoiden for
example prednisone; [0339] antibodies for example trastuzumab (HER2
antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab
ozogamicin, cetuximab, pertuzumab, bevacizumab, alemtuzumab,
eculizumab, ibritumomab tiuxetan, nofetumomab, panitumumab,
tositumomab, CNTO 328; [0340] estrogen receptor antagonists or
selective estrogen receptor modulators or inhibitors of estrogen
synthesis for example tamoxifen, fulvestrant, toremifene,
droloxifene, faslodex, raloxifene or letrozole; [0341] aromatase
inhibitors such as exemestane, anastrozole, letrazole, testolactone
and vorozole; [0342] differentiating agents such as retinoids,
vitamin D or retinoic acid and retinoic acid metabolism blocking
agents (RAMBA) for example accutane; [0343] DNA methyl transferase
inhibitors for example azacytidine or decitabine; [0344]
antifolates for example premetrexed disodium; [0345] antibiotics
for example antinomycin D, bleomycin, mitomycin C, dactinomycin,
caminomycin, daunomycin, levamisole, plicamycin, mithramycin;
[0346] antimetabolites for example clofarabine, aminopterin,
cytosine arabinoside or methotrexate, azacitidine, cytarabine,
floxuridine, pentostatin, thioguanine; [0347] apoptosis inducing
agents and antiangiogenic agents such as Bcl-2 inhibitors for
example YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or
decanoic acid; [0348] tubuline-binding agents for example
combrestatin, colchicines or nocodazole; [0349] kinase inhibitors
(e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI
(multi target kinase inhibitors), mTOR inhibitors) for example
flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib,
lapatinib, lapatinib ditosylate, sorafenib, sunitinib, sunitinib
maleate, temsirolimus; [0350] farnesyltransferase inhibitors for
example tipifarnib; [0351] histone deacetylase (HDAC) inhibitors
for example sodium butyrate, suberoylanilide hydroxamide acid
(SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465,
JNJ-26481585, trichostatin A, vorinostat; [0352] Inhibitors of the
ubiquitin-proteasome pathway for example PS-341, MLN 0.41 or
bortezomib; [0353] Yondelis; [0354] Telomerase inhibitors for
example telomestatin; [0355] Matrix metalloproteinase inhibitors
for example batimastat, marimastat, prinostat or metastat. [0356]
Recombinant interleukins for example aldesleukin, denileukin
diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon
alfa 2b [0357] MAPK inhibitors [0358] Retinoids for example
alitretinoin, bexarotene, tretinoin [0359] Arsenic trioxide [0360]
Asparaginase [0361] Steroids for example dromostanolone propionate,
megestrol acetate, nandrolone (decanoate, phenpropionate),
dexamethasone [0362] Gonadotropin releasing hormone agonists or
antagonists for example abarelix, goserelin acetate, histrelin
acetate, leuprolide acetate [0363] Thalidomide, lenalidomide [0364]
Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,
rasburicase [0365] BH3 mimetics for example ABT-737 [0366] MEK
inhibitors for example PD98059, AZD6244, CI-1040 [0367]
colony-stimulating factor analogs for example filgrastim,
pegfilgrastim, sargramostim; erythropoietin or analogues thereof
(e.g. darbepoetin alfa); interleukin 11; oprelvekin; zoledronate,
zoledronic acid; fentanyl; bisphosphonate; palifermin.
[0368] As stated above, the compounds of the present invention also
have therapeutic applications in sensitising tumour cells for
radiotherapy and chemotherapy.
[0369] Hence the compounds of the present invention can be used as
"radiosensitizer" and/or "chemosensitizer" or can be given in
combination with another "radiosensitizer" and/or
"chemosensitizer".
[0370] The term "radiosensitizer", as used herein, is defined as a
molecule, preferably a low molecular weight molecule, administered
to animals in therapeutically effective amounts to increase the
sensitivity of the cells to ionizing radiation and/or to promote
the treatment of diseases which are treatable with ionizing
radiation.
[0371] The term "chemosensitizer", as used herein, is defined as a
molecule, preferably a low molecular weight molecule, administered
to animals in therapeutically effective amounts to increase the
sensitivity of cells to chemotherapy and/or promote the treatment
of diseases which are treatable with chemotherapeutics.
[0372] Several mechanisms for the mode of action of
radiosensitizers have been suggested in the literature including:
hypoxic cell radiosensitizers (e.g., 2-nitroimidazole compounds,
and benzotriazine dioxide compounds) mimicking oxygen or
alternatively behave like bioreductive agents under hypoxia;
non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines)
can be analogoues of DNA bases and preferentially incorporate into
the DNA of cancer cells and thereby promote the radiation-induced
breaking of DNA molecules and/or prevent the normal DNA repair
mechanisms; and various other potential mechanisms of action have
been hypothesized for radiosensitizers in the treatment of
disease.
[0373] Many cancer treatment protocols currently employ
radiosensitizers in conjunction with radiation of x-rays. Examples
of x-ray activated radiosensitizers include, but are not limited
to, the following: metronidazole, misonidazole,
desmethylmisonidazole, pimonidazole, etanidazole, nimorazole,
mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide,
5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),
bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea,
cisplatin, and therapeutically effective analogs and derivatives of
the same.
[0374] Photodynamic therapy (PDT) of cancers employs visible light
as the radiation activator of the sensitizing agent. Examples of
photodynamic radiosensitizers include the following, but are not
limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin
derivatives, tin etioporphyrin, pheoborbide-a,
bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc
phthalocyanine, and therapeutically effective analogs and
derivatives of the same.
[0375] Radiosensitizers may be administered in conjunction with a
therapeutically effective amount of one or more other compounds,
including but not limited to: compounds which promote the
incorporation of radiosensitizers to the target cells; compounds
which control the flow of therapeutics, nutrients, and/or oxygen to
the target cells; chemotherapeutic agents which act on the tumour
with or without additional radiation; or other therapeutically
effective compounds for treating cancer or other diseases.
[0376] Chemosensitizers may be administered in conjunction with a
therapeutically effective amount of one or more other compounds,
including but not limited to: compounds which promote the
incorporation of chemosensitizers to the target cells; compounds
which control the flow of therapeutics, nutrients, and/or oxygen to
the target cells; chemotherapeutic agents which act on the tumour
or other therapeutically effective compounds for treating cancer or
other disease. Calcium antagonists, for example verapamil, are
found useful in combination with antineoplastic agents to establish
chemosensitivity in tumor cells resistant to accepted
chemotherapeutic agents and to potentiate the efficacy of such
compounds in drug-sensitive malignancies.
[0377] In view of their useful pharmacological properties, the
components of the combinations according to the invention, i.e. the
one or more other medicinal agent and the p53-MDM2 inhibitor
according to the present invention may be formulated into various
pharmaceutical forms for administration purposes. The components
may be formulated separately in individual pharmaceutical
compositions or in a unitary pharmaceutical composition containing
all components.
[0378] The present invention therefore also relates to a
pharmaceutical composition comprising the one or more other
medicinal agent and the p53-MDM2 inhibitor according to the present
invention together with a pharmaceutical carrier.
[0379] The present invention further relates to the use of a
combination according to the invention in the manufacture of a
pharmaceutical composition for inhibiting the growth of tumour
cells.
[0380] The present invention further relates to a product
containing as first active ingredient a p53-MDM2 inhibitor
according to the invention and as further active ingredient one or
more anticancer agent, as a combined preparation for simultaneous,
separate or sequential use in the treatment of patients suffering
from cancer.
[0381] The one or more other medicinal agents and p53-MDM2
inhibitor may be administered simultaneously (e.g. in separate or
unitary compositions) or sequentially in either order. In the
latter case, the two or more compounds will be administered within
a period and in an amount and manner that is sufficient to ensure
that an advantageous or synergistic effect is achieved. It will be
appreciated that the preferred method and order of administration
and the respective dosage amounts and regimes for each component of
the combination will depend on the particular other medicinal agent
and p53-MDM2 inhibitor being administered, their route of
administration, the particular tumour being treated and the
particular host being treated. The optimum method and order of
administration and the dosage amounts and regime can be readily
determined by those skilled in the art using conventional methods
and in view of the information set out herein.
[0382] The weight ratio of the compound according to the present
invention and the one or more other anticancer agent(s) when given
as a combination may be determined by the person skilled in the
art. Said ratio and the exact dosage and frequency of
administration depends on the particular compound according to the
invention and the other anticancer agent(s) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight, gender, diet, time of administration and
general physical condition of the particular patient, the mode of
administration 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 the 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. A particular weight ratio for
the present compound of formula (I) and another anticancer agent
may range from 1/10 to 10/1, more in particular from 1/5 to 5/1,
even more in particular from 1/3 to 3/1.
[0383] The platinum coordination compound is advantageously
administered in a dosage of 1 to 500 mg per square meter
(mg/m.sup.2) of body surface area, for example 50 to 400
mg/m.sup.2, particularly for cisplatin in a dosage of about 75
mg/m.sup.2 and for carboplatin in about 300 mg/m.sup.2 per course
of treatment.
[0384] The taxane compound is advantageously administered in a
dosage of 50 to 400 mg per square meter (mg/m.sup.2) of body
surface area, for example 75 to 250 mg/m.sup.2, particularly for
paclitaxel in a dosage of about 175 to 250 mg/m.sup.2 and for
docetaxel in about 75 to 150 mg/m.sup.2 per course of
treatment.
[0385] The camptothecin compound is advantageously administered in
a dosage of 0.1 to 400 mg per square meter (mg/m.sup.2) of body
surface area, for example 1 to 300 mg/m.sup.2, particularly for
irinotecan in a dosage of about 100 to 350 mg/m.sup.2 and for
topotecan in about 1 to 2 mg/m.sup.2 per course of treatment.
[0386] The anti-tumour podophyllotoxin derivative is advantageously
administered in a dosage of 30 to 300 mg per square meter
(mg/m.sup.2) of body surface area, for example 50 to 250
mg/m.sup.2, particularly for etoposide in a dosage of about 35 to
100 mg/m.sup.2 and for teniposide in about 50 to 250 mg/m.sup.2 per
course of treatment.
[0387] The anti-tumour vinca alkaloid is advantageously
administered in a dosage of 2 to 30 mg per square meter
(mg/m.sup.2) of body surface area, particularly for vinblastine in
a dosage of about 3 to 12 mg/m.sup.2, for vincristine in a dosage
of about 1 to 2 mg/m.sup.2, and for vinorelbine in dosage of about
10 to 30 mg/m.sup.2 per course of treatment.
[0388] The anti-tumour nucleoside derivative is advantageously
administered in a dosage of 200 to 2500 mg per square meter
(mg/m.sup.2) of body surface area, for example 700 to 1500
mg/m.sup.2, particularly for 5-FU in a dosage of 200 to 500
mg/m.sup.2, for gemcitabine in a dosage of about 800 to 1200
mg/m.sup.2 and for capecitabine in about 1000 to 2500 mg/m.sup.2
per course of treatment.
[0389] The alkylating agents such as nitrogen mustard or
nitrosourea is advantageously administered in a dosage of 100 to
500 mg per square meter (mg/m.sup.2) of body surface area, for
example 120 to 200 mg/m.sup.2, particularly for cyclophosphamide in
a dosage of about 100 to 500 mg/m.sup.2, for chlorambucil in a
dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of
about 150 to 200 mg/m.sup.2, and for lomustine in a dosage of about
100 to 150 mg/m.sup.2 per course of treatment.
[0390] The anti-tumour anthracycline derivative is advantageously
administered in a dosage of 10 to 75 mg per square meter
(mg/m.sup.2) of body surface area, for example 15 to 60 mg/m.sup.2,
particularly for doxorubicin in a dosage of about 40 to 75
mg/m.sup.2, for daunorubicin in a dosage of about 25 to 45
mg/m.sup.2, and for idarubicin in a dosage of about 10 to 15
mg/m.sup.2 per course of treatment.
[0391] The antiestrogen agent is advantageously administered in a
dosage of about 1 to 100 mg daily depending on the particular agent
and the condition being treated. Tamoxifen is advantageously
administered orally in a dosage of 5 to 50 mg, preferably 10 to 20
mg twice a day, continuing the therapy for sufficient time to
achieve and maintain a therapeutic effect. Toremifene is
advantageously administered orally in a dosage of about 60 mg once
a day, continuing the therapy for sufficient time to achieve and
maintain a therapeutic effect. Anastrozole is advantageously
administered orally in a dosage of about 1 mg once a day.
Droloxifene is advantageously administered orally in a dosage of
about 20-100 mg once a day. Raloxifene is advantageously
administered orally in a dosage of about 60 mg once a day.
Exemestane is advantageously administered orally in a dosage of
about 25 mg once a day.
[0392] Antibodies are advantageously administered in a dosage of
about 1 to 5 mg per square meter (mg/m.sup.2) of body surface area,
or as known in the art, if different. Trastuzumab is advantageously
administered in a dosage of 1 to 5 mg per square meter (mg/m.sup.2)
of body surface area, particularly 2 to 4 mg/m.sup.2 per course of
treatment. These dosages may be administered for example once,
twice or more per course of treatment, which may be repeated for
example every 7, 14, 21 or 28 days.
[0393] The compounds of formula (I), the pharmaceutically
acceptable acid addition salts and stereoisomeric forms thereof can
have valuable diagnostic properties in that they can be used for
detecting or identifying a p53-MDM2 interaction in a biological
sample comprising detecting or measuring the formation of a complex
between a labelled compound and/or p53 and/or MDM2 and or other
molecules, peptides, proteins, enzymes or receptors.
[0394] The detecting or identifying methods can use compounds that
are labelled with labelling agents such as radioisotopes, enzymes,
fluorescent substances, luminous substances, etc. Examples of the
radioisotopes include .sup.125I, .sup.131I, .sup.3H and .sup.14C.
Enzymes are usually made detectable by conjugation of an
appropriate substrate which, in turn catalyses a detectable
reaction. Examples thereof include, for example,
beta-galactosidase, beta-glucosidase, alkaline phosphatase,
peroxidase and malate dehydrogenase, preferably horseradish
peroxidase. The luminous substances include, for example, luminol,
luminol derivatives, luciferin, aequorin and luciferase. Biological
samples can be defined as body tissue or body fluids. Examples of
body fluids are cerebrospinal fluid, blood, plasma, serum, urine,
sputum, saliva and the like.
[0395] The following examples illustrate the present invention.
EXPERIMENTAL PART
[0396] Hereinafter, "DCM" is defined as dichloromethane, "DMF" is
defined as N,N-dimethylformamide, "DMSO" is defined as
dimethylsulfoxide, "DIEA" is defined as diisopropylethylamine,
"DIPE" is defined as diisopropyl ether, "EtOAc" is defined as ethyl
acetate, "Et.sub.2O" is defined as diethyl ether, "EtOH" is defined
as ethanol, "MeOH" is defined as methanol, and "THF" is defined as
tetrahydrofuran.
A. Preparation of the Intermediate Compounds
Example A1
a) Preparation of Intermediate 1
##STR00090##
[0398] A mixture of 7-nitro-2H-1,4-benzoxazin-3(4H)-one (0.0051
mol), 3-(2-bromoethyl)-1H-indole (0.0062 mol) and cesium carbonate
(0.0062 mol) was dried for 40 minutes. DMF dry (16 ml) and THF dry
(4 ml) were added. The mixture was stirred at 85.degree. C. for 2
hours and half, cooled to room temperature, poured out into ice
water (160 ml), stirred at room temperature for 1 hour, filtered
off, washed with ether (3 times 80 ml). The residue was collected
and dried for a night, yielding 1.63 g (94%) of intermediate 1.
b) Preparation of Intermediate 2
##STR00091##
[0400] Intermediate 1 (0.0037 mol) was added portion wise to
borohydride (1M in THF/0.018 mol) at 0.degree. C. The mixture was
stirred at 60.degree. C. for 1 hour and half, cooled to 0.degree.
C. Methanol dry (3.5 ml) was added. The mixture was stirred at
60.degree. C. for 1 hour, cooled to room temperature. The solvent
was evaporated under reduced pressure. The residue was taken up
with NH.sub.4OH (15%, 4 ml) and water, extracted with chloroform (4
times 80 ml). The organic layers were combined, extracted, dried
over MgSO.sub.4, filtered off and the solvent was evaporated. The
residue was purified by column chromatography over silica gel
(eluent: DCM/cyclohexane/EtOH 50/50/0.1 to 50/50/0.15). The residue
was purified by column chromatography over silica gel (eluent:
cyclohexane/EtOAc 60/40 to 50/50). The pure fractions were
collected and the solvent was evaporated, yielding 0.779 g (65%) of
intermediate 2.
c) Preparation of Intermediate 3
##STR00092##
[0402] A solution of intermediate 2 (0.0022 mol) and Pd/C 10%
(0.712 g) in THF dry (25 ml) was hydrogenated for 1 hour and half,
filtered over celite. Celite was washed with THF. The solvent was
evaporated. The residue (0.692 g) was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40 to
50/50). The pure fractions were collected and the solvent was
evaporated, yielding 0.405 g (62%) of intermediate 3.
Example A2
Preparation of Intermediate 4
##STR00093##
[0404] A solution of intermediate 1 (0.0032 mol) and Pd/C (1.04 g)
in THF dry (20 ml) and methanol dry (10 ml) was hydrogenated for 2
hours and 40 minutes, filtered over celite. Celite was washed with
methanol (250 ml in average). The solvent was evaporated under
reduced pressure. The residue (0.92 g) was purified by column
chromatography over silica gel (eluent: DCM/methanol 100/0 to
99/1). The pure fractions were collected and the solvent was
evaporated, yielding 0.789 g (77%) of intermediate 4.
Example A3
a 1) Preparation of Intermediate 5
##STR00094##
[0406] Potassium hydroxide (124.889 mmol) was added to a mixture of
trimethylsulphoxonium iodide (20.815 mmol) in acetonitrile (40 ml)
and water (5.204 mmol) at 40.degree. C. The reaction mixture was
stirred at 40.degree. C. for 30 minutes. A solution of
3-furaldehyde (20.815 mmol) in acetonitrile (20 ml) was added
dropwise. The reaction mixture was stirred at this temperature for
18 hours more. The reaction mixture was filtered through a pad of
celite and the insoluble material was washed with Et.sub.2O. The
filtrate was evaporated to dryness, yielding 4.5 g of (>100%) of
intermediate 5.
a 2) Preparation of Intermediate 37
##STR00095##
[0408] Trimethylsulphoxonium iodide (24.432 mmol) was added
portionwise at 5.degree. C. under N.sub.2 flow to a suspension of
sodium hydride 60% in oil (23.369 mmol) in DMSO (30 ml). The
reaction mixture was stirred for 30 minutes and a solution of 1-(1'
methylethyl)-4-piperidione in DMSO (10 ml) was added. The reaction
mixture was stirred at room temperature for 18 hours more. The
reaction mixture was poured onto water and extracted with
Et.sub.2O. The organic layer was decanted, washed with a saturated
solution of NaCl, dried over MgSO.sub.4, filtered and evaporated to
dryness, yielding 2.5 g (76%) of intermediate 37.
b 1) Preparation of Intermediate 6
##STR00096##
[0410] A mixture of tryptamine 98% (13.873 mmol) and intermediate 5
(20.81 mmol) in EtOH was stirred at 60.degree. C. for 18 hours. The
reaction mixture was evaporated to dryness and the residue was
purified by high-performance liquid chromatography (Irregular SiOH
20-45 .mu.m 450 g MATREX mobile phase: NH.sub.4OH 0.5%; DCM 92%
MeOH 8%), yielding 650 mg of intermediate 6.
b 2) Preparation of Intermediate 10
##STR00097##
[0412] A mixture of 7-methyltryptamine 98% (11.478 mmol) and
1-oxaspiro(2.5)octane (17.217 mmol) in EtOH (40 ml) was stirred at
60.degree. C. for 18 hours. The reaction mixture was cooled to room
temperature and evaporated to dryness. The residue was purified by
HPLC (H647 300 g SiO.sub.2 15/40 .mu.m--eluent: DCM/MeOH/NH.sub.4OH
90/10/1). The pure fractions were collected and evaporated to
dryness, yielding 2.7 g (82%) of intermediate 10.
c) Preparation of Intermediate 7
##STR00098##
[0414] A mixture of intermediate 6 (2.404 mmol),
3,4-difluoronitrobenzene (3.126 mmol) and NaHCO.sub.3 (4.809 mmol)
in DMSO (6 ml) was stirred at 80.degree. C. for 18 hours. The
reaction mixture was cooled to room temperature, poured onto iced
water and extracted with EtOAc. The organic layer was decanted,
dried over MgSO.sub.4, filtered and evaporated to dryness. The
residue was purified by HPLC (30 g SiO.sub.2 15/40 .mu.m--eluent:
DCM 100). The pure fractions were collected and evaporated to
dryness, yielding 420 mg (42%) of intermediate 7.
d) Preparation of Intermediate 8
##STR00099##
[0416] A mixture of intermediate 7 (1.026 mmol) and sodium hydride
60% in oil (3.59 mmol) in THF (10 ml) was refluxed for 30 minutes.
The reaction mixture was cooled to room temperature, quenched with
water and extracted with DCM. The organic layer was decanted, dried
over MgSO.sub.4, filtered and evaporated to dryness. The residue
was purified by HPLC (30 g SiO.sub.2 15/40 .mu.m--eluent: DCM 100).
The pure fractions were collected and evaporated to dryness,
yielding 130 mg (32%) of intermediate 8.
e) Preparation of Intermediate 9
##STR00100##
[0418] A mixture of intermediate 8 (0.334 mmol) and Raney Nickel
(0.2 g) in MeOH (20 ml) was hydrogenated at room temperature under
atmosphere pressure of H.sub.2 for 2 hours. The catalyst was
removed by filtration over a pad of celite and the filtrate was
evaporated to dryness, yielding 100 mg (83%) of intermediate 9.
[0419] Following intermediates are prepared according to A3
##STR00101##
Example A4
a) Preparation of Intermediate 11
##STR00102##
[0421] A mixture of benzo[b]thiophene-3-ethanamine (0.0274 mol) and
2-chloroethanol (0.0274 mol) in DMSO (20 ml) was heated at
80.degree. C. overnight and cooled to room temperature.
3,4-difluoronitrobenzene (0.0411 mol) and NaHCO.sub.3 (0.0411 mol)
were added. The mixture was heated at 60.degree. C. for 2 hours,
cooled to room temperature, poured out into ice and extracted with
EtOAc. The organic layer was dried over MgSO.sub.4, filtered and
evaporated till dryness. The residue (12.5 g) was purified by
high-performance liquid chromatography (Irregular SiOH 20-45 .mu.m
450 g MATREX mobile phase; cyclohexane 60% EtOAc 40%). The pure
fractions were collected and the solvent was evaporated, yielding
2.95g (30%) of intermediate 11.
b) Preparation of Intermediate 12
##STR00103##
[0423] Sodium hydride (0.0286 mol) was added portionwise to
intermediate 11 (0.00819 mol) in THF (30 ml). The mixture was
heated at 65.degree. C. overnight, poured out into ice and
extracted with EtOAc. The organic layer was dried over MgSO.sub.4,
filtered and evaporated. The residue (3.06 g) was purified by
high-performance liquid chromatography (Irregular SiOH 15-40 .mu.m
300 g MERCK mobile phase; Cyclohexane 80% DCM 20%). The pure
fractions were collected and the solvent was evaporated, yielding
1.1 g (39%) of intermediate 12.
c) Preparation of Intermediate 13
##STR00104##
[0425] A solution of intermediate 12 (0.00323 mol) in MeOH (50 ml)
was hydrogenated for one hour at room temperature with Raney Nickel
(0.9 g) as a catalyst under a 2 bar pressure. The catalyst was
filtered off and the filtrate was evaporated till dryness, yielding
0.9 g (90%) of intermediate 13. This product was used without
further purification in the next step.
Example A5
a) Preparation of Intermediate 16
##STR00105##
[0427] 2-bromo-propanoic acid, methyl ester (0.03 mol) was added to
a solution of potassium fluoride (0.075 mol) in DMF (25 ml). The
mixture was stirred at room temperature for 15 minutes.
2-amino-5-nitro-phenol (0.03 mol) was added. The mixture was
stirred at 60.degree. C. for 6 hours, poured out into ice water
(150 ml), filtered, washed with water and dried, yielding 7 g of
intermediate 16.
b) Preparation of Intermediate 17
##STR00106##
[0429] A mixture of intermediate 16 (0.0144 mol),
3-(2-bromoethyl)-1H-Indole (0.0173 mol) and cesium carbonate
(0.0173 mol) was added to a solution of DMF (96 ml) in THF (24 ml).
The mixture was stirred at 85.degree. C. for 2 hours and half,
cooled to room temperature, poured out into ice water, stirred at
room temperature for 1 hour, filtered off, washed with ether (3
times) and dried, yielding 3.9 g (77%) of intermediate 17.
c) Preparation of Intermediate 18
##STR00107##
[0431] Intermediate 17 (0.0043 mol) was added portion wise to a
solution of tetrahydrofuran-borane (0.0205 mol) at 0.degree. C. The
mixture was stirred at 60.degree. C. for one hour and half. Water
was added at 0.degree. C. The mixture was filtered over celite. The
organic layer was extracted with EtOAc, dried (MgSO.sub.4),
filtered and the solvent was evaporated in vacuum. The residue (2
g) was purified by column chromatography over silica gel (90 g)
(eluent: Cyclohexane/EtOAc 70/30; 15-40 .mu.m). The pure fractions
were collected and the solvent was evaporated, yielding 1 g (70%)
of intermediate 18.
Preparation of Intermediate 19
##STR00108##
[0433] Palladium (0) (0.1 g) was added in a solution of
intermediate 18 (0.003 mol) in MeOH/THF (10/20) (50 ml) under
nitrogen flow. The mixture was hydrogenated at room temperature for
a night under a 1 bar pressure. The mixture was filtered over
celite and the solvent was evaporated, yielding 0.8 g of
intermediate 19.
[0434] Following intermediate is prepared according to A5.
##STR00109##
Example A6
a) Preparation of Intermediate 21
##STR00110##
[0436] A mixture of N-(1,2,3,4-tetrahydro-6-quinolinyl)-carbamic
acid, 1,1-dimethylethyl ester (2.819 mmol),
1H-Indole-3-acetaldehyde (5.638 mmol), sodium cyanotrihydroborate
(3.805 mmol) and acetic acid (100 .mu.l) in MeOH (10 ml) was
stirred at room temperature for 18 hours. The reaction mixture was
quenched with a 10% solution of potassium carbonate and extracted
with DCM. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated to dryness. The residue was purified by
HPLC (30 g SiO.sub.2 15/40 .mu.m--eluent: DCM 100). The pure
fractions were collected and evaporated to dryness, yielding 888 mg
(80%) of intermediate 21.
b) Preparation of Intermediate 22
##STR00111##
[0438] A mixture of intermediate 21 (2.043 mmol) and HCl 3N (10 ml)
in dioxane (10 ml) was heated at 65.degree. C. for 30 minutes. The
reaction mixture was cooled to room temperature, poured onto a 10%
solution of potassium carbonate and extracted with DCM. The organic
layer was decanted, dried over MgSO.sub.4, filtered and evaporated
to dryness, yielding 600 mg (100%) of intermediate 22.
Example A7
a) Preparation of Intermediate 24
##STR00112##
[0440] A mixture of tryptamine (0.0125 mol) and 2-chloroethanol
(0.00892 mol) in DMSO (15 ml) was heated to 80.degree. C. for 18
hours and cooled to room temperature. 3,4-5-trifluoronitrobenzene
(0.0125 mol) and NaHCO.sub.3 (0.0125 mol) were added. The mixture
was heated at 60.degree. C. overnight and cooled to room
temperature. A solution of potassium hydroxide (0.0267 mol) in
water (2 ml) was added. The mixture was heated at 100.degree. C.
overnight, cooled to room temperature, poured out into ice and
extracted with EtOAc. The organic layer was dried over MgSO.sub.4,
filtered and evaporated till dryness. The residue was purified by
HPLC (H651 300 g SiO.sub.2 15/40 .mu.m--eluent: DCM/cyclohexane
70/30). The pure fractions were collected and evaporated to
dryness, yielding 323 mg (10% over 3 steps) of intermediate 24.
b) Preparation of Intermediate 25
##STR00113##
[0442] A mixture of intermediate 24 and Raney Nickel (280 mg) in
MeOH/THF 90/10 (20 ml) was hydrogenated at room temperature under
atmospheric pressure of H.sub.2 for 1.5 hours. The catalyst was
removed by filtration and the filtrate was evaporated to dryness,
yielding 213 mg (83%) of intermediate 25.
Example A8
a) Preparation of Intermediate 26
##STR00114##
[0444] A mixture of 7-methyltryptamine (0.00574 mol) and
2-chloroethanol (0.00383 mol) in DMSO (6 ml) was heated to
80.degree. C. for 5 hours, cooled to room temperature, poured out
into ice and extracted with EtOAc. The organic layer was dried over
MgSO.sub.4, filtered and evaporated till dryness, yielding 0.83 g
(99%) of intermediate 26.
[0445] This product was used without further purification in the
next step.
b) Preparation of Intermediate 27
##STR00115##
[0447] A mixture of 3,4-difluoronitrobenzene (0.0057 mol),
NaHCO.sub.3 (0.0057 mol) and intermediate 26 (0.0038 mol) in DMSO
(7 ml) was heated at 60.degree. C. for 2 hours, cooled to room
temperature, poured onto ice-water and extracted with EtOAc. The
organic layer was dried over MgSO.sub.4, filtered and evaporated
till dryness. The residue was purified by column chromatography
over 300 g of silica gel 15-40 .mu.m (eluent: DCM/MeOH: 99/1). The
pure fractions were collected and the solvent was evaporated,
yielding 0.418 g (31%) of intermediate 27
c) Preparation of Intermediate 28
##STR00116##
[0449] To intermediate 27 (0.000227 mol) in DMSO (6 ml) was added
potassium hydroxide (0.00068 mol) in water (few drops). The mixture
was stirred at room temperature overnight, poured out into ice and
extracted with EtOAc. The organic layer was dried over MgSO.sub.4,
filtered and evaporated till dryness, yielding 0.07 g (91%) of
intermediate 28.
d) Preparation of Intermediate 29
##STR00117##
[0451] A solution of intermediate 28 (0.000978 mol) in MeOH (10 ml)
was hydrogenated for one hour at room temperature with Raney Nickel
(0.3 g) as a catalyst under a 2 bar pressure. The catalyst was
filtered off and the filtrate was evaporated till dryness, yielding
0.3 g (100%) of intermediate 29. This product was used without
further purification in the next step.
Example A9
Preparation of Intermediate 32
##STR00118##
[0453] A mixture of intermediate 31 (see Example A3) (0.432 mmol),
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.518 mmol) and
HCl/dioxane 4N (0.0863 mmol) in acetonitrile (2 ml) and EtOH (16
ml) was heated at 65.degree. C. for 18 hours. The reaction mixture
was cooled to room temperature, diluted with DCM and quenched with
a 10% solution of potassium carbonate. The organic layer was
decanted, dried over MgSO.sub.4, filtered and evaporated to
dryness. The residue was purified by HPLC (10 g SiO.sub.2 15/40
.mu.m--eluent: DCM/MeOH/NH.sub.4OH 95/5/0.5). The pure fractions
were collected and evaporated to dryness, yielding 163 mg (64%) of
intermediate 32.
Example A10
a) Preparation of Intermediate 33
##STR00119##
[0455] A mixture of 1,2,3,4-tetrahydro-6-nitro-quinoxaline (22.324
mmol), di-tert-butyl dicarbonate (22.324 mmol), triethylamine
(44.648 mmol) and 4-dimethylaminopyridine (4.465 mmol) in DCM (40
ml) was stirred at room temperature for 2 hours. The reaction
mixture was poured onto water and extracted with DCM. The organic
layer was decanted, dried over MgSO.sub.4, filtered and evaporated
to dryness. The residue (7.7 g) was purified by HPLC (90 g
SiO.sub.2 15/40 .mu.m--eluent: DCM 100 to DCM/MeOH 99/1). The pure
fractions were collected and evaporated to dryness, yielding 3.55 g
(57%) of intermediate 33.
b) Preparation of Intermediate 34
##STR00120##
[0457] A mixture of intermediate 33 (10.383 mmol), iodomethane
(14.537 mmol) and K.sub.2CO.sub.3 (16.613 mmol) in acetonitrile (30
ml) was heated at 90.degree. C. all over the weekend. The reaction
mixture was quenched with water and extracted with DCM. The organic
layer was decanted, dried over MgSO.sub.4, filtered and evaporated
to dryness. The residue was purified by HPLC (90 g SiO.sub.2 15/40
.mu.m--eluent: DCM 100). The pure fractions were collected and
evaporated to dryness, yielding 2.15 g (70%) of intermediate
34.
c) Preparation of Intermediate 35
##STR00121##
[0459] A mixture of intermediate 34 (3.409 mmol), Raney Nickel (1
g) in MeOH (10 ml) was hydrogenated at room temperature under
atmospheric pressure for 1 hour. The catalyst was removed by
filtration and the filtrate was evaporated to dryness, yielding 814
mg (90%) of intermediate 35.
d) Preparation of Intermediate 36
##STR00122##
[0461] A mixture of intermediate 35 (1.029 mmol),
4-chloro-2-pyridinemethanol (1.235 mmol) and HCl/dioxane 4N (1.235
mmol) in acetonitrile (3 ml) and EtOH (2.4 ml) was heated at
65.degree. C. for 18 hours. The reaction mixture was cooled to room
temperature and HCl 3N (2 ml) was added. The reaction mixture was
heated at 65.degree. C. for 4 hours more. The reaction mixture was
diluted with EtOAc and quenched with a 10% solution of potassium
carbonate. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated to dryness. The residue was purified by
HPLC (30 g SiO.sub.2 15/40 .mu.m--eluent: DCM/MeOH/NH.sub.4OH
90/10/1). The pure fractions were collected and evaporated to
dryness, yielding 185 mg (66%) of intermediate 36.
B. Preparation of the Final Compounds
Example B1
Preparation of Compound 1
##STR00123##
[0463] A mixture of intermediate 3 (0.0004 mol) and
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0005 mol) was
stirred at 150.degree. C. for 20 minutes, cooled to room
temperature, extracted with NaHCO.sub.3/DCM/methanol (few drops) (4
times 40 ml). The organic layers were combined, dried over
MgSO.sub.4, filtered off and the solvent was evaporated. The
residue (0.218 g) was purified by column chromatography over silica
gel (DCM/methanol 95/5, 93/7 to 90/1). The pure fraction was
collected and the solvent was evaporated, yielding 0.150 g (86%) of
compound 1.
Example B2
Preparation of Compound 2
##STR00124##
[0465] A mixture of intermediate 4 (0.0003 mol) and
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0003 mol) was
stirred at 150.degree. C. for 20 minutes, cooled to room
temperature, extracted with NaHCO.sub.3/DCM/methanol (few drops).
The organic layers were combined, dried over MgSO.sub.4, filtered
off and the solvent was evaporated. The residue (0.174 g) was
purified by column chromatography over silica gel (DCM/methanol
95/5, 93/7 to 90/1). The pure fraction was collected and the
solvent was evaporated, yielding 0.097 g (68%) of compound 2.
Example B3
Preparation of Compound 3
##STR00125##
[0467] A mixture of intermediate 3 (0.0006 mol) and
4-chloro-pyridine hydrochloride (0.018 mol) was stirred at
150.degree. C. for 20 minutes, cooled to room temperature,
extracted with NaHCO.sub.3/DCM/methanol (few drops) (4 times 40
ml). The organic layers were combined, dried over MgSO.sub.4,
filtered off and the solvent was evaporated. The residue (0.276 g)
was purified by column chromatography over silica gel (DCM/methanol
95/5, 93/7 to 90/1). The pure fraction was collected and the
solvent was evaporated, yielding 0.118 g (51%) of compound 3.
Example B4
Preparation of Compound 4
##STR00126##
[0469] A mixture of intermediate 4 (0.0005 mol) and
4-chloro-pyridine hydrochloride (0.0015 mol) was stirred at
180.degree. C. for 15 minutes, stirred at 120.degree. C. for 15
minutes, cooled to room temperature. The residue was taken up with
saturated NaHCO.sub.3, extracted with DCM/methanol (few drops). The
organic layer was dried over MgSO.sub.4, filtered off and the
solvent was evaporated. The residue was purified by column
chromatography over silica gel (DCM/methanol 95/5, 93/7 to 90/1).
The pure fraction was collected and the solvent was evaporated,
yielding 0.068 g (30%) of compound 4.
Example B5
Preparation of Compound 5
##STR00127##
[0471] A mixture of intermediate 9 (0.139 mmol) and
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.167 mmol) in
HCl/dioxane 4N (0.0278 mmol) and acetonitrile (1 ml) was heated at
65.degree. C. for 18 hours. The reaction mixture was cooled to room
temperature, diluted with DCM and quenched with a 10% solution of
potassium carbonate. The organic layer was decanted, dried over
MgSO.sub.4, filtered and evaporated to dryness. The residue was
purified by high-performance liquid chromatography (X-Terra-C18 10
.mu.m 19.times.150 mm mobile phase: NH.sub.4HCO.sub.3 0.5%;
Gradient from 40% to 100 of acetonitrile), yielding 24 mg (35%) of
compound 5.
Example B6
a) Preparation of Compound 6
##STR00128##
[0473] A mixture of intermediate 13 (0.000966 mol), 4-bromopyridine
hydrochloride (0.00116 mol) and DIEA (0.000773 mol) in acetonitrile
(3.3 ml) and EtOH (2.6 ml) was heated at 80.degree. C. for 18
hours. The mixture was cooled to room temperature, quenched with a
10% solution of potassium carbonate and extracted with DCM. The
organic layer was decanted, dried over MgSO.sub.4, filtered and
evaporated till dryness. The residue (0.36 g) was purified by
high-performance liquid chromatography (Spherical SiOH 10 .mu.m 60
g PharmPrep MERCK mobile phase: NH.sub.4OH 0.2%; DCM 92% MeOH 8%).
The pure fractions were collected and the solvent was evaporated.
The residue (0.207 g) was crystallized from Et.sub.2O and dried,
yielding 0.161 g (43%) of compound 6.
b) Preparation of Compound 7
##STR00129##
[0475] A mixture of intermediate 15 (see Example A3) (0.239 mmol),
4-bromopyridine hydrochloride (0.287 mmol) and DIEA (0.191 mmol) in
acetonitrile (1 ml) and EtOH (0.8 ml) was heated at 65.degree. C.
for 18 hours. The reaction mixture was cooled to room temperature,
diluted with EtOAc and quenched with a 10% solution of potassium
carbonate. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated to dryness. The residue was purified by
HPLC (H663-30 g SiO2 15/40 .mu.m--eluent: DCM/MeOH/NH.sub.4OH
95/5/0.5 then XBridge C18--eluent: CH.sub.3CN/NH.sub.4CO.sub.3
40/60 to CH.sub.3CN 100). The pure fractions were collected and
evaporated to dryness, yielding 40 mg (38%) of compound 7.
Example B7
Preparation of Compound 8
##STR00130##
[0477] A mixture of intermediate 14 (see Example A3) (0.336 mmol)
and 4-bromopyridine hydrochloride (0.403 mmol) in acetonitrile (2
ml) and EtOH (1.6 ml) was heated at 65.degree. C. for 18 hours. The
reaction mixture was cooled to room temperature, quenched with a
10% solution of potassium carbonate and extracted with DCM. The
organic layer was decanted, dried over MgSO.sub.4, filtered and
evaporated to dryness. The residue was purified by HPLC
(H693-XTerra MS C18 10 .mu.m--eluent: CH.sub.3CN/NH.sub.4HCO.sub.3
0.5% 20/80 to CH.sub.3CN 100). The pure fractions were collected
and evaporated to dryness, yielding 58 mg (36%) of compound 8.
Example B8
a) Preparation of Compound 9
##STR00131##
[0479] A mixture of intermediate 19 (0.0006 mol), 4-bromo-pyridine,
hydrochloride (1:1) (0.0007 mol) and DIEA (0.0005 mol) in
acetonitrile (20 ml) and EtOH (5 ml) was stirred at 65.degree. C.
overnight. Potassium carbonate 10% solution was added. The organic
layer was extracted with EtOAc, dried (MgSO.sub.4), filtered and
the solvent was evaporated. The residue (0.6 g) was purified by
column chromatography over silica gel (300 g) (eluent:
DCM/MeOH/NH.sub.4OH 92/8/1; 15-40 .mu.m). The pure fractions were
collected and the solvent was evaporated, yielding 0.192 g (77%) of
compound 9.
b) Preparation of Compound 24
##STR00132##
[0481] A mixture of intermediate 19 (0.00114 mol),
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.00137 mol) and
HCl 4M in dioxane (0.000228 mol) in acetonitrile (3.5 ml) and EtOH
(2.8 ml) was heated at 80.degree. C. overnight. The mixture was
cooled to room temperature, quenched with a 10% solution of
potassium carbonate and extracted with DCM. The organic layer was
decanted, dried over MgSO.sub.4, filtered and evaporated till
dryness. The residue (0.56 g) was purified by high-performance
liquid chromatography (Spherical SiOH 10 .mu.m 60 g PharmPrep MERCK
mobile phase: NH.sub.4OH 0.5%; DCM 95% MeOH 5%). The pure fractions
were collected and the solvent was evaporated. The residue (200 mg)
was crystallized from Et.sub.2O and dried, yielding 0.164 g (33%)
of compound 24.
Example B9
Preparation of Compound 10
##STR00133##
[0483] A mixture of intermediate 20 (0.0006 mol),
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.0006 mol) and
HCl/dioxane 4M (0.0002 mol) in acetonitrile/EtOH 4/1 (25 ml) was
stirred at 65.degree. C. overnight. The residue was purified by
column chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
from 96/4/0.4 to 86/13/1.2; Sunfire 5 .mu.m). The pure fractions
were collected and the solvent was evaporated, yielding 0.073 g of
compound 10.
Example B10
a) Preparation of Compound 11
##STR00134##
[0485] A mixture of intermediate 22 (0.68 mmol)
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.816 mmol) and
HCl/dioxane 4N (34 .mu.l) in acetonitrile (3 ml) and EtOH (2.4 ml)
was heated at 65.degree. C. for 18 hours. The reaction mixture was
quenched with a 10% solution of potassium carbonate and extracted
with DCM. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated to dryness. The residue (321 mg) was
purified by high-performance liquid chromatography (Spherical SiOH
10 .mu.m 60 g PharmPrep MERCK mobile phase: NH.sub.4OH 0.5%; DCM94%
MeOH6%). The pure fractions were collected and the solvent was
evaporated. The residue (124 mg) was crystallized from
CH.sub.3CN/DIPE. The precipitate was filtered off and dried,
yielding 93 mg (32%) of compound 11.
b) Preparation of Compound 23
##STR00135##
[0487] A mixture of intermediate 22 (0.68 mmol), 4-bromopyridine
hydrochloride (0.748 mmol) and DIEA (0.544 mmol) in acetonitrile (3
ml) and EtOH (2.4 ml) was heated at 65.degree. C. for 18 hours. The
reaction mixture was quenched with a 10% solution of potassium
carbonate and extracted with DCM. The organic layer was decanted,
dried over MgSO.sub.4, filtered and evaporated to dryness. The
residue (250 mg) was purified by high-performance liquid
chromatography (Spherical SiOH 10 .mu.m 60 g PharmPrep MERCK mobile
phase: NH.sub.4OH 0.5%; DCM 92% MeOH 8%). The pure fractions were
collected and the solvent was evaporated. The residue (147 mg) was
crystallized from CH.sub.3CN/DIPE. The precipitate was filtered off
and dried, yielding 103 mg (41%) of compound 23.
Example B11
Preparation of Compound 12
##STR00136##
[0489] A mixture of intermediate 13 (0.000966 mol),
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.00116 mol) and
HC/dioxane 4M (0.000193 mol) in acetonitrile (3.3 ml) and EtOH (2.6
ml) was heated at 80.degree. C. for 18 hours. The mixture was
cooled to room temperature, quenched with a 10% solution of
potassium carbonate and extracted with DCM. The organic layer was
decanted, dried over MgSO.sub.4, filtered and evaporated till
dryness. The residue (0.48 g) was purified by high-performance
liquid chromatography (Spherical SiOH 10 .mu.m 60 g PharmPrep MERCK
mobile phase: NH.sub.4OH 0.1%; DCM 92% MeOH 8%). The pure fractions
were collected and the solvent was evaporated. The residue (0.202
g) was crystallized from Et.sub.2O and dried, yielding 0.139 g
(32%) of compound 12.
Example B12
Preparation of Compound 13
##STR00137##
[0491] A mixture of intermediate 25 (0.228 mmol),
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.274 mmol) and
HCl/dioxane 4M (0.0456 mmol) in acetonitrile (1 ml) and EtOH (0.8
ml) was heated at 65.degree. C. for 18 hours. The reaction mixture
was cooled to room temperature, diluted with EtOAc and quenched
with a 10% solution of potassium, carbonate. The organic layer was
decanted, dried over MgSO.sub.4, filtered and evaporated to
dryness. The residue was purified by HPLC (H660-kromasil 3.5
.mu.m--eluent: DCM/MeOH/NH.sub.4OH 99/1/0.1 to 93/7/0.7). The pure
fractions were collected and evaporated to dryness, yielding 77 mg
(76%) of compound 13.
Example B13
Preparation of Compound 14
##STR00138##
[0493] A mixture of
4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (0.00039 mol),
HCl/dioxane 4M (0.0000651 mol) and intermediate 29 (0.000325 mol)
in acetonitrile (1 ml) and EtOH (0.8 ml) was heated at 65.degree.
C. for 18 hours. The mixture was cooled to room temperature,
quenched with a 10% solution of potassium carbonate and extracted
with DCM. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated till dryness. The residue was purified by
high-performance liquid chromatography over XTerra (eluent:
CH.sub.3CN/0.5% NaHCO.sub.3: 30/70 to 100/0). The pure fractions
were evaporated till dryness, yielding 0.013 g (8%) of compound
14.
Example B14
a) Preparation of Compound 15
##STR00139##
[0495] A mixture of intermediate 30 (0.236 mmol), 4-bromopyridine
hydrochloride (0.283 mmol) and DIEA (0.189 mmol) in acetonitrile (1
ml) and EtOH (0.8 ml) was heated at 65.degree. C. for 18 hours. The
reaction mixture was cooled to room temperature and HCl 3N (0.5 ml)
was added to complete the reaction at 65.degree. C. for 18
hours.
[0496] The reaction mixture was cooled to room temperature, diluted
with DCM and quenched with a 10% solution of potassium carbonate.
The organic layer was decanted, dried over MgSO.sub.4, filtered and
evaporated to dryness. The residue was purified by HPLC
(H677-XTerra MSC18--eluent: CH.sub.3CN/NH.sub.4CO.sub.3 0.5% 20/80
to CH.sub.3CN 100). The pure fractions were collected and
evaporated to dryness, yielding 38 mg (37%) of compound 15.
b) Preparation of Compound 16
##STR00140##
[0498] A mixture of intermediate 30 (0.236 mmol),
4-chloro-2-pyridinemethanol (0.283 mmol) and HCl/dioxane 4M (0.0471
mmol) in acetonitrile (1 ml) and EtOH (0.8 ml) was heated at
65.degree. C. for 18 hours. The reaction mixture was cooled to room
temperature and HCl 3N (0.5 ml) was added to complete the reaction
at 65.degree. C. for 18 hours. The reaction mixture was cooled to
room temperature, diluted with DCM and quenched with a 10% solution
of potassium carbonate. The organic layer was decanted, dried over
MgSO.sub.4, filtered and evaporated to dryness. The residue was
purified by HPLC (H679-XTerra MSC18--eluent:
CH.sub.3CN/NH.sub.4CO.sub.3 0.5% 20/80 to CH.sub.3CN 100). The pure
fractions were collected and evaporated to dryness, yielding 41 mg
of (37%) of compound 16.
Example B15
a) Preparation of Compound 17
##STR00141##
[0500] A mixture of intermediate 31 (0.465 mmol), 4-bromopyridine
hydrochloride (0.511 mmol) and DIEA (0.372 mmol) in acetonitrile (2
ml) and EtOH (1.6 ml) was heated at 65.degree. C. for 18 hours. The
reaction mixture was cooled to room temperature, diluted with DCM
and quenched with a 10% solution of potassium carbonate. The
organic layer was decanted, dried over MgSO.sub.4, filtered and
evaporated to dryness. The residue was purified by Normal phase on
(Cartridge 15-40 .mu.m 30 g Mobile phase: 1% NH.sub.4OH, 90% DCM,
10% MeOH). The pure fractions were collected and evaporated to
dryness. The residue (107 mg) was taken up with DIPE, filtered and
dried, yielding 70 mg (36%) of compound 17.
b) Preparation of Compounds 18 and 19
##STR00142##
[0502] A mixture of intermediate 32 (0.274 mmol) and
Tetra-n-butylammonium fluoride 1M in THF (0.274 mmol) in THF (2 ml)
was stirred at room temperature overnight. The reaction mixture was
quenched with a 10% solution of potassium carbonate and extracted
with EtOAc. The organic layer was decanted, dried over MgSO.sub.4,
filtered and evaporated to dryness. The residue was purified by
Normal phase on (Cartridge 15-40 .mu.m 30 g mobile phase: 1%
NH.sub.4OH, 10% MeOH, 90% DCM) followed by Normal phase on
(Stability 5 .mu.m 150 30, Mobile phase: 0.3% NH4OH, 3% MeOH, 97%
DCM to 1.4/14/86)
[0503] The pure fractions were collected and evaporated to dryness,
yielding 24 mg (12%) of compound 19 and 75 mg (37%) of compound
18.
Example B16
Preparation of Compound 20
##STR00143##
[0505] A mixture of intermediate 36 (0.692 mmol),
1H-Indole-3-acetaldehyde (1.383 mmol), sodium cyanotrihydroborate
(0.934 mmol) and acetic acid (20 .mu.l) in MeOH (3 ml) was stirred
at room temperature for 18 hours. The reaction mixture was quenched
with a 10% solution of potassium carbonate and extracted with DCM.
The organic layer was decanted, dried over MgSO.sub.4, filtered and
evaporated to dryness. The residue (400 mg) was purified by
high-performance liquid chromatography (X-Bridge-C18 5 .mu.m 30*150
mm mobile phase: NH.sub.4HCO.sub.3 0.5%; Gradient from 30% to 100%
of CH.sub.3CN). The pure fractions were collected and the solvent
was evaporated, yielding 15 mg of compound 20.
Example B17
Preparation of Compound 22
##STR00144##
[0507] Compound 21 (0.0013 mol) was added portionwise at 0.degree.
C. to trihydro(tetrahydrofuran)boron (0.0062 mol). The mixture was
stirred at 60.degree. C. for one hour and 30 minutes, then poured
out into water at 0.degree. C. and filtered over celite. The
organic layer was extracted with EtOAc, dried (MgSO.sub.4),
filtered and the solvent was evaporated in vacuo. The residue (0.55
g) was purified by column chromatography over silica gel (eluent:
DCM/MeOH/NH.sub.4OH from 98/2/0.2 to 88/11/1.1, Sunfire 5 .mu.m).
The pure fractions were collected and the solvent was evaporated,
yielding 0.205 g (40%) of compound 22.
[0508] Table 3 lists the compounds that were prepared according to
one of the above Examples (Ex.)
TABLE-US-00003 TABLE 3 ##STR00145## ##STR00146## ##STR00147##
##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152##
##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157##
##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177##
##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182##
##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187##
##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192##
##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197##
##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202##
##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207##
##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##
##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217##
##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## ##STR00225##
C. Pharmacological Example
[0509] A2780 cells are human ovarian carcinoma cells with wild type
p53.
[0510] The capacity of the compounds to preserve p53 in A2780 cells
was measured with the p53 enzyme linked immunosorbent assay
(ELISA). The p53 assay is a "sandwich" enzyme immunoassay employing
two polyclonal antibodies. A polyclonal antibody, specific for the
p53 protein, has been immobilized onto the surface of the plastic
wells. Any p53 present in the sample to be assayed will bind to the
capture antibody. The biotinylated detector polyclonal antibody
also recognizes p53 protein, and will bind to any p53, which has
been retained by the capture antibody. The detector antibody, in
turn, is bound by horseradish peroxidase-conjugated streptavidin.
The horseradish peroxidase catalyses the conversion of the
chromogenic substrate o-phenylene diamine, the intensity of which
is proportional to the amount of p53 protein bound to the plate.
The coloured reaction product is quantified using a
spectrophotometer. Quantitation is achieved by the construction of
a standard curve using known concentrations of purified recombinant
HIS tagged p53 protein (see example C.1).
[0511] Cellular activity of the compounds of formula (I) was
determined on A2780 tumour cells using a colorimetric assay for
cell toxicity or survival (see example C.2).
C.1 p53 ELISA
[0512] A2780 cells (ATCC) were cultivated in RPMI 1640 supplemented
with 10% fetal calf serum (FCS), 2 mM L-glutamine and gentamycin at
37.degree. C. in a humidified incubator with 5% CO.sub.2.
[0513] A2780 cells were seeded at 20.000 cells per well in a 96
well plate, cultured for 24 hours and treated with compound for 16
hours at 37.degree. C. in a humidified incubator. After incubation,
the cells were washed once with phosphate-buffered saline and 30
.mu.l, per well, low salt RIPA buffer (20 mM tris, pH7.0, 0.5 mM
EDTA, 1% Nonidet P40, 0.5% DOC, 0.05% SDS, 1 mM PMSF, 1 .mu.g/ml
aprotinin and 0.5 .mu./ml leupeptin) was added. Plates were placed
on ice for 30 minutes to complete the lysis. p53 protein was
detected in de lysates by using the sandwich ELISA, described
below.
[0514] High binding polystyrene EIA/RIA 96 well plates (Costar
9018) were coated with the capture antibody pAb1801 (Abcam
ab28-100) at a concentration of 1 .mu.g/ml in coating buffer (0.1 M
NaHCO.sub.3 pH8.2), 50 .mu.l per well. The antibody was allowed to
adhere overnight at 4.degree. C. Coated plates were washed once
with phosphate-buffered saline (PBS)/0.05% Tween 20 and 300 .mu.l
of blocking buffer (PBS, 1% bovine serum albumins (BSA)) was added,
for an incubation period of 2 hours at room temperature. Dilutions
of purified recombinant HIS tagged p53 protein, ranging from 3-200
ng/ml, were made in blocking buffer and used as standards.
[0515] Plates were washed twice with PBS/0.05% Tween 20 and
blocking buffer or standards were added at 80 .mu.l/well. To the
standards, 20 .mu.l of lysis buffer was added. The samples were
added to the other wells at 20 .mu.l lysate/well. After an
overnight incubation at 4.degree. C., plates were washed twice with
PBS/0.05% Tween 20. Aliquots of 100 .mu.l secondary polyclonal
antibody p53(FL-393) (Tebubio, sc-6243) at a concentration of 1
.mu.g/ml in blocking buffer were added to each well and allowed to
adhere for 2 hours at room temperature. Plates were washed three
times with PBS/0.05% Tween 20. Detection antibody anti-rabbit HRP
(sc-2004, Tebubio) at 0.04 .mu.g/ml in PBS/1% BSA was added and
incubated for 1 hour at room temperature. Plates were washed three
times with PBS/0.05% Tween 20 and 100 .mu.l of substrate buffer was
added (substrate buffer was prepared shortly before use by adding 1
tablet of 10 mg o-phenylene diamine (OPD) from Sigma and 125 .mu.l
3% H.sub.2O.sub.2 to 25 ml OPD buffer: 35 mM citric acid, 66 mM
Na.sub.2HPO.sub.4, pH5.6). After 5 to 10 minutes, colour reaction
was stopped by adding 50 .mu.l stop buffer (1 M H.sub.2SO.sub.4)
per well. The absorbance at dual wavelengths of 490/655 nm was
measured using a Biorad micro plate reader and the results were
then analyzed.
[0516] For each experiment, controls (containing no drug) and a
blank incubation (containing no cells or drugs) were run in
parallel. The blank value was subtracted from all control and
sample values. For each sample, the value of p53 (in absorbance
units) was expressed as the percentage of the value for p53 present
in the control. Percentage preservation higher than 140% was
defined as significant. Herein the effects of test compounds are
expressed as the lowest dose giving at least 140% of the value for
p53 present in the control (LAD) (see Table 4 below).
[0517] In some of the experiments the assay was adapted for and
used in 384-well culture plates
C.2 Proliferation Assay
[0518] The human A2780 ovarian cancer cells were a kind gift from
Dr. T. C. Hamilton (Fox Chase Cancer Centre, Pennsylvania, U.S.A.).
The cells were cultured in RPMI 1640 medium supplemented with 2 mM
L-Glutamine, 50 .mu.g/ml gentamicin and 10% fetal calf serum.
Reagents Used in the Alamar Blue Assay
[0519] Resazurin was purchased from Aldrich (Prod. No. 199303).
Potassium ferrocyanide, potassium ferricyanide, KH.sub.2PO.sub.4
and K.sub.2HPO.sub.4 were purchased from Sigma (Prod. Nos. P9387,
P8131, P5655 and P8281, respectively).
[0520] Potassium Phosphate Buffer 0.1 M (PPB) was made as follows:
2.72 gram KH.sub.2PO.sub.4 and 13.86 gram K.sub.2HPO.sub.4 were
dissolved in 500 ml milli-Q H.sub.2O, the pH was adjusted to pH 7.4
and the volume was brought to 1 litre with milli-Q H.sub.2O; the
buffer was filter sterilised and stored at room temperature.
Resazurin stock solution (PPB-A) was prepared fresh by dissolving
45 mg resazurin in 15 ml PBS. 30 mM potassium ferricyanide (PPB-B)
was prepared by dissolving 0.987 gram potassium ferricyanide in 100
ml PPB. 30 mM potassium ferrocyanide (PPB-C) was prepared by
dissolving 1.266 gram potassium ferrocyanide in 100 ml PPB.
[0521] Mixture of PPB-A, PPB-B and PPB-C was prepared by mixing
equal volumes of the respective solutions. Resazurin work solution
(herein termed "Alamar Blue" solution) was prepared by diluting
said mixture 20.times. (vol/vol) in PPB and filter sterilising; the
Alamar Blue solution could be kept at 4.degree. C. for a maximum of
2 weeks.
Procedure of the Alamar Blue Assay
[0522] For experiments in 384 wells plates the cells were seeded at
a density of 5.times.10.sup.3 cells/ml in Falcon 384-well culture
plates (Life Technologies, Merelbeke, Belgium), black with clear
bottom, in 45 .mu.l culture medium. Cells were allowed to adhere to
plastic for 24 hr. The tested compound was pre-diluted (1/50 in
culture medium) and 5 .mu.l pre-diluted compound was added to the
wells. Following 4-day incubation, 10 .mu.l of the Alamar Blue
solution was added to each well and the cells were further
incubated for 5 hrs (A2780) at 37.degree. C. The fluorescence
intensity was measured for each well with a Fluorescence plate
reader (Fluorskan, Labsystems, 540 nm excitation and 590 nm
emission)
[0523] The antiproliferative activity was calculated as percentage
of remaining viable cells in treated versus control (untreated
cells) conditions. Within an experiment, the result for each
experimental condition is the mean of 3 replicate wells. When
appropriate, the experiments were repeated to establish full
concentration-response curves. When appropriate, IC.sub.50-values
(concentration of the drug, needed to reduce cell growth to 50% of
the control) were computed using probit analysis for graded data
(Finney, D. J., Probit Analyses, 2.sup.nd Ed. Chapter 10, Graded
Responses, Cambridge University Press, Cambridge 1962). Herein the
effects of test compounds are expressed as pIC.sub.50 (the negative
log value of the IC.sub.50-value) (see Table 4).
TABLE-US-00004 TABLE 4 Results of the compounds that were tested in
the above p53 ELISA protocol (LAD) and proliferation assay
(pIC.sub.50) Comp. No. p53-elisa LAD [microM] pIC.sub.50 1 0.1 6.37
2 1 ~5.22 3 >10.0 <5.0 4 >10.0 <5.0 5 0.3 5.59 6
>10.0 5.26 7 >10.0 5.07 8 >10.0 5.9 9 >10.0 ~5.23 10
0.3 -- 11 0.1 5.63 12 0.3 5.43 13 1 5.35 14 3 5.54 15 >10.0 5.08
16 >10.0 <5 17 >10.0 -- 18 >10 -- 19 >10 -- 20 3
5.32 21 >10.0 <5 22 1 5.64 23 >10.0 5.52 24 3 5.25 25 0.03
~5.25 26 0.03 ~5.22 27 1 5.29 28 3 5.31 29 10 ~5.29 30 >10.0 5.2
31 >10.0 <5 32 3 -- 33 >10.0 5.66 34 0.3 5.36 35 3 5.29 36
>10.0 5.47 37 >10.0 5.45 38 >10.0 5.43 39 >10.0 ~5.32
40 >10.0 ~5.32 41 >10.0 ~5.32 42 >10.0 5.32 43 >10.0
~5.30 44 >10.0 5.3 45 >10.0 5.2 46 >10.0 5.16 47 >10.0
~5.19 48 >10.0 5.46 49 >10.0 5.32 50 >10.0 5.09 51
>10.0 5.52 52 >10.0 5.51 53 >10.0 5.46 54 >10.0 5.44 55
>10.0 5.43 56 >10.0 ~5.32 57 >10.0 -- 58 >10.0 -- 59
>10.0 5.61 60 >10.0 -- 61 >10.0 <5 62 >10.0 5.27 63
>10.0 <5 64 10 -- 65 >10.0 <5 66 3 5.85 67 10 5.3 68
>10.0 5.28 69 10 <5 70 10 5.19 71 >10.0 5.28 72 >10.0
5.33 73 >10.0 -- 74 >10.0 -- 75 >10.0 ~5.28 76 10 5.48 77
3 5.66 78 >10.0 5.21 79 10 -- 80 -- 5.51 81 >10.0 5.38 ~:
means approximate
D. Analytical Data
General Procedure A
[0524] The HPLC measurement was performed using a system comprising
a Dionex P580LPG quaternary gradient pump, a TSP (Thermo
Separation)--or Gilson ASPEC auto sampler, a Dionex UVD340S
diode-array detector (DAD) or a TSP dual wavelengths UV-detector
and a column as specified in the respective methods below. The
column temperature was room temperature. The chromatography data
system was Chromeleon Vs. 6.60 or higher.
[0525] Mass detection was done by Flow injection analysis (FIA)
(e.g. MeOH, 0.2% formic acid) on a Thermo Finnigan AQA.TM. or
Thermo Finnigan MSQ.TM. plus mass spectrometer. Ionisation was
APCI+ (atmospheric pressure chemical ionization). Typically,
measurements were done at 3-4 cone voltages simultaneously. The
cone voltage was modified during the measurement in short intervals
e.g. for Thermo Finnigan AQA.TM. at 5, 15 and 30 V and e.g. for the
Thermo Finnigan MSQ.TM. plus at 40, 50 and 70 V, alternating within
ca. 0.3 seconds. The APCI probe temperature was 350.degree. C. Mass
spectra were acquired by scanning from 100 to 800 within 2.5
seconds. Nitrogen was used as the nebulizer gas.
General Procedure B
[0526] The HPLC measurement was performed using an Alliance HT 2795
(Waters) system comprising a quaternary pump with degasser, an
autosampler, a diode-array detector (DAD) and a column as specified
in the respective methods below, the column is hold at a
temperature of 30.degree. C. Flow from the column was split to a MS
spectrometer. The MS detector was configured with an electrospray
ionization source. The capillary needle voltage was 3 kV and the
source temperature was maintained at 100.degree. C. on the LCT
(Time of Flight Zspray.TM. mass spectrometer from Waters--for LCMS
method 2), and 3.15 kV at 110.degree. C. on the ZQ.TM. (simple
quadrupole Zspray.TM. mass spectrometer from Waters--for LCMS
method 5). Nitrogen was used as the nebulizer gas. Data acquisition
was performed with a Waters-Micromass MassLynx-Openlynx data
system.
General Procedure C
[0527] The LC measurement was performed using a HPLC (Ultra
Performance Liquid Chromatography) Acquity (Waters) system
comprising a binary pump with degasser, an autosampler, a
diode-array detector (DAD) and a column as specified in the
respective methods below, the column is hold at a temperature of
40.degree. C. Flow from the column was brought to a MS detector.
The MS detector was configured with an electrospray ionization
source. The capillary needle voltage was 3 kV and the source
temperature was maintained at 130.degree. C. on the Quattro (triple
quadrupole mass spectrometer from Waters). Nitrogen was used as the
nebulizer gas. Data acquisition was performed with a
Waters-Micromass MassLynx-Openlynx data system.
LCMS Method 1
[0528] In addition to general procedure A: Reversed phase HPLC was
carried out on a Develosil RPAq column (4.6.times.50 mm) with a
flow rate of 1.5 ml/min. UV-detection at 220 nm and 254 nm. A
linear gradient run was employed from 10% acetonitrile and 90%
water (0.1% TFA) to 100% acetonitrile in 5 minutes and hold for 1
minute.
LCMS Method 2
[0529] In addition to the general procedure B: Reversed phase HPLC
was carried out on a Xterra-MS C18 column (5 .mu.m, 4.6.times.150
mm) with a flow rate of 1.0 ml/min. Two mobile phases (mobile phase
A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile;
were employed to run a gradient condition from 85% A, 15% B (hold
for 3 minutes) to 20% A, 80% B in 5 minutes, hold at 20% A and 80%
B for 6 minutes and reequilibrated with initial conditions for 3
minutes. An injection volume of 20 .mu.l was used. Cone voltage was
20 V for positive ionization mode and 20 V for negative ionization
mode. Mass spectra were acquired by scanning from 100 to 900 in 0.8
seconds using an interscan delay of 0.08 seconds.
LCMS Method 3
[0530] In addition to the general procedure C: Reversed phase HPLC
was carried out on a Waters Acquity BEH (bridged
ethylsiloxane/silica hybrid) C18 column (1.7 .mu.m, 2.1.times.100
mm) with a flow rate of 0.35 ml/min. Two mobile phases (mobile
phase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B:
100% acetonitrile) were employed to run a gradient condition from
90% A and 10% B (hold for 0.5 minutes) to 8% A and 92% B in 3.5
minutes, hold for 2 min and back to the initial conditions in 0.5
min, hold for 1.5 minutes. An injection volume of 2 .mu.l was used.
Cone voltage was 20 V for positive and negative ionization mode.
Mass spectra were acquired by scanning from 100 to 1000 in 0.2
seconds using an interscan delay of 0.1 seconds.
LCMS Method 4
[0531] In addition to the general procedure C: Reversed phase HPLC
was carried out on a Waters HSS (High Strength Silica) C18 column
(1.8 .mu.m, 2.1.times.100 mm) with a flow rate of 0.40 ml/min. Two
mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5%
acetonitrile; mobile phase B: 100% acetonitrile) were employed to
run a gradient condition from 72% A and 28% B (hold for 0.5
minutes) to 8% A and 92% B in 3.5 minutes, hold for 2 min and back
to the initial conditions in 0.5 min, hold for 1.5 minutes. An
injection volume of 2 .mu.l was used. Cone voltages were 20, 30,
45, 60 V for positive ionization mode. Mass spectra were acquired
by scanning from 100 to 1000 in 0.2 seconds using an interscan
delay of 0.1 seconds.
LCMS Method 5
[0532] In addition to the general procedure B: Reversed phase HPLC
was carried out on a Xterra-MS C18 column (3.5 .mu.m, 4.6.times.100
mm) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase
A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile;
were employed to run a gradient condition from 80% A, 20% B (hold
for 0.5 minute) to 10% A, 90% B in 4.5 minutes, hold at 10% A and
90% B for 4 minutes and reequilibrated with initial conditions for
3 minutes. An injection volume of 10 .mu.l was used. Cone voltage
was 20 V for positive and negative ionization mode. Mass spectra
were acquired by scanning from 100 to 1000 in 0.4 seconds using an
interscan delay of 0.3 seconds.
TABLE-US-00005 TABLE 5 Analytical LCMS data: R.sub.t is retention
time in minutes; [MH].sup.+ means the mass of the compound;
Compound No. R.sub.t [MH].sup.+ Method 1 3.66 427 1 2 3.39 441 1 3
3.67 371 1 4 3.39 385 1 5 9.24 493 2 7 8.78 441 2 8 7.67 242 2 9
3.44 385 3 14 9.01 441 2 15 7.28 440 2 16 7.20 470 2 18 3.03 471 3
19 3.01 471 3 21 2.81 415 3 22 3.17 401 3 24 3.51 441 3 29 10.21
495 2 31 4.55 496 5 33 7.78 538 2 34 10.12 483 2 35 8.98 467 2 36
7.54 512 2 39 9.27 487 2 41 9.78 469 2 43 7.34 484 2 48 8.98 385 2
49 3.48 372 3 51 7.58 454 2 55 10.27 439 2 56 3.08 457 4 57 3.53
403 3 58 2.86 468 3 59 10.64 453 2 60 3.43 421 3 61 3.11 399 3 62
3.64 399 3 63 3.33 413 3 64 3.25 451 3 65 2.96 429 3 68 3.36 402 3
69 5.55 419 5 70 3.52 428 3 72 8.71 415 2 76 3.24 384 3 77 3.64 455
3 78 3.58 429 3 79 3.37 415 3 80 3.11 455 3 81 3.33 431 3
E. Composition Example
Film-Coated Tablets
Preparation of Tablet Core
[0533] 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 sulphate and 10 g
polyvinyl-pyrrolidone 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 a compound of formula (I).
Coating
[0534] To a solution of 10 g methyl cellulose in 75 ml of
denaturated ethanol there is added a solution of 5 g of ethyl
cellulose in 150 ml of dichloromethane. Then there are 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 are added 2.5 g of magnesium octadecanoate, 5 g of
polyvinyl-pyrrolidone and 30 ml of concentrated colour suspension
and the whole is homogenated. The tablet cores are coated with the
thus obtained mixture in a coating apparatus.
* * * * *