U.S. patent application number 12/498564 was filed with the patent office on 2009-10-29 for benzazole analogues and uses thereof.
This patent application is currently assigned to 4SC AG. Invention is credited to Thomas HERZ, Rolf KRAUSS, Michael KUBBUTAT, Martin LANG, Christoph SCHAECHTELE, Stefan TASLER, Frank TOTZKE.
Application Number | 20090270410 12/498564 |
Document ID | / |
Family ID | 36612682 |
Filed Date | 2009-10-29 |
United States Patent
Application |
20090270410 |
Kind Code |
A1 |
HERZ; Thomas ; et
al. |
October 29, 2009 |
BENZAZOLE ANALOGUES AND USES THEREOF
Abstract
The present invention relates to compounds of the general
formulas (I), (Ia) and (II) and salts and physiologically
functional derivatives thereof, ##STR00001## wherein the
substituents -Y are attached to the 5- or 6-position of the
benzazole.
Inventors: |
HERZ; Thomas; (Stockdorf,
DE) ; KRAUSS; Rolf; (Planegg-Martinsried, DE)
; KUBBUTAT; Michael; (Schallstadt, DE) ; LANG;
Martin; (Graefelfing, DE) ; SCHAECHTELE;
Christoph; (Freiburg, DE) ; TASLER; Stefan;
(Seefeld-Hechendorf, DE) ; TOTZKE; Frank;
(Freiburg, DE) |
Correspondence
Address: |
Baker Donelson Bearman, Caldwell & Berkowitz, PC
555 Eleventh Street, NW, Sixth Floor
Washington
DC
20004
US
|
Assignee: |
4SC AG
Martinsried
DE
|
Family ID: |
36612682 |
Appl. No.: |
12/498564 |
Filed: |
July 7, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11317909 |
Dec 22, 2005 |
7576090 |
|
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12498564 |
|
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60640024 |
Dec 27, 2004 |
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Current U.S.
Class: |
514/252.17 ;
544/357 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 417/14 20130101; C07D 473/34 20130101; C07D 413/12 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/252.17 ;
544/357 |
International
Class: |
A61K 31/497 20060101
A61K031/497; C07D 241/04 20060101 C07D241/04; A61P 35/00 20060101
A61P035/00 |
Claims
1. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a compound of general
formula (I) ##STR00042## or a salt or physiologically functional
derivative thereof, wherein the substituent -Y-R.sup.1 is attached
to the 5- or 6-position of the benzazole; X independently
represents S, O, SO, or SO.sub.2; Y independently represents S, O,
NR.sup.2, SO, or SO.sub.2; A independently represents .rarw.CO--,
.rarw.CS--, .rarw.SO--, .rarw.SO.sub.2, .rarw.CO.sub.2--,
.rarw.CONR.sup.8--, .rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--,
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where indicates the point of attachment
of R.sup.3; R.sup.2 independently represents H, alkyl, cycloalkyl,
--COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, --CN, hydroxyalkyl,
haloalkyl, or haloalkyloxy; R.sup.3 independently represents H,
alkyl, cycloalkyl, aryl, or heteroaryl; R.sup.4 independently
represents H, --COR.sup.6, --CO.sub.2R.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2, --CN, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl, alkoxy, --NH.sub.2,
alkylamino, --NR.sup.7COR.sup.6, halogen, --OH, --SH, alkylthio,
haloalkyl, haloalkyloxy, aryl, or heteroaryl; R.sup.5 independently
represents H, alkyl, cycloalkyl, --COR.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, --CN, hydroxyalkyl, haloalkyl, haloalkyloxy,
aryl or heteroaryl; R.sup.6a independently represents H, alkyl,
cycloalkyl, --NR.sup.8NR.sup.2R.sup.9, --ONR.sup.8R.sup.9,
--NR.sup.8OR.sup.9, aryl or heteroaryl; R.sup.6 independently
represents H, alkyl, cycloalkyl, --NR.sup.8R.sup.9,
--NR.sup.8NR.sup.2R.sup.9, --ONR.sup.8R.sup.9, --NR.sup.8OR.sup.9,
aryl or heteroaryl; R.sup.7 independently represents H, alkyl,
cycloalkyl, or alkoxy; R.sup.8 independently represents H, alkyl,
cycloalkyl, --COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl,
haloalkyloxy, aryl or heteroaryl; R.sup.9 independently represents
H, alkyl, cycloalkyl, --COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
haloalkyl, haloalkyloxy, aryl or heteroaryl; R.sup.1 independently
represents one of the following groups: ##STR00043## where *
indicates the point of attachment Z independently represents O,
NR.sup.8, or S; R.sup.12 independently represents H, halogen,
nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; R.sup.8a independently
represents H, alkyl, cycloalkyl, --COR.sup.6a, --SOR.sup.6,
--SO.sub.2R.sup.6, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R.sup.9a independently represents H, alkyl, cycloalkyl,
--COR.sup.6a, --SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl,
haloalkyloxy, aryl, or heteroaryl; R.sup.13 independently
represents H, halogen, nitro, trifluoromethyl, alkyl, aryl,
heteroaryl, --NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; R.sup.14
independently represents H, halogen, nitro, trifluoromethyl, alkyl,
aryl, heteroaryl, --NR.sup.8aR.sup.9a or --X.sup.2R.sup.16;
R.sup.15 independently represents H, halogen, nitro,
trifluoromethyl, alkyl, aryl, heteroaryl, --NR.sup.8aR.sup.9a or
--X.sup.2R.sup.16; R.sup.17 independently represents H, halogen,
nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; X.sup.2 independently
represents a direct bond, --O--, --CH.sub.2--, --OCO--, carbonyl,
--S--, --SO--, --SO.sub.2--, --NR.sup.8CO--, --CONR.sup.8--,
--SO.sub.2NR.sup.8--, --NR.sup.8SO.sub.2-- or --NR.sup.8a--;
R.sup.16 independently represents H, alkyl, cycloalkyl,
--SOR.sup.6, --SO.sub.2R.sup.6, --OCH.sub.3, hydroxyalkyl,
haloalkyl, haloalkyloxy, or one of the following groups:
##STR00044## where * indicates the point of attachment m
independently represents an integer from 1-3; L is absent or
represents a divalent linkage group selected from alkylene,
cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein
one or more of the (--CH.sub.2--) groups may be replaced by an
oxygen or a NR.sup.8, and wherein one or more carbon atoms may be
independently substituted by one or two substituents selected from
halogen, hydroxy, alkoxy, haloalkyloxy, phosphonooxy, or
phosphonooxyalkyl; X.sup.3 independently represents --COOH,
--COOalkyl, --OH, --SH, --SO.sub.3H, or --SO.sub.2NR.sup.8R.sup.9;
R.sup.18 independently represents H, phosphonooxy, or
phosphonooxyalkyl; R.sup.19 independently represents H, alkyl,
cycloalkyl, alkylamino, or alkoxy; with the proviso that the
following compounds are excluded:
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothazol-2-yl]-2-phenyl-
-acetamide,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-benzothiazol-2-yl]-2-phenyl-acetami-
de,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-3-ph-
enyl-propionamide,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-(3-tr-
ifluoromethyl-phenyl)-acetamide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yloxy)--
5-fluoro-benzothiazol-2-yl]-acetamide,
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yl-o-
xy)-5-fluoro-benzothiazol-2-yl]-acetamide; wherein an alkyl group,
if not stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, a linear or branched C.sub.2-C.sub.6-alkenyl
or a linear or branched C.sub.2-C.sub.6-alkynyl group, which can be
substituted by one or more substituents R'; wherein R'
independently represents H, --CO.sub.2R'', --CONHR'', --CR''O,
--SO.sub.2NR'', --NR''--CO-haloalkyl, --NO.sub.2,
--NR''--SO.sub.2-haloalkyl, --NR''--SO.sub.2-alkyl,
--SO.sub.2-alkyl, --NR''--CO-alkyl, --CN, alkyl, cycloalkyl,
aminoalkyl, alkylamino, alkoxy, --OH, --SH, alkylthio,
hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy,
aryl, arylalkyl or heteroaryl; wherein R'' independently represents
H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or
aminoalkyl; wherein a cycloalkyl group denotes a non-aromatic ring
system containing three to eight carbon atoms, wherein one or more
of the carbon atoms in the ring can be substituted by a group E, E
being O, S, SO, SO.sub.2, N, or NR'', R'' being as defined above;
wherein an alkoxy group denotes an O-alkyl group, the alkyl group
being as defined above; wherein an alkylthio group denotes an
S-alkyl group, the alkyl group being as defined above; wherein an
haloalkyl group denotes an alkyl group which is substituted by one
to five halogen atoms, the alkyl group being as defined above;
wherein a hydroxyalkyl group denotes an HO-alkyl group, the alkyl
group being as defined above; wherein a haloalkyloxy group denotes
an alkoxy group which is substituted by one to five halogen atoms,
the alkyl group being as defined above; wherein a hydroxyalkylamino
group denotes an (HO-alkyl).sub.2-N-- group or HO-alkyl-NH-group,
the alkyl group being as defined above; wherein an alkylamino group
denotes an HN-alkyl or N-dialkyl group, the alkyl group being as
defined above; wherein a halogen group is chlorine, bromine,
fluorine or iodine; wherein an aryl group denotes an aromatic group
having five to fifteen carbon atoms, which can be substituted by
one or more substituents R', where R' is as defined above; wherein
a heteroaryl group denotes a 5- or 6-membered heterocyclic group
which contains at least one heteroatom like O, N, S, wherein the
heterocyclic group can be fused to another ring and can be
substituted by one or more substituents R', wherein R' is as
defined above.
2. The method of claim 1, wherein R.sup.1 is ##STR00045## (*
indicates the point if attachment).
3. The method according to claim 1, wherein X independently
represents S or O; Y represents NH; A represents --CO--; R.sup.5
represents H.
4. The method according to claim 1, wherein X independently
represents S or O; Y represents NH; R.sup.5 represents H; A
represents .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3.
5. The method according to claim 1, wherein the -Y-R.sup.1
substituent is attached to the 6-position of the benzazole.
6. The method according to claim 5, wherein R.sup.12 and R.sup.15
are H, and R.sup.13 and R.sup.14 independently represent --O-alkyl
which may be substituted.
7. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a composition comprising
the compound according to claim 1 and optionally an adjuvant and/or
an additive.
8. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a compound of the
general formula (Ia) ##STR00046## or a salt or physiologically
functional derivative thereof, wherein the substituent
-Y.sup.a-R.sup.1a is attached to the 5- or 6-position of the
benzazole; X.sup.a independently represents S, O, SO, or SO.sub.2;
Y.sup.a independently represents S, NR.sup.2, SO, or SO.sub.2;
A.sup.a independently represents .rarw.CO--, .rarw.CS--,
.rarw.SO--, .rarw.SO.sub.2--, .rarw.CO.sub.2--, .rarw.CONR.sup.8--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where .rarw. indicates the point of
attachment to R.sup.3; R.sup.1a independently represents one of the
following groups: ##STR00047## where * indicates the point if
attachment; R.sup.11 independently represents H, --NHR.sup.8a, or
one of the groups: ##STR00048## where * indicates point of
attachment; R.sup.13a independently represents H, halogen, nitro,
trifluoromethyl, alkyl, --NR.sup.8aR.sup.9a, or --X.sup.2R.sup.16;
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6a, R.sup.7,
R.sup.8, R.sup.8a, R.sup.9, R.sup.9a, R.sup.12, R.sup.13, R.sup.16,
or X.sup.2, are as defined in claim 1.
9. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a composition comprising
the compound according to claim 8 and optionally an adjuvant and/or
an additive.
10. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a compound of the
general formula (II) ##STR00049## or a salt or physiologically
functional derivative thereof, wherein the substituent -Y.sup.b--
is attached to the 5- or 6-position of the benzazole; X.sup.b
independently represents S, O, SO, or SO.sub.2; Y.sup.b
independently represents S, NR.sup.2, SO, or SO.sub.2; A.sup.b
independently represents .rarw.CO--, .rarw.CS--, .rarw.SO--,
.rarw.SO.sub.2--, .rarw.CO.sub.2--, .rarw.CONR.sup.1--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where indicates the point of attachment
to R.sup.3; R.sup.4b independently represents H, --SOR.sup.6,
--SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2, --CN, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl, alkoxy, oxyalkyl,
alkoxyalkyl, --NH.sub.2, alkylamine, aminoalkyl, alkylaminoalkyl,
--NR.sup.7COR.sup.6, halogen, --OH, --SH, alkylthio, hydroxyalkyl,
haloalkyl, haloalkyloxy, aryl, or heteroaryl; R.sup.2, R.sup.3,
R.sup.5, R.sup.6, R.sup.6a, R.sup.7, R.sup.8, R.sup.8a, R.sup.9,
R.sup.9a, R.sup.11, R.sup.12, R.sup.16, X.sup.2 are as defined in
claim 1.
11. A method for the treatment of diseases which are cured or
relieved by the inhibition of one or several kinases comprising
administering to a patient in need thereof a composition comprising
the compound according to claim 10 and optionally an adjuvant
and/or an additive.
12. A method of treating, relieving, and/or preventing cancer
comprising administering comprising administering to a patient in
need thereof a compound of general formula (I) ##STR00050## or a
salt or physiologically functional derivative thereof, wherein the
substituent -Y-R.sup.1 is attached to the 5- or 6-position of the
benzazole; X independently represents S, O, SO, or SO.sub.2; Y
independently represents S, O, NR.sup.2, SO, or SO.sub.2; A
independently represents .rarw.CO--, .rarw.CS--, .rarw.SO--,
.rarw.SO.sub.2, .rarw.CO.sub.2--, .rarw.CONR.sup.8--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--,
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where indicates the point of attachment
of R.sup.3; R.sup.2 independently represents H, alkyl, cycloalkyl,
--COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, --CN, hydroxyalkyl,
haloalkyl, or haloalkyloxy; R.sup.3 independently represents H,
alkyl, cycloalkyl, aryl, or heteroaryl; R.sup.4 independently
represents H, --COR.sup.6, --CO.sub.2R.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2, --CN, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl, alkoxy, --NH.sub.2,
alkylamino, --NR.sup.7COR.sup.6, halogen, --OH, --SH, alkylthio,
haloalkyl, haloalkyloxy, aryl, or heteroaryl; R.sup.5 independently
represents H, alkyl, cycloalkyl, --COR.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, --CN, hydroxyalkyl, haloalkyl, haloalkyloxy,
aryl or heteroaryl; R.sup.6a independently represents H, alkyl,
cycloalkyl, --NR.sup.8NR.sup.2R.sup.9, --ONR.sup.8R.sup.9,
--NR.sup.8OR.sup.9, aryl or heteroaryl; R.sup.6 independently
represents H, alkyl, cycloalkyl, --NR.sup.8R.sup.9,
--NR.sup.8NR.sup.2R.sup.9, --ONR.sup.8R.sup.9, --NR.sup.8OR.sup.9,
aryl or heteroaryl; R.sup.7 independently represents H, alkyl,
cycloalkyl, or alkoxy; R.sup.8 independently represents H, alkyl,
cycloalkyl, --COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl,
haloalkyloxy, aryl or heteroaryl; R.sup.9 independently represents
H, alkyl, cycloalkyl, --COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6,
haloalkyl, haloalkyloxy, aryl or heteroaryl; R.sup.1 independently
represents one of the following groups: ##STR00051## where *
indicates the point of attachment Z independently represents O,
NR.sup.8, or S; R.sup.12 independently represents H, halogen,
nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; R.sup.8a independently
represents H, alkyl, cycloalkyl, --COR.sup.6a, --SOR.sup.6,
--SO.sub.2R.sup.6, haloalkyl, haloalkyloxy, aryl, or heteroaryl;
R.sup.9a independently represents H, alkyl, cycloalkyl,
--COR.sup.6a, --SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl,
haloalkyloxy, aryl, or heteroaryl; R.sup.13 independently
represents H, halogen, nitro, trifluoromethyl, alkyl, aryl,
heteroaryl, --NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; R.sup.14
independently represents H, halogen, nitro, trifluoromethyl, alkyl,
aryl, heteroaryl, --NR.sup.8aR.sup.9a or --X.sup.2R.sup.16;
R.sup.15 independently represents H, halogen, nitro,
trifluoromethyl, alkyl, aryl, heteroaryl, --NR.sup.8aR.sup.9a or
--X.sup.2R.sup.16; R.sup.17 independently represents H, halogen,
nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; X.sup.2 independently
represents a direct bond, --O--, --CH.sub.2--, --OCO--, carbonyl,
--S--, --SO--, --SO.sub.2--, --NR.sup.8CO--, --CONR.sup.8--,
--SO.sub.2NR.sup.8--, --NR.sup.8SO.sub.2-- or --NR.sup.8a--;
R.sup.16 independently represents H, alkyl, cycloalkyl,
--SOR.sup.6, --SO.sub.2R.sup.6, --OCH.sub.3, hydroxyalkyl,
haloalkyl, haloalkyloxy, or one of the following groups:
##STR00052## where * indicates the point of attachment m
independently represents an integer from 1-3; L is absent or
represents a divalent linkage group selected from alkylene,
cycloalkylene, heterocyclylene, arylene, or heteroarylene, wherein
one or more of the (--CH.sub.2--) groups may be replaced by an
oxygen or a NR.sup.8, and wherein one or more carbon atoms may be
independently substituted by one or two substituents selected from
halogen, hydroxy, alkoxy, haloalkyloxy, phosphonooxy, or
phosphonooxyalkyl; X.sup.3 independently represents --COOH,
--COOalkyl, --OH, --SH, --SO.sub.3H, or --SO.sub.2NR.sup.8R.sup.9;
R.sup.18 independently represents H, phosphonooxy, or
phosphonooxyalkyl; R.sup.19 independently represents H, alkyl,
cycloalkyl, alkylamino, or alkoxy; with the proviso that the
following compounds are excluded:
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothazol-2-yl]-2-phenyl-
-acetamide,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-benzothiazol-2-yl]-2-phenyl-acetami-
de,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-3-ph-
enyl-propionamide,
N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-(3-tr-
ifluoromethyl-phenyl)-acetamide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yloxy)--
5-fluoro-benzothiazol-2-yl]-acetamide,
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yl-o-
xy)-5-fluoro-benzothiazol-2-yl]-acetamide; wherein an alkyl group,
if not stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, a linear or branched C.sub.2-C.sub.6-alkenyl
or a linear or branched C.sub.2-C.sub.6-alkynyl group, which can be
substituted by one or more substituents R'; wherein R'
independently represents H, --CO.sub.2R'', --CONHR'', --CR''O,
--SO.sub.2NR'', --NR''-CO-haloalkyl, --NO.sub.2,
--NR''-SO.sub.2-haloalkyl, --NR''-SO.sub.2-alkyl, --SO.sub.2-alkyl,
--NR''-CO-alkyl, --CN, alkyl, cycloalkyl, aminoalkyl, alkylamino,
alkoxy, --OH, --SH, alkylthio, hydroxyalkyl, hydroxyalkylamino,
halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heteroaryl;
wherein R'' independently represents H, haloalkyl, hydroxyalkyl,
alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl; wherein a
cycloalkyl group denotes a non-aromatic ring system containing
three to eight carbon atoms, wherein one or more of the carbon
atoms in the ring can be substituted by a group E, E being O, S,
SO, SO.sub.2, N, or NR'', R'' being as defined above; wherein an
alkoxy group denotes an O-alkyl group, the alkyl group being as
defined above; wherein an alkylthio group denotes an S-alkyl group,
the alkyl group being as defined above; wherein an haloalkyl group
denotes an alkyl group which is substituted by one to five halogen
atoms, the alkyl group being as defined above; wherein a
hydroxyalkyl group denotes an HO-alkyl group, the alkyl group being
as defined above; wherein a haloalkyloxy group denotes an alkoxy
group which is substituted by one to five halogen atoms, the alkyl
group being as defined above; wherein a hydroxyalkylamino group
denotes an (HO-alkyl).sub.2-N-- group or HO-alkyl-NH-group, the
alkyl group being as defined above; wherein an alkylamino group
denotes an HN-alkyl or N-dialkyl group, the alkyl group being as
defined above; wherein a halogen group is chlorine, bromine,
fluorine or iodine; wherein an aryl group denotes an aromatic group
having five to fifteen carbon atoms, which can be substituted by
one or more substituents R', where R' is as defined above; wherein
a heteroaryl group denotes a 5- or 6-membered heterocyclic group
which contains at least one heteroatom like O, N, S, wherein the
heterocyclic group can be fused to another ring and can be
substituted by one or more substituents R', wherein R' is as
defined above.
13. A method of treating, relieving, and/or preventing cancer
comprising administering to a patient in need thereof a composition
comprising the compound according to claim 12 and optionally an
adjuvant and/or an additive.
14. A method of treating, relieving, and/or preventing cancer
comprising administering to a patient in need thereof a compound of
the general formula (Ia) ##STR00053## or a salt or physiologically
functional derivative thereof, wherein the substituent
-Y.sup.a-R.sup.1a is attached to the 5- or 6-position of the
benzazole; X.sup.a independently represents S, O, SO, or SO.sub.2;
Y.sup.a independently represents S, NR.sup.2, SO, or SO.sub.2;
A.sup.a independently represents .rarw.CO--, .rarw.CS--,
.rarw.SO--, .rarw.SO.sub.2--, .rarw.CO.sub.2--, .rarw.CONR.sup.8--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, --NR.sup.8NR.sup.9CO--, --NR.sup.8OCO--,
.rarw.ONR.sup.8CO--, or .rarw.NR.sup.8SO.sub.2--, where indicates
the point of attachment to R.sup.3; R.sup.1a independently
represents one of the following groups: ##STR00054## where *
indicates the point of attachment; R.sup.11 independently
represents H, --NHR.sup.8a, or one of the groups: ##STR00055##
where * indicates point of attachment; R.sup.13a independently
represents H, halogen, nitro, trifluoromethyl, alkyl,
--NR.sup.8aR.sup.9a, or --X.sup.2R.sup.16 R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.6a, R.sup.7, R.sup.8, R.sup.8a,
R.sup.9, R.sup.9a, R.sup.12, R.sup.13, R.sup.16, or X.sup.2, are as
defined in claim 1.
15. A method of treating, relieving, and/or preventing cancer
comprising administering to a patient in need thereof a composition
comprising the compound according to claim 14 and optionally an
adjuvant and/or an additive.
16. A method of treating, relieving, and/or preventing cancer
comprising administering to a patient in need thereof a compound of
the general formula (II) ##STR00056## or a salt or physiologically
functional derivative thereof, wherein the substituent -Y.sup.b- is
attached to the 5- or 6-position of the benzazole; X.sup.b
independently represents S, O, SO, or SO.sub.2; Y.sup.b
independently represents S, NR.sup.2, SO, or SO.sub.2; A.sup.b
independently represents .rarw.CO--, .rarw.CS--, .rarw.SO--,
.rarw.SO.sub.2--, .rarw.CO.sub.2--, .rarw.CONR.sup.1--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where .rarw. indicates the point of
attachment to R.sup.3; R.sup.4b independently represents H,
--SOR.sup.6, --SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2,
--CN, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl,
alkoxy, oxyalkyl, alkoxyalkyl, --NH.sub.2, alkylamine, aminoalkyl,
alkylaminoalkyl, --NR.sup.7COR.sup.6, halogen, --OH, --SH,
alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, or
heteroaryl; R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.6a, R.sup.7,
R.sup.8, R.sup.8a, R.sup.9, R.sup.9a, R.sup.11, R.sup.12, R.sup.16,
X.sup.2 are as defined in claim 1.
17. A method of treating, relieving, and/or preventing cancer
comprising administering to a patient in need thereof a composition
comprising the compound according to claim 16 and optionally an
adjuvant and/or an additive.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. patent application Ser. No.
11/317,909, filed Dec. 22, 2005, which claims priority to U.S.
Provisional Application No. 60/640,024, filed Dec. 27, 2004. The
contents of both applications are incorporated herein in their
entirety.
[0002] The present invention relates to benzazoles of the general
formula (I) or a salt or a physiologically functional derivative or
a stereoisomer thereof, for use as a medicament. The compounds of
the invention are exceptionally useful for the treatment of
diseases associated with abnormal and hyperproliferation of cells
in a mammal, especially humans. In particular, they are useful for
the treatment of all forms of cancer.
[0003] Furthermore a process of preparing said benzazole
derivatives is disclosed.
BACKGROUND OF THE INVENTION
[0004] Protein kinases play a central role in the regulation of
cellular functions. This includes processes like cell growth and
division, cell differentiation and cell death, but also many other
cellular activities. Protein kinases catalyze the transfer of
phosphate residues from ATP on target proteins which as a
consequence of this protein kinase mediated phosphorylation change
their three-dimensional structure and thereby their physiological
function. Depending on the amino acid which becomes phosphorylated
by a protein kinase these enzymes are grouped in two families, the
so-called serine/threonine protein kinases and the tyrosine protein
kinases.
[0005] Based on the human genome project it is known that in human
beings there exist 518 DNA sequences which encode for a protein
kinase-like protein sequence. In the last about 20 years for
several of these 518 proteins it could be shown that modifications
in their related gene sequences (e.g. point mutations, deletions or
gene amplifications) result in pathological changes of the cellular
activities of the corresponding protein kinase. This is in
particular true for protein kinases which are involved in cell
proliferation and cell cycle control, in survival of cells and cell
death, in tumor angiogenesis, and in formation of tumor
metastases.
[0006] Several so-called oncogenes are pathologically modified
genes which in their proto-oncogenic form encode for protein
kinases involved in normal, physiological regulation of cell growth
and division.
[0007] Since protein kinases are key regulators of cell functions
and since they can show dysregulated enzymatic activity in cells
they are promising targets for the development of therapeutic
agents.
[0008] There are many ongoing drug discovery projects in the
pharmaceutical industry with the goal to identify modulators of
protein kinases. The major focus is currently on protein kinases
involved in inflammation and cancer, but besides this protein
kinases are currently discussed as promising targets in almost
every disease area.
[0009] In the tumor field the first protein kinase inhibitors
(Gleevec, Iressa) have already reached the market. In addition, a
great number of protein kinase inhibitors are currently in various
phases of clinical development. In most cases these compounds are
either targeting subtypes of the EGF (Epidermal Growth Factor)
receptor or of the VEGF (Vascular Endothelial Growth Factor)
receptor. All these compounds have been developed with the goal to
specifically inhibit one particular protein kinase, for which there
is evidence that it interferes with one of the four major molecular
processes of tumor progression. These four processes are (1) cell
proliferation/cell cycle control, (2) regulation of programmed cell
death (apoptosis) and cell survival, (3) tumor angiogenesis and (4)
tumor metastasis.
[0010] The present invention relates to benzazole derivatives which
may be useful for inhibition of protein kinases involved in
diseases besides cancer, but which are especially useful as
anti-tumor agents. This includes monospecific protein kinase
inhibitors, which preferentially inhibit one protein kinase which
is causatively involved in tumor progression, but also so-called
multi-target protein kinase inhibitors, which inhibit at least two
different protein kinases which play a role in two or more
different molecular mechanism of tumor progression. As an example,
such a compound could be an inhibitor of tumor angiogenesis and, in
addition, also a stimulator of apoptosis.
[0011] The concept of multi-target protein kinase inhibitors is a
new approach although the idea of developing "multiplex protein
kinase inhibitors" has already been described by J. Adams et al.,
Current Opinion in Chemical Biology 6, 486-492, 2002. Therein
compounds are described, which, at the same time, inhibit several
protein kinases, which however all are involved in one molecular
mechanism of tumor progression, namely tumor angiogenesis.
[0012] In WO 2004/085425 benzazoles are described as kinase
inhibitors. In WO 99/24035 2-aminobenzothiazoles are described.
These compounds have also been published in Das et al., Bioorg.
Med. Chem. Lett 13, 2003, 2587-2590 and in Das et al., Bioorg. Med.
Chem. Lett 13, 2003, 2145-2149. In WO 2000/061580 benzimidazolyl-
and benzoxazolylacetylaminopyridyl butyrates are described as
integrin antagonists. In WO 99/40072 five-membered, benzo-condensed
heterocycles used as antithrombotics of are described.
[0013] The object of the present invention is solved by the
teaching of the independent claims. Further advantageous features,
aspects and details of the invention are evident from the dependent
claims, the description, the figures, and the examples of the
present application.
[0014] Considering the lack of currently available treatment
options for the majority of the conditions associated with protein
kinases like ABL1, ACV-R1, AKT1, AKT2, AKT3, ARK5, Aurora-A,
Aurora-B, Aurora-C, B-RAF, BRK, CDC42BPB, CDK1, CDK2, CDK3, CDK4,
CDK5, CDK6, CDK7, CDK9, CHK1, CK2, COT, CSK, DAPK1, EGF-R, EPHA1,
EPHA2, EPHA4, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2, ERBB4, FAK,
FGF-R1, FGF-R.sup.3, FGF-R4, FGR, FLT3, GSK3-beta, HCK, IGF1-R,
IKK-beta, IKK-epsilon, INS-R, IRAK4, ITK, JAK2, JAK3, JNK3, KIT,
LCK, LYN, MAPKAPK5, MET, MST4, MUSK, NEK2, NEK6, NLK, PAK1, PAK2,
PAK4, PBK, PCTAIRE1, PDGFR-alpha, PDGFR-beta, PDK1, PIM1, PIM2,
PKC-alpha, PKC-beta1, PKC-beta2, PKC-delta, PKC-epsilon, PKC-eta,
PKC-gamma, PKC-iota, PKC-mu, PKC-theta, PKC-zeta, PLK1, PRK1, RET,
ROCK2, S6K, SAK, SGK1, SGK3, SNK, SRC, SRPK2, SYK, TGFB-R1, TIE2,
TSF1, TSK2, TTK, VEGF-R1, VEGF-R.sup.2, VEGF-R.sup.3, VRK1, WEE1,
YES, ZAP70 especially with protein kinases like EGF-R (cell
proliferation), ERBB2 (cell proliferation), PDGFR (cell
proliferation), FLT3 (cell proliferation), Aurora-A (cell cycle
control), Aurora-B (cell cycle control), IGF1-R (apoptosis),
VEGF-R2 (angiogenesis), VEGF-R3 (angiogenesis), TIE2
(angiogenesis), EPHB4 (angiogenesis), FAK (metastasis), and SRC
kinase (metastasis), there is still a great need for new
therapeutic agents that inhibit these protein targets. Herein
described benzazole derivatives are a new group of protein kinase
inhibitors which show differential inhibition of protein kinases,
each of which can be assigned to one of the four molecular
mechanism of tumor development.
[0015] The present invention relates to compounds of the general
formula (I) or a salt or a physiologically functional derivative or
a stereoisomer thereof,
##STR00002##
wherein [0016] the substituent -Y-R.sup.1 is attached to the 5- or
6-position of the benzazole; [0017] X independently represents S,
O, SO, or SO.sub.2; [0018] Y independently represents S, O,
NR.sup.2, SO, or SO.sub.2; [0019] A independently represents
.rarw.CO--, .rarw.CS--, .rarw.SO--, .rarw.SO.sub.2--,
.rarw.CO.sub.2--, .rarw.CONR.sup.8--, .rarw.NR.sup.8Co--,
.rarw.NR.sup.8CONR.sup.9--; .intg.NR.sup.8COO--,
.rarw.NR.sup.8NR.sup.9CO--, .rarw.NR.sup.8OCO--,
.rarw.ONR.sup.8CO--, or .rarw.NR.sup.8SO.sub.2--, where .rarw.
indicates the point of attachment to R.sup.3; [0020] R.sup.2
independently represents H, alkyl, cycloalkyl, --COR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, --CN, hydroxyalkyl, haloalkyl, or
haloalkyloxy; [0021] R.sup.3 independently represents H, alkyl,
cycloalkyl, aryl, or heteroaryl; [0022] R.sup.4 independently
represents H, --COR.sup.6, --CO.sub.2R.sup.6, --SOR.sup.6,
--SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2, --CN, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl, alkoxy, --NH.sub.2,
alkylamino, --NR.sup.7COR.sup.6, halogen, --OH, --SH, alkylthio,
haloalkyl, haloalkyloxy, aryl or heteroaryl; [0023] R.sup.5
independently represents H, alkyl, cycloalkyl, --COR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, --CN, hydroxyalkyl, haloalkyl,
haloalkyloxy, aryl, or heteroaryl; [0024] R.sup.6a independently
represents H, alkyl, cycloalkyl, --NR.sup.8NR.sup.2R.sup.9,
--ONR.sup.8R.sup.9, --NR.sup.8OR.sup.9, aryl or heteroaryl; [0025]
R.sup.6 independently represents H, alkyl, cycloalkyl,
--NR.sup.8R.sup.9, --NR.sup.8NR.sup.2R.sup.9, --ONR.sup.8R.sup.9,
--NR.sup.8OR.sup.9, aryl or heteroaryl; [0026] R.sup.7
independently represents H, alkyl, cycloalkyl, or alkoxy; [0027]
R.sup.8 independently represents H, alkyl, cycloalkyl, --COR.sup.6,
--SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl, haloalkyloxy, aryl or
heteroaryl; [0028] R.sup.9 independently represents H, alkyl,
cycloalkyl, --COR.sup.6, --SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl,
haloalkyloxy, aryl or heteroaryl; [0029] R.sup.1 independently
represents one of the following groups:
[0029] ##STR00003## [0030] where indicates the point of attachment;
[0031] Z independently represents O, NR.sup.8, or S; [0032]
R.sup.12 independently represents H, halogen, nitro,
trifluoromethyl, alkyl, aryl, heteroaryl, --NR.sup.8aR.sup.9a or
--X.sup.2R.sup.16; [0033] R.sup.8a independently represents H,
alkyl, cycloalkyl, --COR.sup.6a, --SOR.sup.6, --SO.sub.2R.sup.6,
haloalkyl, haloalkyloxy, aryl or heteroaryl; [0034] R.sup.9a
independently represents H, alkyl, cycloalkyl, --COR.sup.6a,
--SOR.sup.6, --SO.sub.2R.sup.6, haloalkyl, haloalkyloxy, aryl or
heteroaryl; [0035] R.sup.13 independently represents H, halogen,
nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a or --X.sup.2R.sup.16; [0036] R.sup.14
independently represents H, halogen, nitro, trifluoromethyl, alkyl,
aryl, heteroaryl, --NR.sup.8aR.sup.9a, or --X.sup.2R.sup.16; [0037]
R.sup.15 independently represents H, halogen, nitro,
trifluoromethyl, alkyl, aryl, heteroaryl, --NR.sup.8aR.sup.9a, or
--X.sup.2R.sup.16; [0038] R.sup.17 independently represents H,
halogen, nitro, trifluoromethyl, alkyl, aryl, heteroaryl,
--NR.sup.8aR.sup.9a, or --X.sup.2R.sup.16; [0039] X.sup.2
independently represents a direct bond, --O--, --CH.sub.2--,
--OCO--, carbonyl, --S--, --SO--, --SO.sub.2--, --NR.sup.8CO--,
--CONR.sup.8--, --SO.sub.2NR.sup.8--, --NR.sup.8SO.sub.2-- or
--NR.sup.8a--; [0040] R.sup.16 independently represents H, alkyl,
cycloalkyl, --SOR.sup.6, --SO.sub.2R.sup.6, --OCH.sub.3,
hydroxyalkyl, haloalkyl, haloalkyloxy, or one of the following
groups:
[0040] ##STR00004## [0041] where * indicates the point of
attachment; [0042] m independently represents an integer from 1-3;
[0043] L is absent or represents a divalent linkage group selected
from alkylen, cycloalkylen, heterocyclylen, arylen, or
heteroarylen, wherein one or more of the (--CH.sub.2--) groups may
be replaced by an oxygen or a NR.sup.8, and wherein one or more
carbon atoms may be independently substituted by one or two
substituents selected from halogen, hydroxy, alkoxy, halo-alkyloxy,
phoshonooxy, or phoshonooxyalkyl; [0044] X.sup.3 independently
represents --COOH, --COOalkyl, --OH, --SH, --SO.sub.3H, or
--SO.sub.2NR.sup.8R.sup.9; [0045] R.sup.18 independently represents
H, phosphonooxy, or phosphonooxyalkyl; [0046] R.sup.19
independently represents H, alkyl, cycloalkyl, alkylamino, or
alkoxy; with the proviso that the following compounds are excluded:
N-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-pheny-
l-acetamide
N-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-benzothiazol-2-yl]-2-phenyl-acetami-
de,
N-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-3-ph-
enyl-propionamide,
N-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-(3-tr-
ifluoromethyl-phenyl)-acetamide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-yloxy)--
5-fluoro-benzothiazol-2-yl]-acetamide,
2-(2-Chloro-5-trifluoromethyl-phenyl)-N-[6-(6,7-dimethoxy-quinolin-4-ylox-
y)-5-fluoro-benzothiazol-2-yl]-acetamide; an alkyl group, if not
stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.2-C.sub.6-alkenyl
or a linear or branched C.sub.2-C.sub.6-alkynyl group, which can be
substituted by one or more substituents R'; the
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl and
C.sub.2-C.sub.6-alkynyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R').sub.3, --C.sub.2(R').sub.5, --CH.sub.2--C(R').sub.3,
--C.sub.3(R').sub.7, --C.sub.2H.sub.4--C(R').sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; R' independently
represents H, --CO.sub.2R'', --CONHR'', --CR''O, --SO.sub.2NR'',
--NR''--CO-haloalkyl, --NO.sub.2, --NR''--SO.sub.2-haloalkyl,
--NR''--SO.sub.2-alkyl, --SO.sub.2-alkyl, --NR''--CO-alkyl, --CN,
alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, --OH, --SH,
alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,
haloalkyloxy, aryl, arylalkyl or heteroaryl; R'' independently
represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,
heteroaryl or aminoalkyl; an alkylene group denotes a divalent
linear or branched C.sub.1-C.sub.6-alkylene, preferably a linear or
branched chain of one to five carbon atoms, a linear or branched
C.sub.2-C.sub.6-alkenylene or a linear or branched
C.sub.2-C.sub.6-alkynylene group, which may be substituted by one
or more substituents R'; a cycloalkylene group denotes a divalent
non-aromatic ring system containing three to eight carbon atoms,
preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in the ring may be substituted by a group E, E being
O, S, SO, SO.sub.2, N, or NR'', R'' being as defined above; a
heterocyclylene group denotes a 3 to 8-membered divalent
heterocyclic non-aromatic group which contains at least one
heteroatom selected from O, N, and S, wherein the heterocyclylene
group may be fused to another non-aromatic ring and may be
substituted by one or more substituents R', wherein R' is as
defined above; an arylene group denotes an aromatic divalent group
having five to fifteen carbon atoms, which may be substituted by
one or more substituents R', and may be fused to another aromatic
ring, where R' is as defined above; a heteroarylene group denotes a
divalent 5- or 6-membered heterocyclic group which contains at
least one heteroatom selected from O, N, and S, wherein the
heterocyclylene group may be fused to another aromatic ring and may
be substituted by one or more substituents R', wherein R' is as
defined above; a cycloalkyl group denotes a non-aromatic ring
system containing three to eight carbon atoms, preferably four to
eight carbon atoms, wherein one or more of the carbon atoms in the
ring can be substituted by a group E, E being O, S, SO, SO.sub.2,
N, or NR'', R'' being as defined above; the
C.sub.3-C.sub.8-cycloalkyl residue may be selected from the group
comprising -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7,
-cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11,
-cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, morpholine-4-yl,
piperazinyl, 1-alkylpiperazine-4-yl; an alkoxy group denotes an
O-alkyl group, the alkyl group being as defined above; the alkoxy
group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or
pentoxy group; an alkylthio group denotes an S-alkyl group, the
alkyl group being as defined above; an haloalkyl group denotes an
alkyl group which is substituted by one to five halogen atoms, the
alkyl group being as defined above; the haloalkyl group is
preferably a --C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10)R.sup.10'',
--C.sub.3(R.sup.10).sub.7, or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the
alkyl group being as defined above; an haloalkyloxy group denotes
an alkoxy group which is substituted by one to five halogen atoms,
the alkyl group being as defined above; the haloalkyloxy group is
preferably a --OC(R.sup.10).sub.3, --OCR.sup.10(R.sup.10').sub.2,
--OCR.sup.10(R.sup.10')R.sup.10', --OC.sub.2(R.sup.10).sub.5,
--OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-- group or HO-alkyl-NH-- group, the alkyl group
being as defined above; an alkylamino group denotes an HN-alkyl or
N-dialkyl group, the alkyl group being as defined above; a halogen
group is fluorine, chlorine, bromine, or iodine; an aryl group
denotes an aromatic group having five to fifteen carbon atoms,
which can be substituted by one or more substituents R', where R'
is as defined above; the aryl group is preferably a phenyl group,
-o-C.sub.6H.sub.4-- R', -m-C.sub.6H.sub.4-- R', -p-C.sub.6H.sub.4--
R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl; a
heteroaryl group denotes a 5- or 6-membered heterocyclic group
which contains at least one heteroatom like O, N, S. This
heterocyclic group can be fused to another aromatic ring. For
example, this group can be selected from a thiadiazole,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl,
oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl,
pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl,
4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl,
acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl,
6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl,
5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl,
benzofurazane, benzothiofurazane, benzotriazol-1-yl,
benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,
benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl,
benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl,
cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or
tetrahydroisoquinolinyl, purine, phthalazine, pteridine,
thiatetraazaindene, thiatriazaindene, isothiazolopyrazine,
isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,
imidazopyridazine, imidazopyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine,
triazolopyrazine, triazolopyrimidine, triazolopyridazine group.
This heterocyclic group can be substituted by one or more
substituents R', wherein R' is as defined above; a phosphonooxy
group is --O--P(.dbd.O)(OH).sub.2 or a salt thereof, a
phosphonooxyalkyl group denotes an -alkyl-O--P(.dbd.O)(OH).sub.2
group or a salt thereof, alkyl being as defined above.
[0047] The present invention also relates to compounds of the
general formula (Ia) or a salt or a physiologically functional
derivative or a stereoisomer thereof,
##STR00005##
wherein [0048] the substituent -Y.sup.a-R.sup.1a is attached to the
5- or 6-position of the benzazole; [0049] X.sup.a independently
represents S, O, SO, or SO.sub.2; [0050] Y.sup.a independently
represents S, NR.sup.2, SO, or SO.sub.2; [0051] A.sup.a
independently represents .rarw.CO--, .rarw.CS--, .rarw.SO--,
.rarw.SO.sub.2--, .rarw.CO.sub.2--, .rarw.CONR.sup.8--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where .rarw. indicates the point of
attachment to R.sup.3; [0052] R.sup.1a independently represents one
of the following groups:
[0052] ##STR00006## [0053] where * indicates the point of
attachment; [0054] R.sup.11 independently represents H,
--NHR.sup.8a, or one of the groups:
[0054] ##STR00007## [0055] where * indicates the point of
attachment. [0056] R.sup.13a independently represents H, halogen,
nitro, trifluoromethyl, alkyl, --NR.sup.8aR.sup.9a or
--X.sup.2R.sup.16; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.6a, R.sup.7, R.sup.8, R.sup.8a, R.sup.9, R.sup.9a, R.sup.12,
R.sup.13, R.sup.16, or X.sup.2 are as hereinbefore defined; an
alkyl group, if not stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.2-C.sub.6-alkenyl
or a linear or branched C.sub.2-C.sub.6-alkinyl group, which can be
substituted by one or more substituents R'; the
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl and
C.sub.2-C.sub.6-alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R').sub.3, --C.sub.2(R').sub.5, --CH.sub.2--C(R').sub.3,
--C.sub.3(R').sub.7, --C.sub.2H.sub.4--C(R').sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; R' independently
represents H, --CO.sub.2R'', --CONHR'', --CR'O, --SO.sub.2NR',
--NR'--CO-haloalkyl, --NO.sub.2, --NR'--SO.sub.2-haloalkyl,
--NR'--SO.sub.2-alkyl, --SO.sub.2-alkyl, --NR'--CO-alkyl, --CN,
alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, --OH, --SH,
alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,
haloalkyloxy, aryl, arylalkyl or heteroaryl; R'' independently
represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,
heteroaryl or aminoalkyl; an alkylene group denotes a divalent
linear or branched C.sub.1-C.sub.6-alkylene, preferably a linear or
branched chain of one to five carbon atoms, a linear or branched
C.sub.2-C.sub.6-alkenylene or a linear or branched
C.sub.2-C.sub.6-alkynylene group, which may be substituted by one
or more substituents R'; a cycloalkylene group denotes a divalent
non-aromatic ring system containing three to eight carbon atoms,
preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in the ring may be substituted by a group E, E being
O, S, SO, SO.sub.2, N, or NR'', R'' being as defined above; a
heterocyclylene group denotes a 3 to 8-membered divalent
heterocyclic non-aromatic group which contains at least one
heteroatom selected from O, N, and S, wherein the heterocyclylene
group may be fused to another non-aromatic ring and may be
substituted by one or more substituents R', wherein R' is as
defined above; an arylene group denotes an aromatic divalent group
having five to fifteen carbon atoms, which may be substituted by
one or more substituents R', and may be fused to another aromatic
ring, where R' is as defined above; a heteroarylene group denotes a
divalent 5- or 6-membered heterocyclic group which contains at
least one heteroatom selected from O, N, and S, wherein the
heterocyclylene group may be fused to another aromatic ring and may
be substituted by one or more substituents R', wherein R' is as
defined above; a cycloalkyl group denotes a non-aromatic ring
system containing three to eight carbon atoms, preferably four to
eight carbon atoms, wherein one or more of the carbon atoms in the
ring can be substituted by a group E, E being O, S, SO, SO.sub.2,
N, or NR'', R'' being as defined above; the
C.sub.3-C.sub.8-cycloalkyl residue may be selected from the group
comprising -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7,
-cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11,
-cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, morpholine-4-yl,
piperazinyl, 1-alkylpiperazine-4-yl; an alkoxy group denotes an
O-alkyl group, the alkyl group being as defined above; the alkoxy
group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or
pentoxy group; an alkylthio group denotes an S-alkyl group, the
alkyl group being as defined above; an haloalkyl group denotes an
alkyl group which is substituted by one to five halogen atoms, the
alkyl group being as defined above; the haloalkyl group is
preferably a --C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7, or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the
alkyl group being as defined above; an haloalkyloxy group denotes
an alkoxy group which is substituted by one to five halogen atoms,
the alkyl group being as defined above; the haloalkyloxy group is
preferably a --OC(R.sup.10).sub.3, --OCR.sup.10(R.sup.10').sub.2,
--OCR.sup.10(R.sup.10')R.sup.10'', --OC.sub.2(R.sup.10).sub.5,
--OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10' R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-- group or HO-alkyl-NH-- group, the alkyl group
being as defined above; an alkylamino group denotes an HN-alkyl or
N-dialkyl group, the alkyl group being as defined above; a halogen
group is fluorine, chlorine, bromine, or iodine; an aryl group
denotes an aromatic group having five to fifteen carbon atoms,
which can be substituted by one or more substituents R', where R'
is as defined above; the aryl group is preferably a phenyl group,
-o-C.sub.6H.sub.4--R', -m-C.sub.6H.sub.4--R',
-p-C.sub.6H.sub.4--R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or
2-anthracenyl; a heteroaryl group denotes a 5- or 6-membered
heterocyclic group which contains at least one heteroatom like O,
N, S. This heterocyclic group can be fused to another aromatic
ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl,
oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl,
pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl,
4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl,
acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl,
6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl,
5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl,
benzofurazane, benzothiofurazane, benzotriazol-1-yl,
benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,
benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl,
benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl,
cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or
tetrahydroisoquinolinyl, purine, phthalazine, pteridine,
thiatetraazaindene, thiatriazaindene, isothiazolopyrazine,
isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,
imidazopyridazine, imidazopyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine,
triazolopyrazine, triazolopyrimidine, triazolopyridazine group.
This heterocyclic group can be substituted by one or more
substituents R', wherein R' is as defined above; a phosphonooxy
group is --O--P(.dbd.O)(OH).sub.2 or a salt thereof, a
phosphonooxyalkyl group denotes an -alkyl-O--P(.dbd.O)(OH).sub.2
group or a salt thereof, alkyl being as defined above.
[0057] The present invention also relates to compounds of the
general formula (II) or a salt or a physiologically functional
derivative or a stereoisomer thereof,
##STR00008##
wherein [0058] the substituent -Y.sup.b- is attached to the 5- or
6-position of the benzazole; [0059] X.sup.b independently
represents S, O, SO, or SO.sub.2; [0060] Y.sup.b independently
represents S, NR.sup.2, SO, or SO.sub.2; [0061] A.sup.b
independently represents .rarw.CO--, .rarw.CS--, .rarw.SO--,
.rarw.SO.sub.2--, .rarw.CO.sub.2--, <CONR.sup.8--,
.rarw.NR.sup.8CO--, .rarw.NR.sup.8CONR.sup.9--;
.rarw.NR.sup.8COO--, .rarw.NR.sup.8NR.sup.9CO--,
.rarw.NR.sup.8OCO--, .rarw.ONR.sup.8CO--, or
.rarw.NR.sup.8SO.sub.2--, where .rarw. indicates the point of
attachment to R.sup.3; [0062] R.sup.4b independently represents H,
--SOR.sup.6, --SO.sub.2R.sup.6, --SO.sub.3R.sup.6, --NO.sub.2,
--CN, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, alkyl, cycloalkyl,
alkoxy, --NH.sub.2, alkylamino, --NR.sup.7COR.sup.6, halogen, --OH,
--SH, alkylthio, haloalkyl, haloalkyloxy, aryl or heteroaryl;
R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.6a, R.sup.7, R.sup.8,
R.sup.8a, R.sup.9, R.sup.9a, R.sup.11, R.sup.12, R.sup.16, X.sup.2
are as hereinbefore defined; an alkyl group, if not stated
otherwise, denotes a linear or branched C.sub.1-C.sub.6-alkyl,
preferably a linear or branched chain of one to five carbon atoms,
a linear or branched C.sub.2-C.sub.6-alkenyl or a linear or
branched C.sub.2-C.sub.6-alkinyl group, which can be substituted by
one or more substituents R'; the C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl and C.sub.2-C.sub.6-alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R').sub.3, --C.sub.2(R').sub.5, --CH.sub.2--C(R').sub.3,
--C.sub.3(R').sub.7, --C.sub.2H.sub.4--C(R').sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; R' independently
represents H, --CO.sub.2R'', --CONHR'', --CR''O, --SO.sub.2NR'',
--NR''--CO-haloalkyl, --NO.sub.2, --NR''--SO.sub.2-haloalkyl,
--NR''--SO.sub.2-alkyl, --SO.sub.2-alkyl, --NR''--CO-alkyl, --CN,
alkyl, cycloalkyl, aminoalkyl, alkylamino, alkoxy, --OH, --SH,
alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl,
haloalkyloxy, aryl, arylalkyl or heteroaryl; R'' independently
represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl,
heteroaryl or aminoalkyl; an alkylene group denotes a divalent
linear or branched C.sub.1-C.sub.6-alkylene, preferably a linear or
branched chain of one to five carbon atoms, a linear or branched
C.sub.2-C.sub.6-alkenylene or a linear or branched
C.sub.2-C.sub.6-alkynylene group, which may be substituted by one
or more substituents R'; a cycloalkylene group denotes a divalent
non-aromatic ring system containing three to eight carbon atoms,
preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in the ring may be substituted by a group E, E being
O, S, SO, SO.sub.2, N, or NR'', R'' being as defined above; a
heterocyclylene group denotes a 3 to 8-membered divalent
heterocyclic non-aromatic group which contains at least one
heteroatom selected from O, N, and S, wherein the heterocyclylene
group may be fused to another non-aromatic ring and may be
substituted by one or more substituents R', wherein R' is as
defined above; an arylene group denotes an aromatic divalent group
having five to fifteen carbon atoms, which may be substituted by
one or more substituents R', and may be fused to another aromatic
ring, where R' is as defined above; a heteroarylene group denotes a
divalent 5- or 6-membered heterocyclic group which contains at
least one heteroatom selected from O, N, and S, wherein the
heterocyclylene group may be fused to another aromatic ring and may
be substituted by one or more substituents R', wherein R' is as
defined above; a cycloalkyl group denotes a non-aromatic ring
system containing three to eight carbon atoms, preferably four to
eight carbon atoms, wherein one or more of the carbon atoms in the
ring can be substituted by a group E, E being O, S, SO, SO.sub.2,
N, or NR'', R'' being as defined above; the
C.sub.3-C.sub.8-cycloalkyl residue may be selected from the group
comprising -cyclo-C.sub.3H.sub.5, -cyclo-C.sub.4H.sub.7,
-cyclo-C.sub.5H.sub.9, -cyclo-C.sub.6H.sub.11,
-cyclo-C.sub.7H.sub.13, -cyclo-C.sub.8H.sub.15, morpholine-4-yl,
piperazinyl, 1-alkylpiperazine-4-yl; an alkoxy group denotes an
O-alkyl group, the alkyl group being as defined above; the alkoxy
group is preferably a methoxy, ethoxy, isopropoxy, t-butoxy or
pentoxy group; an alkylthio group denotes an S-alkyl group, the
alkyl group being as defined above; an haloalkyl group denotes an
alkyl group which is substituted by one to five halogen atoms, the
alkyl group being as defined above; the haloalkyl group is
preferably a --C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7, or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkyl group denotes an HO-alkyl group, the
alkyl group being as defined above; an haloalkyloxy group denotes
an alkoxy group which is substituted by one to five halogen atoms,
the alkyl group being as defined above; the haloalkyloxy group is
preferably a --OC(R.sup.10).sub.3, --OCR.sup.10(R.sup.10').sub.2,
--OCR.sup.10(R.sup.10')R.sup.10'', --OC.sub.2(R.sup.10).sub.5,
--OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-- group or HO-alkyl-NH-- group, the alkyl group
being as defined above; an alkylamino group denotes an HN-alkyl or
N-dialkyl group, the alkyl group being as defined above; a halogen
group is fluorine, chlorine, bromine, or iodine; an aryl group
denotes an aromatic group having five to fifteen carbon atoms,
which can be substituted by one or more substituents R', where R'
is as defined above; the aryl group is preferably a phenyl group,
-o-C.sub.6H.sub.4--R', -m-C.sub.6H.sub.4--R',
-p-C.sub.6H.sub.4--R', 1-naphthyl, 2-naphthyl, 1-anthracenyl or
2-anthracenyl; a heteroaryl group denotes a 5- or 6-membered
heterocyclic group which contains at least one heteroatom like O,
N, S. This heterocyclic group can be fused to another aromatic
ring. For example, this group can be selected from a thiadiazole,
thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,
isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl,
oxazol-5-yl, isooxazol-3-yl, isooxazol-4-yl, isooxazol-5-yl,
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,
1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl,
pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl,
4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl,
acridyl, phenazinyl, carbazolyl, phenoxazinyl, indolizine,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl,
6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl,
5-indolinyl, 6-indolinyl, 7-indolinyl, benzo[b]furanyl,
benzofurazane, benzothiofurazane, benzotriazol-1-yl,
benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,
benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl,
benzimidazolyl, benzothiazolyl, quinazolinyl, quinoxazolinyl,
cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, or
tetrahydroisoquinolinyl, purine, phthalazine, pteridine,
thiatetraazaindene, thiatriazaindene, isothiazolopyrazine,
isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,
imidazopyridazine, imidazopyrimidine, imidazopyridine,
imidazolotriazine, triazolotriazine, triazolopyridine,
triazolopyrazine, triazolopyrimidine, triazolopyridazine group.
This heterocyclic group can be substituted by one or more
substituents R', wherein R' is as defined above; a phosphonooxy
group is --O--P(.dbd.O)(OH).sub.2 or a salt thereof, a
phosphonooxyalkyl group denotes an -alkyl-O--P(.dbd.O)(OH).sub.2
group or a salt thereof, alkyl being as defined above.
[0063] The invention also provides a pharmaceutical composition
comprising a compound of formula (I), in free form or in the form
of pharmaceutically acceptable salts and physiologically functional
derivatives, together with a pharmaceutically acceptable diluent or
carrier therefore.
[0064] The term "physiologically functional derivative" as used
herein refers to compounds which are not pharmaceutically active
themselves but which are transformed into their pharmaceutical
active form in vivo, i.e. in the subject to which the compound is
administered. Examples of physiologically functional derivatives
are prodrugs such as those described below in the present
application.
[0065] Prodrugs of the compounds of the present invention include
but are not limited to: esters, which are transformed in vivo into
the corresponding active alcohol, esters, which are transformed in
vivo into the corresponding active acid, imines, which are
transformed in vivo into the corresponding amines, imines which are
metabolized in vivo into the corresponding active carbonyl
derivative (e.g. aldehyde or ketone), 1-carboxy-amines, which are
decarboxylated in vivo into the active amine,
phosphoryloxy-compounds, which are dephosphorylated in vivo by
phosphateases into the active alcohols, and amides which are
metabolized into the corresponding active amine or acid
respectively.
[0066] The term "stereoisomer" as used herein refers to compound
with at least one stereogenic center, which can be R- or
S-configured. It has to be understood, that in compounds with more
than one stereogenic center each of which independently from each
other can be R- or S-configured. The term "stereoisomer" as used
herein also refers to salts of the compounds herein described with
optically active acids or bases.
[0067] In addition, the present invention provides methods for
preparing the compounds of the invention such as compounds of
formula (I).
[0068] The compounds of formula (I), formula (Ia) and formula (II)
may be obtained via various methods. One possibility for the
synthesis of compounds of formula (I) comprises the step of
reacting a compound of formula (VII), wherein R.sup.3, R.sup.4,
R.sup.5, A, X, and Y are defined above in formula (I), formula (Ia)
and formula (II), with a compound of formula (VIII), wherein
R.sup.1 is as defined above and LG comprises a leaving group such
as Cl, Br, and I. Either nucleophilic substitution or
palladium-catalyzed cross-coupling may be applied. If
Y.dbd.NR.sup.2, R.sup.2 may be added before or after addition of
R.sup.1.
##STR00009##
[0069] Another way to synthesize compounds of formula (I), formula
(Ia) and formula (II) comprises the step of adding a R.sup.5 to a
compound of formula (IX), wherein R.sup.1, R.sup.4, X, and Y are as
defined above in formula (I), formula (Ia) and formula (II),
followed by reaction with an acid chloride, a carboxylic acid, a
sulfonic acid chloride, or an isocyanate or vice versa.
##STR00010##
[0070] Compounds of the formula (IX) can be synthesized by reacting
a compound of formula (X), wherein R.sup.4, X, and Y are as defined
above for formula (I), formula (Ia) and formula (II), with a
compound of formula (VIII), wherein R.sup.1 is as defined above in
formula (I), formula (Ia) and formula (II), and LG comprises a
leaving group such as Cl, Br, and I. Either nucleophilic
substitution or palladium-catalyzed cross-coupling may be applied.
Protection (e.g., Boc protection) of the 2-amino group of the
benzazole might be necessary. If Y.dbd.NR.sup.2, R.sup.2 may be
added before or after addition of R.sup.1.
##STR00011##
[0071] The compounds of formula (VII), wherein Y.dbd.NH, can be
synthesized by reduction of a compound of formula (XI), wherein
R.sup.3, R.sup.4, R.sup.5, A, and X are as defined above in formula
(I), formula (Ia) and formula (II). For example heterogeneous
catalytic hydrogenation may be applied.
##STR00012##
[0072] The compounds of formula (XI) can be synthesized by adding a
R.sup.5 to a compound of formula (XII), wherein R.sup.4 and X are
as defined above, followed by reaction with an acid chloride, a
carboxylic acid, a sulfonic acid chloride, or an isocyanate or vice
versa.
##STR00013##
[0073] A preferred embodiment of the invention, are compounds of
the formula (III)
##STR00014##
wherein Y is attached at the 5- or 6-position of the benzazole; A,
X, Y, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13, R.sup.14,
R.sup.15 are as defined above for formula (I).
[0074] Another preferred embodiment of the invention, are compounds
of formula (III),
wherein R.sup.12 and R.sup.15 are H and R.sup.13 and R.sup.14
independently represent O-alkyl which may be substituted.
[0075] A more preferred embodiment of the present invention, are
compounds of formula (III), wherein X independently represents S or
O; Y represents NH; A independently represents --CO-- or
.rarw.NHCO--, where .rarw. indicates the point of attachment to
R.sup.3; R.sup.3 is an optionally substituted aryl or heteroaryl
group, R.sup.5, R.sup.12 and R.sup.15 are H; R.sup.13 and R.sup.14
are --O-alkyl, which may be substituted.
[0076] Another preferred embodiment of the invention, are compounds
of the formula (IV)
##STR00015##
wherein Y is attached at the 5- or 6-position of the benzazole; A,
X, Y, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13 are as defined
above for formula (I).
[0077] Another preferred embodiment of the invention, are compounds
of the formula (V)
##STR00016##
wherein Y is attached at the 5- or 6-position of the benzazole; A,
X, Y, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13,
R.sup.14R.sup.15 are as defined above for formula (I).
[0078] Another preferred embodiment of the invention, are compounds
of the formula (VI)
##STR00017##
wherein Y is attached at the 5- or 6-position of the benzazole; A,
X, Y, R.sup.3, R.sup.4, R.sup.5, R.sup.16 are as defined above for
formula (I).
[0079] Another preferred embodiment of the invention, are compounds
of formula (I), where X represents S; Y represents NH; A represents
--CO--; R.sup.5 represents H.
[0080] Another preferred embodiment of the invention, are compounds
of formula (I),
where X represents S; Y represents NH; A represents .rarw.NHCO--,
where .rarw. indicates the point of attachment to R.sup.3; R.sup.5
represents H.
[0081] Another preferred embodiment of the invention, are compounds
of formula (I),
where X represents O; Y represents NH; A represents --CO--; R.sup.5
represents H.
[0082] Another preferred embodiment of the invention, are compounds
of formula (I),
where X represents O; Y represents NH; A represents .rarw.NHCO--,
where .rarw. indicates the point of attachment to R.sup.3; R.sup.5
represents H.
[0083] Another preferred embodiment of the invention, are compounds
of formula (I),
are compounds where X represents O; Y represents NH; A represents
--CO--; R.sup.3 represents an optionally substituted aryl or
heteroaryl group; R.sup.5 represents H.
[0084] A more preferred embodiment of the present invention, are
compounds of formula (III), wherein the -Y-R.sup.1 substituent is
attached to the 5-position of the benzazole, X independently
represents S or O; Y represents NH; A independently represents
--CO-- or .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3, R.sup.3 is an optionally substituted aryl or
heteroaryl group, R.sup.5, R.sup.12 and R.sup.15 are H; R.sup.13
and R.sup.14 are --O-alkyl, which may be substituted.
[0085] A more preferred embodiment of the present invention, are
compounds of formula (III), wherein the -Y-R.sup.1 substituent is
attached to the 6-position of the benzazole, X independently
represents S or O; Y represents NH; A independently represents
--CO-- or .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3, R.sup.3 is an optionally substituted aryl or
heteroaryl group, R.sup.5, R.sup.12 and R.sup.15 are H; R.sup.13
and R.sup.14 are --O-alkyl, which may be substituted.
[0086] A more preferred embodiment of the present invention, are
compounds of formula (III), wherein the -Y-R.sup.1 substituent is
attached to the 5-position of the benzazole, X independently
represents S or O; Y represents NH; A independently represents
--CO-- or .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3, R.sup.3 is an optionally substituted phenyl,
R.sup.5, R.sup.12 and R.sup.15 are H; R.sup.13 and R.sup.14 are
--O-alkyl, which may be substituted.
[0087] A more preferred embodiment of the present invention, are
compounds of formula (III), wherein the -Y-R.sup.1 substituent is
attached to the 6-position of the benzazole, X independently
represents S or O; Y represents NH; A independently represents
--CO-- or .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3, R.sup.3 is an optionally substituted
phenylaryl or heteroaryl group, R.sup.5, R.sup.12 and R.sup.15 are
H; R.sup.13 and R.sup.14 are --O-alkyl, which may be
substituted.
[0088] Another preferred embodiment of the invention, are compounds
of formula (I),
where R.sup.3 is an optionally substituted aryl or heteroaryl
group.
[0089] Another preferred embodiment of the invention, are compounds
of formula (I),
where R.sup.3 is an optionally substituted phenyl group.
[0090] Another preferred embodiment of the invention, are compounds
of formula (I),
where the -Y-R.sup.1 substituent is attached to the 5-position of
the benzazole.
[0091] Another preferred embodiment of the invention, are compounds
of formula (I),
where the -Y-R.sup.1 substituent is attached to the 6-position of
the benzazole.
[0092] Another preferred embodiment of the invention, are compounds
of formula (III),
where R.sup.3 is an optionally substituted aryl or heteroaryl
group.
[0093] Another preferred embodiment of the invention, are compounds
of formula (III),
where R.sup.3 is an optionally substituted phenyl group.
[0094] Another preferred embodiment of the invention, are compounds
of formula (III),
where the -Y-R.sup.1 substituent is attached to the 5-position of
the benzazole.
[0095] Another preferred embodiment of the invention, are compounds
of formula (III),
where the -Y-R.sup.1 substituent is attached to the 6-position of
the benzazole.
[0096] Another preferred embodiment of the invention, are compounds
of formula (III),
where X represents S; Y represents NH; A represents --CO--; R.sup.5
represents H.
[0097] Another preferred embodiment of the invention, are compounds
of formula (III),
where X represents S; Y represents NH; A represents .rarw. NHCO--,
where .rarw. indicates the point of attachment to R.sup.3; R.sup.5
represents H.
[0098] Another preferred embodiment of the invention, are compounds
of formula (III),
where X represents O; Y represents NH; A represents --CO--; R.sup.5
represents H.
[0099] Another preferred embodiment of the invention, are compounds
of formula (III),
where X represents O; Y represents NH; A represents .rarw.NHCO--,
where .rarw. indicates the point of attachment to R.sup.3; R.sup.5
represents H.
[0100] Another preferred embodiment of the invention, are compounds
of formula (III),
are compounds where X represents O; Y represents NH; A represents
--CO--; R.sup.3 represents an optionally substituted aryl or
heteroaryl group; R.sup.5 represents H.
[0101] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where X.sup.a represents S; Y.sup.a represents NH; A.sup.a
represents --CO--; R.sup.5 represents H.
[0102] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where X.sup.a represents S; Y.sup.a represents NH; A.sup.a
represents .rarw.NHCO--, where .rarw. indicates the point of
attachment to R.sup.3; R.sup.5 represents H.
[0103] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where R.sup.3 is an optionally substituted aryl or heteroaryl
group.
[0104] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where R.sup.3 is an optionally substituted phenyl group.
[0105] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where the -Y.sup.1--R.sup.1a substituent is attached to the
5-position of the benzazole.
[0106] Another preferred embodiment of the invention, are compounds
of formula (Ia),
where the -Y.sup.1--R.sup.1a substituent is attached to the
6-position of the benzazole.
[0107] Another preferred embodiment of the invention, are compounds
of formula (II),
where X.sup.b represents S; Y.sup.b represents NH; A.sup.b
represents --CO--; R.sup.5 represents H.
[0108] Another preferred embodiment of the invention, are compounds
of formula (II),
where X.sup.b represents S; Y.sup.b represents NH; A represents
.rarw.NHCO--, where .rarw. indicates the point of attachment to
R.sup.3; R.sup.5 represents H.
[0109] Another preferred embodiment of the invention, are compounds
of formula (II),
where R.sup.3 is an optionally substituted aryl or heteroaryl
group.
[0110] Another preferred embodiment of the invention, are compounds
of formula (II),
where R.sup.3 is an optionally substituted phenyl group.
[0111] Another preferred embodiment of the invention, are compounds
of formula (II),
where the -Y.sup.b- substituent is attached to the 5-position of
the benzazole.
[0112] Another preferred embodiment of the invention, are compounds
of formula (II),
where the -Y.sup.b- substituent is attached to the 6-position of
the benzazole.
[0113] Another preferred embodiment are compositions containing one
or more compounds of the present invention and a pharmaceutical
acceptable carrier or diluent.
[0114] The compounds of the present invention can form salts with
inorganic or organic acids or bases. Examples of pharmaceutically
acceptable salts comprise without limitation non-toxic inorganic or
organic salts such as acetate derived from acetic acid, aconitate
derived from aconitic acid, ascorbate derived from ascorbic acid,
benzoate derived from benzoic acid, cinnamate derived from cinnamic
acid, citrate derived from citric acid, embonate derived from
embonic acid, enantate derived from heptanoic acid, formiate
derived from formic acid, fumarate derived from fumaric acid,
glutamate derived from glutamic acid, glycolate derived from
glycolic acid, chloride derived from hydrochloric acid, bromide
derived from hydrobromic acid, lactate derived from lactic acid,
maleate derived from maleic acid, malonate derived from malonic
acid, mandelate derived from mandelic acid, methanesulfonate
derived from methanesulfonic acid, naphtaline-2-sulfonate derived
from naphtaline-2-sulfonic acid, nitrate derived from nitric acid,
perchlorate derived from perchloric acid, phosphate derived from
phosphoric acid, phthalate derived from phthalic acid, salicylate
derived from salicylic acid, sorbate derived from sorbic acid,
stearate derived from stearic acid, succinate derived from succinic
acid, sulphate derived from sulphuric acid, tartrate derived from
tartaric acid, toluene-p-sulfate derived from p-toluenesulfonic
acid and others.
[0115] Salts of phosphonoxy- and phosphonoxyalkyl groups may be
those formed with alkali metal ions e.g. sodium or potassium, or
those formed with alkaline earth metal ions e.g. calcium or
magnesium, or those formed with zinc ions.
[0116] Such salts of the compounds of the present invention may be
anhydrous or solvated. Such salts can be produced by methods known
to someone of skill in the art and described in the prior art.
[0117] Other salts like oxalate derived from oxalic acid, which is
not considered as pharmaceutically acceptable can be appropriate as
intermediates for the production of compounds of the present
invention or a pharmaceutically acceptable salt thereof or
physiologically functional derivative or a stereoisomer
thereof.
[0118] The compounds according to the invention and medicaments
prepared therewith are generally useful for the treatment of cell
proliferation disorders, for the treatment or prophylaxis of
immunological diseases and conditions (as for instance inflammatory
diseases, neuroimmunological diseases, autoimmune diseases or
other).
[0119] The compounds of the present invention are useful for the
treatment of diseases which are caused by malignant cell
proliferation, such as all forms of solid tumors, leukemias and
lymphomas. Therefore the compounds according to the invention and
medicaments prepared therewith are generally useful for regulating
cell activation, cell proliferation, cell survival, cell
differentiation, cell cycle, cell maturation and cell death or to
induce systemic changes in metabolism such as changes in sugar,
lipid or protein metabolism. They can also be used to support cell
generation poiesis, including blood cell growth and generation
(prohematopoietic effect) after depletion or destruction of cells,
as caused by, for example, toxic agents, radiation, immunotherapy,
growth defects, malnutrition, malabsorption, immune dysregulation,
anemia and the like or to provide a therapeutic control of tissue
generation and degradation, and therapeutic modification of cell
and tissue maintenance and blood cell homeostasis.
[0120] These diseases and conditions include but are not limited to
cancer as hematological (e.g. leukemia, myeloma), or lymphomas
(e.g. Hodgkin's and non-Hodgkin's lymphomas), or solid tumors (for
example breast, prostate, liver, bladder, lung, esophageal,
stomach, colorectal, genitourinary, gastrointestinal, skin,
pancreatic, brain, uterine, colon, head and neck, and ovarian,
melanoma, astrocytoma, small cell lung cancer, glioma, basal and
squameous cell carcinoma, sarcomas as Kaposi's sarcoma and
osteosarcoma).
[0121] Other aspects of the present invention relate to benzazole
derivatives as new pharmaceutically active agents, especially for
the preparation of a pharmaceutical composition for the treatment
of diseases which are cured or relieved by the inhibition of one or
several kinases and/or phosphatases.
[0122] In another more preferred embodiment of the invention the
compounds of the present invention may be used for treating and/or
preventing diseases by inhibition of one or more kinases like:
Aurora A, Aurora B, EGF-R, ERBB2, IGF1-R, PDGFR, FLT3 VEGF-R.sup.2,
VEGF-R.sup.3, EPHB4, Tie2, FAK and SRC.
[0123] The compounds according to the present invention or a
pharmaceutically acceptable salt or physiologically functional
derivative or a stereoisomer thereof if desired with appropriate
adjuvants and additives for the production of a medicament for the
treatment or prevention of a disease characterized by
hyperproliferation of keratinocytes and/or T cells, especially
inflammatory disorders and immune disorders, preferably selected
from the group consisting of Addison's disease, alopecia greata,
Ankylosing spondylitis, haemolytic anemia (anemia haemolytica),
pernicious anemia (anemia perniciosa), aphthae, aphthous
stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis,
rheumatoid arthritis, aspermiogenese, asthma bronchiale,
auto-immune asthma, auto-immune hemolysis, Bechet's disease,
Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma,
Crohn's disease, chorioiditis, colitis ulcerosa, Coeliac disease,
cryoglobulinemia, dermatitis herpetiformis, dermatomyositis,
insulin-dependent type I diabetes, juvenile diabetes, idiopathic
diabetes insipidus, insulin-dependent diabetes mellisis, autoimmune
demyelinating diseases, Dupuytren's contracture, encephalomyelitis,
encephalomyelitis allergica, endophthalmia phacoanaphylactica,
enteritis allergica, autoimmune enteropathy syndrome, erythema
nodosum leprosum, idiopathic facial paralysis, chronic fatigue
syndrome, febris rheumatica, glomerulo nephritis, Goodpasture's
syndrome, Graves' disease, Hamman-Rich's disease, Hashimoto's
disease, Hashimoto's thyroiditis, sudden hearing loss, sensoneural
hearing loss, hepatitis chronica, Hodgkin's disease,
haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis,
iritis, leucopenia, leucemia, lupus erythematosus disseminatus,
systemic lupus erythematosus, cutaneous lupus erythematosus,
lymphogranuloma malignum, mononucleosis infectiosa, myasthenia
gravis, traverse myelitis, primary idiopathic myxedema, nephrosis,
ophthalmia symphatica, orchitis granulomatosa, pancreatitis,
pemphigus, pemphigus vulgaris, polyarteritis nodosa, polyarthritis
chronica primaria, polymyositis, polyradiculitis acuta, psoriasis,
purpura, pyoderma gangrenosum, Quervain's thyreoiditis, Reiter's
syndrome, sarcoidosis, ataxic sclerosis, progressive systemic
sclerosis, scleritis, sclerodermia, multiple sclerosis, sclerosis
disseminata, acquired spenic atrophy, infertility due to
antispermatozoan antibodies, thrombocytopenia, idiopathic
thrombocytopenia purpura, thymoma, acute anterior uveitis,
vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated
diseases such as Sjorgren's syndrome, virus (AIDS or EBV)
associated B cell lymphoma, parasitic diseases such as Leishmania,
and immunesuppressed disease states such as viral infections
following allograft transplantations, AIDS, cancer, chronic active
hepatitis diabetes, toxic chock syndrome and food poisoning.
[0124] "Treatment" according to the present invention is intended
to mean complete or partial healing of a disease, prevention of a
disease, or alleviation of a disease or stop of progression of a
given disease.
[0125] The compounds of the present invention can further be used
for diseases that are caused by protozoal infestations in humans
and animals.
[0126] The compounds of the present invention can further be used
for viral infections or other infections caused for instance by
Pneumocystis carinii.
[0127] Furthermore, the invention relates to a method of treatment
or prevention of diseases which comprises the administration of an
effective amount of compounds of the formula (I) or a
pharmaceutically acceptable salt or physiologically functional
derivative or a stereoisomer thereof.
[0128] The compounds of the according invention and their
pharmacologically acceptable salts can be administered to animals,
preferably to mammals, and in particular to humans, as therapeutics
per se, as mixtures with one another or in the form of
pharmaceutical preparations which allow enteral or parenteral use
and which as active constituent contain an effective dose of at
least one compound of the present invention or a salt thereof, in
addition to customary pharmaceutically innocuous excipients and
additives.
[0129] The production of medicaments containing the compounds
according to the present invention and their application can be
performed according to well-known pharmaceutical methods.
[0130] While the compounds according to the invention for use in
therapy may be administered in the form of the raw chemical
compound, it is preferred to introduce the active ingredient,
optionally in the form of a physiologically acceptable salt in a
pharmaceutical composition together with one or more adjuvants,
excipients, carriers, buffers, diluents, and/or other customary
pharmaceutical auxiliaries. Such salts of the compounds may be
anhydrous or solvated.
[0131] In a preferred embodiment, the invention provides
medicaments comprising compounds according to the present
invention, or a pharmaceutically acceptable salt or physiologically
functional derivative or a stereoisomer thereof, together with one
or more pharmaceutically acceptable carriers thereof, and,
optionally, other therapeutic and/or prophylactic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not harmful to
the recipient thereof.
[0132] A medicament of the invention may be those suitable for
oral, rectal, bronchial, nasal, topical, buccal, sub-lingual,
transdermal, vaginal or parenteral (including cutaneous,
subcutaneous, intramuscular, intraperitoneal, intravenous,
intraarterial, intracerebral, intraocular injection or infusion)
administration, or those in a form suitable for administration by
inhalation or insufflation, including powders and liquid aerosol
administration, or by sustained release systems. Suitable examples
of sustained release systems include semipermeable matrices of
solid hydrophobic polymers containing the compound of the
invention, which matrices may be in form of shaped articles, e.g.
films or microcapsules.
[0133] For preparing a medicament from a compounds of the present
invention and pharmaceutically acceptable carriers can be either
solid or liquid. Solid form preparations include powders, tablets,
pills, capsules, cachets, suppositories, and dispersible granules.
A solid carrier can be one or more substances which may also act as
diluents, flavouring agents, solubilizers, lubricants, suspending
agents, binders, preservatives, tablet disintegrating agents, or an
encapsulating material.
[0134] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding capacity in suitable proportions and compacted in the shape
and size desired. Suitable carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as carrier
providing a capsule in which the active component, with or without
carriers, is surrounded by a carrier, which is thus in association
with it. Similarly, cachets and lozenges are included. Tablets,
powders, capsules, pills, cachets, and lozenges can be used as
solid forms suitable for oral administration.
[0135] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glyceride or cocoa butter, is first melted
and the active component is dispersed homogeneously therein, as by
stirring. The molten homogenous mixture is then poured into
convenient sized moulds, allowed to cool, and thereby to solidify.
Compositions suitable for vaginal administration may be presented
as pessaries, tampons, creams, gels, pastes, foams or sprays
containing in addition to the active ingredient such carriers as
are known in the art to be appropriate. Liquid preparations include
solutions, suspensions, and emulsions, for example, water or
water-propylene glycol solutions. For example, parenteral injection
liquid preparations can be formulated as solutions in aqueous
polyethylene glycol solution.
[0136] The compounds according to the present invention may thus be
formulated for parenteral administration (e.g. by injection, for
example bolus injection or continuous infusion) and may be
presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added
preservative. The compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may
contain formulation agents such as suspending, stabilising and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilization from solution, for constitution with a suitable
vehicle, e.g. sterile, pyrogen-free water, before use.
[0137] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavours, stabilising and thickening agents, as desired.
Aqueous suspensions suitable for oral use can be made by dispersing
the finely divided active component in water with viscous material,
such as natural or synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, or other well known suspending agents.
[0138] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavours, stabilisers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0139] In an especially preferred embodiment of the present
invention the medicament is applied topically. This reduces
possible side effects and limits the necessary treatment to those
areas affected.
[0140] Preferably the medicament is prepared in form of an
ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream
of a mixed phase or amphiphilic emulsion system
(oil/water-water/oil mixed phase), a liposome, a transfersome, a
paste or a powder.
[0141] Ointments and creams may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening
and/or gelling agents. Lotions may be formulated with an aqueous or
oily base and will in general also contain one or more emulsifying
agents, stabilising agents, dispersing agents, suspending agents,
thickening agents, or colouring agents.
[0142] Compositions suitable for topical administration in the
mouth include lozenges comprising the active agent in a flavoured
base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerine or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0143] Solutions or suspensions are applied directly to the nasal
cavity by conventional means, for example with a dropper, pipette
or spray. The compositions may be provided in single or multi-dose
form. In the latter case of a dropper or pipette, this may be
achieved by the patient administering an appropriate, predetermined
volume of the solution or suspension. In the case of a spray, this
may be achieved for example by means of a metering atomising spray
pump.
[0144] Administration to the respiratory tract may also be achieved
by means of an aerosol formulation in which the active ingredient
is provided in a pressurised pack with a suitable propellant such
as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, carbon
dioxide, or other suitable gas. The aerosol may conveniently also
contain a surfactant such as lecithin. The dose of drug may be
controlled by provision of a metered valve.
[0145] Alternatively the active ingredients may be provided in the
form of a dry powder, for example a powder mix of the compound in a
suitable powder base such as lactose, starch, starch derivatives
such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone
(PVP). Conveniently the powder carrier will form a gel in the nasal
cavity The powder composition may be presented in unit dose form
for example in capsules or cartridges of, e.g., gelatin, or blister
packs from which the powder may be administered by means of an
inhaler.
[0146] In compositions intended for administration to the
respiratory tract, including intranasal compositions, the compound
will generally have a small particle size for example of the order
of 5 microns or less. Such a particle size may be obtained by means
known in the art, for example by micronization.
[0147] When desired, compositions adapted to give sustained release
of the active ingredient may be employed.
[0148] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packaged
tablets, capsules, and powders in vials or ampoules.
[0149] Also, the unit dosage form can be a capsule, tablet, cachet,
or lozenge itself, or it can be the appropriate number of any of
these in packaged form. Tablets or capsules for oral administration
and liquids for intravenous administration and continuous infusion
are preferred compositions.
[0150] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co. Easton, Pa.).
[0151] Pharmaceutical compositions can also contain two or more
compounds of the present invention or their pharmacologically
acceptable salts and also other therapeutically active
substances.
[0152] Thus, the compounds of the present invention can be used in
the form of one compound alone or in combination with other active
compounds--for example with medicaments already known for the
treatment of the aforementioned diseases, whereby in the latter
case a favorable additive, amplifying effect is noticed.
[0153] To prepare the pharmaceutical preparations, pharmaceutically
inert inorganic or organic excipients can be used. To prepare
pills, tablets, coated tablets and hard gelatin capsules, for
example, lactose, corn starch or derivatives thereof, talc, stearic
acid or its salts, etc. can be used. Excipients for soft gelatin
capsules and suppositories are, for example, fats, waxes,
semi-solid and liquid polyols, natural or hardened oils etc.
Suitable excipients for the production of solutions and syrups are,
for example, water, sucrose, invert sugar, glucose, polyols etc.
Suitable excipients for the production of injection solutions are,
for example, water, alcohols, glycerol, polyols or vegetable
oils.
[0154] The dose can vary within wide limits and is to be suited to
the individual conditions in each individual case. For the above
uses the appropriate dosage will vary depending on the mode of
administration, the particular condition to be treated and the
effect desired. In general, however, satisfactory results are
achieved at dosage rates of about 1 to 100 mg/kg animal body weight
preferably 1 to 50 mg/kg. Suitable dosage rates for larger mammals,
for example humans, are of the order of from about 10 mg to 3
g/day, conveniently administered once, in divided doses 2 to 4
times a day, or in sustained release form.
[0155] The following examples and figures are included to
demonstrate preferred embodiments of the invention. It should be
appreciated by those of skill in the art that the techniques
disclosed in the examples that follow represent techniques
discovered by the inventors to function well in the practice of the
invention, and thus can be considered preferred modes for its
practice. However, those of skill in the art should, in light of
the present disclosure, appreciate that many changes can be made in
the specific embodiments that are disclosed without departing from
the spirit and scope of the invention as set out in the appended
claims. All references cited are incorporated herein by
reference.
EXAMPLES
[0156] Abbreviations: min, minute(s); h, hour(s); r.t., room
temperature; R.sub.t, retention time; .PSI., pseudo; s, singlet; t,
triplet, quint, quintet; br., broad; J, coupling constant; pTLC,
preparative thin layer chromatography; DMAP,
4-dimethylaminopyridine, IM, Intermediate.
[0157] NMR spectra: Bruker Avance 300 MHz. The .sup.1H NMR spectra
were recorded at 300 MHz using the residual solvent peak as an
internal standard (CDCl.sub.3, .delta..sub.H=7.26).
[0158] Analytical LC/ESI-MS: 2.times. Waters 600 Multisolvent
Delivery System. 50 .mu.l Sample loop. Column, Chromolith Speed ROD
RP18e (Merck, Darmstadt), 50.times.4.6 mm, with 2 .mu.m prefilter
(Merck). Eluent A, H.sub.2O+0.1% HCO.sub.2H; eluent B, MeCN.
Gradient, 5% B to 100% B within 5 min; flow, 3 ml/min. Waters LCZ
single quadrupol mass spectrometer with electrospray source. MS
method, MS8minPM-80-800-20V; positive/negative ion mode scanning,
m/z 80-800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V;
multiplier voltage, 400 V; probe and desolvation gas temperature,
120.degree. C. and 350.degree. C., respectively. Waters 2487 Dual X
Absorbance Detector, set to 254 nm.
[0159] Preparative HPLC-MS: Waters 600 Multisolvent Delivery System
with preparative pump heads. 2000 .mu.l or 5000 .mu.l Sample loop.
Column, Waters X-Terra RP18, 7 .mu.m, 19.times.150 mm with X-Terra
RP18 guard cartridge 7 .mu.m, 19.times.10 mm; used at flow rate 20
ml/min or YMC ODS-A, 120 .ANG., 40.times.150 mm with X-Terra RP18
guard cartridge 7 .mu.m, 19.times.10 mm; used at flow rate 50
ml/min. Make-up solvent: MeCN-H.sub.2O--HCO.sub.2H 80:20:0.05
(v:v:v). Eluent A, H.sub.2O+0.1% HCO.sub.2H; eluent B, MeCN.
Different linear gradients from 5-100% eluent B, adapted to sample.
Injection volume: 500 .mu.l-2000 .mu.l depending on sample. Waters
ZQ single quadrupol mass spectrometer with electrospray source.
Positive or negative ion mode scanning m/z 80-800 in 1 s;
capillary, 3.5 kV or 3.0 kV; cone voltage, 20 V; multiplier
voltage, 400 V; probe and desolvation gas temperature, 120.degree.
C. and 350.degree. C., respectively. Waters Fraction Collector II
with mass-triggered fraction collection. Waters 996 photo diode
array detector.
Syntheses of Intermediates
Intermediate 1: N-(6-Aminobenzoxazol-2-yl)benzamide
[0160] Step 1. A solution of cyanogen bromide (3.50 g, 33 mmol;
caution: highly toxic! Waste disposal: addition of excess NaOCl to
a basic aqueous solution of cyanogen bromide) in tetrahydrofuran (3
mL) was added to a solution of 2-amino-5-nitrophenol (4.62 g, 30
mmol) in tetrahydrofuran (20 mL). After stirring for 1 day at r.t.,
a precipitate had formed which was dissolved by addition of water
(5 mL). After stirring further 3 days at r.t., water (10 mL) was
added and NaOH was added until the mixture turned basic. The
tetrahydrofuran was removed in vacuo and the precipitate formed in
the remaining aqueous phase was separated by filtration, washed
with water and recrystallized from methanol (100 mL). Upon
additional fractional crystallisation of the mother liquor, a total
of 3.80 g (21.2 mmol, 71%) of 2-amino-6-nitrobenzoxazole was
obtained as a brown solid. LC/ESI-MS: m/z=180 [M+H].sup.+; m/z=178
[M-H].sup.-; R.sub.t=2.52 min.
[0161] Step 2. Benzoyl chloride (1.17 mL, 10.0 mmol) was added to a
suspension of 2-amino-6-nitrobenzoxazole (1.50 g, 8.37 mmol) in
pyridine (10 mL). After stirring for 24 h at 80.degree. C., the
solution was poured into water (250 mL). The mixture was stirred
overnight at r.t. and the resulting precipitate was separated by
filtration. N-(6-Nitrobenzoxazol-2-yl)benzamide (2.08 g, 7.32 mmol,
88%) was thus obtained as a yellow solid. LC/ESI-MS: m/z=284
[M+H].sup.+; m/z=282 [M-H].sup.-; R.sub.t=3.13 min.
[0162] Step 3. To a solution of N-(6-nitrobenzoxazol-2-yl)benzamide
(2.03 g, 7.17 mmol) in dimethylformamide (60 mL), palladium on
charcoal (1.52 g, 10% Pd, 1.43 mmol Pd) was added and the air was
replaced with hydrogen (1 bar). The mixture was stirred for 2 h at
60.degree. C. and then overnight at r.t. The palladium was removed
by filtration through a pad of celite. After concentration to 20
mL, water was added and the resulting precipitate was separated by
filtration to obtain N-(6-aminobenzoxazol-2-yl)benzamide (0.823 g,
3.25 mmol, 45%) as a brown solid. LC/ESI-MS: m/z=254 [M+H].sup.+;
m/z=252 [M-H].sup.-; R.sub.t=1.92 min.
Intermediate 2: N-(6-Aminobenzothiazol-2-yl)benzamide
[0163] Step 1. To a suspension of 2-amino-6-nitrobenzothiazole
(Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl
chloride (1.74 mL, 15 mmol) was added. After stirring overnight at
r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and
the mixture was stirred at 60.degree. C. After completion of the
reaction, the mixture was poured into water (250 mL) and stirred
overnight at r.t. Separation of the resulting precipitate yielded
N-(6-nitrobenzothiazol-2-yl)-benzamide (3.87 g, 12.9 mmol, 86%) as
a yellow solid. LC/ESI-MS: m/z=300 [M+H].sup.+; m/z=298
[M-H].sup.-; R.sub.t=3.93 min.
[0164] Step 2. A mixture of N-(6-nitrobenzothiazol-2-yl)benzamide
(3.77 g, 12.6 mmol), palladium on charcoal (2 g, 10% Pd, 1.88 mmol
Pd), dimethyl formamide (80 mL) and ethyl acetate (20 mL) was
hydrogenated (1 bar) for 2 h at 60.degree. C. The palladium was
removed by filtration through a pad of celite. After concentration
to 20 mL, water was added and the resulting precipitate was
separated by filtration to obtain
N-(6-aminobenzothiazol-2-yl)benzamide (3.15 g, 11.7 mmol, 93%) as a
grey solid. LC/ESI-MS: m/z=270 [M+H].sup.+; m/z=268 [M-H].sup.-;
R.sub.t=2.27 min.
Intermediate 3: N-(6-Aminobenzothiazol-2-yl)isonicotinamide
[0165] Step 1. To a mixture of 2-amino-6-nitrobenzothiazole (Sigma
Aldrich, 1.95 g, 10 mmol) and pyridine (40 mL), benzoyl chloride
(2.1 mL, 18 mmol) was added. After stirring for 5 h at 80.degree.
C., water (10 mL) was added. The mixture was stirred for 0.5 h at
r.t., then methanol (30 mL) and water (50 mL) were added. The
precipitated N-(6-nitrobenzothiazol-2-yl)isonicotinamide was
separated by filtration. The crude product was taken up in
dimethylformamide and precipitated again by addition of methanol
and water (2.53 g, 8.42 mmol, 84%). LC/ESI-MS: m/z=301 [M+H].sup.+;
m/z=299 [M-H].sup.-; R.sub.t=3.48 min.
[0166] Step 2. N-(6-Nitrobenzothiazol-2-yl)isonicotinamide (2.42 g,
8.04 mmol) was suspended in ethyl acetate (150 mL), and
dimethylformamide was added until dissolution occurred. After
addition of palladium on charcoal (4.25 g, 10% Pd, 4 mmol Pd) the
mixture was hydrogenated (1 bar) at 60.degree. C. until completion
of the reaction. The palladium was removed by filtration through a
pad of celite and the solvent was evaporated. The residue was taken
up in little methanol and precipitated by addition of water to
obtain N-(6-aminobenzothiazol-2-yl)isonicotinamide (1.73 g, 6.4
mmol, 80%). LC/ESI-MS: m/z=271 [M+H].sup.+; m/z=269 [M-H].sup.-;
R.sub.t=1.43 min.
Intermediate 4: N-(6-Aminobenzothiazol-2-yl)nicotinamide
[0167] Step 1. A mixture of 2-amino-6-nitrobenzothiazole (0.976 g,
5 mmol), nicotinoyl chloride hydrochloride (1.07 g, 6 mmol),
triethylamine (1.9 ml, 13.8 mmol), DMAP (catalytic amount) and
dioxane (50 mL) was heated to reflux for 7 h. After addition of
nicotinoyl chloride hydrochloride (0.89 g, 5 mmol) and
triethylamine (1.8 mL, 12.5 mmol), heating was continued for 5 h.
After cooling to r.t., the precipitate was separated by filtration.
The solid was treated with boiling methanol (25 mL) to remove
soluble impurities. There was thus obtained
N-(6-nitro-benzothiazol-2-yl)nicotinamide (1.36 g, 4.53 mmol, 91%).
LC/ESI-MS: m/z=301 [M+H].sup.+; m/z=299 [M-H].sup.-; R.sub.t=3.54
min.
[0168] Step 2. N-(6-Nitrobenzothiazol-2-yl)nicotinamide (0.50 g,
1.67 mmol) was dissolved in dimethylsulfoxide (50 mL) by warming.
After addition of palladium on charcoal (0.089 g, 10% Pd, 0.08 mmol
Pd), the mixture was hydrogenated for 5.5 h at 80.degree. C. The
palladium was removed by hot filtration through a pad of silica.
After removal of the solvent,
N-(6-aminobenzothiazol-2-yl)nicotinamide (0.45 g, 1.67 mmol, 100%)
was obtained as a brownish solid. LC/ESI-MS: m/z=271 [M+H].sup.+;
m/z=269 [M-H].sup.-; R.sub.t=1.67 min.
Intermediate 5: N-(5-Aminobenzothiazol-2-yl)benzamide
[0169] Step 1. Ammonium thiocyanate (8.55 g, 112.5 mmol) was
dissolved in acetone (80 mL) and acetyl chloride (8.83 g, 112.5
mmol) was added dropwise. After stirring for 1 h at r.t., the solid
was filtered off, and the filtrate was added to a solution of
2-fluoro-5-nitroaniline in acetone (45 mL). The mixture was
refluxed for 6 h, then the solution was concentrated and stored
overnight at r.t. The precipitated
1-acetyl-3-(2-fluoro-5-nitrophenyl)thiourea was filtered off,
washed with acetone and dried. The mother liquor was concentrated
and recrystallized from acetone to yield another batch of the
product. A total of 12.55 g (48.8 mmol, 43%) of a grey solid was
obtained. LC/ESI-MS: m/z=258 [M+H].sup.+; R.sub.t=3.42 min.
[0170] Step 2. A solution of
1-acetyl-3-(2-fluoro-5-nitrophenyl)thiourea (9.63 g, 37.4 mmol) in
methanol (400 mL) was quickly poured into a solution of sodium
methanolate (concentration, 0.5 mol/L) in methanol (100 mL). The
solution was stored overnight without stirring. The precipitated
2-amino-5-nitrobenzothiazole was filtered off, washed with methanol
and dried (yellow crystals, 6.87 g, 35.2 mmol, 94%). LC/ESI-MS:
m/z=196 [M+H].sup.+; m/z=194 [M-H].sup.-; R.sub.t=2.71 min.
[0171] Step 3. A mixture of 2-amino-5-nitrobenzothiazole (1.52 g,
7.8 mmol), benzoyl chloride (1.36 mL, 11.7 mmol) and pyridine (15
mL) was heated to 60.degree. C. for 24 h. The mixture was poured
into water (250 mL), and the resulting precipitate was separated by
filtration to yield N-(5-nitro-benzothiazol-2-yl)benzamide (1.83 g,
6.12 mmol, 78%) as a yellow solid.
[0172] Step 4. A mixture of N-(5-nitrobenzothiazol-2-yl)benzamide
(1.79 g, 6.00 mmol) and palladium on charcoal (0.95 g, 10% Pd, 0.9
mmol Pd) in dimethylformamide (40 mL) was hydrogenated (1 bar) for
2 h at 100.degree. C. The palladium was removed by filtration
through a pad of celite and the filtrate was concentrated to a
small volume. Upon addition of water (200 mL), a precipitate formed
which was separated by filtration. There was thus obtained
N-(5-aminobenzothiazol-2-yl)benzamide (1.39 g, 5.14 mmol, 86%) as a
grey solid. LC/ESI-MS: m/z=300 [M+H].sup.+; m/z=298 [M-H].sup.-;
R.sub.t=4.2 min.
Intermediate 7:
4-Chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
[0173] Step 1. To a solution of methyl vanillate (7.29 g, 40 mmol)
in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol)
and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was
heated to 100.degree. C. for 3 h. After cooling to r.t., water was
added and the product was extracted several times with ethyl
acetate. The combined organic phases were washed with water and
brine. After drying over Na.sub.2SO.sub.4, the solvent was removed
to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol,
99%) as a grey solid which was used without further purification.
LC/ESI-MS: m/z=273 [M+H].sup.+; R.sub.t=3.82 min.
[0174] Step 2. Methyl 4-benzyloxy-3-methoxybenzoate (10.9 g, 40.0
mmol) was converted into methyl
4-benzyloxy-5-methoxy-2-nitrobenzoate (11.6 g, 36.6 mmol, 91%) as
described in U.S. Ser. No. 02/0026052 A1, page 51, reference
example 15. LC/ESI-MS: m/z=318 [M+H].sup.+; R.sub.t=3.85 min.
[0175] Step 3. In a 1 l Schlenk flask filled with argon, methyl
4-benzyloxy-5-methoxy-2-nitrobenzoate (11.60 g, 36.6 mmol) and
palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined
and tetrahydrofuran (250 mL) was added. The argon was replaced with
hydrogen (1 bar), and the mixture was vigorously stirred at r.t.
until completion of the reaction. The palladium was separated by
filtration through a pad of celite and the solvent was removed to
obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0
mmol, 98%) which was used without further purification. LC/ESI-MS:
m/z=166 [M-CH.sub.4O+H].sup.+; R.sub.t=2.17 min.
[0176] Step 4. A mixture of formamide (29 mL), ammonium formate
(3.41 g, 54 mmol) and methyl 2-amino-4-hydroxy-5-methoxybenzoate
(6.56 g, 36.0 mmol) was heated to 140.degree. C. for 4 h. After
cooling to r.t., water (75 mL) was added. After stirring for 1 h,
the precipitated 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one
was filtered off, washed with water and dried (grey solid, 5.86 g,
30.5 mmol, 85%). LC/ESI-MS: m/z=193 [M+H].sup.+; m/z=191
[M-H].sup.-; R.sub.t=1.53 min.
[0177] Step 5. A mixture of
7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.86 g, 30.5 mmol)
and acetic anhydride (21.5 mL, 229 mmol) in pyridine (4.9 mL, 61
mmol) was heated to 100.degree. C. for 4 h. After cooling to r.t.,
ice water (200 mL) was added and the mixture was vigorously stirred
for 1 h. The precipitated
7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one was filtered off,
washed with water and dried (grey solid, 6.64 g, 28.3 mmol, 93%).
LC/ESI-MS: m/z=235 [M+H].sup.+; m/z=233 [M-H].sup.-; R.sub.t=2.88
min. Cf. also WO 04/043472, page 32.
[0178] Step 6. 7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one
(2.34 g, 10.0 mmol) was converted into
4-chloro-7-hydroxy-6-methoxyquinazoline (1.22 g, 5.79 mmol, 58%) as
described in WO 04/043472, page 32. LC/ESI-MS: m/z=211
[M(.sup.35Cl)+H].sup.+; m/z=209 [M(.sup.35Cl)-H].sup.-;
R.sub.t=2.45 min.
[0179] Step 7. Di-tert-butyl azodicarboxylate (0.478 g, 2.08 mmol)
was added portionwise to a mixture of
4-chloro-7-hydroxy-6-methoxyquinazoline (0.350 g, 1.66 mmol),
3-(4-methylpiperazin-1-yl)-propan-1-ol (Intermediate 9, 0.276 g,
1.74 mmol), and triphenylphosphine (0.544 g, 2.08 mmol) in
dichloromethane (20 mL) at r.t. If necessary, further alcohol was
added. After stirring for 2 h, the solution was concentrated to 10
mL, mounted on silica and chromatographed (gradient,
dichloromethane to dichloromethane:methanol=3:2 within 1 h) to
obtain
4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
(brownish solid, 0.431 g, 1.23 mmol, 74%). LC/ESI-MS: m/z=351
[M(.sup.35Cl)+H].sup.+; R.sub.t=1.88 min. Cf. also WO 04/043472,
page 32.
Intermediate 8:
4-Chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
[0180] Step 1. Methyl isovanillate (2.73 g, 15 mmol) was converted
into methyl 3-benzyloxy-4-methoxybenzoate (3.91 g, 14.4 mmol, 96%)
in analogy to the preparation of Intermediate 7, Step 1. LC/ESI-MS:
m/z=273 [M+H].sup.+; R.sub.t=3.90 min.
[0181] Step 2. Methyl 3-benzyloxy-4-methoxybenzoate (2.83 g, 10.4
mmol) was converted into methyl
5-benzyloxy-4-methoxy-2-nitrobenzoate (3.08 g, 9.71 mmol, 94%) in
analogy to the preparation of Intermediate 7, Step 2. LC/ESI-MS:
m/z=318 [M+H].sup.+; R.sub.t=4.00 min.
[0182] Step 3. Methyl 5-benzyloxy-4-methoxy-2-nitrobenzoate (4.11
g, 13.0 mmol) was converted into methyl
2-amino-5-hydroxy-4-methoxybenzoate (2.56 g, 13.0 mmol, 100%) in
analogy to the preparation of Intermediate 7, Step 3. LC/ESI-MS:
m/z=166 [M-CH.sub.4O+H].sup.+; R.sub.t=1.95 min.
[0183] Step 4. 2-Amino-5-hydroxy-4-methoxybenzoate (2.56 g, 13.0
mmol) was converted into
6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (1.91 g, 9.94 mmol,
76%) in analogy to the preparation of Intermediate 7, Step 4.
LC/ESI-MS: m/z=193 [M+H].sup.+; m/z=191 [M-H].sup.-; R.sub.t=1.77
min.
[0184] Step 5. 6-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one
(1.90 g, 9.86 mmol) was converted into
6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (2.22 g, 9.48 mmol,
96%) in analogy to the preparation of Intermediate 7, Step 5.
LC/ESI-MS: m/z=235 [M+H].sup.+; m/z=233 [M-H].sup.-; R.sub.t=2.20
min.
[0185] Step 6. 6-Acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one
(0.468 g, 2.00 mmol) was converted into
4-chloro-6-hydroxy-7-methoxyquinazoline (0.398 g, 1.89 mmol, 95%)
in analogy to the preparation of Intermediate 7, Step 6. LC/ESI-MS:
m/z=211 [M(.sup.35Cl)+H].sup.+; m/z=209 [M(.sup.35Cl)-H].sup.-;
R.sub.t=2.40 min.
[0186] Step 7. 4-Chloro-6-hydroxy-7-methoxyquinazoline (0.373 g,
1.77 mmol) was converted into
4-chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
(0.451 g, 1.29 mmol, 73%) in analogy to the preparation of
Intermediate 7, Step 7. LC/ESI-MS: m/z=351 [M(.sup.35Cl)+H].sup.+;
R.sub.t=1.82 min.
Intermediate 9: 3-(4-Methylpiperazin-1-yl)-propan-1-ol
[0187] 1-Methylpiperazine (6.99 mL, 63 mol) was dissolved in
toluene (30 mL). 3-Bromopropanol (2.62 mL, 30 mmol) was added
slowly and the mixture was stirred overnight at r.t. After heating
to 80.degree. C. for 2 h and cooling to r.t., the mixture was
filtered and the filter cake was thoroughly washed with toluene.
After removal of the solvent, the residue was subjected to
distillation (b.p., 180.degree. C./2 mbar) to obtain a colourless
oil (4.08 g, 25.8 mmol, 86%). .sup.1H NMR (CDCl.sub.3):
.delta.=1.70 (.PSI.-quint, J.apprxeq.5.8 Hz, 2H), 2.26 (s, 3H),
2.35-2.6 (m, 8H), 2.60 (.PSI.-t, J=5.8 Hz, 2H), 3.77 (.PSI.-t,
J=5.3 Hz, 2H), 4.09 (s, br., 1H).
Intermediate 10: 2-Chloro-4-(4-methylpiperazin 1-yl)pyrimidine
[0188] A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol),
1-methylpiperazine (0.65 g, 6.40 mmol), and ethyldiisopropylamine
(2.8 mL, 16.22 mmol) in ethanol (13 mL) was stirred at -10.degree.
C. for 2 h and then at r.t. overnight. The mixture was partitioned
between H.sub.2O/brine (3:1; 100 mL) and chloroform (3.times.70
mL). The combined organic phases were washed once with brine (50
mL) and dried over MgSO.sub.4. Removal of solvent yielded a
pale-beige solid, which was washed with ethyl acetate/ultrasound to
give the desired product as a colourless powder, which was further
washed with Et.sub.2O. Additional product was obtained upon
fractional crystallization of the washing solution. A total of
0.741 g (3.48 mmol, 54%) of
2-chloro-4-(4-methylpiperazin1-yl)pyrimidine was obtained.
LC/ESI-MS: m/z=213 [M(.sup.35Cl)+H].sup.+; R.sub.t=0.5 min.
Intermediate 11:
2-Chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine
[0189] A mixture of 2,4-dichloropyrimidine (0.967 g, 6.49 mmol),
3-amino-5-methylpyrazole (0.63 g, 6.40 mmol), and
ethyldiisopropylamine (2.8 mL, 16.22 mmol) in ethanol (13 mL) was
stirred at -10.degree. C. for 2 h, then at r.t. overnight, and
finally at 50.degree. C. for 3.5 h. The mixture was concentrated to
a total volume of approximately 10 mL. Upon repeated addition of
diethylether, (2-chloro-pyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine
(0.258 g, 1.23 mmol, 19%) was obtained as colourless crystals.
LC/ESI-MS: m/z=210 [M(.sup.35Cl)+H].sup.+; m/z=208
[M(.sup.35Cl)-H].sup.-; R.sub.t=2.30 min.
Intermediate 12:
N.sup.6-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-y-
l}-benzothiazole-2,6-diamine hydrochloride
[0190] Intermediate 7 (0.285 mmol) and benzothiazole-2,6-diamine
(47 mg, 0.285 mmol) were dissolved in butanol (5 mL). HCl in
dioxane (0.214 mL, 4 M solution) was added. The reaction was
finished after 6 h at 100.degree. C. The resulting precipitate was
filtered, washed with dichloromethane, and dried in vacuo (97%
yield). LC/ESI-MS: m/z=480 [M+H].sup.+.
Intermediate 13:
N.sup.5-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-y-
l}-benzothiazole-2,5-diamine hydrochloride
[0191] Intermediate 7 (0.285 mmol) and benzothiazole-2,5-diamine
(47 mg, 0.285 mmol) were dissolved in butanol (5 mL). HCl in
dioxane (0.214 mL, 4 M solution) was added. The reaction was
finished after 6 h at 100.degree. C. The resulting precipitate was
filtered, washed with dichloromethane, and dried in vacuo (97%
yield). LC/ESI-MS: m/z=480 [M+H].sup.+.
Intermediate 14:
1-[6-(6-Chloro-pyrimidin-4-ylamino)-benzothiazol-2-yl]-3-(2-methoxy-5-met-
hyl-phenyl)-urea
[0192] A mixture of 4,6-dichloropyrimidine (180 mg, 1.21 mmol),
benzothiazole-2,6-diamine (200 mg, 1.21 mmol), sodium iodide (216
mg, 1.45 mmol), ethyl diisopropylamine (0.25 mL, 1.45 mmol) and DMF
(10 mL) was heated at 85.degree. C. for 3 h.
2-Methoxy-5-methylphenyl isocyanate (0.20 mL, 1.33 mmol) was added
and heating was continued at 85.degree. C. for 3 h. The solvent was
removed and the residue treated with CH.sub.2Cl.sub.2. The
precipitate was separated (0.57 g, 85%). LC/EST-MS: m/z=441
[M+H].sup.+; m/z=439 [M-H].sup.-; R.sub.t=3.64 min.
Syntheses of the Examples
Example 1
[0193]
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzoxazol-2-yl]benzamide
was prepared by heating a mixture of
N-(6-aminobenzoxazol-2-yl)benzamide (IM 1, 30 mg, 0.118 mmol) and
4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 26.5 mg, 0.118 mmol)
in ethanol (3 mL) to 80.degree. C. for 2 h. The resulting
precipitate was separated by filtration, washed with ethanol and
dried (yellow solid, 38 mg, 85 .mu.mol, 72%). LC/ESI-MS: m/z=442
[M+H].sup.+; m/z=440 [M-H].sup.-; R.sub.t=2.43 min.
Example 2
[0194]
N-[6(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]benzamide
was prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 30 mg, 0.111 mmol) and
4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111 mmol)
in ethylene glycol (0.7 mL) to 100.degree. C. for 2 h. Brine (25
mL) and saturated sodium hydrogencarbonate solution (25 mL) were
added and the product was extracted with chloroform (3.times.40
mL). After drying over Na.sub.2SO.sub.4, the solvent was removed
and the residue was purified by pTLC (petroleum
ether:dichloromethane:methanol=12:14:3) to yield a yellow solid (19
mg, 41 .mu.mol, 37) LC/ESI-MS: m/z=458 [M+H].sup.+; m/z=456
[M-H].sup.-; R.sub.t=2.88 min.
Example 3
[0195]
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]isonicoti-
namide was prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)isonicotinamide (Intermediate 3, 50 mg,
0.185 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 42
mg, 0.185 mmol in ethanol (3 mL) to 80.degree. C. for 2 h. The
resulting precipitate was separated by filtration, washed with
ethanol and dried (yellow solid, 82 mg, 0.179 mmol, 97%).
LC/ESI-MS: m/z=459 [M+H].sup.+; m/z=457 [M-H].sup.-; R.sub.t=2.65
min.
Example 4
[0196]
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]nicotinam-
ide was prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)nicotinamide (IM 4, 30 mg, 0.11 mmol)
and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.11
mmol) in ethanol (3 mL) to 80.degree. C. for 2 h. The resulting
precipitate was separated by filtration, washed with ethanol and
dried (yellow solid, 44 mg, 96 .mu.mol, 87%). LC/ESI-MS: m/z=459
[M+H].sup.+; m/z=457 [M-H].sup.-; R.sub.t=2.60 min.
Example 5
[0197]
N-(6-{6-Methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-y-
lamino}-benzothiazol-2-yl)benzamide was prepared by heating a
mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 30 mg,
0.111 mmol),
4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
(Intermediate 7, 39 mg, 0.111 mmol), ethyldiisopropylamine (40
.mu.L, 0.222 mmol), and HCl (84 .mu.L, 4 M solution in dioxane,
0.333 mmol) in n-butanol (3 mL) to 110.degree. C. for 2 h.
Saturated sodium hydrogencarbonate solution was added and the
product was extracted with chloroform. After washing with water and
drying over Na.sub.2SO.sub.4, the solvent was removed. The residue
was taken up in little methanol, then water was slowly added. After
stirring the mixture overnight, a brownish solid was obtained (38
mg, 65 .mu.mol, 59%). LC/ESI-MS: m/z=584 [M+H].sup.+; m/z=582
[M-H].sup.-; R.sub.t=2.27 min.
Example 6
[0198]
N-(6-{7-Methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-y-
lamino}-benzothiazol-2-yl)benzamide was prepared by heating a
mixture of N-(6-aminobenzothiazol-2-yl)benzamide (Intermediate 2,
40 mg, 0.148 mmol),
4-chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-
e (IM 8, 52 mg, 0.148 mmol), and HCl (112 .mu.L, 4 M solution in
dioxane, 0.444 mmol) in n-butanol (6 mL) to 110.degree. C. for 5 h.
Saturated sodium hydrogencarbonate solution was added and the
product was extracted with ethyl acetate. After washing with water
and drying over Na.sub.2SO.sub.4, the solvent was removed. The
residue was taken up in little methanol, then water was slowly
added. After stirring the mixture overnight, a grey solid was
obtained (39 mg, 66 .mu.mol, 45%). LC/ESI-MS: m/z=584 [M+H].sup.+;
m/z=582 [M-H].sup.-; R.sub.t=2.26 min.
Example 7
[0199] N-[6-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was
prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and
6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80.degree.
C. for 4 h. The resulting precipitate was separated by filtration
and washed with ethanol (69 mg, 0.178 mmol, 96%). LC/ESI-MS:
m/z=388 [M+H].sup.+; m/z=386 [M-H].sup.-; R.sub.t=3.07 min.
Example 8
[0200]
N-{6-[4-(4-Methylpiperazin-1-yl)pyrimidin-2-ylamino]benzothiazol-2--
yl}benzamide was prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and
2-chloro-4-(4-methylpiperazin1-yl)pyrimidine (IM 10, 40 mg, 0.186
mmol) in ethanol (3 mL) to 80.degree. C. for 4 days. After
dissolving the precipitate by addition of dimethylformamide, pTLC
(dichloromethane:methanol=4:1) yielded a solid (44 mg, 0.100 mmol,
54%). LC/ESI-MS: m/z=446 [M+H].sup.+; m/z=444 [M-H].sup.-;
R.sub.t=2.12 min.
Example 9
[0201]
N-{6-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-
-2-yl}-benzamide was prepared by heating a mixture of
N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 35 mg, 0.13 mmol) and
(2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg,
0.143 mmol) in ethanol (3 mL) to 80.degree. C. for 9 h. The
precipitate was separated by filtration, washed with ethanol and
dried (38 mg, 85 .mu.mol, 66%). LC/ESI-MS: m/z=443 [M+H].sup.+;
m/z=441 [M-H].sup.-; R.sub.t=2.80 min.
Example 10
[0202]
N-[5-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-2-yl]benzamide
was prepared by heating a mixture of
N-(5-aminobenzothiazol-2-yl)benzamide (IM; 5, 30 mg, 0.111 mmol)
and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 25 mg, 0.111
mmol) in ethylene glycol (0.7 mL) to 100.degree. C. for 2 h. Brine
(25 mL) and saturated sodium hydrogencarbonate solution (25 mL)
were added and the product was extracted with chloroform
(3.times.40 mL). After drying over Na.sub.2SO.sub.4, the solvent
was removed and ethyl acetate and petroleum ether were added to the
residue. Filtration yielded a yellow solid (28 mg, 60 .mu.mol,
55%). LC/ESI-MS: m/z=458 [M+H].sup.+; m/z=456 [M-H].sup.-;
R.sub.t=3.20 min.
Example 11
[0203] N-[5-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was
prepared by heating a mixture of
N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and
6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80.degree.
C. for 4 h. The resulting precipitate was separated by filtration
and washed with ethanol (68 mg, 0.174 mmol, 94%). LC/ESI-MS:
m/z=388 [M+H].sup.+; m/z=386 [M-H].sup.-; R.sub.t=3.13 min.
Example 12
[0204]
N-{5-[4-(4-Methylpiperazin-1-yl)pyrimidin-2-ylamino]benzothiazol-2--
yl}benzamide was prepared by heating a mixture of
N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and
2-chloro-4-(4-methylpiperazin1-yl)pyrimidine (IM 10, 40 mg, 0.186
mmol) in ethanol (3 mL) to 80.degree. C. for 4 days. Brine (25 mL)
and saturated sodium hydrogencarbonate solution (25 mL) were added
and the product was extracted with chloroform (3.times.40 mL) and
ethyl acetate (40 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4 and the solvent was removed. The residue was
purified by pTLC (dichloromethane:methanol=4:1) to yield a solid
(44 mg, 99 mol, 53%). LC/ESI-MS: m/z=446 [M+H].sup.+; m/z=444
[M-H].sup.-; R.sub.t=2.38 min.
Example 13
[0205]
N-{5-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-
-2-yl}-benzamide was prepared by heating a mixture of
N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol) and
(2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg,
0.143 mmol) in ethanol (3 mL) to 80.degree. C. for 9 h. The
precipitate was separated by filtration, washed with ethanol and
dried (32 mg, 72 .mu.mol, 56%). LC/ESI-MS: m/z=443 [M+H].sup.+;
m/z=441 [M-H].sup.-; R.sub.t=2.92 min.
Example 15
[0206]
N-(6-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin--
4-ylamino}-benzooxazol-2-yl)-benzamide was prepared by reaction of
intermediate 1 (0.138 mM) with intermediate 7 (0.138 mM) in butanol
(3 mL) under acidic katalysis (3.0 eq., 0.105 mL, 4 M HCl in
Dioxane) at 110.degree. C. The reaction was finished after 5 h.
After cooling the reaction was partitioned between saturated
aqueous NaHCO.sub.3 solution and ethyl acetate. The layers were
separated, the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed neutral with water and dried
with Na.sub.2SO.sub.4. After filtration and removal of the solvent
in vacuo the product was purified by prep. HPLC.
Example 16
[0207]
N-(5-{7-Methoxy-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin--
4-ylamino}-benzothiazol-2-yl)-benzamide was prepared by heating a
mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13
mmol),
4-chloro-7-methoxy-6-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline
(IM 8, 46 mg, 0.13 mmol) and 4 M HCl in dioxane (0.09 mL, 0.39
mmol) in n-butanol (3 mL) to 110.degree. C. for 5 h. The HCl salt
of the product precipitated. It was separated by filtration and
washed twice with CH.sub.2Cl.sub.2. No further purification was
necessary (65 mg, 0.11 mmol, 93%). LC/ESI-MS: m/z=620 [M+H].sup.+;
m/z=618 [M-H].sup.-; R.sub.t=2.43 min.
Example 17
[0208]
N-(5-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin--
4-ylamino}-benzothiazol-2-yl)-benzamide was prepared according to
the procedure described for example 15 from intermediate 5 and
intermediate 7.
Example 18
[0209]
3-Chloro-N-(6-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-qu-
inazolin-4-ylamino}-benzothiazol-2-yl)-benzamide was prepared by
reaction of intermediate 12 (30 mg, 58 .mu.mol) with
3-chloro-benzoyl chloride (8 .mu.L, 63 .mu.mol) in a mixture of
pyridine and DMF (1:1, 4 mL total) in the presence of triethylamine
(100 .mu.L, 0.71 mmol) at 60.degree. C. The reaction was controlled
several times, if necessary further acid chloride was added. The
reaction mixture was partitioned between saturated aqueous
NaHCO.sub.3 solution and DCM. After extraction with dichloromethane
the combined organic layers were dried with Na.sub.2SO.sub.4. The
solvent was removed in vacuo after filtration and the product
purified by prep. HPLC (20 mg, 55% yield).
Example 19
[0210]
3-Chloro-N-(5-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-qu-
inazolin-4-ylamino}-benzothiazol-2-yl)-benzamide was prepared
following the procedure described for example 18 starting from
intermediate 13.
Example 20
[0211]
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(6-{6-methoxy-7-[3-(4-methy-
l-piperazin-1-yl)-propoxy]-quinazolin-4-ylamino}-benzothiazol-2-yl)-urea
was prepared by reaction of intermediate 12 (58 .mu.mol, 30 mg)
with 1-chloro-4-isocyanato-2-trifluoromethyl-benzene (13 mg, 58
.mu.mol) in dichloromethane in the presence of triethylamine (5
drops). The product was purified by prep. HPLC (5 mg, 15%
yield).
Example 21
[0212]
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(5-{6-methoxy-7-[3-(4-methy-
l-piperazin-1-yl)-propoxy]-quinazolin-4-ylamino}-benzothiazol-2-yl)-urea
was prepared according to the procedure described for example 20
starting from intermediate 13.
Example 22
[0213]
1-(2-Methoxy-5-methyl-phenyl)-3-(6-{6-methoxy-7-[3-(4-methyl-pipera-
zin-1-yl)-propoxy]-quinazolin-4-ylamino}-benzothiazol-2-yl)-urea
was prepared according to the procedure described for example 20
starting from intermediate 12 and
2-isocyanato-1-methoxy-4-methyl-benzene.
Example 23
[0214]
1-(6-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin--
4-ylamino}-benzothiazol-2-yl)-3-(2-methoxy-phenyl)-urea was
prepared according to the procedure described for example 20
starting from intermediate 12 and
1-isocyanato-2-methoxy-benzene.
Example 24
[0215]
1-{6-[6-(2-Hydroxy-ethylamino)-pyrimidin-4-ylamino]-benzothiazol-2--
yl}-3-(2-methoxy-5-methyl-phenyl)-urea was prepared by heating a
mixture of IM 14 (100 mg, 0.227 mmol) and 3-aminoethanol (1 mL) at
85.degree. C. for 3 h. The product was precipitated by the addition
of water (47 mg, 45%).
Example 25
[0216]
1-{6-[6-(3-Hydroxy-propylamino)-pyrimidin-4-ylamino]-benzothiazol-2-
-yl}-3-(2-methoxy-5-methyl-phenyl)-urea was prepared by heating a
mixture of IM 14 (100 mg, 0.227 mmol) and 3-aminopropanol (1 mL) at
85.degree. C. for 3 h. The product was precipitated by the addition
of water (42 mg, 39%).
Analytical Data of Compounds of Formula (I) of the Present
Invention:
TABLE-US-00001 [0217] LC/ESI-MS: Example Compound Structure [M + H]
m/z = Rt 1 ##STR00018## 442 2.43 2 ##STR00019## 458 2.880 3
##STR00020## 459 2.65 4 ##STR00021## 459 2.60 5 ##STR00022## 584
2.27 6 ##STR00023## 584 2.26 7 ##STR00024## 388 3.07 10
##STR00025## 458 3.20 11 ##STR00026## 388 3.13 15 ##STR00027## 568
2.22 16 ##STR00028## 584 2.43 17 ##STR00029## 584 2.34 18
##STR00030## 618 3.20 19 ##STR00031## 618 2.27 20 ##STR00032## 701
2.87 21 ##STR00033## 701 3.07 22 ##STR00034## 643 2.62 23
##STR00035## 629 2.52
Analytical Data of Compounds of Formula (Ia) of the Present
Invention:
TABLE-US-00002 [0218] LC/ESI-MS: Example Compound Structure [M + H]
m/z = Rt 24 ##STR00036## 466 2.87 25 ##STR00037## 480 2.94
Analytical Data of Compounds of Formula (II) of the Present
Invention:
TABLE-US-00003 [0219] LC/ESI-MS: Example Compound Structure [M + H]
m/z = Rt 8 ##STR00038## 446 2.12 9 ##STR00039## 443 2.80 12
##STR00040## 446 2.38 13 ##STR00041## 443 2.38
Materials and Methods
Protein Kinase Assay
[0220] The effect of the benzazole derivatives was tested on
recombinant, human protein kinases. All protein kinases were
expressed in Sf9 insect cells as human recombinant GST-fusion
proteins or as His-tagged proteins by means of the baculovirus
expression system. Protein kinases were purified by affinity
chromatography using either GSH-agarose or Ni-NTH-agarose. The
purity and identity of each was checked by SDS-PAGE/silver staining
and by western blot analysis with specific antibodies.
[0221] A proprietary protein kinase assay (33 PanQinase.RTM.
Activity Assay) was used for measuring the kinase activity. All
kinase assays were performed in 96-well FlashPlates.TM. in a 50
.mu.l reaction volume. The assay for all enzymes contained 60 mM
HEPES-NaOH, pH 7.5, 3 mM MgCl.sub.2, 3 mM MnCl.sub.2, 3 .mu.M
Na-orthovanadate, 1.2 mM DTT, 50 .mu.g/ml PEG.sub.20000 and 1 .mu.M
[.gamma.-.sup.33P]-ATP (approx. 5.times.10.sup.5 cpm per well).
[0222] The reaction cocktails were incubated at 30.degree. C. for
80 minutes. The reaction was stopped with 50 .mu.l of 2% (v/v)
H.sub.3PO.sub.4, plates were aspirated and washed two times with
200 .mu.l of 0.9% (w/v) NaCl. Incorporation of 33 .mu.l was
determined with a microplate scintillation counter. All assays were
performed with a BeckmanCoulter/Sagian robotic system.
Cellular Receptor Tyrosine Kinase Assay
[0223] The effect of thiazole derivatives was tested by determining
the inhibition of different receptor tyrosine kinases (RTKs) in
various cell lines which expressed the following growth factor
receptors: EGF-R, PDGF-R, TIE2, IGF-1R, EPHB4, and VEGF-R.sup.2.
Receptor autophosphorylation was induced by specific ligands for
each receptor. Stimulation of cells resulted in maximal
autophosphorylation in control cells (high control) without
inhibitor. Test compounds were applied to cells prior to
stimulation. Cells were lysed using a standard lysis buffer
preserving the distinct phosphoprotein levels. RTK-phosphorylation
was quantified via sandwich ELISA using receptor-specific capture
antibodies and a phosphotyrosine antibody. Sigmoidal inhibitor
curves based on relative inhibition compared with phosphorylation
levels under high control conditions were generated which allowed
the determination of IC.sub.50 values for each test compound.
Cellular Aurora-B Kinase Assay
[0224] The effect of thiazole derivatives was tested in a cellular
Aurora-B assay by measuring the effect of the test compounds on the
endoreduplication (EndoR) of genomic DNA. Endoreduplication is
detectable in cells as DNA-content higher then 4 n. Propidium
Iodine (PI) was used to quantify the DNA content using a
fluorescence activated cell sorter (FACS).
[0225] In the experiment, HT29 colon-carcinoma cells were treated
with test compounds at different concentrations for 3 days. On day
5 cells were harvested and fixed in methanol. On day 6 cells were
rehydrated and incubated with RNAse A and PI. Incorporated PI was
detected by FACS measuring fluorescence emission at 650 nm upon
excitation at 488 nm. For each compound concentration the
percentage of EndoR-population as compared to the whole cell
population was determined. For estimation of IC.sub.50 values of
Aurora-B inhibition the percentages of EndoR-populations were
plotted versus compound concentrations.
Cellular Aurora-B Kinase Histone H3 Phosphorylation Assay
[0226] The effect of compounds was tested in a cellular Aurora-B
assay measuring phosphorylation of the Aurora B-substrate protein
Histone H3 at Serine 10 (His H3-pS10). Inhibition of Aurora B
results in reduction of His H3-pS10 which was detected in a
specific immuno-assay. In the experiment, HT-29 colon-carcinoma
cells were seeded on day 1 and on day 2 test compounds at different
concentrations were added. Cells were incubated with test compounds
for 1 hour. Subsequently, Calyculin A was added for 30 min. For
DELFIA.RTM.-detection (PerkinElmer) of His H3-pS10, lysates were
transferred to a microtiterplate and incubated with detecting
antibody directed against His H3-pS10 and Europium-labelled
secondary anti-IgG-antibody. Emission at 615 nm was measured upon
excitation at 340 nm and the percentage of inhibition was
calculated for each concentration of the test compounds relative to
controls without inhibitor. Mean values of His H3-pS10 percentage
were plotted versus compound concentration for calculation of
IC.sub.50-values.
Results
[0227] The following examples show IC.sub.50 values lower than 500
nM on at least one kinase selected from Aurora A, Aurora B, EGF-R,
ERBB2, PDGFR, IGF1-R, VEGF-R.sup.2, VEGF-R.sup.3, EPHB4, Tie2, and
SRC or display a beneficial activity profile by inhibiting at least
two kinases from at least two different molecular mechanisms of
tumor progression with IC.sub.50 values lower than 500 nM: 1, 2, 5,
6, 9, 11, 15, 17, 18, 20, 21, 22.
[0228] The compounds of the present invention show IC.sub.50 values
lower than 10 .mu.M in the Cellular Receptor Tyrosine Kinase Assays
and/or the Cellular Aurora-B Kinase Assays.
* * * * *