U.S. patent application number 13/164310 was filed with the patent office on 2012-02-23 for quinazoline derivatives as angiogenesis inhibitors.
Invention is credited to Laurent Francois Andre Hennequin.
Application Number | 20120046300 13/164310 |
Document ID | / |
Family ID | 27839732 |
Filed Date | 2012-02-23 |
United States Patent
Application |
20120046300 |
Kind Code |
A1 |
Hennequin; Laurent Francois
Andre |
February 23, 2012 |
Quinazoline Derivatives as Angiogenesis Inhibitors
Abstract
The present invention relates to compounds of the formula I:
##STR00001## wherein: ring C is an 8, 9, 10, 12 or 13-membered
bicyclic or tricyclic moiety which moiety may be saturated or
unsaturated, which may be aromatic or non-aromatic, and which
optionally may contain 1-3 heteroatoms selected independently from
O, N and S; is --O-- --NH-- or --S--; is 0, 1, 2, 3, 4 or 5; is 0,
1, 2 or 3; and R.sup.2 and R.sup.1 are as defined herein; and salts
thereof; their use in the manufacture of a medicament for use in
the production of an antiangiogenic and/or vascular permeability
reducing effect in warm-blooded animals; processes for the
preparation of such compounds; pharmaceutical compositions
containing a compound of formula I or a pharmaceutically acceptable
salt thereof and methods of treating disease states involving
angiogenesis by administering a compound of formula I or a
pharmaceutically acceptable salt thereof. The compounds of formula
I inhibit the effects of VEGF, a property of value in the treatment
of a number of disease states including cancer and rheumatoid
arthritis.
Inventors: |
Hennequin; Laurent Francois
Andre; (Reims, FR) |
Family ID: |
27839732 |
Appl. No.: |
13/164310 |
Filed: |
June 20, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10566842 |
Feb 2, 2006 |
7989460 |
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PCT/GB2004/003376 |
Aug 5, 2004 |
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13164310 |
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Current U.S.
Class: |
514/252.17 ;
514/266.22; 514/266.24; 544/284 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 7/00 20180101; A61P 19/02 20180101; A61P 29/00 20180101; C07D
403/10 20130101; A61P 13/12 20180101; A61P 27/02 20180101; A61P
3/10 20180101; A61P 43/00 20180101; A61P 9/00 20180101; A61P 9/10
20180101; C07D 401/14 20130101; A61P 15/00 20180101; C07D 403/14
20130101; A61P 35/02 20180101; A61P 17/02 20180101; A61P 17/10
20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/252.17 ;
544/284; 514/266.22; 514/266.24 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61P 7/00 20060101 A61P007/00; C07D 401/12 20060101
C07D401/12 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2003 |
GB |
0318422.3 |
Claims
1. A compound of the formula I: ##STR00075## wherein: ring C is an
8-, 9-, 10-, 12- or 13-membered bicyclic or tricyclic moiety which
moiety may be saturated or unsaturated, which may be aromatic or
non-aromatic, and which optionally may contain 1-3 heteroatoms
selected independently from O, N and S; Z is --O--, --NH-- or
--S--; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; R.sup.2
represents hydrogen, hydroxy, halogeno, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or R.sup.5X.sup.1-- (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OC(O)--, --C(O)--,
--S--, --SO--, --SO.sub.2--, --NR.sup.6C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8--, --NR.sup.9SO.sub.2-- or --NR.sup.10--
(wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.5 is selected from one of
the following twenty-two groups: 1) hydrogen,
oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be unsubstituted
or which may be substituted with one or more groups selected from
hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2 represents --O--
or --NR.sup.12-- (in which R.sup.12 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.11
represents C.sub.1-3alkyl, --NR.sup.13R.sup.14 or --OR.sup.5
(wherein R.sup.13, R.sup.14 and R.sup.15 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.16
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.17C(O)--, --C(O)NR.sup.18--,
SO.sub.2NR.sup.19--, --NR.sup.20SO.sub.2-- or --NR.sup.21--
(wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.23C(O)--, --C(O)NR.sup.24--,
--SO.sub.2NR.sup.25--, --NR.sup.26SO.sub.2-- or --NR.sup.27--
(wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26 and R.sup.27 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.22 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.28
(wherein R.sup.28 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.28 (wherein R.sup.28 is as
defined herein); 7) C.sub.2-5alkenylR.sup.28 (wherein R.sup.28 is
as defined herein); 8) C.sub.2-5alkynylR.sup.28 (wherein R.sup.28
is as defined herein); 9) R.sup.29 (wherein R.sup.29 represents a
pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3
heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents selected
from oxo, hydroxy, halogeno, amino, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl, C.sub.1-4aminoalkyl,
C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy, carboxy,
trifluoromethyl, cyano, --C(O)NR.sup.30R.sup.31,
--NR.sup.32C(O)R.sup.33 (wherein R.sup.30, R.sup.31, R.sup.32 and
R.sup.33, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is
as defined herein); 11) C.sub.2-5alkenylR.sup.29 (wherein R.sup.29
is as defined herein); 12) C.sub.2-5alkynylR.sup.29 (wherein
R.sup.29 is as defined herein); 13) C.sub.1-5alkylX.sup.6R.sup.29
(wherein X.sup.6 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.34C(O)--, --C(O)NR.sup.35--, --SO.sub.2NR.sup.36--,
--NR.sup.37SO.sub.2-- or --NR.sup.38-- (wherein R.sup.34, R.sup.35,
R.sup.36, R.sup.37 and R.sup.38 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined herein); 14) C.sub.2-5alkenylX.sup.7R.sup.29
(wherein X.sup.7 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.39C(O)--, --C(O)NR.sup.40--, --SO.sub.2NR.sup.41--,
--NR.sup.42SO.sub.2-- or --NR.sup.43-- (wherein R.sup.39, R.sup.40,
R.sup.41, R.sup.42 and R.sup.43 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined herein); 15) C.sub.2-5alkynylX.sup.8R.sup.29
(wherein X.sup.8 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.44C(O)--, --C(O)NR.sup.45--, --SO.sub.2NR.sup.46--,
--NR.sup.47SO.sub.2-- or --NR.sup.48-- (wherein R.sup.44, R.sup.45,
R.sup.46, R.sup.47 and R.sup.48 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined herein); 16)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.29 (wherein X.sup.9
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.49C(O)--,
--C(O)NR.sup.50--, --SO.sub.2NR.sup.51--, --NR.sup.52SO.sub.2-- or
--NR.sup.53-- (wherein R.sup.49, R.sup.50, R.sup.51, R.sup.52 and
R.sup.53 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined herein);
17) C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9
and R.sup.28 are as defined herein); 18) C.sub.2-5alkenyl which may
be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl, N-C.sub.1-4
alkylaminosulphonyl and N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19)
C.sub.2-5alkynyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro,
amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N-C.sub.1-4 alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined herein); 21)
C.sub.2-5alkynylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined herein); and 22)
C.sub.1-4alkylR.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9 is as defined herein, q is 0 or 1, r is 0 or 1,
and R.sup.54 and R.sup.55 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.fC.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl), with the proviso that R.sup.54 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); R.sup.1 represents
hydrogen, oxo, halogeno, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4alkoxymethyl, C.sub.1-4alkanoyl, C.sub.1-4haloalkyl,
cyano, amino, C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-3alkanoyloxy, nitro, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N-C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl,
N-(C.sub.1-4alkylsulphonyl)amino,
N-(C.sub.1-4alkylsulphonyl)-N-(C.sub.1-4alkyl)amino,
N,N-di(C.sub.1-4alkylsulphonyl)amino, a C.sub.3-7alkylene chain
joined to two ring C carbon atoms,
C.sub.1-4alkanoylaminoC.sub.1-4alkyl, carboxy or a group
R.sup.56X.sup.10 (wherein X.sup.10 represents a direct bond, --O--,
--CH.sub.2--, --OC(O)--, --C(O)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.57C(O)--, --C(O)NR.sup.58--, --SO.sub.2NR.sup.59--,
--NR.sup.60SO.sub.2-- or --NR.sup.61-- (wherein R.sup.57, R.sup.58,
R.sup.59, R.sup.60 and R.sup.61 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), and
R.sup.56 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.11C(O)R.sup.62 (wherein X.sup.11 represents
--O-- or --NR.sup.63-- (in which R.sup.63 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.62
represents C.sub.1-3alkyl, --NR.sup.64R.sup.65 or --OR.sup.66
(wherein R.sup.64, R.sup.65 and R.sup.66 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.12R.sup.67
(wherein X.sup.12 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.68C(O)--, --C(O)NR.sup.69--,
--SO.sub.2NR.sup.70--, --NR.sup.71SO.sub.2-- or --NR.sup.72--
(wherein R.sup.68, R.sup.69, R.sup.70, R.sup.71 and R.sup.72 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.67 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.13C.sub.1-5alkylX.sup.14R.sup.73 (wherein
X.sup.13 and X.sup.14 which may be the same or different are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.74C(O)--,
--C(O)NR.sup.75--, --SO.sub.2NR.sup.76--, --NR.sup.77SO.sub.2-- or
--NR.sup.78-- (wherein R.sup.74, R.sup.75, R.sup.76, R.sup.77 and
R.sup.78 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.73 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.79
(wherein R.sup.79 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79 is as
defined herein); 7) C.sub.2-5alkenylR.sup.79 (wherein R.sup.79 is
as defined herein); 8) C.sub.2-5alkynylR.sup.79 (wherein R.sup.79
is as defined herein); 9) R.sup.80 (wherein R.sup.80 represents a
pyridone group, a phenyl group or a 5-6-membered aromatic
heterocyclic group (linked via carbon or nitrogen) with 1-3
heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents selected
from oxo, hydroxy, halogeno, amino, C
.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --C(O)NR.sup.81R.sup.82,
--NR.sup.83C(O)R.sup.84 (wherein R.sup.81, R.sup.82, R.sup.83 and
R.sup.84, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.80 (wherein R.sup.80 is
as defined herein); 11) C.sub.2-5alkenylR.sup.80 (wherein R.sup.80
is as defined herein); 12) C.sub.2-5alkynylR.sup.80 (wherein
R.sup.80 is as defined herein); 13) C.sub.1-5alkylX.sup.15R.sup.80
(wherein X.sup.15 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.85C(O)--, --C(O)NR.sup.86--, --SO.sub.2NR.sup.87--,
--NR.sup.88SO.sub.2-- or --NR.sup.89-- (wherein R.sup.85, R.sup.86,
R.sup.87, R.sup.88 and R.sup.89 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.80 is as defined herein); 14)
C.sub.2-5alkenylX.sup.16R.sup.80 (wherein X.sup.16 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.90C(O)--,
--C(O)NR.sup.91--, --SO.sub.2NR.sup.92--, --NR.sup.93SO.sub.2-- or
--NR.sup.94-- (wherein R.sup.90, R.sup.91, R.sup.92, R.sup.93 and
R.sup.94 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined herein);
15) C.sub.2-5alkynylX.sup.17R.sup.80 (wherein X.sup.17 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.95C(O)--,
--C(O)NR.sup.96--, --SO.sub.2NR.sup.97--, --NR.sup.98SO.sub.2-- or
--NR.sup.99-- (wherein R.sup.95, R.sup.96, R.sup.97, R.sup.98 and
R.sup.99 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined herein);
16) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.80 (wherein X.sup.18
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.100C(O)--,
--C(O)NR.sup.101--, --SO.sub.2NR.sup.102--, --NR.sup.103SO.sub.2--
or --NR.sup.104-- (wherein R.sup.100, R.sup.101, R.sup.102,
R.sup.103 and R.sup.104 each independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as
defined herein); 17) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79
(wherein X.sup.18 and R.sup.79 are as defined herein); 18)
C.sub.2-5alkenyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro,
amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined herein); 21)
C.sub.2-5alkynylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined herein); and 22)
C.sub.1-4alkylR.sup.105(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106
(wherein X.sup.18 is as defined herein, x is 0 or 1, y is 0 or 1,
and R.sup.105 and R.sup.106 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl) with the proviso that R.sup.105 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
which is linked to X.sup.10 may bear one or more substituents
selected from hydroxy, halogeno and amino); with the proviso that
one or more R.sup.1 and/or one or more R.sup.2 are selected from
Q.sup.1X.sup.1-- wherein X.sup.1 is as defined herein and Q.sup.1
is selected from one of the following groups: 1)
C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 is C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or may bear 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), and
Q.sup.14 is a 5-6-membered saturated or partially unsaturated
heterocyclic group containing at least one nitrogen atom and
optionally containing a further nitrogen atom wherein Q.sup.14 is
linked to C.sub.1-6alkanoyl through a nitrogen atom and wherein
Q.sup.14 optionally bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylsulphonylC.sub.1-4alkyl,
C.sub.1-4alkoxycarbonyl, C.sub.1-4aminoalkyl, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); 2) Q.sup.2
(wherein Q.sup.2 is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group bears
either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.1-6alkanoylC.sub.1-6alkyl and
optionally bears a further 1 or 2 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkanoylC.sub.1-6alkyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 3)
C.sub.1-5alkylW.sup.1Q.sup.2 (wherein W.sup.1 represents --O--,
--S--, --SO--, --SO.sub.2--, --OC(O)--, --NQ.sup.3C(O)--,
--C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-, --NQ.sup.6SO.sub.2-- or
--NQ.sup.7- (wherein Q.sup.3, Q.sup.4, Q.sup.5, Q.sup.6 and Q.sup.7
each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined herein); 4)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined herein); 5)
C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2 is as defined herein); 6)
C.sub.2-5alkynylQ.sup.2 (wherein Q.sup.2 is as defined herein); 7)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9-, --SO.sub.2NQ.sup.10-, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined herein); 8)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined herein); 9)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined herein); 10)
C.sub.1-4alkylQ.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16
(wherein W.sup.2 is as defined herein, j is 0 or 1, k is 0 or 1,
and Q.sup.15 and Q.sup.16 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or may bear 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
provisos that Q.sup.15 cannot be hydrogen and one or both of
Q.sup.15 and Q.sup.16 must be a 5-6-membered saturated or partially
unsaturated heterocyclic group as defined herein which heterocyclic
group bears either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.1-6alkanoylC.sub.1-6alkyl and
optionally bears 1 or 2 further substituents selected from those
defined herein); 11)
C.sub.1-4alkylQ.sup.15C.sub.1-4alkanoylQ.sup.16n wherein Q.sup.15
is as defined herein and is not hydrogen and Q.sup.16n is a
5-6-membered saturated or partially unsaturated heterocyclic group
containing at least one nitrogen atom and optionally containing a
further nitrogen atom wherein Q.sup.16n is linked to
C.sub.1-6alkanoyl through a nitrogen atom and wherein Q.sup.16n
bears either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, C.sub.1-4alkylaminoC
.sub.1-4alkoxy, di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); with the
proviso that one or both of Q.sup.15 and Q.sup.16n must be a
5-6-membered saturated or partially unsaturated heterocyclic group
as defined herein which heterocyclic group bears either one
substituent selected from methylenedioxy or ethylenedioxy to form a
bicyclic ring, or bears at least one substituent selected from
C.sub.1-6alkanoylC.sub.1-6alkyl and optionally bears 1 or 2 further
substituents selected from those defined herein; and additionally
wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or C.sub.2-5alkynyl
group in Q.sup.1X.sup.1-- which is linked to X.sup.1 may bear one
or more substituents selected from hydroxy, halogeno and amino); or
a salt thereof.
2. A compound according to claim 1 wherein ring C is a
9-10-membered heteroaromatic bicyclic moiety which contains 1 or 2
nitrogen atoms.
3. A compound according to claim 1 wherein Z is --O-- or --S--.
4. A compound according to claim 1 wherein R.sup.1 represents
methyl or fluoro.
5. A compound according to claim 1 of the formula IIb: ##STR00076##
wherein: M is --CH-- or --N--; nc is 0, 1 or 2; R.sup.2c is linked
to a carbon atom of the 5-membered ring and is selected from
hydrogen and methyl; R.sup.2d is linked to a carbon atom of the
6-membered ring and is selected from hydrogen and fluoro; each
independently selected from hydrogen, hydroxy, halogeno, cyano,
nitro, trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3aR.sup.4a (wherein R.sup.3a and
R.sup.4a, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), and Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined in claim 1; Z.sup.a is --O-- or --S--; with
the proviso that at least one of R.sup.2a and R.sup.2b is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined in claim
1; or a salt thereof.
6. A compound according to claim 5 wherein one of R.sup.2a and
R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein X.sup.1
is --O-- and Q.sup.1 is selected from one of the following groups:
1) C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl, ##STR00077## wherein
Q.sup.14 is linked to C.sub.1-6alkanoyl through a nitrogen atom; 2)
Q.sup.2 (wherein Q.sup.2 is a 5-6-membered heterocyclic group
selected from pyrrolidinyl, piperidinyl, piperazinyl, ##STR00078##
which heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.2-4alkanoylC.sub.1-3alkyl and optionally bears a further 1 or
2 substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.2-4alkanoylC.sub.1-3alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 3)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined herein); 4)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 is as
defined in claim 1 and Q.sup.2 is as defined herein); 5)
C.sub.1-4alkylQ.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16
(wherein W.sup.2 is as defined in claim 1, j is 0 or 1, k is 0 or
1, and Q.sup.15 and Q.sup.16 are each independently selected from a
5-6-membered heterocyclic group selected from pyrrolidinyl,
piperidinyl, piperazinyl, ##STR00079## which heterocyclic group may
bear either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or may bear 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.2-4alkanoylC.sub.1-3alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
proviso one or both of Q.sup.15 and Q.sup.16 must be a 5-6-membered
heterocyclic group as defined herein which heterocyclic group bears
either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.2-4alkanoylC.sub.1-3alkyl and
optionally bears 1 or 2 further substituents selected from those
defined herein); 6)
C.sub.1-4alkylQ.sup.15C.sub.1-4alkanoylQ.sup.16n wherein Q.sup.15
is as defined herein and Q.sup.16n is a 5-6-membered heterocyclic
group selected from pyrrolidinyl, piperidinyl, piperazinyl,
##STR00080## wherein Q.sup.16n is linked to C.sub.1-6alkanoyl
through a nitrogen atom and wherein Q.sup.16n bears either one
substituent selected from methylenedioxy or ethylenedioxy to form a
bicyclic ring, or bears 1, 2 or 3 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, C.sub.2-4alkanoylC.sub.1-3alkyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); with the
proviso that one or both of Q.sup.15 and Q.sup.16n must be a
5-6-membered heterocyclic group as defined herein which
heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.2-4alkanoylC.sub.1-3alkyl and optionally bears 1 or 2 further
substituents selected from those defined herein; and additionally
wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or C.sub.2-5alkynyl
group in .sup.1X.sup.1-- which is linked to X.sup.1 may bear one or
more substituents selected from hydroxy, halogeno and amino).
7. A compound according to claim 5 wherein one of R.sup.2a and
R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein X.sup.1
is --O-- and Q.sup.1 is
C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl, ##STR00081## wherein
Q.sup.14 is linked to C.sub.1-6alkanoyl through a nitrogen
atom.
8. A compound according to claim 5 wherein one of R.sup.2a and
R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein X.sup.1
is --O-- and Q.sup.1 is selected from one of the following groups:
1) Q.sup.2 (wherein Q.sup.2 is a 5-6-membered heterocyclic group
selected from pyrrolidinyl, piperidinyl, piperazinyl, ##STR00082##
which heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
one substituent selected from C.sub.2-4alkanoylC.sub.1-3alkyl; and
2) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined
herein).
9. A compound according to claim 7 wherein R.sup.2a is methoxy.
10. A compound according to claim 1 selected from:
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-ind-
ol-5-yl)oxy]quinazoline,
7-{([1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-6-yl)oxy]quinazoline,
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-5-yl)oxy]quinazoline,
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline,
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline,
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline,
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxol-
o[4,5-c]pyrrol-5-yl)ethoxy]quinazoline,
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxol-
o[4,5-c]pyrrol-5-yl)ethoxy]quinazoline,
4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1,3]di-
oxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1-
,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(2,3-dimethyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(3-methyl-1H-in-
dol-5yl)oxy]quinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-ind-
ol-5-yl)oxy]-6-methoxyquinazoline,
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{2-[4-(pyrrolidin-1-ylacetyl)-
piperazin-1-yl]ethoxy}quinazoline,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-6-
-yl)oxy]quinazoline,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-5-
-yl)oxy]quinazoline,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline, or a salt thereof.
11. A compound according to claim 1 selected from:
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1-
,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-ind-
ol-5-yl)oxy]-6-methoxyquinazoline, or a salt thereof.
12. A compound according to claim 1 in the form of a
pharmaceutically acceptable salt.
13. A process for the preparation of a compound according to claim
1 of the formula I or salt thereof which comprises: (a) the
reaction of a compound of the formula III: ##STR00083## (wherein
R.sup.2 and m are as defined in claim 1 and L.sup.1 is a
displaceable moiety), with a compound of the formula IV:
##STR00084## (wherein ring C, R.sup.1, Z and n are as defined in
claim 1) optionally followed by the addition of a substituent on a
heterocyclic ring of R.sup.1 or R.sup.2; (b) for compounds of
formula I and salts thereof wherein at least one R.sup.2 is
R.sup.5X.sup.1 or Q.sup.1X.sup.1 wherein R.sup.5 and Q.sup.1 are as
defined in claim 1, and X.sup.1 is --O--, --S--, --OC(O)-- or
--NR.sup.10-- (wherein R.sup.10 independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) the reaction of a
compound of the formula V: ##STR00085## (wherein ring C, Z, R.sup.2
and n are as defined in claim 1 and X.sup.1 is as defined in this
section and s is an integer from 0 to 2) with one of the compounds
of the formulae VIa-b: R.sup.5-L.sup.1 (VIa) Q.sup.1-L.sup.1 (VIb)
(wherein R.sup.5 and Q.sup.1 are as defined in claim 1 and L.sup.1
is as defined herein); (c) for compounds of the formula I and salts
thereof wherein at least one R.sup.2 is R.sup.5X.sup.1 or
Q.sup.1X.sup.1 wherein R.sup.5 and Q.sup.1 are as defined in claim
1, and X.sup.1 is --O--, --S--, --OC(O)-- or --NR.sup.10-- (wherein
R.sup.10 represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) the reaction of a compound of the
formula VII: ##STR00086## with one of the compounds of the formulae
VIIIa-b: R.sup.5--X.sup.1--H (VIIIa) Q.sup.1-X.sup.1--H (VIIIb)
(wherein R.sup.1, R.sup.2, R.sup.5, Q.sup.1, ring C, Z and n are as
defined in claim 1, L.sup.1 and s are as defined herein and X.sup.1
is as defined in this section; (d) for compounds of the formula I
and salts thereof wherein at least one R.sup.2 is R.sup.5X.sup.1 or
Q.sup.1X.sup.1 wherein X.sup.1 is as defined in claim 1, R.sup.5 is
C.sub.1-5alkylR.sup.113, wherein R.sup.113 is selected from one of
the following nine groups: 1) X.sup.19C.sub.1-3alkyl (wherein
X.sup.19 represents --O--, --S--, --SO.sub.2--, --NR.sup.114C(O)--
or --NR.sup.115SO.sub.2-- (wherein R.sup.114 and R.sup.115 which
may be the same or different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl); 2)NR.sup.116R.sup.117 (wherein
R.sup.116 and R.sup.117 which may be the same or different are each
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 3)
X.sup.20C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.20 represents
--O--, --S--, --SO.sub.2--, --NR.sup.118C(O)--,
--NR.sup.119SO.sub.2-- or --NR.sup.120-- (wherein R.sup.118,
R.sup.119, and R.sup.120 which may be the same or different are
each hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
X.sup.5 and R.sup.22 are as defined in claim 1); 4) R.sup.28
(wherein R.sup.28 is as defined in claim 1); 5) X.sup.21R.sup.29
(wherein X.sup.21 represents --O--, --S--, --SO.sub.2--,
--NR.sup.121C(O)--, --NR.sup.122-- su or --NR.sup.123-- (wherein
R.sup.121, R.sup.122, and R.sup.123 which may be the same or
different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined in claim
1); 6) X.sup.22C.sub.1-3alkylR.sup.29 (wherein X.sup.22 represents
--O--, --S--, --SO.sub.2--, --NR.sup.124C(O)--,
--NR.sup.125SO.sub.2-- or --NR.sup.126-- (wherein R.sup.124,
R.sup.125 and R.sup.126 each independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as
defined in claim 1); 7) R.sup.29 (wherein R.sup.29 is as defined in
claim 1); 8) X.sup.22C.sub.1-4alkylR.sup.28 (wherein X.sup.22 and
R.sup.28 are as defined in claim 1); and 9)
R.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55 (wherein q,
r, X.sup.9, R.sup.54 and R.sup.55 are as defined in claim 1);
Q.sup.1 is C.sub.1-5alkylQ.sup.27 wherein Q.sup.27 is selected from
one of the following six groups: 1)
Q.sup.13-C(O)--C.sub.1-4alkylQ.sup.14 (wherein Q.sup.13 and
Q.sup.14 are as defined in claim 1); 2) W.sup.1Q.sup.2(wherein
W.sup.1 and Q.sup.2 are as defined in claim 1); 3) Q.sup.2 (wherein
Q.sup.2 is as defined in claim 1); 4) W.sup.2C.sub.1-4alkylQ.sup.2
(wherein W.sup.2 and Q.sup.2 are as defined in claim 1); 5)
Q.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16 (wherein
W.sup.2, j, k, Q.sup.15 and Q.sup.16 are as defined in claim 1); 6)
Q.sup.15C.sub.1-4alkanoylQ.sup.16n (wherein Q.sup.15 and Q.sup.16n
are as defined in claim 1); the reaction of a compound of the
formula IX: ##STR00087## (wherein X.sup.1, R.sup.1, R.sup.2, ring
C, Z and n are as defined in claim 1 and L.sup.1 and s are as
defined herein) with one of the compounds of the formulae Xa-b:
R.sup.113--H (Xa) Q.sup.27-H (Xb) (wherein R.sup.113 and Q.sup.27
are as defined herein) optionally followed by the addition of a
substituent on a heterocyclic ring of R.sup.1 or R.sup.2; and when
a salt of a compound of formula I is required, reaction of the
compound obtained with an acid or base whereby to obtain the
desired salt.
14. A pharmaceutical composition which comprises a compound of the
formula I as defined in claim 1 or a pharmaceutically acceptable
salt thereof, in association with a pharmaceutically acceptable
excipient or carrier.
15. Use of a compound of the formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof in the manufacture of a
medicament for use in the production of an antiangiogenic and/or
vascular permeability reducing effect in a warm-blooded animal.
16. A method for producing an antiangiogenic and/or vascular
permeability reducing effect in a warm-blooded animal, such as a
human being, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
formula I as defined in claim 1 or a pharmaceutically acceptable
salt thereof.
Description
[0001] The present invention relates to quinazoline derivatives,
processes for their preparation, pharmaceutical compositions
containing them as active ingredient, methods for the treatment of
disease states associated with angiogenesis and/or increased
vascular permeability, to their use as medicaments and to their use
in the manufacture of medicaments for use in the production of
antiangiogenic and/or vascular permeability reducing effects in
warm-blooded animals such as humans.
[0002] Normal angiogenesis plays an important role in a variety of
processes including embryonic development, wound healing and
several components of female reproductive function. Undesirable or
pathological angiogenesis has been associated with disease states
including diabetic retinopathy, psoriasis, cancer, rheumatoid
arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al,
1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature
Medicine 1: 27-31). Alteration of vascular permeability is thought
to play a role in both normal and pathological physiological
processes (Cullinan-Bove et al, 1993, Endocrinology 133: 829-837;
Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324).
Several polypeptides with in vitro endothelial cell growth
promoting activity have been identified including, acidic and basic
fibroblast growth factors (aFGF & bFGF) and vascular
endothelial growth factor (VEGF). By virtue of the restricted
expression of its receptors, the growth factor activity of VEGF, in
contrast to that of the FGFs, is relatively specific towards
endothelial cells. Recent evidence indicates that VEGF is an
important stimulator of both normal and pathological angiogenesis
(Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al,
1995, Breast Cancer Research and Treatment, 36:139-155) and
vascular permeability (Connolly et al, 1989, J. Biol. Chem. 264:
20017-20024). Antagonism of VEGF action by sequestration of VEGF
with antibody can result in inhibition of tumour growth (Kim et al,
1993, Nature 362: 841-844). Basic FGF (bFGF) is a potent stimulator
of angiogenesis (e.g. Hayek et al, 1987, Biochem. Biophys. Res.
Commun. 147: 876-880) and raised levels of FGFs have been found in
the serum (Fujimoto et al, 1991, Biochem. Biophys. Res. Commun.
180: 386-392) and urine (Nguyen et al, 1993, J. Natl. Cancer. Inst.
85: 241-242) of patients with cancer.
[0003] Receptor tyrosine kinases (RTKs) are important in the
transmission of biochemical signals across the plasma membrane of
cells. These transmembrane molecules characteristically consist of
an extracellular ligand-binding domain connected through a segment
in the plasma membrane to an intracellular tyrosine kinase domain.
Binding of ligand to the receptor results in stimulation of the
receptor-associated tyrosine kinase activity which leads to
phosphorylation of tyrosine residues on both the receptor and other
intracellular molecules. These changes in tyrosine phosphorylation
initiate a signalling cascade leading to a variety of cellular
responses. To date, at least nineteen distinct RTK subfamilies,
defined by amino acid sequence homology, have been identified. One
of these subfamilies is presently comprised by the fins-like
tyrosine kinase receptor, Flt-1, the kinase insert
domain-containing receptor, KDR (also referred to as Flk-1), and
another fins-like tyrosine kinase receptor, Flt-4. Two of these
related RTKs, Flt-1 and KDR, have been shown to bind VEGF with high
affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al,
1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding
of VEGF to these receptors expressed in heterologous cells has been
associated with changes in the tyrosine phosphorylation status of
cellular proteins and calcium fluxes.
[0004] The present invention is based on the discovery of compounds
that surprisingly inhibit the effects of VEGF, a property of value
in the treatment of disease states associated with angiogenesis
and/or increased vascular permeability such as cancer, diabetes,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
lymphoedema, acute and chronic nephropathies, atheroma, arterial
restenosis, autoimmune diseases, acute inflammation, excessive scar
formation and adhesions, endometriosis, dysfunctional uterine
bleeding and ocular diseases with retinal vessel proliferation
including macular degeneration.
[0005] VEGF is a key stimulus for vasculogenesis and angiogenesis.
This cytokine induces a vascular sprouting phenotype by inducing
endothelial cell proliferation, protease expression and migration,
and subsequent organisation of cells to form a capillary tube
(Keck, P. J., Hauser, S. D., Krivi, G., Sanzo, K., Warren, T.,
Feder, J., and Connolly, D. T., Science (Washington D.C.), 246:
1309-1312, 1989; Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A.,
Hasty, K. A., and Charles, S. T., Microvasc. Res., 55: 29-42, 1998;
Pepper, M. S., Montesano, R., Mandroita, S. J., Orci, L. and
Vassalli, J. D., Enzyme Protein, 49: 138-162, 1996.). In addition,
VEGF induces significant vascular permeability (Dvorak, H. F.,
Detmar, M., Claffey, K. P., Nagy, J. A., van de Water, L., and
Senger, D. R., (Int. Arch. Allergy Immunol., 107: 233-235, 1995;
Bates, D. O., Heald, R. I., Curry, F. E. and Williams, B. J.
Physiol. (Lond.), 533: 263-272, 2001), promoting formation of a
hyper-permeable, immature vascular network which is characteristic
of pathological angiogenesis.
[0006] It has been shown that activation of KDR alone is sufficient
to promote all of the major phenotypic responses to VEGF, including
endothelial cell proliferation, migration, and survival, and the
induction of vascular permeability (Meyer, M., Clauss, M.,
Lepple-Wienhues, A., Waltenberger, J., Augustin, H. G., Ziche, M.,
Lanz, C., Biittner, M., Rziha, H-J., and Dehio, C., EMBO J., 18:
363-374, 1999; Zeng, H., Sanyal, S. and Mukhopadhyay, D., J. Biol.
Chem., 276: 32714-32719, 2001; Gille, H., Kowalski, J., Li, B.,
LeCouter, J., Moffat, B, Zioncheck, T. F., Pelletier, N. and
Ferrara, N., J. Biol. Chem., 276: 3222-3230, 2001).
[0007] International patent application publication number WO
00/47212 describes VEGF receptor tyrosine kinase inhibitors.
Compounds of WO 00/47212 possess activity against VEGF receptor
tyrosine kinase (RTK) such that they may be used in an amount
sufficient to inhibit VEGF RTK whilst demonstrating no significant
activity against EGF RTK. Their VEGF RTK inhibitory activity is due
both to activity against KDR and against Flt-1, but generally they
are more potent against KDR. Generally they have extended plasma
pharmacokinetics. Some VEGF RTK inhibitors have been found to act
as potassium channel blockers and are positive in a hERG assay;
such activity may give rise to ECG (electrocardiogram) changes in
vivo. Compounds of WO 00/47212 have predominantly basic side
chains.
[0008] Surprisingly we have now found compounds of the present
invention to be very potent KDR inhibitors but to have less
activity against Flt-1 than compounds of WO 00/47212, to have less
extended plasma pharmacokinetics than compounds of WO 00/47212 and
to be inactive or only weakly active in a hERG assay. Compounds of
the present invention have predominantly neutral side chains.
Compounds of the present invention have a beneficial toxicological
profile compared to compounds of WO 00/47212.
[0009] According to one aspect of the present invention there is
provided the use of a compound of the formula I:
##STR00002##
wherein: ring C is an 8, 9, 10, 12 or 13-membered bicyclic or
tricyclic moiety which moiety may be saturated or unsaturated,
which may be aromatic or non-aromatic, and which optionally may
contain 1-3 heteroatoms selected independently from O, N and S;
Z is --O--, --NH-- or --S--;
[0010] n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; R.sup.2
represents hydrogen, hydroxy, halogen, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or R.sup.5X.sup.1-- (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OC(O)--, --C(O)--,
--S--, --SO--, --SO.sub.2--, --NR.sup.6C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8--, --NR.sup.9SO.sub.2-- or --NR.sup.10--
(wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.5 is selected from one of
the following twenty-two groups: 1) hydrogen,
oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be unsubstituted
or which may be substituted with one or more groups selected from
hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2 represents --O--
or --NR.sup.12-- (in which R.sup.12 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.11
represents C.sub.1-3alkyl, --NR.sup.13R.sup.14 or --OR.sup.15
(wherein R.sup.13, R.sup.14 and R.sup.15 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.16
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.17C(O)--, --C(O)NR.sup.18--,
--SO.sub.2NR.sup.19--, --NR.sup.20SO.sub.2--, or --NR.sup.21--
(wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.23C(O)--, --C(O)NR.sup.24--,
--SO.sub.2NR.sup.25--, --NR.sup.26SO.sub.2--, or --NR.sup.27--
(wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26 and R.sup.27 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.22 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.28
(wherein R.sup.28 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4-alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4 alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, C.sub.1-4
alkylaminoC.sub.1-4 alkoxy, di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy
and a group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f
is 0 or 1, g is 0 or 1 and ring D is a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which cyclic group may bear one or more
substituents selected from C.sub.1-4alkyl)); 6)
C.sub.1-5alkylR.sup.28 (wherein R.sup.28 is as defined
hereinbefore); 7) C.sub.2-5alkenylR.sup.28 (wherein R.sup.28 is as
defined hereinbefore); 8) C.sub.2-5alkynylR.sup.28 (wherein
R.sup.28 is as defined hereinbefore); 9) R.sup.29 (wherein R.sup.29
represents a pyridone group, a phenyl group or a 5-6-membered
aromatic heterocyclic group (linked via carbon or nitrogen) with
1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or
aromatic heterocyclic group may carry up to 5 substituents selected
from oxo, hydroxy, halogeno, amino, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl, C.sub.1-4aminoalkyl,
C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy, carboxy,
trifluoromethyl, cyano, --C(O)NR.sup.30R.sup.31,
--NR.sup.32C(O)R.sup.33 (wherein R.sup.30, R.sup.31, R.sup.32 and
R.sup.33, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.29 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.34C(O)--, --C(O)NR.sup.35--,
--SO.sub.2NR.sup.36--, --NR.sup.37SO.sub.2-- or --NR.sup.38--
(wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.29 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.39C(O)--,
--C(O)NR.sup.40--, --SO.sub.2NR.sup.41--, --NR.sup.42SO.sub.2-- or
--NR.sup.43-- (wherein R.sup.39, R.sup.40, R.sup.41, R.sup.42 and
R.sup.43 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.29 (wherein X.sup.8
represents --O--, --S--, --SO--, --NR.sup.44C(O)--,
--C(O)NR.sup.45--, --SO.sub.2NR.sup.46--, --NR.sup.47SO.sub.2-- or
--NR.sup.48-- (wherein R.sup.44, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.29
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.49C(O)--, --C(O)NR.sup.50--, --SO.sub.2NR.sup.51--,
--NR.sup.52SO.sub.2-- or --NR.sup.53-- (wherein R.sup.49, R.sup.50,
R.sup.51, R.sup.52 and R.sup.53 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined hereinbefore); 17)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.2-5alkenyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9 is as defined hereinbefore, q is 0 or 1, r is 0 or
1, and R.sup.54 and R.sup.55 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl), with the proviso that R.sup.54 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); R.sup.1 represents
hydrogen, oxo, halogeno, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4alkoxymethyl, C.sub.1-4alkanoyl, C.sub.1-4haloalkyl,
cyano, amino, C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-3alkanoyloxy, nitro, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N-C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl,
N-(C.sub.1-4alkylsulphonyl)amino,
N-(C.sub.1-4alkylsulphonyl)-N-(C.sub.1-4alkyl)amino,
N,N-di(C.sub.1-4alkylsulphonyl)amino, a C.sub.3-7alkylene chain
joined to two ring C carbon atoms,
C.sub.1-4alkanoylaminoC.sub.1-4alkyl, carboxy or a group
R.sup.56X.sup.10 (wherein X.sup.10 represents a direct bond, --O--,
--CH.sub.2--, --OC(O)--, --C(O)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.57C(O)--, --C(O)NR.sup.58--, --SO.sub.2NR.sup.59--,
--NR.sup.60SO.sub.2-- or --NR.sup.61-- (wherein R.sup.57, R.sup.58,
R.sup.59, R.sup.60 and R.sup.61 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), and
R.sup.56 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.11C(O)R.sup.62 (wherein X.sup.11 represents
--O-- or --NR.sup.63-- (in which R.sup.63 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.62
represents C.sub.1-3alkyl, --NR.sup.64R.sup.65 or --OR.sup.66
(wherein R.sup.64, R.sup.65 and R.sup.66 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.12R.sup.67
(wherein X.sup.12 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.68C(O)--, --C(O)NR.sup.69--,
--SO.sub.2NR.sup.70--, --NR.sup.71SO.sub.2-- or --NR.sup.72--
(wherein R.sup.68, R.sup.69, R.sup.70, R.sup.71 and R.sup.72 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.67 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogen and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.13C.sub.1-5alkylX.sup.14R.sup.73 (wherein
X.sup.13 and X.sup.14 which may be the same or different are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.74C(O)--,
NR.sup.74C(O)--, --C(O)NR.sup.75--, --SO.sub.2NR.sup.76--,
--NR.sup.77SO.sub.2-- or --NR.sup.78-- (wherein R.sup.74, R.sup.75,
R.sup.76, R.sup.77 and R.sup.78 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.73 represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.79 (wherein R.sup.79 is a
5-6-membered saturated heterocyclic group (linked via carbon or
nitrogen) with 1-2 heteroatoms, selected independently from O, S
and N, which heterocyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4akylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.79 (wherein
R.sup.79 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); 9) R.sup.80 (wherein
R.sup.80 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C
.sub.1-4hydroxyalkoxy, carboxy, trifluoromethyl, cyano,
--C(O)NR.sup.81R.sup.82, --NR.sup.83C(O)R.sup.84 (wherein R.sup.81,
R.sup.82, R.sup.83 and R.sup.84, which may be the same or
different, each represents hydrogen, C.sub.1-4alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.80 (wherein R.sup.80 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); 12) C.sub.2-5alkenylR.sup.80
(wherein R.sup.80 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.15R.sup.80 (wherein X.sup.15 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.85C(O)--, --C(O)NR.sup.86--,
--SO.sub.2NR.sup.87--, --NR.sup.88SO.sub.2-- or --NR.sup.89--
(wherein R.sup.85, R.sup.86, R.sup.87, R.sup.88 and R.sup.89 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.16R.sup.80 (wherein
X.sup.16 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.90C(O)--, --C(O)NR.sup.91--, --SO.sub.2NR.sup.92--,
--NR.sup.93SO.sub.2-- or --NR.sup.94-- (wherein R.sup.90, R.sup.91,
R.sup.92, R.sup.93 and R.sup.94 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.80 is as defined hereinbefore); 15)
C.sub.2-5alkynylX.sup.17R.sup.80 (wherein X.sup.17 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.95C(O)--,
--C(O)NR.sup.96--, --SO.sub.2NR.sup.97--, --NR.sup.98SO.sub.2-- or
--NR.sup.99-- (wherein R.sup.95, R.sup.96, R.sup.97, R.sup.98 and
R.sup.99 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.80
(wherein X.sup.18 represents --O--, --S--, --SO--, --SO.sub.2--,
--C(O)NR.sup.101--, --SO.sub.2NR.sup.102--, --NR.sup.103SO.sub.2--
or --NR.sup.104 (wherein R.sup.100, R.sup.101, R.sup.102, R.sup.103
and R.sup.104 each independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as
defined hereinbefore); 17)
C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18 and
R.sup.79 are as defined hereinbefore); 18) C.sub.2-5alkenyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl;
[0011] 19) C.sub.2-5alkynyl which may be unsubstituted or which may
be substituted with one or more groups selected from hydroxy,
fluoro, amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl;
20) C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein
X.sup.18 and R.sup.79 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.105
(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106 (wherein X.sup.18
is as defined hereinbefore, x is 0 or 1, y is 0 or 1, and R.sup.105
and R.sup.106 are each independently selected from hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a 5-6-membered
saturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which C.sub.1-3alkyl group may bear
1 or 2 substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl) with the proviso that R.sup.105 cannot be
hydrogen); and additionally wherein any C.sub.1-4alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
which is linked to X.sup.10 may bear one or more substituents
selected from hydroxy, halogeno and amino); with the proviso that
one or more R.sup.1 and/or one or more R.sup.2 are selected from
Q.sup.1X.sup.1-- wherein X.sup.1 is as defined hereinbefore and
Q.sup.1 is selected from one of the following groups: 1)
C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 is C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or may bear 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), and
Q.sup.14 is a 5-6-membered saturated or partially unsaturated
heterocyclic group containing at least one nitrogen atom and
optionally containing a further nitrogen atom wherein Q.sup.14 is
linked to C.sub.1-6alkanoyl through a nitrogen atom and wherein
Q.sup.14 optionally bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogen, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); 2) Q.sup.2
(wherein Q.sup.2 is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group bears
either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.1-6alkanoylC.sub.1-6alkyl and
optionally bears a further 1 or 2 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, C.sub.1-6alkanoylC.sub.1-6alkyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 3)
C.sub.1-5alkylW.sup.1Q.sup.2 (wherein W.sup.1 represents --O--,
--S--, --SO--, --SO.sub.2--, --OC(O)--, --NQ.sup.3C(O)--,
--C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-, --NQ.sup.6SO.sub.2-- or
--NQ.sup.7- (wherein Q.sup.3, Q.sup.4, Q.sup.5, Q.sup.6 and Q.sup.7
each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore; 4)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined hereinbefore);
5) C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2 is as defined
hereinbefore); 6) C.sub.2-5alkynylQ.sup.2 (wherein Q.sup.2 is as
defined hereinbefore); 7)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9-, --SO.sub.2N.sup.10--, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore); 8)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 9)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 10)
C.sub.1-4alkylQ.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.15 and Q.sup.16 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or may bear 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
provisos that Q.sup.15 cannot be hydrogen and one or both of
Q.sup.15 and Q.sup.16 must be a 5-6-membered saturated or partially
unsaturated heterocyclic group as defined hereinbefore which
heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.1-6alkanoylC.sub.1-6alkyl and optionally bears 1 or 2 further
substituents selected from those defined hereinbefore); 11)
C.sub.1-4alkylQ.sup.15Cl.sub.1-4alkanoylQ.sup.16n wherein Q.sup.15
is as defined hereinbefore and is not hydrogen and Q.sup.16n is a
5-6-membered saturated or partially unsaturated heterocyclic group
containing at least one nitrogen atom and optionally containing a
further nitrogen atom wherein Q.sup.16n is linked to
C.sub.1-6alkanoyl through a nitrogen atom and wherein Q.sup.16n
bears either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears 1, 2 or 3
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); with the
proviso that one or both of Q.sup.15 and Q.sup.16n must be a
5-6-membered saturated or partially unsaturated heterocyclic group
as defined hereinbefore which heterocyclic group bears either one
substituent selected from methylenedioxy or ethylenedioxy to form a
bicyclic ring, or bears at least one substituent selected from
C.sub.1-6alkanoylC.sub.1-6alkyl and optionally bears 1 or 2 further
substituents selected from those defined hereinbefore; and
additionally wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino); or a salt thereof, or a prodrug thereof for
example an ester or an amide, in the manufacture of a medicament
for use in the production of an antiangiogenic and/or vascular
permeability reducing effect in warm-blooded animals such as
humans.
[0012] According to one aspect of the present invention there is
provided the use of a compound of the formula I:
##STR00003##
wherein: ring C is an 8, 9, 10, 12 or 13-membered bicyclic or
tricyclic moiety which moiety may be saturated or unsaturated,
which may be aromatic or non-aromatic, and which optionally may
contain 1-3 heteroatoms selected independently from O, N and S;
Z is --O--, --NH-- or --S--;
[0013] n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; R.sup.2
represents hydrogen, hydroxy, halogeno, cyano, nitro,
trifluoromethyl, C.sub.1-3, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or R.sup.5X.sup.1-- (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OC(O)--, --C(O)--,
--S--, --SO--, --SO.sub.2--, --NR.sup.6C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8--, --NR.sup.9SO.sub.2-- or --NR.sup.10--
(wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.5 is selected from one of
the following twenty-two groups: 1) hydrogen,
oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be unsubstituted
or which may be substituted with one or more groups selected from
hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2 represents --O--
or --NR.sup.12-- (in which R.sup.12 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.11
represents C.sub.1-3alkyl, --NR.sup.13R.sup.14 or --OR.sup.15
(wherein R.sup.13, R.sup.14 and R.sup.15 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.16
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.17C(O)--, --C(O)NR.sup.18--,
--SO.sub.2NR.sup.19--, --NR.sup.20SO.sub.2-- or --NR.sup.21--
(wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.23C(O)--, --C(O)NR.sup.24--,
--SO.sub.2NR.sup.25--, --NR.sup.26SO.sub.2-- or --NR.sup.27--
(wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26 and R.sup.27 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.22 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.28
(wherein R.sup.28 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.28 (wherein R.sup.28 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.28 (wherein
R.sup.28 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.28
(wherein R.sup.28 is as defined hereinbefore); 9) R.sup.29 (wherein
R.sup.29 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogen, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --C(O)NR.sup.30R.sup.31,
--NR.sup.32C(O)R.sup.33 (wherein R.sup.30, R.sup.31, R.sup.32 and
R.sup.33, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.29 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.34C(O)--, --C(O)NR.sup.35--,
--SO.sub.2NR.sup.36--, --NR.sup.37SO.sub.2-- or --NR.sup.38--
(wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.32 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.29 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.39C(O)--,
--C(O)NR.sup.40--, --SO.sub.2NR.sup.41--, --NR.sup.42SO.sub.2-- or
NR.sup.43-- (wherein R.sup.39, R.sup.40, R.sup.41, R.sup.42 and
R.sup.43 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.29 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.44C(O) --,
--C(O)NR.sup.45--, --SO.sub.2NR.sup.46--, --NR.sup.47SO.sub.2-- or
--NR.sup.48-- (wherein R.sup.44, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.29
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.49C(O)--, --C(O)NR.sup.50--, --SO.sub.2NR.sup.51--,
--NR.sup.52SO.sub.2-- or --NR.sup.53-- (wherein R.sup.49, R.sup.50,
R.sup.51, R.sup.52 and R.sup.53 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined hereinbefore); 17)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.2-5alkenyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9 is as defined hereinbefore, q is 0 or 1, r is 0 or
1, and R.sup.54 and R.sup.55 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl), with the proviso that R.sup.54 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); R.sup.1 represents
hydrogen, oxo, halogeno, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4alkoxymethyl, C.sub.1-4alkanoyl, cyano, amino,
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-3alkanoyloxy, nitro,
C.sub.1-4alkanoylamino, C.sub.1-4alkoxycarbonyl,
C.sub.1-4alkylsulphanyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N-C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl,
N-(C.sub.1-4alkylsulphonyl)amino,
N-(C.sub.1-4alkylsulphonyl)-N-(C.sub.1-4alkyl)amino,
N,N-di(C.sub.1-4alkylsulphonyl)amino, a C.sub.3-7alkylene chain
joined to two ring C carbon atoms,
C.sub.1-4alkanoylaminoC.sub.1-4alkyl, carboxy or a group
R.sup.56X.sup.10 (wherein X.sup.10 represents a direct bond, --O--,
--CH.sub.2--, --OC(O)--, --C(O)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.57C(O)--, --C(O)NR.sup.58--, --SO.sub.2NR.sup.59--,
--NR.sup.60SO.sub.2-- or --NR.sup.61-- (wherein R.sup.57, R.sup.58,
R.sup.59, R.sup.60 and R.sup.61 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), and
R.sup.56 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.11C(O)R.sup.62 (wherein X.sup.11 represents
--O-- or --NR.sup.63-- (in which R.sup.63 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.62
represents C.sub.1-3alkyl, --NR.sup.64R.sup.65 or --OR.sup.66
(wherein R.sup.64, R.sup.65 and R.sup.66 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.12R.sup.67
(wherein X.sup.12 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.68C(O)--, --C(O)NR.sup.69--,
--SO.sub.2NR.sup.70--, --NR.sup.71SO.sub.2-- or --NR.sup.72--
(wherein R.sup.68, R.sup.69, R.sup.70, R.sup.71 and R.sup.72 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.67 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogen, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.13C.sub.1-5alkylX.sup.14R.sup.73 (wherein
X.sup.13 and X.sup.14 which may be the same or different are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.74C(O)--,
--C(O)NR.sup.75--, --SO.sub.2NR.sup.76--, --NR.sup.77SO.sub.2-- or
--NR.sup.78-- (wherein R.sup.74, R.sup.75, R.sup.76, R.sup.77 and
R.sup.78 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.73 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3lkoxyC.sub.2-3alkyl); 5) R.sup.79
(wherein R.sup.79 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogen, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.79 (wherein
R.sup.79 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); 9) R.sup.80 (wherein
R.sup.80 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogen, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4hydroxyalkoxy, carboxy,
trifluoromethyl, cyano, --C(O)NR.sup.81R.sup.82,
--NR.sup.83C(O)R.sup.84 (wherein R.sup.81, R.sup.82, R.sup.83 and
R
.sup.84, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.80 (wherein R.sup.80 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.80
(wherein R.sup.80 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.15R.sup.80 (wherein X.sup.15 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.85C(O)--, --C(O)NR.sup.86--,
--SO.sub.2NR.sup.87--, --NR.sup.88SO.sub.2-- or --NR.sup.89--
(wherein R.sup.85, R.sup.86, R.sup.87, R.sup.88 and R.sup.89 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.16R.sup.80 (wherein
X.sup.16 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.90C(O)--, --C(O)NR.sup.91--, --SO.sub.2NR.sup.92--,
--NR.sup.93SO.sub.2-- or --NR.sup.94-- (wherein R.sup.90, R.sup.91,
R.sup.92, R.sup.93 and R.sup.94 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.80 is as defined hereinbefore); 15)
C.sub.2-5alkynylX.sup.17R.sup.80 (wherein X.sup.17 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.95C(O)--,
--C(O)NR.sup.96--, --SO.sub.2NR.sup.97--, --NR.sup.98SO.sub.2-- or
--NR.sup.99-- (wherein R.sup.95, R.sup.96, R.sup.97, R.sup.98 and
R.sup.99 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.80
(wherein X.sup.18 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.100C(O)--, --C(O)NR.sup.101, --SO.sub.2NR.sup.102--,
--NR.sup.103SO.sub.2-- or --NR.sup.104-- (wherein R.sup.100,
R.sup.101, R.sup.102, R.sup.103 and R.sup.104 each independently
represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 17) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79
(wherein X.sup.18 and R.sup.79 are as defined hereinbefore); 18)
C.sub.2-5alkenyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro,
amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N-C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.105(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106
(wherein X.sup.18 is as defined hereinbefore, x is 0 or 1, y is 0
or 1, and R.sup.105 and R.sup.106 are each independently selected
from hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogen
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl) with the proviso that R.sup.105 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
which is linked to X.sup.10 may bear one or more substituents
selected from hydroxy, halogen and amino); with the proviso that
one or more R.sup.1 and/or one or more R.sup.2 are selected from
the following group:
Q.sup.1X.sup.1--
wherein X.sup.1 is as defined hereinbefore and Q.sup.1 is
C.sub.1-4alkyl-Q.sup.13n-C(O)--C.sub.1-4alkyl-Q.sup.14n wherein
Q.sup.13n is C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.t(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), and
Q.sup.14n is a 5-6-membered saturated or partially unsaturated
heterocyclic group containing at least one nitrogen atom and
optionally containing a further nitrogen atom wherein Q.sup.14n is
linked to C.sub.1-6alkanoyl through a nitrogen atom and wherein
Q.sup.14n optionally bears 1, 2 or 3 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); and
additionally wherein the C.sub.1-4alkyl group in Q.sup.1X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); or a salt thereof, or a
prodrug thereof for example an ester or an amide, in the
manufacture of a medicament for use in the production of an
antiangiogenic and/or vascular permeability reducing effect in
warm-blooded animals such as humans.
[0014] According to one aspect of the present invention ring C is a
9-10-membered aromatic bicyclic moiety which may optionally contain
1-3 heteroatoms selected independently from O, N and S.
[0015] According to one aspect of the present invention ring C is a
9-10-membered heteroaromatic bicyclic moiety which contains 1-3
heteroatoms selected independently from O, N and S.
[0016] According to one aspect of the present invention ring C is a
9-10-membered heteroaromatic bicyclic moiety which contains 1 or 2
nitrogen atoms.
[0017] According to one aspect of the present invention ring C is
indolyl, quinolinyl, indazolyl or azaindolyl.
[0018] According to one aspect of the present invention ring C is
indolyl, indazolyl or azaindolyl.
[0019] According to one aspect of the present invention ring C is
indolyl or azaindolyl.
[0020] According to one aspect of the present invention ring C is
azaindolyl.
[0021] According to one aspect of the present invention ring C is
indolyl.
[0022] According to one aspect of the present invention ring C is
indazolyl.
[0023] According to one aspect of the present invention Z is --O--
or --S--.
[0024] According to one aspect of the present invention Z is
--O--.
[0025] In one embodiment of the present invention X.sup.1
represents a direct bond, --O--, --S--, --NR.sup.6C(O)--,
--NR.sup.9SO.sub.2-- or --NR.sup.10-- (wherein R.sup.6, R.sup.9 and
R.sup.10 each independently represents hydrogen, C.sub.1-2 alkyl or
C.sub.1-2alkoxyethyl).
[0026] In one embodiment of the present invention X.sup.1
represents a direct bond, --O--, --S--, --NR.sup.6C(O)--,
--NR.sup.9SO.sub.2-- (wherein R.sup.6 and R.sup.9 each
independently represents hydrogen or C.sub.1-2alkyl) or NH.
[0027] In one embodiment of the present invention X.sup.1
represents --O--, --S--, --NR.sup.6C(O)-- (wherein R.sup.6
represents hydrogen or C.sub.1-2alkyl) or NH.
[0028] In one embodiment of the present invention X.sup.1
represents --O-- or --NR.sup.6C(O)-- (wherein R.sup.6 represents
hydrogen or C.sub.1-2alkyl).
[0029] In one embodiment of the present invention X.sup.1
represents --O-- or --NHC(O)--.
[0030] In one embodiment of the present invention X.sup.1
represents --O--.
[0031] According to another aspect of the present invention X.sup.1
represents --O-- or a direct bond.
[0032] In one embodiment of the present invention R.sup.1 is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore, and/or R.sup.1 represents oxo, hydroxy,
C.sub.1-2alkoxymethyl, amino, halogeno, C.sub.1-2alkyl,
C.sub.1-2alkoxy, trifluoromethyl, cyano, nitro,
C.sub.2-3alkanoyl.
[0033] According to one aspect of the present invention R.sup.1
represents methyl, ethyl, trifluoromethyl or halogeno.
[0034] According to another aspect of the present invention R.sup.1
represents methyl, fluoro, chloro or bromo.
[0035] According to another aspect of the present invention R.sup.1
represents methyl or fluoro.
[0036] In one embodiment of the present invention n is 3.
[0037] In one embodiment of the present invention n is 2.
[0038] In one embodiment of the present invention n is 1.
[0039] In one embodiment of the present invention n is 0.
[0040] In one embodiment of the present invention n is 0, 1 or
2.
[0041] In one embodiment of the present invention m is 1 or 2.
[0042] In one embodiment of the present invention m is 1.
[0043] In one embodiment of the present invention m is 2.
[0044] In one embodiment of the present invention X.sup.3
represents --O--, --S--, --SO--, --SO.sub.2--,
--SO.sub.2NR.sup.19-- or --NR.sup.21-- (wherein R.sup.19 and
R.sup.21 each independently represents hydrogen, C.sub.1-2alkyl or
C.sub.1-2 alkoxyethyl).
[0045] In one embodiment of the present invention X.sup.3
represents --O-- or --NR.sup.21-- (wherein R.sup.21 represents
hydrogen or C.sub.1-2alkyl).
[0046] In one embodiment of the present invention X.sup.3
represents --O--.
[0047] In one embodiment of the present invention X.sup.4 and
X.sup.5 which may be the same or different each represents --O--,
--S-- or --NR.sup.27-- (wherein R.sup.27 represents hydrogen,
C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0048] In one embodiment of the present invention X.sup.4 and
X.sup.5 which may be the same or different each represents --O-- or
--NH--.
[0049] In one embodiment of the present invention X.sup.4 and
X.sup.5 each represents --O--.
[0050] In one embodiment of the present invention X.sup.6
represents --O--, --S-- or --NR.sup.38-- (wherein R.sup.38
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0051] In one embodiment of the present invention X.sup.6
represents --O-- or --NR.sup.38-- (wherein R.sup.38 represents
hydrogen or C.sub.1-2alkyl).
[0052] In one embodiment of the present invention X.sup.6
represents --O--.
[0053] In one embodiment of the present invention X.sup.7
represents --O--, --S-- or --NR.sup.43-- (wherein R.sup.43
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0054] In one embodiment of the present invention X.sup.7
represents --O-- or --NR.sup.43-- (wherein R.sup.43 represents
hydrogen or C.sub.1-2alkyl).
[0055] In one embodiment of the present invention X.sup.7
represents --O--.
[0056] In one embodiment of the present invention X.sup.8
represents --O--, --S-- or --NR.sup.48-- (wherein R.sup.48
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0057] In one embodiment of the present invention X.sup.8
represents --O-- or --NR.sup.48-- (wherein R.sup.48 represents
hydrogen or C.sub.1-2alkyl).
[0058] In one embodiment of the present invention X.sup.8
represents --O--.
[0059] In one embodiment of the present invention X.sup.9
represents --O--, --S-- or NR.sup.53-- (wherein R.sup.53 represents
hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0060] In one embodiment of the present invention X.sup.9
represents --O-- or --NR.sup.53-- (wherein R.sup.53 represents
hydrogen or C.sub.1-2alkyl).
[0061] In one embodiment of the present invention X.sup.9
represents --O--.
[0062] In one embodiment of the present invention R.sup.28 is
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,
1,3-dioxolan-2-yl, morpholino or thiomorpholino which group may
bear 1 or 2 substituents selected from oxo, hydroxy, halogen,
cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3 alkyl, C.sub.1-2
alkylsulphonylC.sub.1-3alkyl, C.sub.1-3alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino,
C.sub.1-3alkylaminoC.sub.1-3alkyl, di(C.sub.1-3
alkyl)aminoC.sub.1-3alkyl, C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3 alkoxy and a group
--(--O--).sub.f(C.sub.1-3alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a heterocyclic group selected from
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, morpholino
and thiomorpholino, which cyclic group may bear one or more
substituents selected from C.sub.1-3alkyl).
[0063] In one embodiment of the present invention R.sup.28 is
pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl,
morpholino or thiomorpholino which group may bear 1 or 2
substituents selected from oxo, hydroxy, halogen, cyano,
C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl and
C.sub.1-2alkylsulphonylC.sub.1-3 alkyl.
[0064] In one embodiment of the present invention R.sup.29 is
phenyl, pyridyl, imidazolyl, thiazolyl or triazolyl group which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, cyano and
--NR.sup.32C(O)R.sup.33 (wherein R.sup.32 and R.sup.33 are each
independently selected from hydrogen and C.sub.1-4alkyl).
[0065] In one embodiment of the present invention R.sup.54 and
R.sup.55 are each selected from pyrrolidinyl, piperazinyl,
piperidinyl, imidazolidinyl, morpholino and thiomorpholino which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, cyano, C.sub.1-3cyanoalkyl, C.sub.1-3 alkyl,
C.sub.1-3hydroxyalkyl, C.sub.1-3 alkoxy, C.sub.1-2alkoxyC.sub.1-3
alkyl, C.sub.1-2alkylsulphonylC.sub.1-3alkyl,
C.sub.1-3alkoxycarbonyl and a group
--(--O--).sub.f(C.sub.1-3alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a heterocyclic group selected from
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, morpholino
and thiomorpholino, which cyclic group may bear one or more
substituents selected from C.sub.1-3alkyl).
[0066] In one embodiment of the present invention R.sup.2 is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; and/or R.sup.2 represents 6,7-methylenedioxy,
6,7-ethylenedioxy, hydroxy, C.sub.1-3alkyl, amino or
R.sup.5X.sup.1-- [wherein X.sup.1 is as hereinbefore defined and
R.sup.5 represents methyl, ethyl, benzyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,
2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl,
2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,
2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,
2-(methylamino)ethyl, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-O-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-(N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0067] In one embodiment of the present invention R.sup.2 is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore, and/or R.sup.2 represents 6,7-methylenedioxy,
6,7-ethylenedioxy, hydroxy, C.sub.1-3alkyl, amino or
R.sup.5X.sup.1-- [wherein X.sup.1 is --O-- and R.sup.5 represents
methyl, ethyl, benzyl, trifluoromethyl, 2,2,2-trifluoroethyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,
2-(methylsulphinypethyl, 2-(methylsulphonyl)ethyl,
2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,
2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,
2-sulphamoylethyl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-(N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0068] In one embodiment of the present invention R.sup.2
substituents are at the 6- and/or 7-positions of the quinazoline
ring.
[0069] In one embodiment of the present invention R.sup.2 is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore and/or R.sup.2 represents methoxy.
[0070] According to another aspect of the present invention there
are provided compounds of the formula I.
[0071] According to another aspect of the present invention there
are provided compounds of the formula Ia:
##STR00004##
wherein: ring C.sup.a is indolyl, indazolyl or azaindolyl; R.sup.1a
is selected from oxo, hydroxy, C.sub.1-2alkoxymethyl, amino,
halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, trifluoromethyl, cyano,
nitro, C.sub.1-3alkanoyl and Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined hereinbefore; R.sup.2 is as defined
hereinbefore; ma is 0, 1, 2 or 3;
Z.sup.a is --O-- or --S--;
[0072] and na is 0, 1 or 2; with the proviso that at least one
R.sup.2 is selected from Q.sup.1X.sup.1 as defined hereinbefore in
the definitions of R.sup.2, and/or R.sup.1a is selected from
Q.sup.1X.sup.1 as defined hereinbefore; and salts thereof, and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0073] According to another aspect of the present invention there
are provided compounds of the formula II:
##STR00005##
wherein: ring C.sup.a is indolyl, indazolyl or azaindolyl; R.sup.1a
is selected from oxo, hydroxy, C.sub.1-2alkoxymethyl, amino,
halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, trifluoromethyl, cyano,
nitro, C.sub.1-3alkanoyl and Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined hereinbefore; R.sup.2a and R.sup.2b, are
each independently selected from hydrogen, hydroxy, halogeno,
cyano, nitro, trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3aR.sup.4a (wherein R.sup.3a and
R.sup.4a, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), and Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined hereinbefore;
Z.sup.a is --O-- or --S--;
[0074] and na is 0, 1 or 2; with the proviso that at least one of
R.sup.2a and R.sup.2b is Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1
are as defined hereinbefore; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0075] According to another aspect of the present invention there
are provided compounds of the formula IIa as defined hereinbefore
wherein at least one of R.sup.2a and R.sup.2b is Q.sup.1X.sup.1
wherein Q.sup.1 and X.sup.1 are as defined hereinbefore.
[0076] In one embodiment of the present invention Z.sup.a is
--O--.
[0077] In one embodiment of the present invention C.sup.a is
indol-5-yl, indol-6-yl, 7-azaindol-5-yl, indazol-5-yl,
indazol-6-yl.
[0078] In one embodiment of the present invention C.sup.a is
indol-5-yl, 7-azaindol-5-yl or indazol-5-yl.
[0079] In one embodiment of the present invention C.sup.a is
indol-5-yl or indol-6-yl.
[0080] In one embodiment of the present invention C.sup.a is
indol-5-yl.
[0081] In one embodiment of the present invention C.sup.a is
7-azaindol-5-yl.
[0082] In one embodiment of the present invention R.sup.1a is
halogeno or C.sub.1-3alkyl.
[0083] In one embodiment of the present invention R.sup.1a is
fluoro or methyl.
[0084] In one embodiment of the present invention R.sup.2a is
methoxy and R.sup.2b is Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1
are as defined hereinbefore.
[0085] In another embodiment of the present invention R.sup.2b is
methoxy and R.sup.2a is Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1
are as defined hereinbefore.
[0086] According to another aspect of the present invention there
are provided compounds of the formula IIb:
##STR00006##
wherein:
M is --CH-- or --N--;
[0087] nc is 0, 1 or 2; R.sup.2c is linked to a carbon atom of the
5-membered ring and is selected from hydrogen and methyl; R.sup.2d
is linked to a carbon atom of the 6-membered ring and is selected
from hydrogen and fluoro; Z.sup.a, R.sup.2a and R.sup.2b, are as
defined hereinbefore; with the proviso that at least one of
R.sup.2a and R.sup.2b is Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1
are as defined hereinbefore; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0088] According to another aspect of the present invention there
are provided compounds of the formula IId:
##STR00007##
[wherein:
M is --CH-- or --N--;
[0089] nc is 0, 1 or 2;
Z.sup.a is --O-- or --S--;
[0090] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; one of R.sup.2a and R.sup.2b is methoxy and the other
is Q.sup.1X.sup.1 wherein X.sup.1 is as defined hereinbefore and
Q.sup.1 is selected from one of the following groups: 1)
C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4 alkyl-Q.sup.14 wherein
Q.sup.13 is as defined hereinbefore and Q.sup.14 is selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00008##
wherein Q.sup.14 is linked to C.sub.1-6alkanoyl through a nitrogen
atom; 2) Q.sup.2 (wherein Q.sup.2 is a 5-6-membered heterocyclic
group selected from pyrrolidinyl, piperidinyl, piperazinyl,
##STR00009##
which heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.1-6alkanoylC.sub.1-6alkyl and optionally bears a further 1 or
2 substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 3)
C.sub.1-5alkylW.sup.1Q.sup.2 (wherein W.sup.1 and Q.sup.2 are as
defined hereinbefore; 4) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is
as defined hereinbefore); 5) C.sub.2-5alkenylQ.sup.2 (wherein
Q.sup.2 is as defined hereinbefore); 6) C.sub.2-5alkynylQ.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 7)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 8)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 9)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 10)
C.sub.1-4alkylQ.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.15 and Q.sup.16 are each independently selected from a
5-6-membered heterocyclic group selected from pyrrolidinyl,
piperidinyl, piperazinyl,
##STR00010##
which heterocyclic group may bear either one substituent selected
from methylenedioxy or ethylenedioxy to form a bicyclic ring, or
may bear 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyano alkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)amino
C.sub.1-4alkyl, C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
proviso one or both of Q.sup.15 and Q.sup.16 must be a 5-6-membered
heterocyclic group as defined hereinbefore which heterocyclic group
bears either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.1-6alkanoylC.sub.1-6alkyl and
optionally bears 1 or 2 further substituents selected from those
defined hereinbefore); 11)
Cl.sub.1-4alkylQ.sup.15C.sub.1-4alkanoylQ.sup.16n wherein Q.sup.15
is as defined hereinbefore and Q.sup.16n is a 5-6-membered
heterocyclic group selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00011##
wherein Q.sup.16nis linked to C.sub.1-6alkanoyl through a nitrogen
atom and wherein Q.sup.16n bears either one substituent selected
from methylenedioxy or ethylenedioxy to form a bicyclic ring, or
bears 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6alkanoylC.sub.1-6alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogen, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); with the
proviso that one or both of Q.sup.15 and Q.sup.16n must be a
5-6-membered heterocyclic group as defined hereinbefore which
heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.1-6alkanoylC.sub.1-6alkyl and optionally bears 1 or 2 further
substituents selected from those defined hereinbefore; and
additionally wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino); and salts thereof, and prodrugs thereof for
example esters, amides and sulphides, preferably esters and
amides.
[0091] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
groups:
1) C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00012##
wherein Q.sup.14 is linked to C.sub.1-6alkanoyl through a nitrogen
atom; 2) Q.sup.2 (wherein Q.sup.2 is a 5-6-membered heterocyclic
group selected from pyrrolidinyl, piperidinyl, piperazinyl,
##STR00013##
which heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.2-4alkanoylC.sub.1-3alkyl and optionally bears a further 1 or
2 substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.2-4alkanoylC.sub.1-3alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 3)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined hereinbefore);
4) C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 5) C.sub.1-4alkylQ.sup.15
(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16 (wherein W.sup.2 is
as defined hereinbefore, j is 0 or 1, k is 0 or 1, and Q.sup.15 and
Q.sup.16 are each independently selected from a 5-6-membered
heterocyclic group selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00014##
which heterocyclic group may bear either one substituent selected
from methylenedioxy or ethylenedioxy to form a bicyclic ring, or
may bear 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.2-4alkanoylC.sub.1-3alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
proviso one or both of Q.sup.15 and Q.sup.16 must be a 5-6-membered
heterocyclic group as defined hereinbefore which heterocyclic group
bears either one substituent selected from methylenedioxy or
ethylenedioxy to form a bicyclic ring, or bears at least one
substituent selected from C.sub.2-4alkanoylC.sub.1-3alkyl and
optionally bears 1 or 2 further substituents selected from those
defined hereinbefore); 6)
C.sub.1-4alkylQ.sup.15C.sub.1-4alkanoylQ.sup.16n wherein Q.sup.15
is as defined hereinbefore and Q.sup.16n is a 5-6-membered
heterocyclic group selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00015##
wherein Q.sup.16n linked to C.sub.1-6alkanoyl through a nitrogen
atom and wherein Q.sup.16n bears either one substituent selected
from methylenedioxy or ethylenedioxy to form a bicyclic ring, or
bears 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.2-4alkanoylC.sub.1-3alkyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); with the
proviso that one or both of Q.sup.15 and Q.sup.16n must be a
5-6-membered heterocyclic group as defined hereinbefore which
heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
at least one substituent selected from
C.sub.2-4alkanoylC.sub.1-3alkyl and optionally bears 1 or 2 further
substituents selected from those defined hereinbefore; and
additionally wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogen and amino).
[0092] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is
C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 wherein
Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00016##
wherein Q.sup.14 is linked to C.sub.1-6alkanoyl through a nitrogen
atom.
[0093] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
groups:
1) Q.sup.2 (wherein Q.sup.2 is a 5-6-membered heterocyclic group
selected from pyrrolidinyl, piperidinyl, piperazinyl,
##STR00017##
which heterocyclic group bears either one substituent selected from
methylenedioxy or ethylenedioxy to form a bicyclic ring, or bears
one substituent selected from C.sub.2-4alkanoylC.sub.1-3alkyl; and
2) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined
hereinbefore). In one embodiment of the present invention R.sup.2a
is methoxy.
[0094] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is
C.sub.1-4alkyl-Q.sup.13n-C(O)--C.sub.1-4alkyl-Q.sup.14n and
Q.sup.13n and Q.sup.14n are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00018##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, halogen, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl; with the proviso
that at least one of Q.sup.13n and Q.sup.14n bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-4fluoroalkyl, C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-4alkyl group in Q.sup.1X.sup.1-- which is linked to X.sup.1
may bear one or more substituents selected from hydroxy, halogen
and amino).
[0095] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is
C.sub.1-4alkyl-Q.sup.13''-C(O)--C.sub.1-4alkyl-Q.sup.14n and
Q.sup.13n and Q.sup.14n are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00019##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4alkanoyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, halogen, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl; with the proviso
that at least one of Q.sup.13n and Q.sup.14n bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-4alkyl group in Q.sup.1X.sup.1-- which is linked to X.sup.1
may bear one or more substituents selected from hydroxy, halogen
and amino).
[0096] Examples of compounds of the present invention include
[0097]
7-({1-[(4-acetylpiperazin-1-yl)acetyl]piperidin-4-yl}methoxy)-4-[(4-fluor-
o-2-methyl-1H-indol)-5-yloxy]-6-methoxyquinazoline, [0098]
4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-7-{[1-(pyrrolidin-1-yl-
acetyl)piperidin-4-yl]methoxy}quinazoline, [0099]
4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-7-{[1-(piperidin-1-yla-
cetyl)piperidin-4-yl]methoxy}quinazoline, [0100]
4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-7-{[1-(morpholin-4-yla-
cetyl)piperidin-4-yl]methoxy}quinazoline, [0101]
4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-7-({1-[(3aR,6aS)-tetra-
hydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-ylacetyl]piperidin-4-yl}methoxy)quina-
zoline, [0102]
(3S)-4-[(4-fluoro-2-methyl-1H-indol)-5-yloxy]-7-({1-[(3-hydroxypyrrolidin-
-1-yl)acetyl]piperidin-4-yl}methoxy)-6-methoxyquinazoline, [0103]
7-({1-[(3,3-difluoropyrrolidin-1-yl)acetyl]piperidin-4-yl}methoxy)-4-[(4--
fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-quinazoline, and salts
thereof.
[0104] Examples of compounds of the present invention include:
[0105]
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-ind-
ol-5-yl)oxy]quinazoline, [0106]
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-6-yl)oxy]quinazoline, [0107]
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-5-yl)oxy]quinazoline, [0108]
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline, [0109]
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline, [0110]
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline, [0111]
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxol-
o[4,5-c]pyrrol-5-yl)ethoxy]quinazoline, [0112]
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxol-
o[4,5-c]pyrrol-5-yl)ethoxy]quinazoline, [0113]
4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1,3]di-
oxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline, [0114]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1-
,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline, [0115]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(2,3-dimethyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline, [0116]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(3-methyl-1H-in-
dol-5-yl)oxy]quinazoline, [0117]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline, [0118]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-ind-
ol-5-yl)oxy]-6-methoxyquinazoline, [0119]
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{2-[4-(pyrrolidin-1-ylacetyl)-
piperazin-1-yl]ethoxy}quinazoline, [0120]
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-6-
-yl)oxy]quinazoline, [0121]
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-5-
-yl)oxy]quinazoline, [0122]
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline, and salts thereof.
[0123] Particularly preferred compounds of the present invention
include: [0124]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydr-
o-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline, [0125]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline, [0126]
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-ind-
ol-5-yl)oxy]-6-methoxyquinazoline, and salts thereof.
[0127] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined` or `defined hereinbefore` the said group encompasses the
first occurring and broadest definition as well as each and all of
the preferred definitions for that group.
[0128] In this specification unless stated otherwise the term
"alkyl" includes both straight and branched chain alkyl groups but
references to individual alkyl groups such as "propyl" are specific
for the straight chain version only. An analogous convention
applies to other generic terms. Unless otherwise stated the term
"alkyl" advantageously refers to chains with 1-6 carbon atoms,
preferably 1-4 carbon atoms. The term "alkoxy" as used herein,
unless stated otherwise includes "alkyl"-O-groups in which "alkyl"
is as hereinbefore defined. The term "aryl" as used herein unless
stated otherwise includes reference to a C.sub.6-10 aryl group
which may, if desired, carry one or more substituents selected from
halogen, alkyl, alkoxy, nitro, trifluoromethyl and cyano, (wherein
alkyl and alkoxy are as hereinbefore defined). The term "aryloxy"
as used herein unless otherwise stated includes "aryl"-O-groups in
which "aryl" is as hereinbefore defined. The term "sulphonyloxy" as
used herein refers to alkylsulphonyloxy and arylsulphonyloxy groups
in which "alkyl" and "aryl" are as hereinbefore defined. The term
"alkanoyl" as used herein unless otherwise stated includes formyl
and alkylC.dbd.O groups in which "alkyl" is as defined
hereinbefore, for example C.sub.2alkanoyl is ethanoyl and refers to
CH.sub.3C.dbd.O, C.sub.1alkanoyl is formyl and refers to CHO.
Butanoyl refers to CH.sub.3--CH.sub.2--CH.sub.2--C(O), isobutyryl
refers to (CH.sub.3).sub.2.CH--C(O). In this specification unless
stated otherwise the term "alkenyl" includes both straight and
branched chain alkenyl groups but references to individual alkenyl
groups such as 2-butenyl are specific for the straight chain
version only. Unless otherwise stated the term "alkenyl"
advantageously refers to chains with 2-5 carbon atoms, preferably
3-4 carbon atoms. In this specification unless stated otherwise the
term "alkynyl" includes both straight and branched chain alkynyl
groups but references to individual alkynyl groups such as
2-butynyl are specific for the straight chain version only. Unless
otherwise stated the term "alkynyl" advantageously refers to chains
with 2-5 carbon atoms, preferably 3-4 carbon atoms. Unless stated
otherwise the term "haloalkyl" refers to an alkyl group as defined
hereinbefore which bears one or more halogeno groups, such as for
example trifluoromethyl.
[0129] In this specification the term azaindolyl refers to the
moiety (1H-pyrrolo[2,3-b]pyridinyl) and an analogous convention
applies to similar groups. For example 7-azaindol-5-yl is
(1H-pyrrolo[2,3-b]pyridin-5-yl) and is the group:
##STR00020##
[0130] Within the present invention it is to be understood that a
compound of the formula I or a salt thereof may exhibit the
phenomenon of tautomerism and that the formulae drawings within
this specification can represent only one of the possible
tautomeric forms. It is to be understood that the invention
encompasses any tautomeric form which inhibits VEGF receptor
tyrosine kinase activity and is not to be limited merely to any one
tautomeric form utilised within the formulae drawings. The formulae
drawings within this specification can represent only one of the
possible tautomeric forms and it is to be understood that the
specification encompasses all possible tautomeric forms of the
compounds drawn not just those forms which it has been possible to
show graphically herein.
[0131] It will be appreciated that compounds of the formula I or a
salt thereof may possess an asymmetric carbon atom. Such an
asymmetric carbon atom is also involved in the tautomerism
described above, and it is to be understood that the present
invention encompasses any chiral form (including both pure
enantiomers, scalemic and racemic mixtures) as well as any
tautomeric form which inhibits VEGF receptor tyrosine kinase
activity, and is not to be limited merely to any one tautomeric
form or chiral form utilised within the formulae drawings. It is to
be understood that the invention encompasses all optical and
diastereomers which inhibit VEGF receptor tyrosine kinase activity.
It is further to be understood that in the names of chiral
compounds (R,S) denotes any scalemic or racemic mixture while (R)
and (S) denote the enantiomers. In the absence of (R,S), (R) or (S)
in the name it is to be understood that the name refers to any
scalemic or racemic mixture, wherein a scalemic mixture contains R
and S enantiomers in any relative proportions and a racemic mixture
contains R and S enantiomers in the ration 50:50.
[0132] It is also to be understood that certain compounds of the
formula I and salts thereof can exist in solvated as well as
unsolvated forms such as, for example, hydrated forms. It is to be
understood that the invention encompasses all such solvated forms
which inhibit VEGF receptor tyrosine kinase activity.
[0133] For the avoidance of any doubt, it is to be understood that
when X.sup.1 is, for example, a group of formula --NR.sup.6C(O)--,
it is the nitrogen atom bearing the R.sup.6 group which is attached
to the quinazoline ring and the carbonyl (C(O)) group is attached
to R.sup.5, whereas when X.sup.1 is, for example, a group of
formula --C(O)NR.sup.7--, it is the carbonyl group which is
attached to the quinazoline ring and the nitrogen atom bearing the
R.sup.7 group is attached to R.sup.5. A similar convention applies
to the other two atom X.sup.1 linking groups such as
--NR.sup.9SO.sub.2-- and --SO.sub.2NR.sup.8--. When X.sup.1 is
--NR.sup.10-- it is the nitrogen atom bearing the R.sup.10 group
which is linked to the quinazoline ring and to R.sup.5. An
analogous convention applies to other groups. It is further to be
understood that when X.sup.1 represents --NR.sup.10-- and R.sup.10
is C.sub.1-3alkoxyC.sub.2-3alkyl it is the C.sub.2-3alkyl moiety
which is linked to the nitrogen atom of X.sup.1 and an analogous
convention applies to other groups.
[0134] For the avoidance of any doubt, it is to be understood that
in a compound of the formula I when R.sup.5 is, for example, a
group of formula C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.29, it is
the terminal C.sub.1-3alkyl moiety which is linked to X.sup.1,
similarly when R.sup.5 is, for example, a group of formula
C.sub.2-5alkenylR.sup.28 it is the C.sub.2-5alkenyl moiety which is
linked to X.sup.1 and an analogous convention applies to other
groups. When R.sup.5 is a group 1-R.sup.29prop-1-en-3-yl it is the
first carbon to which the group R.sup.29 is attached and it is the
third carbon which is linked to X.sup.1 and an analogous convention
applies to other groups.
[0135] For the avoidance of any doubt, it is to be understood that
in a compound of the formula I when R.sup.5 is, for example,
R.sup.28 and R.sup.28 is a pyrrolidinyl ring which bears a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD, it is the --O-- or
C.sub.1-4alkyl which is linked to the pyrrolidinyl ring, unless f
and g are both 0 when it is ring D which is linked to the
pyrrolidinyl ring and an analogous convention applies to other
groups.
[0136] For the avoidance of any doubt, it is to be understood that
when R.sup.29 carries a C.sub.1-4aminoalkyl substituent it is the
C.sub.1-4alkyl moiety which is attached to R.sup.29 whereas when
R.sup.29 carries a C.sub.1-4alkylamino substituent it is the amino
moiety which is attached to R.sup.29 and an analogous convention
applies to other groups.
[0137] For the avoidance of any doubt, it is to be understood that
when R.sup.28 carries a C.sub.1-4alkoxyC.sub.1-4alkyl substituent
it is the C.sub.1-4alkyl moiety which is attached to R.sup.28 and
an analogous convention applies to other groups.
[0138] For the avoidance of any doubt, it is to be understood that
when R.sup.2 is
--X.sup.1--C.sub.1-4alkyl-Q.sup.13-C(O)--C.sub.1-4alkyl-Q.sup.14 it
is X.sup.1 that is linked to the quinazoline ring, Q.sup.13 is
linked to the C.sub.1-4alkyl chain and to the carbonyl group, the
carbonyl group is also linked to the terminal C.sub.1-4alkyl chain
and Q.sup.14 is linked to the terminal C.sub.1-4alkyl chain.
[0139] A particular value of C.sub.1-6alkanoylC.sub.1-6alkyl is
acetylmethyl.
[0140] The present invention relates to the compounds of formula I
as hereinbefore defined as well as to the salts thereof. Salts for
use in pharmaceutical compositions will be pharmaceutically
acceptable salts, but other salts may be useful in the production
of the compounds of formula I and their pharmaceutically acceptable
salts. Pharmaceutically acceptable salts of the invention may, for
example, include acid addition salts of the compounds of formula I
as hereinbefore defined which are sufficiently basic to form such
salts. Such acid addition salts include for example salts with
inorganic or organic acids affording pharmaceutically acceptable
anions such as with hydrogen halides (especially hydrochloric or
hydrobromic acid of which hydrochloric acid is particularly
preferred) or with sulphuric or phosphoric acid, or with
trifluoroacetic, citric or maleic acid. In addition where the
compounds of formula I are sufficiently acidic, pharmaceutically
acceptable salts may be formed with an inorganic or organic base
which affords a pharmaceutically acceptable cation. Such salts with
inorganic or organic bases include for example an alkali metal
salt, such as a sodium or potassium salt, an alkaline earth metal
salt such as a calcium or magnesium salt, an ammonium salt or for
example a salt with methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0141] A compound of the formula I, or salt thereof, and other
compounds of the invention (as herein defined) may be prepared by
any process known to be applicable to the preparation of
chemically-related compounds. Such processes include, for example,
those illustrated in International Patent Application Number WO
00/47212 and in European Patent Applications Publication Nos.
0520722, 0566226, 0602851 and 0635498. Such processes also include,
for example, solid phase synthesis. Such processes, are provided as
a further feature of the invention and are as described
hereinafter. Necessary starting materials may be obtained by
standard procedures of organic chemistry. The preparation of such
starting materials is described within the accompanying
non-limiting Examples. Alternatively necessary starting materials
are obtainable by analogous procedures to those illustrated which
are within the ordinary skill of an organic chemist.
[0142] Thus, the following processes (a) to (f) and (i) to (vi)
constitute further features of the present invention.
Synthesis of Compounds of Formula I
[0143] (a) Compounds of the formula I and salts thereof may be
prepared by the reaction of a compound of the formula III:
##STR00021##
(wherein R.sup.2 and m are as defined hereinbefore and L.sup.1 is a
displaceable moiety), with a compound of the formula IV:
##STR00022##
(wherein ring C, R.sup.1, Z and n are as defined hereinbefore) to
obtain compounds of the formula I and salts thereof. A convenient
displaceable moiety L.sup.1 is, for example, a halogeno, alkoxy
(preferably C.sub.1-4alkoxy), aryloxy, alkylsulphanyl,
arylsulphanyl, alkoxyalkylsulphanyl or sulphonyloxy group, for
example a chloro, bromo, methoxy, phenoxy, methylsulphanyl,
2-methoxyethylsulphanyl, methanesulphonyloxy or
toluene-4-sulphonyloxy group.
[0144] The reaction is advantageously effected in the presence of a
base. Such a base is, for example, an organic amine base such as,
for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, morpholine,
N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene,
tetramethylguanidine or for example, an alkali metal or alkaline
earth metal carbonate or hydroxide, for example sodium carbonate,
potassium carbonate, calcium carbonate, cesium carbonate, sodium
hydroxide or potassium hydroxide. Alternatively such a base is, for
example, an alkali metal hydride, for example sodium hydride, or an
alkali metal or alkaline earth metal amide, for example sodium
amide, sodium bis(trimethylsilyl)amide, potassium amide or
potassium bis(trimethylsilyl)amide. The reaction is preferably
effected in the presence of an inert solvent or diluent, for
example an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic
hydrocarbon solvent such as toluene, or a dipolar aprotic solvent
such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is
conveniently effected at a temperature in the range, for example,
10 to 150.degree. C., preferably in the range 20 to 90.degree.
C.
[0145] Where R.sup.1 or R.sup.2 contains a heterocyclic ring with a
substituent it is possible to add the substituent after process (a)
above using standard procedures of organic chemistry. Thus for
example a compound of formula III as defined hereinbefore but
wherein R.sup.2 contains an unsubstituted heterocyclic ring may be
reacted with a compound of formula IV as defined hereinbefore to
give an intermediate compound in which R.sup.2 contains an
unsubstituted heterocyclic ring. The intermediate compound can then
be substituted on the heterocyclic ring in R.sup.2 using standard
organic chemistry techniques to give a final compound of formula
I.
[0146] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide, for example
hydrogen chloride, sulphuric acid, a sulphonic acid, for example
methane sulphonic acid, or a carboxylic acid, for example acetic or
citric acid, using a conventional procedure.
(b) Production of those compounds of formula I and salts thereof
wherein at least one R.sup.2 is R.sup.5X.sup.1 or Q.sup.1X.sup.1
wherein R.sup.5, Q.sup.1 are as defined hereinbefore, and X.sup.1
is --O--, --S--, --OC(O)-- or --NR.sup.10-- (wherein R.sup.10
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) can be achieved by the reaction,
conveniently in the presence of a base (as defined hereinbefore in
process (a)) of a compound of the formula V:
##STR00023##
(wherein ring C, Z, R.sup.1, R.sup.2 and n are as hereinbefore
defined and X.sup.1 is as hereinbefore defined in this section and
s is an integer from 0 to 2) with one of the compounds of the
formulae VIa-b:
R.sup.5-L.sup.1 (VIa)
Q.sup.1-L.sup.1 (VIb)
(wherein R.sup.5, Q.sup.1 and L.sup.1 are as hereinbefore defined),
L.sup.1 is a displaceable moiety for example a halogeno or
sulphonyloxy group such as a bromo, methanesulphonyloxy or
toluene-4-sulphonyloxy group, or L.sup.1 may be generated in situ
from an alcohol under standard Mitsunobu conditions ("Organic
Reactions", John Wiley & Sons Inc, 1992, vol 42, chapter 2,
David L Hughes). The reaction is preferably effected in the
presence of a base (as defined hereinbefore in process (a)) and
advantageously in the presence of an inert solvent or diluent (as
defined hereinbefore in process (a)), advantageously at a
temperature in the range, for example 10 to 150.degree. C.,
conveniently at about 50.degree. C. (c) Compounds of the formula I
and salts thereof wherein at least one R.sup.2 is R.sup.5X.sup.1 or
Q.sup.1X.sup.1 wherein R.sup.5 and Q.sup.1 are as defined
hereinbefore, and X.sup.1 is --O--, --S--, --OC(O)-- or
--NR.sup.10-- (wherein R.sup.10 represents hydrogen, C.sub.1-3alkyl
or C.sub.1-3alkoxyC.sub.2-3alkyl) may be prepared by the reaction
of a compound of the formula VII:
##STR00024##
with one of the compounds of the formulae VIIIa-b:
R.sup.5--X.sup.1--H (VIIIa)
Q.sup.1-X.sup.1 (VIIIb)
(wherein L.sup.1, R.sup.1, R.sup.2, R.sup.5, Q.sup.1 ring C, Z, n
and s are all as hereinbefore defined and X.sup.1 is as
hereinbefore defined in this section). The reaction may
conveniently be effected in the presence of a base (as defined
hereinbefore in process (a)) and advantageously in the presence of
an inert solvent or diluent (as defined hereinbefore in process
(a)), advantageously at a temperature in the range, for example 10
to 150.degree. C., conveniently at about 100.degree. C. (d)
Compounds of the formula I and salts thereof wherein at least one
R.sup.2 is R.sup.5X.sup.1 or Q.sup.1X.sup.1 wherein X.sup.1 is as
defined hereinbefore, R.sup.5 is C.sub.1-5alkylR.sup.113, wherein
R.sup.113 is selected from one of the following nine groups: 1)
X.sup.19C.sub.1-3alkyl (wherein X.sup.19 represents --O--, --S--,
--SO.sub.2--, NR.sup.114C(O)-- or --NR.sup.115SO.sub.2-- (wherein
R.sup.114 and R.sup.115 which may be the same or different are each
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 2)
NR.sup.116R.sup.117 (wherein R.sup.116 and R.sup.117 which may be
the same or different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl);
3)X.sup.20C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.20
represents --O--, --S--, --SO.sub.2--, or --NR.sup.118C(O)--,
--NR.sup.119SO.sub.2-- or --NR.sup.120-- (wherein R.sup.118,
R.sup.119, and R.sup.120 which may be the same or different are
each hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
X.sup.5 and R.sup.22 are as defined hereinbefore); 4) R.sup.28
(wherein R.sup.28 is as defined hereinbefore); 5) X.sup.21R.sup.29
(wherein X.sup.21 represents --O--, --S--, --SO.sub.2--,
NR.sup.121C(O)--, --NR.sup.122SO.sub.2--, or --NR.sup.123--
(wherein R.sup.121, R.sup.122, and R.sup.123 which may be the same
or different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); and 6) X.sup.22C.sub.1-3alkylR.sup.29 (wherein
X.sup.22 represents --O--, --S--, --SO.sub.2--, --NR.sup.124C(O)--,
--NR.sup.125SO.sub.2-- or --NR.sup.126-- (wherein R.sup.124,
R.sup.125 and R.sup.126 each independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as
defined hereinbefore); 7) R.sup.29 (wherein R.sup.29 is as defined
hereinbefore); 8) X.sup.22C.sub.1-4alkylR.sup.28 (wherein X.sup.22
and R.sup.28 are as defined hereinbefore); and 9)
R.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55 (wherein q,
r, X.sup.9, R.sup.54 and R.sup.55 are as defined hereinbefore);
Q.sup.1 is C.sub.1-5alkylQ.sup.27 wherein Q.sup.27 is selected from
one of the following six groups: 1)
Q.sup.13-C(O)--C.sub.1-4alkylQ.sup.14 (wherein Q.sup.13 and
Q.sup.14 are as defined hereinbefore); 2) W.sup.1Q.sup.2 (wherein
W.sup.1 and Q.sup.2 are as defined hereinbefore); 3) Q.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 4)
W.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and Q.sup.2 are as
defined hereinbefore); 5)
Q.sup.15(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.16 (wherein
W.sup.2, j, k, Q.sup.15 and Q.sup.16 are as defined hereinbefore);
6) Q.sup.15C.sub.1-4alkanoylQ.sup.16n (wherein Q.sup.15 and
Q.sup.16 are as defined hereinbefore); may be prepared by reacting
a compound of the formula IX:
##STR00025##
(wherein L.sup.1, X.sup.1, R.sup.1, R.sup.2, ring C, Z, n and s are
as hereinbefore defined) with one of the compounds of the formulae
Xa-b:
R.sup.113--H (Xa)
Q.sup.27-H (Xb)
(wherein R.sup.113 and Q.sup.27 are as defined hereinbefore) to
give a compound of the formula I or salt thereof. The reaction may
conveniently be effected in the presence of a base (as defined
hereinbefore in process (a)) and advantageously in the presence of
an inert solvent or diluent (as defined hereinbefore in process
(a)), and at a temperature in the range, for example 0 to
150.degree. C., conveniently at about 50.degree. C.
[0147] Where R.sup.1 or R.sup.2 contains a heterocyclic ring with a
substituent it is possible to add the substituent after process (d)
above using standard procedures of organic chemistry. Thus for
example a compound of formula III as defined hereinbefore but
wherein R.sup.2 contains an unsubstituted heterocyclic ring may be
reacted with a compound of formula IV as defined hereinbefore to
give an intermediate compound in which R.sup.2 contains an
unsubstituted heterocyclic ring. The intermediate compound can then
be substituted on the heterocyclic ring in R.sup.2 using standard
organic chemistry techniques to give a final compound of formula
I.
[0148] Processes (a), (b) and (d) are preferred over process
(c).
[0149] Processes (a) and (b) are the more preferred.
[0150] Process (d) is also preferred.
(e) The production of those compounds of the formula I and salts
thereof wherein one or more of the substituents (R.sup.2).sub.m is
represented by --NR.sup.127R.sup.128, where one (and the other is
hydrogen) or both of R.sup.127 and R.sup.128 are C.sub.1-3alkyl,
may be effected by the reaction of compounds of formula I wherein
the substituent (R.sup.2).sub.m is an amino group and an alkylating
agent, preferably in the presence of a base as defined
hereinbefore. Such alkylating agents are C.sub.1-3alkyl moieties
bearing a displaceable moiety as defined hereinbefore such as
C.sub.1-3alkyl halides for example C.sub.1-3alkyl chloride, bromide
or iodide. The reaction is preferably effected in the presence of
an inert solvent or diluent (as defined hereinbefore in process
(a)) and at a temperature in the range, for example, 10 to
100.degree. C., conveniently at about ambient temperature. The
production of compounds of formula I and salts thereof wherein one
or more of the substituents R.sup.2 is an amino group may be
effected by the reduction of a corresponding compound of formula I
wherein the substituent(s) at the corresponding position(s) of the
quinazoline group is/are a nitro group(s). The reduction may
conveniently be effected as described in process (i) hereinafter.
The production of a compound of formula I and salts thereof wherein
the substituent(s) at the corresponding position(s) of the
quinazoline group is/are a nitro group(s) may be effected by the
processes described hereinbefore and hereinafter in processes (a-d)
and (i-v) using a compound selected from the compounds of the
formulae (I-XXII) in which the substituent(s) at the corresponding
position(s) of the quinazoline group is/are a nitro group(s). (f)
Compounds of the formula I and salts thereof wherein X.sup.1 is
--SO-- or --SO.sub.2-- may be prepared by oxidation from the
corresponding compound in which X.sup.1 is --S-- or --SO-- (when
X.sup.1 is --SO.sub.2-- is required in the final product).
Conventional oxidation conditions and reagents for such reactions
are well known to the skilled chemist.
Synthesis of Intermediates
[0151] (i) The compounds of formula III and salts thereof in which
L.sup.1 is halogeno may for example be prepared by halogenating a
compound of the formula XI:
##STR00026##
wherein R.sup.2 and m are as hereinbefore defined).
[0152] Convenient halogenating agents include inorganic acid
halides, for example thionyl chloride, phosphorus(III)chloride,
phosphorus(V)oxychloride and phosphorus(V) chloride. The
halogenation reaction may be effected in the presence of an inert
solvent or diluent such as for example a halogenated solvent such
as methylene chloride, trichloromethane or carbon tetrachloride, or
an aromatic hydrocarbon solvent such as benzene or toluene, or the
reaction may be effected without the presence of a solvent. The
reaction is conveniently effected at a temperature in the range,
for example 10 to 150.degree. C., preferably in the range 40 to
100.degree. C.
[0153] The compounds of formula XI and salts thereof may, for
example, be prepared by reacting a compound of the formula XII:
##STR00027##
(wherein R.sup.2, s and L.sup.1 are as hereinbefore defined) with
one of the compounds of formulae VIIIa-d as hereinbefore defined.
The reaction may conveniently be effected in the presence of a base
(as defined hereinbefore in process (a)) and advantageously in the
presence of an inert solvent or diluent (as defined hereinbefore in
process (a)), advantageously at a temperature in the range, for
example 10 to 150.degree. C., conveniently at about 100.degree.
C.
[0154] Compounds of formula XI and salts thereof wherein at least
one R.sup.2 is R.sup.5X.sup.1 or Q.sup.1X.sup.1, wherein R.sup.5
and Q.sup.1 are as defined hereinbefore, and wherein X.sup.1 is
--O--, --S--, --SO--, --SO.sub.2--, --C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8-- or --NR.sup.10-- (wherein R.sup.7, R.sup.8 and
R.sup.10 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), may for example also be prepared by
the reaction of a compound of the formula XIII:
##STR00028##
(wherein R.sup.2 and s are as hereinbefore defined and X.sup.1 is
as hereinbefore defined in this section) with one of the compounds
of formulae VIa-b as hereinbefore defined. The reaction may for
example be effected as described for process (b) hereinbefore. The
pivaloyloxymethyl group can then be cleaved by reacting the product
with a base such as, for example, aqueous ammonia, triethylamine in
water, an alkali metal or alkaline earth metal hydroxide or
alkoxide, preferably aqueous ammonia, aqueous sodium hydroxide or
aqueous potassium hydroxide, in a polar protic solvent such as an
alcohol, for example methanol or ethanol. The reaction is
conveniently effected at a temperature in the range 20 to
100.degree. C., preferably in the range 20 to 50.degree. C.
[0155] The compounds of formula XI and salts thereof may also be
prepared by cyclising a compound of the formula XIV:
##STR00029##
(wherein R.sup.2 and m, are as hereinbefore defined, and A.sup.1 is
an hydroxy, alkoxy (preferably C.sub.1-4alkoxy) or amino group)
whereby to form a compound of formula XI or salt thereof. The
cyclisation may be effected by reacting a compound of the formula
XIV, where A.sup.1 is an hydroxy or alkoxy group, with formamide or
an equivalent thereof effective to cause cyclisation whereby a
compound of formula XI or salt thereof is obtained, such as
[3-(dimethylamino)-2-azaprop-2-enylidene]dimethylammonium chloride.
The cyclisation is conveniently effected in the presence of
formamide as solvent or in the presence of an inert solvent or
diluent such as an ether for example 1,4-dioxan. The cyclisation is
conveniently effected at an elevated temperature, preferably in the
range 80 to 200.degree. C. The compounds of formula XI may also be
prepared by cyclising a compound of the formula XIV, where A.sup.1
is an amino group, with formic acid or an equivalent thereof
effective to cause cyclisation whereby a compound of formula XI or
salt thereof is obtained. Equivalents of formic acid effective to
cause cyclisation include for example a tri-C.sub.1-4alkoxymethane,
for example triethoxymethane and trimethoxymethane. The cyclisation
is conveniently effected in the presence of a catalytic amount of
an anhydrous acid, such as a sulphonic acid for example
p-toluenesulphonic acid, and in the presence of an inert solvent or
diluent such as for example a halogenated solvent such as methylene
chloride, trichloromethane or carbon tetrachloride, an ether such
as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon
solvent such as toluene. The cyclisation is conveniently effected
at a temperature in the range, for example 10 to 100.degree. C.,
preferably in the range 20 to 50.degree. C.
[0156] Compounds of formula XIV and salts thereof may for example
be prepared by the reduction of the nitro group in a compound of
the formula XV:
##STR00030##
(wherein R.sup.2, m and A.sup.1 are as hereinbefore defined) to
yield a compound of formula XIV as hereinbefore defined. The
reduction of the nitro group may conveniently be effected by any of
the procedures known for such a transformation. The reduction may
be carried out, for example, by stirring a solution of the nitro
compound under hydrogen at 1 to 4 atmospheres pressure in the
presence of an inert solvent or diluent as defined hereinbefore in
the presence of a metal effective to catalyse hydrogenation
reactions such as palladium or platinum. A further reducing agent
is, for example, an activated metal such as activated iron
(produced for example by washing iron powder with a dilute solution
of an acid such as hydrochloric acid). Thus, for example, the
reduction may be effected by heating the nitro compound under
hydrogen at 2 atmospheres pressure in the presence of the activated
metal and a solvent or diluent such as a mixture of water and
alcohol, for example methanol or ethanol, at a temperature in the
range, for example 50 to 150.degree. C., conveniently at about
70.degree. C.
[0157] Compounds of the formula XV and salts thereof may for
example be prepared by the reaction of a compound of the formula
XVI:
##STR00031##
(wherein R.sup.2, s, L.sup.1 and A.sup.1 are as hereinbefore
defined) with one of the compounds of formulae VIIIa-d as
hereinbefore defined to give a compound of the formula XV. The
reaction of the compounds of formulae XVI and VIIIa-b is
conveniently effected under conditions as described for process (c)
hereinbefore.
[0158] Compounds of formula XV and salts thereof wherein at least
one R.sup.2 is R.sup.5X.sup.1 or Q.sup.1X.sup.1, wherein R.sup.5
and Q.sup.1 are as defined hereinbefore, and wherein X.sup.1 is
--O--, --S--, --SO.sub.2--, --C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8-- or --NR.sup.10-- (wherein R.sup.7, R.sup.8 and
R.sup.10 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), may for example also be prepared by
the reaction of a compound of the formula XVII:
##STR00032##
(wherein R.sup.2, s and A.sup.1 are as hereinbefore defined and
X.sup.1 is as hereinbefore defined in this section) with one of the
compounds of formulae VIa-b as hereinbefore defined to yield a
compound of formula XV as hereinbefore defined. The reaction of the
compounds of formulae XVII and VIa-d is conveniently effected under
conditions as described for process (b) hereinbefore.
[0159] The compounds of formula III and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 and wherein X.sup.1 is
--CH.sub.2-- may be prepared for example as described above from a
compound of the formula XV (in which R.sup.2 is --CH.sub.3) or MI
(in which HX.sup.1-- is --CH.sub.3), by radical bromination or
chlorination to give a --CH.sub.2Br or --CH.sub.2Cl group which may
then be reacted with a compound of the formula R.sup.5--H under
standard conditions for such substitution reactions.
[0160] The compounds of formula III and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 and wherein X.sup.1 is a direct
bond may be prepared for example as described above from a compound
of the formula XI, wherein the R.sup.5 group is already present in
the intermediate compounds (for example in a compound of the
formula XV) used to prepare the compound of formula XI.
[0161] The compounds of formula III and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 and wherein X.sup.1 is
--NR.sup.6C(O)-- or --NR.sup.9SO.sub.2-- may be prepared for
example from a compound of the formula XIII in which HX.sup.1-- is
an --NHR.sup.6-- or --NHR.sup.9-- group (prepared for example from
an amino group (later functionalised if necessary) by reduction of
a nitro group) which is reacted with an acid chloride or sulfonyl
chloride compound of the formula R.sup.5COCl or
R.sup.5SO.sub.2Cl.
[0162] The compounds of formula III and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 or Q.sup.1X.sup.1, wherein
R.sup.5 and Q.sup.1 are as defined hereinbefore, and wherein
X.sup.1 is --O--, --S--, --OC(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8-- or --NR.sup.10-- (wherein R.sup.7, R.sup.8 and
R.sup.10 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), may also be prepared for example by
reacting a compound of the formula XVIII:
##STR00033##
(wherein R.sup.2 and s are as hereinbefore defined, X.sup.1 is as
hereinbefore defined in this section and L.sup.2 represents a
displaceable protecting moiety) with one of the compounds of
formulae VIa-b as hereinbefore defined, whereby to obtain a
compound of formula III in which L.sup.1 is represented by
L.sup.2.
[0163] A compound of formula XVIII is conveniently used in which
L.sup.2 represents a phenoxy group which may if desired carry up to
5 substituents, preferably up to 2 substituents, selected from
halogeno, nitro and cyano. The reaction may be conveniently
effected under conditions as described for process (b)
hereinbefore.
[0164] The compounds of formula XVIII and salts thereof may for
example be prepared by deprotecting a compound of the formula
XIX:
##STR00034##
(wherein R.sup.2, s and L.sup.2 are as hereinbefore defined,
P.sup.1 is a protecting group and X.sup.1 is as hereinbefore
defined in the section describing compounds of the formula XVIII).
The choice of protecting group P.sup.1 is within the standard
knowledge of an organic chemist, for example those included in
standard texts such as "Protective Groups in Organic Synthesis" T.
W. Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, including
N-sulphonyl derivatives (for example, p-toluenesulphonyl),
carbamates (for example, t-butyl carbonyl), N-alkyl derivatives
(for example, 2-chloroethyl, benzyl) and amino acetal derivatives
(for example benzyloxymethyl). The removal of such a protecting
group may be effected by any of the procedures known for such a
transformation, including those reaction conditions indicated in
standard texts such as that indicated hereinbefore, or by a related
procedure. Deprotection may be effected by techniques well known in
the literature, for example where P.sup.1 represents a benzyl group
deprotection may be effected by hydrogenolysis or by treatment with
trifluoroacetic acid.
[0165] One compound of formula III may if desired be converted into
another compound of formula III in which the moiety L.sup.1 is
different. Thus for example a compound of formula III in which
L.sup.1 is other than halogeno, for example optionally substituted
phenoxy, may be converted to a compound of formula III in which
L.sup.1 is halogeno by hydrolysis of a compound of formula III (in
which L.sup.1 is other than halogeno) to yield a compound of
formula XI as hereinbefore defined, followed by introduction of
halide to the compound of formula XI, thus obtained as hereinbefore
defined, to yield a compound of formula III in which L.sup.1
represents halogen.
(ii) Compounds of formula IV and salts thereof in which ring C is
indolyl may be prepared by any of the methods known in the art,
such as for example those described in "Indoles Part I", "Indoles
Part II", 1972 John Wiley & Sons Ltd and "Indoles Part III",
1979, John Wiley & Sons Ltd, edited by W. J. Houlihan.
Compounds of formula IV and salts thereof in which ring C is
indolyl may be prepared by any of the methods described in
International Patent Application No. PCT/GB03/00343 or in WO
00/47212.
[0166] Compounds of formula IV and salts thereof in which ring C is
quinolinyl may be prepared by any of the methods known in the art,
such as for example those described in "The Chemistry of
Heterocyclic Compounds: Quinolines Parts I, II and III", 1982
(Interscience publications) John Wiley & Sons Ltd, edited by G.
Jones, and in "Comprehensive Heterocyclic Chemistry Vol II by A. R.
Katritzky", 1984 Pergamon Press, edited by A. J. Boulton and A
McKillop.
[0167] Compounds of formula IV and salts thereof in which ring C is
indazolyl may be prepared by any of the methods known in the art,
such as for example those described in Petitcoles, Bull. Soc. Chim.
Fr. 1950, 466 and Davies, J. Chem. Soc. 1955, 2412.
[0168] Compounds of formula N and salts thereof in which ring C is
azaindolyl may be prepared by any of the methods known in the art,
such as for example those described in Heterocycles 50, (2),
1065-1080, 1999.
(iii) Compounds of formula V as hereinbefore defined and salts
thereof may be made by deprotecting the compound of formula XX:
##STR00035##
(wherein ring C, Z, R.sup.1, R.sup.2, P.sup.1 n and s are as
hereinbefore defined and X.sup.1 is as hereinbefore defined in the
section describing compounds of the formula V) by a process for
example as described in (i) above.
[0169] Compounds of the formula XX and salts thereof may be made by
reacting compounds of the formulae XIX and N as hereinbefore
defined, under the conditions described in (a) hereinbefore, to
give a compound of the formula XX or salt thereof.
(iv) Compounds of the formula VII and salts thereof may be made by
reacting a compound of the formula XXI:
##STR00036##
(wherein R.sup.2, s and each L.sup.1 are as hereinbefore defined
and the L.sup.1 in the 4-position and the other L.sup.1 in a
further position on the quinazoline ring may be the same or
different) with a compound of the formula IV as hereinbefore
defined, the reaction for example being effected by a process as
described in (a) above. (v) Compounds of formula IX as defined
hereinbefore and salts thereof may for example be made by the
reaction of compounds of formula V as defined hereinbefore with
compounds of the formula XXII:
L.sup.1-C.sub.1-5alkyl-L.sup.1 (XXII)
(wherein L.sup.1 is as hereinbefore defined) to give compounds of
formula IX or salts thereof. The reaction may be effected for
example by a process as described in (b) above. (vi) Intermediate
compounds wherein X.sup.1 is --SO-- or --SO.sub.2-- may be prepared
by oxidation from the corresponding compound in which X.sup.1 is
--S-- or --SO-- (when X.sup.1 is --SO.sub.2-- is required in the
final product). Conventional oxidation conditions and reagents for
such reactions are well known to the skilled chemist.
[0170] When a pharmaceutically acceptable salt of a compound of the
formula I is required, it may be obtained, for example, by reaction
of said compound with, for example, an acid using a conventional
procedure, the acid having a pharmaceutically acceptable anion.
[0171] Many of the intermediates defined herein are novel and these
are provided as a further feature of the invention. The preparation
of these compounds is as described herein and/or is by methods well
known to persons skilled in the art of organic chemistry.
[0172] The identification of compounds which inhibit angiogenesis
and/or increased vascular permeability, which potently inhibit the
tyrosine kinase activity associated with the VEGF receptor KDR and
are selective for KDR over Flt-1, which have less extended plasma
pharmacokinetics and which are inactive or only weakly active in
the hERG assay, is desirable and is the subject of the present
invention.
[0173] These properties may be assessed, for example, using one or
more of the procedures set out below:
(a) In Vitro Receptor Tyrosine Kinase Inhibition Test
[0174] This assay determines the ability of a test compound to
inhibit tyrosine kinase activity. DNA encoding VEGF, FGF or EGF
receptor cytoplasmic domains may be obtained by total gene
synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25,
1987) or by cloning. These may then be expressed in a suitable
expression system to obtain polypeptide with tyrosine kinase
activity. For example VEGF, FGF and EGF receptor cytoplasmic
domains, which were obtained by expression of recombinant protein
in insect cells, were found to display intrinsic tyrosine kinase
activity. In the case of the VEGF receptor Flt-1 (Genbank accession
number X51602), a 1.7 kb DNA fragment encoding most of the
cytoplasmic domain, commencing with methionine 783 and including
the termination codon, described by Shibuya et al (Oncogene, 1990,
5: 519-524), was isolated from cDNA and cloned into a baculovirus
transplacement vector (for example pAcYM1 (see The Baculovirus
Expression System: A Laboratory Guide, L. A. King and R. D. Possee,
Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from
Invitrogen Corporation)). This recombinant construct was
co-transfected into insect cells (for example Spodoptera frugiperda
21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare
recombinant baculovirus. (Details of the methods for the assembly
of recombinant DNA molecules and the preparation and use of
recombinant baculovirus can be found in standard texts for example
Sambrook et al, 1989, Molecular cloning--A Laboratory Manual, 2nd
edition, Cold Spring Harbour Laboratory Press and O'Reilly et al,
1992, Baculovirus Expression Vectors--A Laboratory Manual, W. H.
Freeman and Co, New York). For other tyrosine kinases for use in
assays, cytoplasmic fragments starting from methionine 806 (KDR,
Genbank accession number L04947), methionine 668 (EGF receptor,
Genbank accession number X00588) and methionine 399 (FGF R1
receptor, Genbank accession number X51803) may be cloned and
expressed in a similar manner.
[0175] For expression of cFlt-1 tyrosine kinase activity, Sf21
cells were infected with plaque-pure cFlt-1 recombinant virus at a
multiplicity of infection of 3 and harvested 48 hours later.
Harvested cells were washed with ice cold phosphate buffered saline
solution (PBS) (10 mM sodium phosphate pH7.4, 138 mM sodium
chloride, 2.7 mM potassium chloride) then resuspended in ice cold
HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodium chloride, 10% v/v
glycerol, 1% v/v Triton X100, 1.5 mM magnesium chloride, 1 mM
ethylene glycol-bis(.beta.aminoethyl ether) N,N,N',N'-tetraacetic
acid (EGTA), 1 mM PMSF (phenylmethylsulphonyl fluoride); the PMSF
is added just before use from a freshly-prepared 100 mM solution in
methanol) using 1 ml HNTG/PMSF per 10 million cells. The suspension
was centrifuged for 10 minutes at 13,000 rpm at 4.degree. C., the
supernatant (enzyme stock) was removed and stored in aliquots at
-70.degree. C. Each new batch of stock enzyme was titrated in the
assay by dilution with enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM
sodium orthovanadate, 0.1% v/v Triton X100, 0.2 mM dithiothreitol).
For a typical batch, stock enzyme is diluted 1 in 2000 with enzyme
diluent and 500 of dilute enzyme is used for each assay well.
[0176] A stock of substrate solution was prepared from a random
copolymer containing tyrosine, for example Poly (Glu, Ala, Tyr)
6:3:1 (Sigma P3899), stored as 1 mg/ml stock in PBS at -20.degree.
C. and diluted 1 in 500 with PBS for plate coating.
[0177] On the day before the assay 100 .mu.l of diluted substrate
solution was dispensed into all wells of assay plates (Nunc
maxisorp 96-well immunoplates) which were sealed and left overnight
at 4.degree. C.
[0178] On the day of the assay the substrate solution was discarded
and the assay plate wells were washed once with PBST (PBS
containing 0.05% v/v Tween 20) and once with 50 mM Hepes pH7.4.
[0179] Test compounds were diluted with 10% dimethylsulphoxide
(DMSO) and 25 .mu.l of diluted compound was transferred to wells in
the washed assay plates. "Total" control wells contained 10% DMSO
instead of compound. Twenty five microlitres of 40 mM
manganese(II)chloride containing 8 .mu.M adenosine-5'-triphosphate
(ATP) was added to all test wells except "blank" control wells
which contained manganese(II)chloride without ATP. To start the
reactions 50 .mu.l of freshly diluted enzyme was added to each well
and the plates were incubated at ambient temperature for 20
minutes. The liquid was then discarded and the wells were washed
twice with PBST. One hundred microlitres of mouse IgG
anti-phosphotyrosine antibody (Upstate Biotechnology Inc. product
05-321), diluted 1 in 6000 with PBST containing 0.5% w/v bovine
serum albumin (BSA), was added to each well and the plates were
incubated for 1 hour at ambient temperature before discarding the
liquid and washing the wells twice with PBST. One hundred
microlitres of horse radish peroxidase (HRP)-linked sheep
anti-mouse Ig antibody (Amersham product NXA 931), diluted 1 in 500
with PBST containing 0.5% w/v BSA, was added and the plates were
incubated for 1 hour at ambient temperature before discarding the
liquid and washing the wells twice with PBST. One hundred
microlitres of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic
acid) (ABTS) solution, freshly prepared using one 50 mg ABTS tablet
(Boehringer 1204 521) in 50 ml freshly prepared 50 mM
phosphate-citrate buffer pH5.0+0.03% sodium perborate (made with 1
phosphate citrate buffer with sodium perborate (PCSB) capsule
(Sigma P4922) per 100 ml distilled water), was added to each well.
Plates were then incubated for 20-60 minutes at ambient temperature
until the optical density value of the "total" control wells,
measured at 405 nm using a plate reading spectrophotometer, was
approximately 1.0. "Blank" (no ATP) and "total" (no compound)
control values were used to determine the dilution range of test
compound which gave 50% inhibition of enzyme activity.
(b) In Vitro HUVEC Proliferation Assay
[0180] This assay determines the ability of a test compound to
inhibit the growth factor-stimulated proliferation of human
umbilical vein endothelial cells (HUVEC).
[0181] HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v
foetal calf serum (FCS) and were plated out (at passage 2 to 8), in
MCDB 131+2% v/v FCS+3 .mu.g/ml heparin+1 .mu.g/ml hydrocortisone,
at a concentration of 1000 cells/well in 96 well plates. After a
minimum of 4 hours they were dosed with the appropriate growth
factor (i.e. VEGF 3 ng/ml, EGF 3 ng/ml or b-FGF 0.3 ng/ml) and
compound. The cultures were then incubated for 4 days at 37.degree.
C. with 7.5% CO.sub.2. On day 4 the cultures were pulsed with 1
.mu.Ci/well of tritiated-thymidine (Amersham product TRA 61) and
incubated for 4 hours. The cells were harvested using a 96-well
plate harvester (Tomtek) and then assayed for incorporation of
tritium with a Beta plate counter. Incorporation of radioactivity
into cells, expressed as cpm, was used to measure inhibition of
growth factor-stimulated cell proliferation by compounds.
(c) In Vivo Solid Tumour Disease Model
[0182] This test measures the capacity of compounds to inhibit
solid tumour growth.
[0183] CaLu-6 tumour xenografts were established in the flank of
female athymic Swiss nu/nu mice, by subcutaneous injection of
1.times.10.sup.6 CaLu-6 cells/mouse in 100 .mu.l of a 50% (v/v)
solution of Matrigel in serum free culture medium. Ten days after
cellular implant, mice were allocated to groups of 8-10, so as to
achieve comparable group mean volumes. Tumours were measured using
vernier calipers and volumes were calculated as: (l.times.w).times.
(l.times.w).times.(.pi./6), where l is the longest diameter and w
the diameter perpendicular to the longest. Test compounds were
administered orally once daily for a minimum of 21 days, and
control animals received compound diluent. Tumours were measured
twice weekly. The level of growth inhibition was calculated by
comparison of the mean tumour volume of the control group versus
the treatment group using a Student T test and/or a Mann-Whitney
Rank Sum Test. The inhibitory effect of compound treatment was
considered significant when p<0.05.
(d) hERG-encoded Potassium Channel Inhibition Test
[0184] This assay determines the ability of a test compound to
inhibit the tail current flowing through the human
ether-a-go-go-related-gene (hERG)-encoded potassium channel.
[0185] Human embryonic kidney (HEK) cells expressing the
hERG-encoded channel were grown in Minimum Essential Medium Eagle
(EMEM; Sigma-Aldrich catalogue number M2279), supplemented with 10%
Foetal Calf Serum (Labtech International; product number
4-101-500), 10% M1 serum-free supplement (Egg Technologies; product
number 70916) and 0.4 mg/ml Geneticin G418 (Sigma-Aldrich;
catalogue number G7034). One or two days before each experiment,
the cells were detached from the tissue culture flasks with
Accutase (TCS Biologicals) using standard tissue culture methods.
They were then put onto glass coverslips resting in wells of a 12
well plate and covered with 2 ml of the growing media.
[0186] For each cell recorded, a glass coverslip containing the
cells was placed at the bottom of a Perspex chamber containing bath
solution (see below) at ambient temperature (.about.20.degree. C.).
This chamber was fixed to the stage of an inverted, phase-contrast
microscope. Immediately after placing the coverslip in the chamber,
bath solution was perfused into the chamber from a gravity-fed
reservoir for 2 minutes at a rate of .about.2 ml/min. After this
time, perfusion was stopped.
[0187] A patch pipette made from borosilicate glass tubing (GC120F,
Harvard Apparatus) using a P-97 micropipette puller (Sutter
Instrument Co.) was filled with pipette solution (see hereinafter).
The pipette was connected to the headstage of the patch clamp
amplifier (Axopatch 200B, Axon Instruments) via a silver/silver
chloride wire. The headstage ground was connected to the earth
electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
[0188] The cell was recorded in the whole cell configuration of the
patch clamp technique. Following "break-in", which was done at a
holding potential of -80 mV (set by the amplifier), and appropriate
adjustment of series resistance and capacitance controls,
electrophysiology software (Clampex, Axon Instruments) was used to
set a holding potential (-80 mV) and to deliver a voltage protocol.
This protocol was applied every 15 seconds and consisted of a 1 s
step to +40 mV followed by a 1 s step to -50 mV. The current
response to each imposed voltage protocol was low pass filtered by
the amplifier at 1 kHz. The filtered signal was then acquired, on
line, by digitising this analogue signal from the amplifier with an
analogue to digital converter. The digitised signal was then
captured on a computer running Clampex software (Axon Instruments).
During the holding potential and the step to +40 mV the current was
sampled at 1 kHz. The sampling rate was then set to 5 kHz for the
remainder of the voltage protocol.
[0189] The compositions, pH and osmolarity of the bath and pipette
solution are tabulated below.
TABLE-US-00001 Salt Pipette (mM) Bath (mM) NaCl -- 137 KCl 130 4
MgCl.sub.2 1 1 CaCl.sub.2 -- 1.8 HEPES 10 10 glucose -- 10
Na.sub.2ATP 5 -- EGTA 5 --
TABLE-US-00002 Parameter Pipette Bath pH 7.18-7.22 7.40 pH
adjustment with 1M KOH 1M NaOH Osmolarity (mOsm) 275-285
285-295
[0190] The amplitude of the hERG-encoded potassium channel tail
current following the step from +40 mV to -50 mV was recorded
on-line by Clampex software (Axon Instruments). Following
stabilisation of the tail current amplitude, bath solution
containing the vehicle for the test substance was applied to the
cell. Providing the vehicle application had no significant effect
on tail current amplitude, a cumulative concentration effect curve
to the compound was then constructed.
[0191] The effect of each concentration of test compound was
quantified by expressing the tail current amplitude in the presence
of a given concentration of test compound as a percentage of that
in the presence of vehicle.
[0192] Test compound potency (IC.sub.50) was determined by fitting
the percentage inhibition values making up the concentration-effect
to a four parameter Hill equation using a standard data-fitting
package. If the level of inhibition seen at the highest test
concentration did not exceed 50%, no potency value was produced and
a percentage inhibition value at that concentration was quoted.
[0193] Although the pharmacological properties of the compounds of
formula I vary with structural change, in general, activity
possessed by compounds of the formula I, may be demonstrated at the
following concentrations or doses in one or more of the above tests
(a), (b) and (c)
[0194] Test (a):--IC.sub.50 in the range, for example, <5
.mu.M;
[0195] Test (b):--IC.sub.50 in the range, for example, 0.001-5
.mu.M;
[0196] Test (c):--activity in the range, for example, 0.1-100
mg/kg;
[0197] Example 11 of the present application has an IC.sub.50 value
in the enzyme assay (a) of 0.104 .mu.M against KDR.
[0198] Example 11 of the present application has an IC.sub.50 of
10.1 .mu.M in the hERG assay (d).
[0199] Plasma pharmacokinetics may be assessed by measuring plasma
half-life in vivo. The longer the plasma half-life in vivo the more
extended are the plasma pharmacokinetics.
[0200] Compounds of the present invention have less extended plasma
pharmacokinetics than compounds of WO 00/47212. Compounds of the
present invention have shorter half-lives in vivo than compounds of
WO 00/47212.
[0201] Plasma half-life in vivo may be determined by standard
methods which are well-known in the art of plasma pharmacokinetics.
Any species may be used and the plasma half-life determined by
standard methodology, for example plasma half-life may be measured
in rat, dog, monkey or human.
[0202] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
the formula I as defined hereinbefore or a pharmaceutically
acceptable salt thereof; in association with a pharmaceutically
acceptable excipient or carrier.
[0203] The composition may be in a form suitable for oral
administration, for example as a tablet or capsule, for parenteral
injection (including intravenous, subcutaneous, intramuscular,
intravascular or infusion) for example as a sterile solution,
suspension or emulsion, for topical administration for example as
an ointment or cream or for rectal administration for example as a
suppository. In general the above compositions may be prepared in a
conventional manner using conventional excipients.
[0204] The compositions of the present invention are advantageously
presented in unit dosage form. The compound will normally be
administered to a warm-blooded animal at a unit dose within the
range 5-5000 mg per square metre body area of the animal, i.e.
approximately 0.1-100 mg/kg. A unit dose in the range, for example,
1-100 mg/kg, preferably 1-50 mg/kg is envisaged and this normally
provides a therapeutically-effective dose. A unit dose form such as
a tablet or capsule will usually contain, for example 1-250 mg of
active ingredient.
[0205] According to a further aspect of the present invention there
is provided a compound of the formula I or a pharmaceutically
acceptable salt thereof as defined hereinbefore for use in a method
of treatment of the human or animal body by therapy.
[0206] We have found that compounds of the present invention
inhibit VEGF receptor tyrosine kinase activity and are therefore of
interest for their antiangiogenic effects and/or their ability to
cause a reduction in vascular permeability.
[0207] A further feature of the present invention is a compound of
formula I, or a pharmaceutically acceptable salt thereof, for use
as a medicament, conveniently a compound of formula I, or a
pharmaceutically acceptable salt thereof, for use as a medicament
for producing an antiangiogenic and/or vascular permeability
reducing effect in a warm-blooded animal such as a human being.
[0208] Thus according to a further aspect of the invention there is
provided the use of a compound of the formula I, or a
pharmaceutically acceptable salt thereof in the manufacture of a
medicament for use in the production of an antiangiogenic and/or
vascular permeability reducing effect in a warm-blooded animal such
as a human being.
[0209] According to a further feature of the invention there is
provided a method for producing an antiangiogenic and/or vascular
permeability reducing effect in a warm-blooded animal, such as a
human being, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof as defined
hereinbefore.
[0210] As stated above the size of the dose required for the
therapeutic or prophylactic treatment of a particular disease state
will necessarily be varied depending on the host treated, the route
of administration and the severity of the illness being treated.
Preferably a daily dose in the range of 0.1-50 mg/kg is employed.
However the daily dose will necessarily be varied depending upon
the host treated, the particular route of administration, and the
severity of the illness being treated. Accordingly the optimum
dosage may be determined by the practitioner who is treating any
particular patient.
[0211] The antiangiogenic and/or vascular permeability reducing
treatment defined hereinbefore may be applied as a sole therapy or
may involve, in addition to a compound of the invention, one or
more other substances and/or treatments. Such conjoint treatment
may be achieved by way of the simultaneous, sequential or separate
administration of the individual components of the treatment. In
the field of medical oncology it is normal practice to use a
combination of different forms of treatment to treat each patient
with cancer. In medical oncology the other component(s) of such
conjoint treatment in addition to the antiangiogenic and/or
vascular permeability reducing treatment defined hereinbefore may
be: surgery, radiotherapy or chemotherapy. Such chemotherapy may
cover three main categories of therapeutic agent:
(i) other antiangiogenic agents such as those which inhibit the
effects of vascular endothelial growth factor, (for example the
anti-vascular endothelial cell growth factor antibody bevacizumab
[Avastin.TM.], and those that work by different mechanisms from
those defined hereinbefore (for example linomide, inhibitors of
integrin .alpha.v.beta.3 function, angiostatin, razoxin,
thalidomide), and including vascular targeting agents (for example
combretastatin phosphate and compounds disclosed in International
Patent Applications WO00/40529, WO 00/41669, WO01/92224, WO02/04434
and WO02/08213 and the vascular damaging agents described in
International Patent Application Publication No. WO 99/02166 the
entire disclosure of which document is incorporated herein by
reference, (for example N-acetylcolchinol-O-phosphate)); (ii)
cytostatic agents such as antioestrogens (for example tamoxifen,
toremifene, raloxifene, droloxifene, iodoxyfene), oestrogen
receptor down regulators (for example fulvestrant), progestogens
(for example megestrol acetate), aromatase inhibitors (for example
anastrozole, letrazole, vorazole, exemestane), antiprogestogens,
antiandrogens (for example flutamide, nilutamide, bicalutamide,
cyproterone acetate), LHRH agonists and antagonists (for example
goserelin acetate, luprolide, buserelin), inhibitors of
5.alpha.-reductase (for example finasteride), anti-invasion agents
(for example metalloproteinase inhibitors like marimastat and
inhibitors of urokinase plasminogen activator receptor function)
and inhibitors of growth factor function, (such growth factors
include for example platelet derived growth factor and hepatocyte
growth factor), such inhibitors include growth factor antibodies,
growth factor receptor antibodies, (for example the anti-erbb2
antibody trastuzumab [Herceptin.TM.] and the anti-erbb1 antibody
cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase
inhibitors for example inhibitors of the epidermal growth factor
family (for example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)) and serine/threonine kinase inhibitors); and
(iii) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as antimetabolites (for
example antifolates like methotrexate, fluoropyrimidines like
5-fluorouracil, tegafur, purine and adenosine analogues, cytosine
arabinoside); antitumour antibiotics (for example anthracyclines
like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin and
idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum
derivatives (for example cisplatin, carboplatin); alkylating agents
(for example nitrogen mustard, melphalan, chlorambucil, busulphan,
cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic
agents (for example vinca alkaloids like vincristine, vinblastine,
vindesine, vinorelbine, and taxoids like taxol, taxotere);
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan, camptothecin and
also irinotecan); also enzymes (for example asparaginase); and
thymidylate synthase inhibitors (for example raltitrexed); and
additional types of chemotherapeutic agent include: (iv) biological
response modifiers (for example interferon); (v) antibodies (for
example edrecolomab); (vi) antisense therapies, for example those
which are directed to the targets listed above, such as ISIS 2503,
an anti-ras antisense; (vii) gene therapy approaches, including for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and (viii)
immunotherapy approaches, including for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells,
such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell anergy, approaches using transfected
immune cells such as cytokine-transfected dendritic cells,
approaches using cytokine-transfected tumour cell lines and
approaches using anti-idiotypic antibodies.
[0212] For example such conjoint treatment may be achieved by way
of the simultaneous, sequential or separate administration of a
compound of formula I as defined hereinbefore, and a vascular
targeting agent described in WO 99/02166 such as
N-acetylcolchinol-O-phosphate (Example 1 of WO 99/02166).
[0213] It is known from WO 01/74360 that antiangiogenics can be
combined with antihypertensives. A compound of the present
invention can also be administered in combination with an
antihypertensive. An antihypertensive is an agent which lowers
blood pressure, see WO 01/74360 which is incorporated herein by
reference.
[0214] Thus according to the present invention there is provided a
method of treatment of a disease state associated with angiogenesis
which comprises the administration of an effective amount of a
combination of a compound of the present invention or a
pharmaceutically acceptable salt thereof and an anti-hypertensive
agent to a warm-blooded animal, such as a human being.
[0215] According to a further feature of the present invention
there is provided the use of a combination of a compound of the
present invention or a pharmaceutically acceptable salt thereof and
an anti-hypertensive agent for use in the manufacture of a
medicament for the treatment of a disease state associated with
angiogenesis in a warm-blooded mammal, such as a human being.
[0216] According to a further feature of the present invention
there is provided a pharmaceutical composition comprising a
compound of the present invention or a pharmaceutically acceptable
salt thereof and an anti-hypertensive agent for the treatment of a
disease state associated with angiogenesis in a warm-blooded
mammal, such as a human being.
[0217] According to a further aspect of the present invention there
is provided a method for producing an anti-angiogenic and/or
vascular permeability reducing effect in a warm-blooded animal,
such as a human being, which comprises administering to said animal
an effective amount of a combination of a compound of the present
invention or a pharmaceutically acceptable salt thereof and an
anti-hypertensive agent.
[0218] According to a further aspect of the present invention there
is provided the use of a combination of a compound of the present
invention or a pharmaceutically acceptable salt thereof and an
anti-hypertensive agent for the manufacture of a medicament for
producing an anti-angiogenic and/or vascular permeability reducing
effect in a warm-blooded mammal, such as a human being.
[0219] Preferred antihypertensive agents are calcium channel
blockers, angiotensin converting enzyme inhibitors (ACE
inhibitors), angiotensin II receptor antagonists (A-II
antagonists), diuretics, beta-adrenergic receptor blockers
(.beta.-blockers), vasodilators and alpha-adrenergic receptor
blockers (.alpha.-blockers). Particular antihypertensive agents are
calcium channel blockers, angiotensin converting enzyme inhibitors
(ACE inhibitors), angiotensin II receptor antagonists (A-II
antagonists) and beta-adrenergic receptor blockers
(.beta.-blockers), especially calcium channel blockers.
[0220] As stated above the compounds defined in the present
invention are of interest for their antiangiogenic and/or vascular
permeability reducing effects. Such compounds of the invention are
expected to be useful in a wide range of disease states including
cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's
sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies,
atheroma, arterial restenosis, autoimmune diseases, acute
inflammation, excessive scar formation and adhesions,
endometriosis, dysfunctional uterine bleeding and ocular diseases
with retinal vessel proliferation including age-related macular
degeneration. Cancer may affect any tissue and includes leukaemia,
multiple myeloma and lymphoma. In particular such compounds of the
invention are expected to slow advantageously the growth of primary
and recurrent solid tumours of, for example, the colon, breast,
prostate, lungs and skin. More particularly such compounds of the
invention are expected to inhibit any form of cancer associated
with VEGF including leukaemia, multiple myeloma and lymphoma and
also, for example, the growth of those primary and recurrent solid
tumours which are associated with VEGF, especially those tumours
which are significantly dependent on VEGF for their growth and
spread, including for example, certain tumours of the colon,
breast, prostate, lung, vulva and skin.
[0221] In addition to their use in therapeutic medicine, the
compounds of formula I and their pharmaceutically acceptable salts
are also useful as pharmacological tools in the development and
standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of VEGF receptor tyrosine
kinase activity in laboratory animals such as cats, dogs, rabbits,
monkeys, rats and mice, as part of the search for new therapeutic
agents.
[0222] It is to be understood that where the term "ether" is used
anywhere in this specification it refers to diethyl ether.
[0223] The invention will now be illustrated in the following
non-limiting Examples in which, unless otherwise stated:--
[0224] (i) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids such as drying agents by filtration;
[0225] (ii) operations were carried out at ambient temperature,
that is in the range 18-25.degree. C. and under an atmosphere of an
inert gas such as argon;
[0226] (iii) column chromatography (by the flash procedure) and
medium pressure liquid chromatography (MPLC) were performed on
Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art.
9303) reversed-phase silica obtained from E. Merck, Darmstadt,
Germany;
[0227] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0228] (v) melting points are uncorrected and were determined using
a Mettler SP62 automatic melting point apparatus, an oil-bath
apparatus or a Koffler hot plate apparatus.
[0229] (vi) the structures of the end-products of the formula I
were confirmed by nuclear (generally proton) magnetic resonance
(NMR) and mass spectral techniques; proton magnetic resonance
chemical shift values were measured on the delta scale and peak
multiplicities are shown as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad; q, quartet, quip, quintet;
[0230] (vii) intermediates were not generally fully characterised
and purity was assessed by thin layer chromatography (TLC),
high-performance liquid chromatography (HPLC), infra-red (IR) or
NMR analysis;
[0231] (viii) HPLC were run under 2 different conditions:
1) on a TSK Gel super ODS 2 .mu.M 4.6 mm.times.5 cm column, eluting
with a gradient of methanol in water (containing 1% acetic acid) 20
to 100% in 5 minutes. Flow rate 1.4 ml/minute. Detection: U.V. at
254 nm and light scattering detections; 2) on a TSK Gel super ODS 2
.mu.M 4.6 mm.times.5 cm column, eluting with a gradient of methanol
in water (containing 1% acetic acid) 0 to 100% in 7 minutes. Flow
rate 1.4 ml/minute. Detection: U.V. at 254 nm and light scattering
detections.
[0232] (ix) petroleum ether refers to that fraction boiling between
40-60.degree. C.
[0233] (x) the following abbreviations have been used:--
[0234] DMF N,N-dimethylformamide
[0235] DMSO dimethylsulphoxide
[0236] trifluoroacetic acid
[0237] DMA dimethylacetamide
[0238] LC-MS HPLC coupled to mass spectrometry
EXAMPLE 1
##STR00037##
[0240] A mixture of
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline (0.2 g), chloroacetone (0.046 ml), potassium carbonate (0.1
g) and DMF (6 ml) was stirred and heated to 70.degree. C. for 1
hour. The mixture was cooled to ambient temperature, the
precipitate was removed by filtration, the solvent was removed by
evaporation under vacuum and the residue was purified by column
chromatography on silica using increasingly polar solvent mixtures,
starting with dichloromethane and ending dichloromethane/methanol
(93/7). Evaporation of the solvents gave a foam which was
triturated under ether/pentane (70/30) to give a solid which was
collected by filtration and dried under vacuum to give
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-ind-
ol-5-yl)oxy]quinazoline (0.074 g).
[0241] Mass Spectrum: M+H.sup.+475
[0242] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (m, 2H), 1.80 (m,
3H), 2.05 (m, 5H), 2.25 (s, 3H), 2.80 (d, 2H), 3.15 (s, 2H), 4.0
(s, 3H), 4.10 (d, 2H), 6.95 (d, 1H), 7.20 (s, 1H), 7.35 (m, 3H),
7.60 (s, 1H), 8.50 (s, 1H)
[0243] Elemental Analysis: Found C, 68.38; H, 6.59; N, 11.68;
[0244] C.sub.27H.sub.30N4O.sub.4 Requires C, 68.34; H, 6.37; N,
11.81%
[0245] The starting material was prepared as follows:
##STR00038##
[0246] A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g,
0.04 mol), (J. Med. Chem. 1977, vol 20, 146-149), and Gold's
reagent (7.4 g, 0.05mol) in dioxane (100 ml) was stirred and heated
at reflux for 24 hours. Sodium acetate (3.02 g, 0.037mol) and
acetic acid (1.65 ml, 0.029mol) were added to the reaction mixture
and it was heated for a further 3 hours. The mixture was
evaporated, water was added to the residue, the solid was filtered
off, washed with water and dried (MgSO.sub.4). Recrystallisation
from acetic acid gave
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
[0247] 10% Palladium on carbon (8.3 g) was added to a suspension of
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (50 g, 0.177 mol)
in dimethylformamide (800 ml) under nitrogen. Ammonium formate
(111.8 g, 1.77 mol) was then added in portions over 5 minutes. The
reaction mixture was stirred for one hour at ambient temperature
then heated to 80.degree. C. for a further hour. The reaction
mixture was filtered hot through diatomaceous earth and the
residues washed with dimethylformamide. The filtrate was then
concentrated and the residue suspended in water. The pH was
adjusted to 7.0 using 2M sodium hydroxide and the resulting mixture
was stirred at ambient temperature for one hour. The solid was
filtered, washed with water and dried over phosphorus pentoxide
yielding 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white
solid (20.52 g, 60%).
[0248] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.85 (s, 3H), 6.95 (s,
1H), 7.40 (s, 1H), 7.85 (s, 1H)
[0249] MS-ESI: 193 [M+H]+
[0250] Pyridine (20 ml) was added to a suspension of
7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.5 g, 107 mmol)
in acetic anhydride (150 ml, 1.6 mol). The reaction mixture was
heated to 120.degree. C. for three hours, during which time the
solid dissolved. The reaction mixture was allowed to cool then
poured into ice-water (900 ml). The reaction mixture was stirred
for one hour then the solid was removed by filtration and dried
over phosphorus pentoxide yielding
7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid
(20.98 g, 84%).
[0251] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.25 (s, 3H), 3.85 (s,
3H), 7.40 (s, 1H), 7.60 (s, 1H), 8.00 (s, 1H)
[0252] MS-ESI: 235 [M+H]+
[0253] 7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1 g, 4.3
mmol) was suspended in thionyl chloride (10.5 ml). One drop of
dimethylformamide was added and the reaction was heated to
80.degree. C. for two hours, during which time the solid dissolved.
The reaction mixture was cooled and the thionyl chloride was
removed in vacuo. The residue was azeotroped with toluene before
being suspended in methylene chloride. A solution of 10% ammonia in
methanol (40 ml) was added and the reaction mixture was heated to
80.degree. C. for 15 minutes. After cooling the solvents were
removed in vacuo and the residue redissolved in water (10 ml) and
the pH adjusted to 7.0 with 2M hydrochloric acid. The resulting
solid was filtered, washed with water and dried over phosphorus
pentoxide yielding 4-chloro-7-hydroxy-6-methoxyquinazoline as a
white solid (680 mg, 75%).
[0254] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.00 (s, 3H), 7.25 (s,
1H), 7.35 (s, 1H), 8.75 (s, 1H)
[0255] MS-ESI: 211-213 [M+H]+
[0256] While maintaining the temperature in the range 0-5.degree.
C., a solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in
ethyl acetate (75 ml) was added in portions to a solution of ethyl
4-piperidinecarboxylate (30 g, 0.19 mol) in ethyl acetate (150 ml)
cooled at 5.degree. C. After stirring for 48 hours at ambient
temperature, the mixture was poured onto water (300 ml). The
organic layer was separated, washed successively with water (200
ml), 0.1N aqueous hydrochloric acid (200 ml), saturated sodium
hydrogen carbonate (200 ml) and brine (200 ml), dried (MgSO.sub.4)
and evaporated to give ethyl
4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 98%).
[0257] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.25 (t, 3H); 1.45 (s,
9H); 1.55-1.70 (m, 2H); 1.8-2.0 (d, 2H); 2.35-2.5 (m, 1H); 2.7-2.95
(t, 2H); 3.9-4.1 (br s, 2H); 4.15 (q, 2H)
[0258] A solution of 1M lithium aluminium hydride in THF (133 ml,
0.133mol) was added in portions to a solution of ethyl
4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 0.19 mol)
in dry THF (180 ml) cooled at 0.degree. C. After stirring at
0.degree. C. for 2 hours, water (30 ml) was added followed by 2N
sodium hydroxide (10 ml). The precipitate was removed by filtration
through diatomaceous earth and washed with ethyl acetate. The
filtrate was washed with water, brine, dried (MgSO.sub.4) and
evaporated to give
1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (36.3 g,
89%).
[0259] To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline
(10 g) in dichloromethane (250 ml) were successively added:
triphenyl phosphine (18.7 g)
1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine (12.2 g) and
di-tert-butyl azodicarboxylate (16.4 g). The reaction mixture was
stirred at ambient temperature for 18 hours. The mixture was
concentrated to a third and purified by column chromatography on
silica using a mixture of ethyl acetate/petroleum ether (3/7) as
eluent. Removal of the solvent by evaporation gave
7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquin-
azoline as a beige solid (14 g).
[0260] Mass Spectrum: M+H.sup.+408 and 410
##STR00039##
[0261] A mixture of
7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquin-
azoline (4.6 g), 5-hydroxy-3-methylindole (2 g), (Journal of
Organic Chemistry 1993, 58, 3757), potassium carbonate (3.1 g) and
DMF (20 ml) was stirred and heated to 90.degree. C. for 2 hours.
The solid was removed by filtration washed with acetonitrile and
the combined filtrates concentrated to dryness under vacuum. The
product so obtained was triturated under ether/petroleum ether
(8/2), collected by filtration and dried to give
7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-
-1H-indol-5-yl)oxy]quinazoline (5.8 g).
[0262] Mass Spectrum: M+H.sup.+519
##STR00040##
[0263]
7-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3--
methyl-1H-indol-5-yl)oxy]quinazoline (5.8 g) was suspended in
dichloromethane (40 ml) and cooled with an ice bath. TFA (17 ml)
was added and the reaction mixture was stirred at this temperature
for 1 hour. The volatiles were removed under vacuum and the residue
triturated under water and dichloromethane. The pH was made basic
to 12.5 with a 30% aqueous solution of sodium hydroxide while
cooling with an ice bath. Extraction was done with a mixture of
dichloromethane and methanol. The combined extracts were washed in
turn with water and brine and dried over magnesium sulphate. The
solvent was evaporated under vacuum and the residue was triturated
under ether, filtered and dried to give
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline (3.6 g).
[0264] Mass Spectrum: M+H.sup.+419
[0265] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3CO.sub.2D)
1.50 (m, 2H), 2.0 (m, 2H), 2.20 (m, 1H), 2.25 (s, 3H), 2.95 (m,
2H), 2.40 (m, 2H), 4.05 (s, 3H), 4.20 (d, 2H), 7.05 (d, 1H), 7.25
(s, 1H), 7.40 (d, 1H), 7.45 (d, 1H), 7.50 (s, 1H), 7.75 (s, 1H),
8.90 (s, 1H)
EXAMPLE 2
##STR00041##
[0267]
6-Methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)methox-
y]quinazoline (0.2 g) was reacted with chloracetone (0.046 ml)
using an analogous procedure to that described in Example 1 to
give, after work up and purification,
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-6-yl)oxy]quinazoline (0.155 g) as a solid.
[0268] Mass Spectrum: M+H.sup.+475
[0269] .sup.1H NMR. Spectrum: (DMSOd.sub.6) 1.40 (m, 2H), 1.80 (m,
3H), 2.05 (m, 5H), 2.40 (s, 3H), 2.80 (d, 2H), 3.15 (s, 2H), 3.95
(s, 3H), 4.10 (d, 2H), 6.15 (s, 1H), 6.85 (d, 1H), 7.15 (s, 1H),
7.35 (s, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 8.50 (s, 1H)
[0270] Elemental Analysis Found C, 67.52; H, 6.55; N, 11.75;
[0271] C.sub.27H.sub.30N.sub.4O.sub.4 0.2 H.sub.2O Requires C,
68.34; H, 6.37; N, 11.81%
[0272] The starting material was prepared using an analogous
procedure to that described in Example 1 but replacing
5-hydroxy-3-methylindole with 6-hydroxy-2-methylindole, (Eur. J.
Med. Chem. 1975, 10, 187). Thus
7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquin-
azoline (4.6 g) and 6-hydroxy-2-methylindole (2 g) gave after
coupling and deprotection 2.6 g of
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline.
[0273] Mass Spectrum: M+H.sup.+419
[0274] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3CO.sub.2D)
1.55 (m, 2H), 2.0 (m, 2H), 2.25 (m, 1H), 2.40 (s, 3H), 2.95 (m,
2H), 3.35 (m, 2H), 4.05 (s, 3H), 4.20 (d, 2H), 6.20 (s, 1H), 6.90
(d, 1H), 7.25 (s, 1H), 7.50 (d, 1H), 7.55 (s, 1H), 7.80 (s, 1H),
8.95 (s, 1H)
EXAMPLE 3
##STR00042##
[0276]
6-Methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methox-
y]quinazoline (0.25 g) was reacted with chloracetone (0.057 ml)
using an analogous procedure to that described in Example 1 to
give, after work up and purification,
7-{[1-(acetylmethyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-5-yl)oxy]quinazoline (0.207 g) as a solid.
[0277] Mass Spectrum: M+H.sup.+475
[0278] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (m, 2H), 1.80 (m,
3H), 2.05 (m, 5H), 2.40 (s, 3H), 2.80 (d, 2H), 3.15 (s, 2H), 3.95
(s, 3H), 4.10 (d, 2H), 6.15 (s, 1H), 6.85 (d, 1H), 7.25 (s, 1H),
7.20 (d, 1H), 7.35 (s, 1H), 7.6 (s, 1H), 8.50 (s, 1H)
[0279] Elemental Analysis Found C, 67.56; H, 6.44; N, 11.66;
[0280] C.sub.27H.sub.30N.sub.4O.sub.4 0.3 H.sub.2O 0.01ether
Requires C, 68.34; H, 6.37; N, 11.81%
[0281] The starting material was prepared using an analogous
procedure to that described in Example 1 but replacing
5-hydroxy-3-methylindole with 5-hydroxy-2-methylindole. Thus
7-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-chloro-6-methoxyquin-
azoline (3 g) and 5-hydroxy-2-methylindole (1.3 g) gave after
coupling and deprotection 1.7 g of
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline.
[0282] Mass Spectrum: M+H.sup.+419
[0283] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.55 (m, 2H), 2.0 (m,
2H), 2.25 (m, 1H), 2.40 (s, 3H), 2.95 (m, 2H), 3.35 (m, 2H), 4.05
(s, 3H), 4.20 (d, 2H), 6.20 (s, 1H), 6.95 (d, 1H), 7.35 (m, 2H),
7.50 (s, 1H), 7.75 (s, 1H), 8.95 (s, 1H)
EXAMPLE 4
##STR00043##
[0285] A mixture of
7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-ind-
ol-5-yl)oxy]quinazoline (0.118 g), pyrrolidine (0.059 ml),
potassium iodide (0.01 g) and DMF (3 ml) was stirred and heated to
80.degree. C. for 40 minutes. The mixture was cooled to ambient
temperature, the solvent was removed by evaporation under vacuum
and the residue was purified by column chromatography on silica
using increasingly polar solvent mixtures, starting with
dichloromethane and ending dichloromethane/methanol saturated with
ammonia (3.5M) (94/6). Evaporation of the solvents gave a foam
which was triturated under ether/pentane (70/30) to give a solid
which was collected by filtration and dried under vacuum to give
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline (0.096 g).
[0286] Mass Spectrum: M+H.sup.+530
[0287] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3CO.sub.2D)
1.25 (m, 1H), 1.40 (m, 1H), 1.90 (m, 4H), 2.05 (m, 2H), 2.25 (m,
4H), 2.80 (m, 1H), 3.05 (m, 2H), 3.15 (m, 1H), 3.60 (m, 2H), 3.70
(m, 1H), 4.05 (s, 3H), 4.15 (d, 2H), 4.40 (m, 3H), 7.0 (d, 1H),
7.25 (s, 1H), 7.40 (d, 7.45 (d, 1H), 7.50 (s, 1H), 7.75 (s, 1H),
8.90 (s, 1H)
[0288] Elemental Analysis Found C, 67.31; H, 7.01; N, 12.94;
[0289] C.sub.30H.sub.35N.sub.5O.sub.4 0.3 H.sub.2O 0.1 ether
Requires C, 67.31; H, 6.80; N, 12.91%
[0290] The starting material was prepared as follows:
##STR00044##
[0291]
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methox-
y]quinazoline (0.4 g), prepared as described for the starting
material in Example 1, was dissolved in dichloromethane (15 ml).
PS-DIEA resin (0.6 g; 4 mmol/g) was added followed by chloroacetyl
chloride (0.091 ml). The reaction mixture was stirred at ambient
temperature for 3 hours then diluted with methanol and the resin
removed by filtration. The solvent was evaporated under vacuum and
the residue was purified by column chromatography on silica using
increasingly polar solvent mixtures, starting with dichloromethane
and ending with dichloromethane/methanol (92/8). Removal of the
solvents by evaporation gave
7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-ind-
ol-5-yl)oxy]quinazoline (0.237 g) as a solid foam.
[0292] Mass Spectrum: M+H.sup.+495 and 497
[0293] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.20 (m, 1H), 1.40 (m,
1H), 1.85 (m, 2H), 2.20 (m, 1H), 2.25 (s, 3H), 2.75 (m, 1H), 3.15
(m, 1H), 3.90 (m, 1H), 4.0 (s, 3H), 4.10 (d, 2H), 4.40 (m, 3H),
6.95 (d, 1H), 7.20 (s, 1H), 7.40 (m, 2H), 7.60 (s, 1H), 8.50 (s,
1H)
EXAMPLE 5
##STR00045##
[0295]
7-{[1-(Chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl--
1H-indol-6-yl)oxy]quinazoline (0.116 g) was reacted with
pyrrolidine (0.059 ml) using an analogous procedure to that
described in Example 4 to give, after work up and purification,
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline (0.087 g) as a solid.
[0296] Mass Spectrum: M+H.sup.+530
[0297] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3CO.sub.2D)
1.25 (m, 1H), 1.40 (m, 1H), 1.90 (m, 4H), 2.05 (m, 2H), 2.25 (m,
1H), 2.40 (s, 3H), 2.80 (t, 1H), 3.05 (m, 2H), 3.15 (t, 1H), 3.6
(m, 2H), 3.70 (m, 1H), 4.05 (s, 3H), 4.15 (d, 2H), 4.35 (s, 1H),
4.45 (d, 2H), 6.20 (s, 1H), 6.90 (d, 1H), 7.20 (s, 1H), 7.50 (m,
2H), 7.75 (s, 1H), 8.90 (s, 1H)
[0298] Elemental Analysis Found C, 66.64; H, 6.73; N, 12.98;
[0299] C.sub.30H.sub.35N.sub.5O.sub.4 0.5 H.sub.2O 0.05 ether
Requires C, 66.88; H, 6.78; N, 12.91%
##STR00046##
[0300] The starting material was prepared using analogous
procedures to those described in Examples 1 and 4 but replacing
5-hydroxy-3-methylindole with 6-hydroxy-2-methylindole, (Eur. J.
Med. Chem. 1975, 10, 187). Thus
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline (0.4 g) gave
7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-6-yl)oxy]quinazoline (0.233 g).
[0301] Mass Spectrum: M+H.sup.+495 and 497
[0302] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.20 (m, 1H), 1.40 (m,
1H), 1.85 (m, 2H), 2.20 (m, 1H), 2.40 (s, 3H), 2.70 (m, 1H), 3.15
(m, 1H), 3.90 (m, 1H), 4.0 (s, 3H), 4.10 (d, 2H), 4.40 (m, 3H),
6.15 (s, 1H), 6.80 (d, 1H), 7.15 (s, 1H), 7.40 (s, 1H), 7.45 (d,
1H), 7.60 (s, 1H), 8.50 (s, 1H)
EXAMPLE 6
##STR00047##
[0304]
7-{[1-(Chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl--
1H-indol-5-yl)oxy]quinazoline (0.157 g) was reacted with
pyrrolidine (0.077 ml) using an analogous procedure to that
described in Example 4 to give, after work up and purification,
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)pi-
peridin-4-yl]methoxy}quinazoline (0.130 g) as a solid.
[0305] Mass Spectrum: M+H.sup.+530
[0306] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3CO.sub.2D)
1.25 (m, 1H), 1.40 (m, 1H), 1.90 (m, 4H), 2.0 (m, 2H), 2.25 (m,
1H), 2.45 (s, 3H), 2.80 (t, 1H), 3.10 (m, 2H), 3.15 (t, 1H), 3.6
(m, 2H), 3.70 (m, 1H), 4.05 (s, 3H), 4.20 (d, 2H), 4.35 (s, 1H),
4.45 (d, 2H), 6.20 (s, 1H), 6.95 (d, 1H), 7.30 (d, 1H), 7.35 (d,
1H), 7.50 (s, 1H), 7.75 (s, 1H), 8.90 (s, 1H)
[0307] Elemental Analysis Found C, 65.38; H, 6.62; N, 13.56;
[0308] C.sub.30H.sub.35N.sub.5O.sub.4 0.7 H.sub.2O 0.4 DMF Requires
C, 65.57; H, 6.91; N, 13.23%
##STR00048##
[0309] The starting material was prepared using analogous
procedures to those described in Examples 1 and 4 but replacing
5-hydroxy-3-methylindole with 5-hydroxy-2-methylindole. Thus
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)methoxy]quin-
azoline (0.42 g) gave
7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(2-methyl-1H-ind-
ol-5-yl)oxy]quinazoline (0.315 g).
[0310] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.20 (m, 1H), 1.40 (m,
1H), 1.85 (m, 2H), 2.20 (m, 1H), 2.40 (s, 3H), 2.70 (m, 1H), 3.15
(m, 1H), 3.90 (m, 1H), 4.0 (s, 3H), 4.1 (d, 2H), 4.40 (m, 3H), 6.15
(s, 1H), 6.90 (d, 1H), 7.25 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.50 (s, 1H)
EXAMPLE 7
##STR00049##
[0312] A mixture of
7-(2-chloroethoxy)-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline
(0.15 g), tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride
(0.10 g), potassium carbonate (0.09 g) and potassium iodide (0.1 g)
in DMA (1.5 ml) was stirred and heated at 80.degree. C. for 12
hours. The mixture was diluted in DMF (0.8 ml), filtrated and
purified by preparative LCMS (Hypersil C18-.beta.-Basic column
using a solvent gradient consisting of acetonitrile and water
buffered with a 5% ammonium carbonate solution (100 g/L, pH 8.9).
The solvent was removed by evaporation under vacuum and the residue
was triturated under diethyl ether, filtered and dried to give
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]--
dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline (0.10 g) as a pale
yellow solid.
[0313] Mass Spectrum: M+H.sup.+463
[0314] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.30 (d, 2H), 2.40 (s,
3H), 2.80 (t, 2H), 3.15 (d, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 4.60
(s, 2H), 4.80 (s, 1H), 4.95 (s, 1H), 6.15 (s, 1H), 6.90 (d, 1H),
7.25 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s,
1H)
[0315] Elemental Analysis Found C, 62.51; H, 5.64; N, 11.63;
[0316] C.sub.25H.sub.26N.sub.4O.sub.5 Requires C, 62.53; H, 5.99;
N, 11.48%
[0317] The starting material was prepared as follows:
##STR00050##
[0318] 4-Chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (4.0 g) was
reacted with 5-hydroxy-2-methylindole (2.8 g) and potassium
carbonate (3.3 g) using a procedure analogous to that described in
Example 1 to give, after work up and purification,
7-(2-chloroethoxy)-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline
(4.8 g) as a beige solid.
[0319] Mass Spectrum: M+H.sup.+384 and 386
[0320] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 4.00 (s,
3H), 4.05 (t, 2H), 4.50 (t, 2H), 6.15 (s, 1H), 7.00 (d, 1H), 7.25
(s, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0321] The 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline was
prepared as follows:
##STR00051##
[0322] A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g,
40 mmol), (J. Med. Chem. 1977, vol 20, 146-149), and Gold's reagent
(7.4 g, 50 mmol) in dioxane (100 mL) was stirred and heated at
reflux for 24 hours. Sodium acetate (3.02 g, 37 mmol) and acetic
acid (1.65 mL, 29 mmol) were added to the reaction mixture and it
was heated for a further 3 hours. The volatiles were removed by
evaporation, water was added to the residue, the solid was
collected by filtration, washed with water and dried.
Recrystallisation from acetic acid gave
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
[0323] Sodium hydride (1.44 g of a 60% suspension in mineral oil,
36 mmol) was added in portions over 20 minutes to a solution of
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.46 g, 30
mmol), in DMF (70 mL) and the mixture was stirred for 1.5 hours.
Chloromethyl pivalate (5.65 g, 37.5 mmol) was added dropwise and
the mixture stirred for 2 hours at ambient temperature. The mixture
was diluted with ethyl acetate (100 mL) and poured onto ice/water
(400 mL) and 2M hydrochloric acid (4 mL). The organic layer was
separated and the aqueous layer extracted with ethyl acetate, the
combined extracts were washed with brine, dried over magnesium
sulphate and the solvent removed by evaporation. The residue was
triturated with a mixture of ether and petroleum ether, the solid
was collected by filtration and dried under vacuum to give
7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(10 g, 84%).
[0324] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.11 (s, 9H), 3.89 (s,
3H), 5.3 (s, 2H), 5.9 (s, 2H), 7.27 (s, 1H), 7.35 (m, 1H), 7.47 (t,
2H), 7.49 (d, 2H), 7.51 (s, 1H), 8.34 (s, 1H)
[0325] A mixture of
7-benzyloxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(7 g, 17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg) in
ethyl acetate (250 mL), DMF (50 mL), methanol (50 mL) and acetic
acid (0.7 mL) was stirred under hydrogen at atmospheric pressure
for 40 minutes. The catalyst was removed by filtration and the
solvent removed from the filtrate by evaporation. The residue was
triturated with ether, collected by filtration and dried under
vacuum to give
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(4.36 g, 80%).
[0326] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.1 (s, 9H), 3.89 (s,
3H), 5.89 (s, 2H), 7.0 (s, 1H), 7.48 (s, 1H), 8.5 (s, 1H)
[0327]
7-Hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-
-one (85 g, 270 mmol, several batches pooled together) was
dissolved in DMF (400 mL), potassium carbonate (77 g, 550 mmol) and
dichloroethane (400 mL, 5130 mmol) were added and the reaction
mixture was stirred overnight at 70.degree. C. The solid was
removed by filtration and washed with DMF. The solvent was
evaporated and the solid so obtained was washed with water and
dried at 50.degree. C. over P.sub.2O.sub.5. The crude product was
purified by flash chromatography using dichloromethane/ethyl
acetate (85/15 up to 75/25). Evaporation of the solvent gave
7-(2-chloroethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazoli-
n-4-one (65.6 g, 66%) as a white solid.
[0328] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2 (s, 9H), 3.9 (t, 2H),
4.0 (s, 3H), 4.4 (t, 2H), 5.95 (s, 2H), 7.1 (s, 1H), 7.7 (s, 1H),
8.2 (s, 1H)
[0329] Mass Spectrum: M+H.sup.+369 and 371
[0330]
7-(2-Chloroethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroqui-
nazolin-4-one (65 g) was suspended in methanol saturated with
ammonia gas (1.6 L) and stirred at ambient temperature for 2 days.
The solvent was concentrated to about one-fourth and the
precipitate collected by filtration and washed with ether to give
7-(2-chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (44 g,
100%) as a white solid.
[0331] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.9 (s, 3H), 4.05 (t,
2H), 4.4 (t, 2H), 7.15 (s, 1H), 7.45 (s, 1H), 8.0 (s, 1H)
[0332] Mass Spectrum: M+H.sup.+255 and 257
[0333] 7-(2-Chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (5
g, 19 mmol) was suspended in thionyl chloride (28 mL) and DMF (0.7
mL) was added. The mixture was heated at 80.degree. C. for 1.5
hours under anhydrous conditions. The excess thionyl chloride was
evaporated off and toluene was added to remove the last traces by
azeotropic distillation (repeated twice). The solid was suspended
in ice-water and the pH adjusted to 7.5 with sodium hydroxide 2N
first then with a saturated sodium hydrogen carbonate solution. The
solid was collected by filtration, washed with water, ether and
dried over P.sub.2O.sub.5 under vacuum. The crude product was
purified by flash chromatography using dichloromethane/acetonitrile
(95/5 up to 90/10). Evaporation of the solvent gave
4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (3.06 g, 59%).
[0334] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.95 (t, 2H), 4.1 (s,
3H), 4.5 (t, 2H), 7.35 (s, 1H), 7.45 (s, 1H), 8.9 (s, 1H)
[0335] Mass Spectrum: M+H.sup.+ 273 and 275
[0336] The tetrahydro-3aH-[1,3]-dioxolo[4,5-c]pyrrole hydrochloride
was made as follows:
##STR00052##
[0337] A mixture of 3-pyrroline (2,5-dihydro-1H-pyrrole) (25 g;
0.36 mole; 65% pure containing pyrrolidine) and ethyl acetate (125
mL) was cooled to 0.degree. C. and a solution of Boc.sub.2O (78.95
g; 0.36mol) in ethyl acetate (125 mL) was added dropwise while
keeping the temperature between 5 and 10.degree. C. The reaction
mixture was then left to rise to ambient temperature overnight. The
organic phase was washed successively with water, HCl 0.1N, water,
saturated sodium hydrogen carbonate, brine and dried over magnesium
sulphate. Filtration and evaporation of the solvent gave a
colourless oil (62 g) containing 37% of pyrrolidine-Boc in addition
to the desired tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (62
g, 100% based on conversion of both pyrroline and pyrrolidine).
[0338] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 4.1 (d,
4H), 6.75 (m, 2H)
[0339] Pyrrolidone-Boc: 1.50 (s, 9H), 1.80 (br s, 4H), 3.3 (br s,
4H)
[0340] A solution of the crude tert-butyl
2,5-dihydro-1H-pyrrole-1-carboxylate mixture (57.5 g; 0.22 mol) in
acetone (500 mL) was added dropwise to a mixture of N-methyl
morpholine-N-oxide (28.45 g; 0.243mol), osmium tetroxide (1.0 g;
0.004 mol) and water (500 mL) while keeping the temperature below
25.degree. C. The reaction mixture was then stirred for 5 hours at
ambient temperature. Acetone was evaporated off and the organic
phase extracted with ethyl acetate. The combined organic phases
were washed in turn with water and brine and dried over magnesium
sulphate. The solvent was evaporated under vacuum and the residue
was purified by column chromatography on silica using increasingly
polar solvent mixtures, starting with ethyl acetate/petroleum ether
(1/1) and ending with pure ethyl acetate. A second flash
chromatography using increasingly polar solvent mixtures, starting
with methanol/dichloromethane (2/98) and ending with
methanol/dichloromethane (5/95) was done. Evaporation of the
solvent gave tert-butyl
(3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (34.6 g; 77%) as a
brown oil.
[0341] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 2.65 (m,
2H), 3.35 (m, 2H), 3.6 (m, 2H), 4.25 (m, 2H)
[0342] tert-Butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate
(34.6 g; 0.17 mol) was dissolved in DMF (400 mL) under argon and
cooled down to 0-5.degree. C. Sodium hydride (15 g; 0.375mol) was
added portionwise. The reaction mixture formed a foam which was
difficult to stir. After 1 hour at 5.degree. C., dibromomethane
(15.6 mL; 0.22mol) was added. After an additional 30 minutes at the
same temperature, the reaction mixture was left to rise to ambient
temperature. The temperature rose to 35.degree. C. and was stirred
overnight. The DMF was evaporated off and the residue partitioned
between ethyl acetate and water. The water phase was extracted with
ethyl acetate, the organic phases were combined and washed with
water, brine, dried over magnesium sulphate and evaporated. The
residue was dissolved in a minimum of dichloromethane and purified
by flash chromatography using ethyl acetate/petroleum ether (3/7).
Evaporation of the solvent gave tert-butyl
tetrahydro-5H-[1,3]dioxolo[4,5-e]pyrrole-5-carboxylate (19.77 g;
54%) as a colorless oil.
[0343] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 3.35 (m,
2H), 3.75 (br s, 2H), 4.65 (m, 2H), 4.9 (s, 1H), 5.1 (s, 1H)
[0344] tert-Butyl
tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate (19.77 g)
was dissolved in dichloromethane (500 mL) and cooled in an ice
bath. Cold (from the fridge) HCl in isopropanol (150 mL; 5N)
solution was added and the reaction mixture was stirred at ambient
temperature for 4 hours. The solvents were evaporated off and the
residue triturated under ether. The precipitate was collected by
filtration, washed with ether and dried to give
tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride (13.18 g;
95%) as a beige solid.
[0345] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.15 (m, 2H), 3.35 (m,
2H), 4.65 (s, 1H), 4.8 (m, 2H), 5.1 (s, 1H)
EXAMPLE 8
##STR00053##
[0347]
7-(2-Chloroethoxy)-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazo-
line (0.15 g) was reacted with
tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride, prepared
as described in Example 7, (0.18 g), potassium carbonate (0.16 g)
and potassium iodide (0.13 g) using an analogous procedure to that
described in Example 7 to give, after work up and purification,
6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-[2-(tetrahydro-5H-[1,3]dioxol-
o[4,5-e]pyrrol-5-yl)ethoxy]quinazoline (0.07 g) as a pale yellow
solid.
[0348] Mass Spectrum: M+H.sup.+463
[0349] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.25 (s, 3H), 2.30 (d,
2H), 2.80 (t, 2H), 3.15 (d, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 4.55
(s, 2H), 4.80 (s, 1H), 4.95 (s, 1H), 6.95 (d, 1H), 7.20 (s, 1H),
7.35 (m, 3H), 7.60 (s, 1H), 8.50 (s, 1H)
[0350] Elemental Analysis Found C, 64.24; H, 5.89; N, 11.94;
[0351] C.sub.25H.sub.26N.sub.4O.sub.5 Requires C, 64.30; H, 5.78;
N, 11.90%.
[0352] The starting material was prepared as follows:
##STR00054##
[0353] 4-Chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (1 g),
prepared as described in Example 7, was reacted with
5-hydroxy-3-methylindole (0.65 g), (Journal of Organic Chemistry
1993, 58, 3757), and potassium carbonate (0.76 g) using an
analogous procedure to that described in Example 1 to give, after
work up and purification,
7-(2-chloroethoxy)-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline
(0.81 g) as a white solid.
[0354] Mass Spectrum: M+H.sup.+384 and 386
[0355] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.25 (s, 3H), 4.00 (s,
3H), 4.05 (t, 2H), 4.50 (t, 2H), 7.00 (d, 1H), 7.20 (s, 1H), 7.35
(s, 1H), 7.40 (d, 1H), 7.45 (s, 1H), 7.65 (s, 1H), 8.50 (s, 1H)
EXAMPLE 9
##STR00055##
[0357]
7-(2-Chloroethoxy)-4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxyqui-
nazoline (0.15 g) was reacted with
tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride, prepared
as described in Example 7, (0.23 g), potassium carbonate (0.26 g)
and potassium iodide (0.09 g) using an analogous procedure to that
described in Example 7 to give, after work up and purification,
4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1,3]di-
oxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazoline (0.03 g) as a pale
yellow solid.
[0358] Mass Spectrum: M+H.sup.+477
[0359] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H), 2.25 (d,
2H), 2.35 (s, 3H), 2.80 (t, 2H), 3.15 (d, 2H), 4.00 (s, 3H), 4.30
(t, 2H), 4.55 (s, 2H), 4.80 (s, 1H), 5.00 (s, 1H), 6.90 (d, 1H),
7.20 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s,
1H)
[0360] Elemental Analysis: Found C, 64.45; H, 6.12; N, 11.22;
[0361] C.sub.26H.sub.28N.sub.4O.sub.5 Requires C, 64.63; H, 5.86;
N, 11.55%
[0362] The starting material was prepared as follows:
##STR00056##
[0363] A mixture of
4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (5.0 g), prepared
as described in Example 7, 2,3-dimethyl-5-hydroxyindole (3.5 g),
(Arch. Pharm. 1972, 305, 159), and potassium carbonate (4.0 g) in
DMF (70 ml) was stirred and heated at 90.degree. C. for 3 hours.
The mixture was filtrated and the solvent was removed by
evaporation under vacuum. The residue was purified by column
chromatography on silica using the solvent mixture
dichloromethane/ethyl acetate/methanol (50/48/2). The solvent was
evaporated under vacuum to give
7-(2-chloroethoxy)-4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxyquinazoli-
ne (4.9 g) as a beige solid.
[0364] Mass Spectrum: M+H.sup.+398 and 400
[0365] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H), 2.35 (s,
3H), 4.00 (s, 3H), 4.10 (t, 2H), 4.50 (t, 2H), 6.85 (d, 1H), 7.20
(s, 1H), 7.25 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
EXAMPLE 10
##STR00057##
[0367]
7-(2-Chloroethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-metho-
xyquinazoline (0.15 g) was reacted with
tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole hydrochloride, prepared
as described in Example 7, (0.10 g) using an analogous procedure to
that described in Example 7 to give, after work up and
purification,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(tetrahydro-5H-[1-
,3]dioxolo[4,5-c]pyrrol-5-yl)ethoxy]quinazollne (0.09 g) as a beige
solid.
[0368] Mass Spectrum: M+H.sup.+ 481
[0369] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.30 (d, 2H), 2.40 (s,
3H), 2.80 (t, 2H), 3.15 (d, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 4.55
(s, 2H), 4.80 (s, 1H), 4.95 (s, 1H), 6.25 (s, 1H), 7.00 (t, 1H),
7.15 (d, 1H), 7.45 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0370] The starting material was prepared as follows:
##STR00058##
[0371] A mixture of
4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (4.0 g), prepared
as described in Example 7, was reacted with
4-fluoro-5-hydroxy-2-methylindole (3.1 g), prepared by any of the
methods described in WO 00/47212, see in particular Example 237
therein, and potassium carbonate (3.3 g) using an analogous
procedure to that described in Example 1 to give, after work up and
purification,
7-(2-chloroethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquin-
azoline (5.0 g) as a solid.
[0372] Mass Spectrum: M+H.sup.+ 402 and 404
[0373] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 4.00 (s,
3H), 4.05 (t, 2H), 4.50 (t, 2H), 6.25 (s, 1H), 7.00 (t, 1H), 7.15
(d, 1H), 7.45 (s, 1H), 7.65 (s, 1H), 8.50 (s, 1H)
EXAMPLE 11
##STR00059##
[0375]
7-(2-Chloroethoxy)-4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxyqui-
nazoline (0.14 g), prepared as described in Example 9, was reacted
with 1-(acetylmethyl)piperazine (0.21 g), potassium carbonate (0.15
g) and potassium iodide (0.09 g) using an analogous procedure to
that described in Example 7 to give, after work up and
purification,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(2,3-dimethyl-4H-indol-5--
yl)oxy]-6-methoxyquinazoline (0.03 g) as a solid.
[0376] Mass Spectrum: M+H.sup.+504
[0377] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H), 2.15 (s,
3H), 2.35 (s, 3H), 2.45 (m, 4H), 2.65 (m, 4H), 2.80 (t, 2H), 3.15
(s, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 6.85 (d, 1H), 7.20 (s, 1H),
7.25 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0378] Elemental Analysis Found C, 64.86; H, 6.32; N, 13.80;
[0379] C.sub.28H.sub.33N.sub.5O.sub.4 Requires C, 65.06; H, 6.49;
N, 13.41%
[0380] The starting material was prepared as follows:
##STR00060##
[0381] A mixture of benzyl 1-piperazinecarboxylate (4.1 ml),
chloromethyl acetone (1.8 ml) and potassium carbonate (8.8 g) in
acetonitrile (40 ml) was stirred overnight at ambient temperature.
The reaction mixture was diluted in diethyl ether and the solution
was partitioned between diethyl ether and water. The water phase
was extracted with diethyl ether, the organic phases were combined
and washed with water, brine, dried over magnesium sulphate and
evaporated. The residue was purified by flash chromatography using
dichloromethane/methanol saturated with ammonia (3.5 M) (98/2).
Evaporation of the solvent gave benzyl
4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g, 63%) as a yellow
oil.
[0382] Mass Spectrum: M+H.sup.+ 277
[0383] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.05 (s, 3H), 2.40 (m,
4H), 3.20 (s, 2H), 3.40 (m, 4H), 5.05 (s, 2H), 7.35 (m, 5H)
[0384] 10% Palladium-on-charcoal catalyst (0.3 g) was added to a
solution of benzyl 4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g)
in ethanol (45 ml). The reaction mixture was stirred under hydrogen
at 3 atmospheres pressure for 1.5 hours. The catalyst was removed
by filtration and the solvent removed from the filtrate by
evaporation. The residue was purified by flash chromatography using
dichloromethane/methanol saturated with ammonia (3.5 M) (97/3).
Evaporation of the solvent gave 1-(acetylmethyl)piperazine (1.5 g,
80%) as a yellow oil.
[0385] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.07 (s, 3H), 2.35 (m,
4H), 2.65 (m, 4H), 3.10 (s, 2H)
EXAMPLE 12
##STR00061##
[0387]
7-(2-Chloroethoxy)-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazo-
line (0.15 g), prepared as described in Example 8, was reacted with
1-(acetylmethyl)piperazine (0.17 g) and potassium iodide (0.13 g)
using an analogous procedure to that described in Example 7 to
give, after work up and purification,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(3-methyl-1H-in-
dol-5-yl)oxy]quinazoline (0.03 g) as a white solid.
[0388] Mass Spectrum: M+H.sup.+490
[0389] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H), 2.25 (s,
3H), 2.45 (m, 4H), 2.55 (m, 4H), 2.80 (t, 2H), 3.15 (s, 2H), 4.00
(s, 3H), 4.30 (t, 2H), 6.95 (d, 1H), 7.20 (s, 1H), 7.35 (s, 1H),
7.40 (m, 2H), 7.60 (s, 1H), 8.50 (s, 1H)
[0390] Elemental Analysis Found C, 64.77; H, 6.64; N, 13.92;
[0391] C.sub.28H.sub.33N.sub.5O.sub.4 Requires C, 64.96; H, 6.48;
N, 13.98%
EXAMPLE 13
##STR00062##
[0393] A mixture of
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]qui-
nazoline (0.15 g), chloroacetone (0.036 ml), potassium carbonate
(0.05 g) and DMA (1.3 ml) was stirred and heated to 70.degree. C.
for 1.5 hours. The mixture was cooled to ambient temperature, the
precipitate was filtered off and the residue was purified by
preparative LCMS (Hypersil C18-.beta.-Basic column using a solvent
gradient consisting of acetonitrile and water buffered with a 5%
ammonium carbonate solution (100 g/L, pH 8.9). Evaporation of the
solvents gave
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-4H-in-
dol-5-yl)oxy]quinazoline as a pale yellow solid (0.10 g), which was
dried under vacuum.
[0394] Mass Spectrum: M+H.sup.+490
[0395] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H), 2.40 (s,
3H), 2.45 (m, 4H), 2.55 (m, 4H), 2.80 (t, 2H), 3.15 (s, 2H), 4.00
(s, 3H), 4.30 (t, 2H), 6.15 (s, 1H), 6.90 (d, 1H), 7.25 (s, 1H),
7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0396] The starting material was prepared as follows:
[0397]
7-(2-Chloroethoxy)-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazo-
line (2.5 g), prepared as described in Example 7, was reacted with
tert-butyl 1-piperazinecarboxylate (2.4 g), potassium iodide (1.6
g) and potassium carbonate (0.4 g) using an analogous procedure to
that described in Example 7 to give, after work up and purification
on silica (dichloromethane/ethyl acetate/methanol (50/48/2)),
7-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methy-
l-1H-indol-5-yl)oxy]quinazoline (2.7 g) as a pale yellow solid.
[0398] Mass Spectrum: M+H.sup.+534
[0399] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 2.40 (s,
3H), 2.50 (m, 4H), 2.80 (m, 2H), 3.35 (m, 4H), 4.00 (s, 3H), 4.30
(t, 2H), 6.15 (s, 1H), 6.85 (d, 1H), 7.25 (s, 1H), 7.30 (d, 1H),
7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0400] TFA (8 ml) was added to a solution of
7-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methy-
l-1H-indol-5-yl)oxy]quinazoline (2.75 g) in dichloromethane (30 ml)
at 0.degree. C. and the reaction mixture was stirred at this
temperature for 1 hour before being concentrated in vacuum in a
cold bath (.about.20.degree. C.). Cold water was added to the
residue and the pH was adjusted to 10.5 with 1N sodium hydroxide.
After several extractions with dichloromethane, the combined
organic layers were dried over magnesium sulphate, filtered and
concentrated in vacuum to give
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]qui-
nazoline (1.8 g) as a white solid.
[0401] Mass Spectrum: M+H.sup.+434
[0402] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.45 (m,
4H), 2.70 (m, 4H), 2.75 (t, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 6.15
(s, 1H), 6.90 (d, 1H), 7.25 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.50 (s, 1H)
EXAMPLE 14
##STR00063##
[0404]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(piperazin--
1-yl)ethoxy]quinazoline (0.15 g) was reacted with chloroacetone
(0.034 ml) using an analogous procedure to that described in
Example 13 to give, after work up and purification,
7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-ind-
ol-5-yl)oxy]-6-methoxyquinazoline (0.10 g) as a beige solid.
[0405] Mass Spectrum: M+H.sup.+508
[0406] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H), 2.40 (s,
3H), 2.40 (m, 4H), 2.55 (m, 4H), 2.80 (t, 2H), 3.15 (s, 2H), 4.00
(s, 3H), 4.30 (t, 2H), 6.20 (s, 1H), 7.00 (t, 1H), 7.15 (d, 1H),
7.45 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0407] The starting material was prepared as follows:
[0408]
7-(2-Chloroethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-metho-
xyquinazoline (2.5 g), prepared as described in Example 10, was
reacted with tert-butyl 1-piperazinecarboxylate (2.3 g), potassium
iodide (1.6 g) and potassium carbonate (0.4 g) using an analogous
procedure to that described in Example 7 to give, after work up and
purification,
7-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-
-1H-indol-5-yl)oxy]-6-methoxyquinazoline (3.0 g) as a solid.
[0409] Mass Spectrum: M+H.sup.+552
[0410] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 2.40 (s,
3H), 2.50 (m, 4H), 2.85 (t, 2H), 3.35 (m, 4H), 4.00 (s, 3H), 4.30
(t, 2H), 6.25 (s, 1H), 7.00 (t, 1H), 7.15 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.50 (s, 1H)
[0411]
7-{2-[4-(text-Butoxycarbonyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2--
methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (3.0 g) was reacted
with TFA (8.5 ml) using an analogous procedure to that described in
Example 13 to give, after work up and purification
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[2-(piperazin-1-yl)e-
thoxy]quinazoline (1.8 g) as a white solid.
[0412] Mass Spectrum: M+H.sup.+452
[0413] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.45 (m,
4H), 2.70 (m, 4H), 2.75 (t, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 6.25
(s, 1H), 7.00 (t, 1H), 7.15 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H),
8.50 (s, 1H)
EXAMPLE 15
##STR00064##
[0415] A mixture of
7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline (0.130 g), pyrrolidine (0.04 ml),
potassium iodide (0.01 g) and DMF (3.5 ml) was stirred and heated
to 80.degree. C. for 1 hour. The mixture was cooled to ambient
temperature, the solvent evaporated under vacuum and the residue
was purified by column chromatography on silica using increasingly
polar solvent mixtures, starting with dichloromethane and ending
with dichloromethane/methanol saturated with ammonia (3.5M) (95/5).
Evaporation of the solvents gave a foam, which was triturated under
ether to give
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-{2-[4-(pyrrolidin-1-ylacetyl)-
piperazin-1-yl]ethoxy}quinazoline (0.09 g) as a pale yellow solid
which was collected by filtration and dried under vacuum.
[0416] Mass Spectrum: M+H.sup.+545
[0417] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.70 (m, 4H), 2.40 (s,
3H), 2.50 (m, 8H), 2.80 (t, 2H), 3.25 (s, 2H), 3.45 (m, 2H), 3.55
(m, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 6.15 (s, 1H), 6.90 (d, 1H),
7.25 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s,
1H)
[0418] The starting material was prepared as follows:
[0419] Chloroacetyl chloride (0.09 ml) was added dropwise to a
solution of
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]qui-
nazoline (0.45 g), prepared as described in Example 13, and PS-DIEA
resin (0.66 g) in dichloromethane (15 ml). After 1 hour at ambient
temperature, methanol was added and the reaction mixture was
filtered. Solvents were removed by evaporation in vacuum and the
residue was triturated under diethyl ether, filtrated and dried to
give
7-{2-[4-(chloroacetyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-in-
dol-5-yl)oxy]quinazoline (0.36 g) as a solid.
[0420] Mass Spectrum: M+H.sup.+510 and 512
[0421] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.55 (m,
2H), 2.60 (m, 2H), 2.85 (t, 2H), 3.50 (m, 4H), 4.00 (s, 3H), 4.35
(t, 2H), 4.40 (s, 2H), 6.15 (s, 1H), 6.90 (d, 1H), 7.25 (s, 1H),
7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
EXAMPLE 16
##STR00065##
[0423]
6-Methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)oxy]qu-
inazoline (0.25 g) was reacted with chloroacetone (0.054 ml) using
an analogous procedure to that described in Example 1 to give,
after work up and purification,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-6-
-yl)oxy]quinazoline (0.21 g) as a white solid.
[0424] Mass Spectrum: M+H.sup.+461
[0425] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.75 (m, 2H), 2.05 (m,
2H), 2.10 (s, 3H), 2.35 (m, 2H), 2.40 (s, 3H), 2.75 (m, 2H), 3.20
(s, 2H), 3.95 (s, 3H), 4.75 (s, 1H), 6.15 (s, 1H), 6.8 (d, 1H),
7.15 (s, 1H), 7.40 (m, 2H), 7.6 (s, 1H), 8.50 (s, 1H)
[0426] Elemental Analysis Found C, 67.74; H, 6.28; N, 11.66;
[0427] C.sub.26H.sub.28N.sub.4O.sub.4 0.1 ether Requires C, 67.76;
H, 6.25; N, 11.97%
[0428] The starting material was prepared as follows:
##STR00066##
[0429] A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline
(11.5 g), prepared as described in Example 1, in dichloromethane
(250 ml) was treated with triphenylphosphine (21.5 g),
1-(tert-butoxycarbonyl)-4-hydroxypiperidine (13.2 g) and
di-test-butyl azodicarboxylate (19 g) and the mixture stirred at
ambient temperature overnight. The crude reaction mixture was
concentrated to a third and loaded onto a silica column and eluted
using ethyl acetate/petroleum ether (35/65) as solvent. The
relevant fractions were combined and evaporated under vacuum to
give
7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyquinazo-
line as a white solid (20 g).
[0430] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 1.60 (m,
2H), 2.05 (m, 2H), 3.2 (m, 2H), 3.70 (m, 2H), 4.0 (s, 3H), 4.95 (m,
1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.90 (s, 1H)
##STR00067##
[0431]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyq-
uinazoline (5 g) was dissolved in DMF (100 ml).
6-Hydroxy-2-methylindole (2.3 g), (Eur. J. Med. Chem. 1975, 10,
187), and potassium carbonate (2.6 g), were added and the mixture
heated at 90.degree. C. for 3 hours. The solid was removed by
filtration and the filtrate was concentrated to dryness under
vacuum. The residue was purified by column chromatography on silica
using increasingly polar solvent mixtures, starting with ethyl
acetate/petroleum ether (1/1) and ending with (75/25). Evaporation
of the solvents gave,
7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-
-indol-6-yl)oxy]quinazoline (5.4 g) as a yellow foam.
[0432] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 1.60 (m,
2H), 2.05 (m, 2H), 2.30 (s, 3H), 3.20 (m, 2H), 3.70 (m, 2H), 4.0
(s, 3H), 4.90 (s, 1H), 6.20 (s, 1H), 6.85 (d, 1H), 7.15 (s, 1H),
7.40 (d, 1H), 7.50 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
##STR00068##
[0433]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-6-methoxy-4-[(2-met-
hyl-1H-indol-6-yl)oxy]quinazoline (1 g) was dissolved in
dichloromethane (5 ml) and cooled in an ice bath. TFA (2.5 ml) was
added and the reaction mixture stirred at this temperature for 35
minutes. The volatiles were removed by filtration and the residue
taken up into ice cold water. The pH was adjusted to 12 with sodium
hydroxide 2N and extracted twice with dichloromethane. The combined
extracts were washed in turn with water and brine and dried over
magnesium sulphate and the solvent evaporated under vacuum to give
6-methoxy-4-[(2-methyl-1H-indol-6-yl)oxy]-7-[(piperidin-4-yl)oxy]quinazol-
ine (0.765 g) as a solid foam.
[0434] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.55 (m, 2H), 2.05 (m,
2H), 2.40 (s, 3H), 2.65 (m, 2H), 2.95 (m, 2H), 4.0 (s, 3H), 4.75
(m, 1H), 6.15 (s, 1H), 6.80 (d, 1H), 7.15 (s, 1H), 7.45 (m, 2H),
7.60 (s, 1H), 8.45 (s, 1H)
EXAMPLE 17
##STR00069##
[0436]
6-Methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)oxy]qu-
inazoline (0.25 g) was reacted with chloroacetone (0.054 ml) using
an analogous procedure to that described in Example 1 to give,
after work up and purification,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-indol-5-
-yl)oxy]quinazoline (0.216 g).
[0437] Mass Spectrum: M+H.sup.+461
[0438] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.75 (m, 2H), 2.05 (m,
2H), 2.10 (s, 3H), 2.35 (m, 2H), 2.40 (s, 3H), 2.75 (m, 2H), 3.20
(s, 2H), 3.95 (s, 3H), 4.70 (m, 1H), 6.15 (s, 1H), 6.90 (d, 1H),
7.25 (s, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.50 (s,
1H)
[0439] Elemental Analysis Found C, 67.79; H, 5.99; N, 12.07;
[0440] C.sub.26H.sub.28N.sub.4O.sub.4 Requires C, 67.81; H, 6.13;
N, 12.17%
[0441] The starting material was prepared as follows:
##STR00070##
[0442]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyq-
uinazoline (5 g), prepared as described in Example 16, was reacted
with 5-hydroxy-2-methylindole (2.3 g) using an analogous procedure
to that described in Example 16 to give, after work up and
purification,
7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-6-methoxy-4-[(2-methyl-1H-
-indol-5-yl)oxy]quinazoline (2.3 g).
[0443] Mass Spectrum: M+H.sup.+ 505
[0444] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 1.60 (m,
2H), 2.05 (m, 2H), 2.40 (s, 3H), 3.20 (m, 2H), 3.75 (m, 2H), 4.0
(s, 3H), 4.90 (s, 1H), 6.15 (s, 1H), 6.85 (d, 1H), 7.25 (s, 1H),
7.30 (d, 1H), 7.50 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
##STR00071##
[0445]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-6-methoxy-4-[(2-met-
hyl-1H-indol-5-yl)oxy]quinazoline (2.3 g) was reacted with TFA (7
ml) using an analogous procedure to that described in Example 16 to
give, after work up and purification,
6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[(piperidin-4-yl)oxy]quinazol-
ine (1.6 g).
[0446] Mass Spectrum: M+H.sup.+ 405
EXAMPLE 18
##STR00072##
[0448]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(piperidin-4--
yl)oxy]quinazoline (0.18 g) was reacted with chloroacetone (0.038
ml) using an anaolgous procedure to that described in Example 1 to
give, after work up and purification,
7-{[1-(acetylmethyl)piperidin-4-yl]oxy}-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline (0.14 g).
[0449] Mass Spectrum: M+H.sup.+479
[0450] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.75 (m, 2H), 2.05 (m,
2H), 2.10 (s, 3H), 2.35 (m, 2H), 3.40 (s, 3H), 2.70 (m, 2H), 3.20
(s, 3H), 4.0 (s, 3H), 4.70 (m, 1H), 6.20 (s, 1H), 6.95 (m, 1H),
7.15 (d, 1H), 7.45 (s, 1H), 7.60 (s, 1H), 8.50 (s, 1H)
[0451] Elemental Analysis Found C, 65.04; H, 5.55; N, 11.53;
[0452] C.sub.26H.sub.27N.sub.4O.sub.4F Requires C, 65.26; H, 5.69;
N, 11.71%
[0453] The starting material was prepared as follows:
##STR00073##
[0454]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyq-
uinazoline (3 g), prepared as described in Example 16, was reacted
with 4-fluoro-5-hydroxy-2-methylindole (1.4 g), prepared by any of
the methods described in WO 00/47212, see in particular Example 237
therein, using an analogous procedure to that described in Example
16 to give, after work up and purification,
7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-[(4-fluoro-2-methyl-1H--
indol-5-yl)oxy]-6-methoxyquinazoline (1.76 g).
[0455] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H), 1.60 (m,
2H), 2.05 (m, 2H), 2.40 (s, 3H), 3.20 (m, 2H), 3.70 (m, 2H), 4.0
(s, 3H), 4.90 (m, 1H), 6.25 (s, 1H), 6.95 (m, 1H), 7.15 (d, 1H),
7.55 (s, 1H), 7.65 (s, 1H), 8.50 (s, 1H)
##STR00074##
[0456]
7-{[1-(tert-Butoxycarbonyl)-piperidin-4-yl]oxy}-4-[(4-fluoro-2-meth-
yl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (1.7 g) was reacted with
TFA (5 ml) using an analogous procedure to that described in
Example 16 to give, after work up and purification,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(piperidin-4-yl)oxy-
]quinazoline (1.2 g).
[0457] Mass Spectrum: M+H.sup.+423
EXAMPLE 19
[0458] The following illustrate representative pharmaceutical
dosage forms containing the compound of formula I, or a
pharmaceutically acceptable salt thereof (hereafter compound X),
for therapeutic or prophylactic use in humans:
TABLE-US-00003 (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur
182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste)
2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50
Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)
Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose
Ph.Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml)
Compound X 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M
Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400
4.5% w/v Water for injection to 100% (f) Injection II 10 mg/ml)
Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium
hydroxide solution 15.0% v/v Water for injection to 100% (1 mg/ml,
(g) Injection III buffered to pH6) Compound X 0.1% w/v Sodium
phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol
400 3.5% w/v Water for injection to 100% Note The above
formulations may be obtained by conventional procedures well known
in the pharmaceutical art. The tablets (a)-(c) may be enteric
coated by conventional means, for example to provide a coating of
cellulose acetate phthalate.
* * * * *