U.S. patent application number 11/169122 was filed with the patent office on 2006-01-05 for quinazoline derivatives as angiogenesis inhibitors.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Laurent FA Hennequin, Darren McKerrecher, Patrick Ple, Elaine SE Stokes.
Application Number | 20060004017 11/169122 |
Document ID | / |
Family ID | 8241873 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060004017 |
Kind Code |
A1 |
Stokes; Elaine SE ; et
al. |
January 5, 2006 |
Quinazoline derivatives as angiogenesis inhibitors
Abstract
##STR1## The invention relates to the use of compounds of
formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered
bicyclic or tricyclic moiety which optionally may contain 1-3
heteroatoms selected independently from O, N and S; Z is --O--,
--NH--, --S--, --CH.sub.2-- or a direct bond; n is 0-5; m is 0-3;
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.t-- (wherein X.sup.1
and R.sup.5 are as defined herein; 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 and R.sup.56 are as defined
herein); and salts thereof, 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 as active ingredient and compounds of
formula (I). The compounds of formula (I) and the pharmaceutically
acceptable salts thereof inhibit the effects of VEGF, a property of
value in the treatment of a number of disease states including
cancer and rheumatoid arthritis.
Inventors: |
Stokes; Elaine SE;
(Macclesfield, GB) ; McKerrecher; Darren;
(Macclesfield, GB) ; Hennequin; Laurent FA;
(Reims, FR) ; Ple; Patrick; (Reims, FR) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
ASTRAZENECA AB
|
Family ID: |
8241873 |
Appl. No.: |
11/169122 |
Filed: |
June 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09913020 |
May 6, 2002 |
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PCT/GB00/00373 |
Feb 8, 2000 |
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11169122 |
Jun 29, 2005 |
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Current U.S.
Class: |
514/252.17 ;
514/266.22; 544/284 |
Current CPC
Class: |
A61K 31/505 20130101;
A61P 17/06 20180101; C07D 417/14 20130101; C07D 233/56 20130101;
C07D 471/04 20130101; A61P 29/00 20180101; C07D 401/14 20130101;
C07D 417/12 20130101; C07D 249/08 20130101; A61K 31/517 20130101;
C07D 239/88 20130101; C07D 231/12 20130101; A61P 37/00 20180101;
C07D 405/12 20130101; C07D 403/14 20130101; C07D 405/14 20130101;
A61P 21/00 20180101; A61P 43/00 20180101; A61P 27/02 20180101; C07D
413/14 20130101; C07D 239/94 20130101; C07D 401/12 20130101; A61P
9/10 20180101; A61P 19/02 20180101; A61P 37/02 20180101; A61P 13/02
20180101; A61P 3/10 20180101; A61P 9/14 20180101; A61P 35/00
20180101; A61P 13/12 20180101; A61P 15/00 20180101; C07D 403/12
20130101; A61P 13/00 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/252.17 ;
514/266.22; 544/284 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 43/02 20060101 C07D043/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 10, 1999 |
EP |
99400305.1 |
Claims
1-30. (canceled)
31. A process for the preparation of a compound of formula I:
##STR148## 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--, --S-- or --CH.sub.2--; n is an
integer from 0 to 5; m is an integer from 0 to 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.2 represents a group
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.1-5salkylX.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.213 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 4-6-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--)K(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g is 0
or 1 and ring D is a 4-6-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 4-6-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 4-6-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 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 4-6-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.14alkyl)); 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
SO.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.52and
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.1-4alkylaminosulphonyl 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 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
4-6-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 4-6-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--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 R.sup.1 represents
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.sub.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.71and 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 4-6-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 4-6-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.14 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 4-6-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 4-6-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 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 4-6-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.93and
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(X18).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
4-6-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 4-6-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--may
bear one or more substituents selected from hydroxy, halogeno and
amino; or a salt or prodrug thereof. which process comprises: (a)
the reaction of a compound of the formula III: ##STR149## (wherein
R.sup.2 and m are as defined above and L.sup.1 is a displaceable
moiety), with a compound of the formula IV: ##STR150## (wherein
ring C, R.sup.1, Z and n are as defined above); (b) a compound of
formula I or a salt thereof wherein at least one R.sup.2 is
R.sup.5X.sup.1 wherein R.sup.5 is as defined above 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) may be prepared by the reaction of a
compound of the formula V: ##STR151## (wherein ring C, Z, R.sup.1,
R.sup.2 and n are as defined above and X.sup.1 is as herein defined
in this section and s is an integer from 0 to 2) with a compound of
formula VI: R.sup.5-L.sup.1 (VI) (wherein R.sup.5is as defined
above and L.sup.1 is as herein defined); (c) a compound of the
formula I or a salt thereof wherein at least one R.sup.2 is
R.sup.5X.sup.1 wherein R.sup.5is as defined above 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: ##STR152## with a compound of the
formula VIII: R.sup.5--X.sup.1--H (VIII) (wherein R.sup.1, R.sup.2,
R.sup.5, ring C, Z and n are as defined above and L.sup.1, s and
X.sup.1 are as herein defined); (d) a compound of the formula I or
a salt thereof wherein at least one R.sup.2 is R.sup.5X.sup.1
wherein X.sup.1 is as defined above and 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.1-3 alkyl 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 above); 4) R.sup.28 (wherein
R.sup.28 is as defined above); 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 above); 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 above);
7) R.sup.29 (wherein R.sup.29 is as defined above); 8)
X.sup.22C.sub.1-4alkylR.sup.28 (wherein X.sup.22 and R.sup.28 are
as defined above); 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 above); may be
prepared by reacting a compound of the formula IX: ##STR153##
(wherein X.sup.1, R.sup.1, R.sup.2, ring C, Z and n are as defined
above and L.sup.1 and s are as herein defined) with a compound of
the formula X: R.sup.113--H (X) (wherein R.sup.113 is as defined
herein); (e) a compound of the formula I or a salt 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; or (f) a
compound of the formula I or a salt 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--; and
optionally reacting the compound of formula I with an acid or base
whereby to obtain a compound of formula I in salt form.
32. The compound 4-fluoro-5-hydroxy-2-methylindole or a salt
thereof.
33. The compound 4-fluoro-5-hydroxyindole or a salt thereof.
34. The compound 6-fluoro-5-hydroxy-2-methylindole or a salt
thereof.
35. The compound 6-fluoro-5-hydroxyindole or a salt thereof.
36. A process for the preparation the compound of claim 32
comprising the steps of: (i) reacting 2-fluoro-4-nitroanisole with
4-chlorophenoxyacetonitrile to give a mixture of
4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole; (ii)
reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with
di-tert-butyl dicarbonate to give a mixture of
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole; (iii) reacting
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with
tert-butyllithium followed by deprotection to give
6-fluoro-5-methoxy-2-methylindole and
4-fluoro-5-methoxy-2-methylindole; and (iv) de-alkylating
4-fluoro-5-methoxy-2-methylindole to give
4-fluoro-5-hydroxy-2-methylindole.
37. A process for the preparation of the compound of claim 32
comprising the steps: (i) reacting alkyl or aryl acetoacetate and
1,2,3-trifluoro-4-nitrobenzene to give
3-acetylmethyl-1,2-difluoro-4-nitrobenzene; (ii) reacting
3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to
give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene; (iii)
reacting benzyl alcohol or substituted benzyl alcohol or ethanol or
propanol with sodium hydride and
1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give
3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene; and (iv)
hydrogenating 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene to
give 4-fluoro-5-hydroxy-2-methylindole.
38. A process for the preparation of the compound of claim 32
comprising the steps: (i) reacting alkyl or aryl acetoacetate and
1,2,3-trifluoro-4-nitrobenzene to give
3-acetymethyl-1,2-difluoro-4-nitrobenzene; (ii) reacting
3-acetymethyl-1,2-difluoro-4-nitrobenzene with an orthoformate to
give 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene; (iii)
reacting sodium methoxide with
1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene to give
3-acetylmethyl-2-fluoro-methoxy-4-nitrobenzene; (iv) reacting
3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene with titanium
trichloride to give 4-fluoro-5-methoxy-2-methylindole; and (v)
dealkylating 4-fluoro-5-methoxy-2-methylindole to give
4-fluoro-5-hydroxy-2-methylindole.
39. A process for the preparation of a compound of claim 33 or
claim 35, comprising the steps: (i) reacting 2-fluoro-4-nitrophenol
and benzyl bromide to give 2-fluoro-4-nitrobenzyloxybenzene; (ii)
reacting 2-fluoro-4-nitro-benzyloxybenzene with
4-chlorophenoxyacetonitrile to give a mixture of
3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and
5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene; and (iii)
hydrogenating a mixture of
3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and
5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene to give
4-fluoro-5-hydroxyindole and 6-fluoro-5-hydroxyindole.
40. A process for the preparation of a compound of claim 34
comprising the steps: (i) reacting 2-fluoro-4-nitroanisole with
4-chlorophenoxyacetonitrile to give a mixture of
4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole; (ii)
reacting 4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole with
di-tert-butyl dicarbonate to give a mixture of
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole; (iii) reacting
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole with
tert-butyllithium followed by deprotection to give
6-fluoro-5-methoxy-2-methylindole and
4-fluoro-5-methoxy-2-methylindole; and (iv) de-alkylating
6-fluoro-5-methoxy-2-methylindole to give
6-fluoro-5-hydroxy-2-methylindole.
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 fms-like
tyrosine kinase receptor, Flt or Flt1, the kinase insert
domain-containing receptor, KDR (also referred to as Flk-1), and
another fms-like tyrosine kinase receptor, Flt4. Two of these
related RTKs, Flt 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,
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. Compounds of the
present invention generally possess higher potency against VEGF
receptor tyrosine kinase than against epidermal growth factor (EGF)
receptor tyrosine kinase. Compounds of the invention which have
been tested possess activity against VEGF receptor tyrosine kinase
such that they may be used in an amount sufficient to inhibit VEGF
receptor tyrosine kinase whilst demonstrating no significant
activity against EGF receptor tyrosine kinase. Compounds of the
present invention generally possess higher potency against VEGF
receptor tyrosine kinase than against FGF R1 receptor tyrosine
kinase. Compounds of the invention which have been tested possess
activity against VEGF receptor tyrosine kinase such that they may
be used in an amount sufficient to inhibit VEGF receptor tyrosine
kinase whilst demonstrating no significant activity against FGF R1
receptor tyrosine kinase.
[0005] According to one aspect of the present invention there is
provided the use of a compound of the formula I: ##STR2## wherein:
[0006] 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;
[0007] Z is --O--, --NH--, --S--, --CH.sub.2-- or a direct bond;
[0008] n is an integer from 0 to 5; [0009] m is an integer from 0
to 3; [0010] 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: [0011] 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; [0012] 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)); [0013] 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)); [0014] 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); [0015] 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)); [0016] 6) C.sub.1-5alkylR.sup.28 (wherein
R.sup.28 is as defined hereinbefore); [0017] 7)
C.sub.2-5alkenylR.sup.28 (wherein R.sup.28 is as defined
hereinbefore); [0018] 8) C.sub.2-5alkynylR.sup.28 (wherein R.sup.28
is as defined hereinbefore); [0019] 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 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)); [0020] 10) C.sub.1-5alkylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0021] 11)
C.sub.2-5alkenylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0022] 12) C.sub.2-5alkynylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0023] 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.3--,
--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); [0024] 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); [0025] 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); [0026] 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); [0027] 17)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0028] 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; [0029] 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; [0030] 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0031] 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 [0032] 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-- may
bear one or more substituents selected from hydroxy, halogeno and
amino); [0033] 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:
[0034] 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;
[0035] 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)); [0036] 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--)(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)); [0037] 4) C.sub.1-5alkylX.sup.13
C.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--NR.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 R78 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); [0038] 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.1-4alkylsulphonylC.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)); [0039] 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79
is as defined hereinbefore); [0040] 7) C.sub.2-5alkenylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); [0041] 8)
C.sub.2-5alkynylR.sup.79 (wherein R.sup.79 is as defined
hereinbefore); [0042] 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 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)); [0043] 10) C.sub.1-5alkylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); [0044] 11)
C.sub.2-5alkenylR.sup.80 (wherein R.sup.80 is as defined
hereinbefore); [0045] 12) C.sub.2-5alkynylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); [0046] 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); [0047] 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); [0048] 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); [0049] 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.103 SO.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); [0050] 17)
C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18 and
R.sup.79 are as defined hereinbefore); [0051] 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; [0052] 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; [0053] 20)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); [0054] 21)
C.sub.2-5alkylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18 and
R.sup.79 are as defined hereinbefore); and [0055] 22)
C.sub.1-4alkylR.sup.105(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106(wh-
erein 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.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
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.
[0056] According to another aspect of the present invention there
is provided the use of compounds of the formula I: ##STR3##
wherein: [0057] ring C is a 9-10-membered bicyclic moiety which 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; [0058] Z is --O--, --NH--, --S--,
--CH.sub.2-- or a direct bond; [0059] 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 or a C.sub.3-7alkylene chain
joined to two ring C carbon atoms; [0060] n is an integer from 0 to
5; [0061] m is an integer from 0 to 3; [0062] 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-one groups:
[0063] 1) hydrogen or C.sub.1-5alkyl which may be unsubstituted or
which may be substituted with one or more groups selected from
hydroxy, fluoro and amino; [0064] 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.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); [0065] 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, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl and C.sub.1-4alkoxy); [0066] 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 or
C.sub.1-3alkyl); [0067] 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 and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl); [0068] 6)
C.sub.1-5alkylR.sup.28 (wherein R.sup.28 is as defined
hereinbefore); [0069] 7) C.sub.2-5alkenylR.sup.28 (wherein R.sup.28
is as defined hereinbefore); [0070] 8) C.sub.2-5alkynylR.sup.28
(wherein R.sup.28 is as defined hereinbefore); [0071] 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 on an available carbon atom selected from 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 and --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.1-3alkyl)); [0072] 10) C.sub.1-5alkylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); [0073] 11)
C.sub.2-5alkenylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0074] 12) C.sub.2-5alkynylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0075] 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
independent represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); [0076] 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); [0077] 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); [0078] 16)
C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.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); [0079] 17)
C.sub.1-3alkylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0080] 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; [0081] 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; [0082] 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0083] 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 salts thereof, and
prodrugs thereof for example esters, amides and sulphides, 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.
[0084] Preferably ring C is a 9-10-membered aromatic bicyclic
moiety which may optionally contain 1-3 heteroatoms selected
independently from O, N and S.
[0085] More preferably ring C is a 9-10-membered heteroaromatic
bicyclic moiety which contains 1-3 heteroatoms selected
independently from O, N and S.
[0086] Particularly ring C is a 9-10-membered heteroaromatic
bicyclic moiety which contains 1 or 2 nitrogen atoms.
[0087] According to one aspect of the present invention ring C is a
9-membered heteroaromatic bicyclic moiety which contains 1 or 2
nitrogen atoms, for example indolyl.
[0088] According to another aspect of the present invention ring C
is a 10-membered heteroaromatic bicyclic moiety which contains 1 or
2 nitrogen atoms, for example quinolinyl.
[0089] Especially ring C is indolyl or quinolinyl.
[0090] Preferably Z is --O--, --NH--, --S-- or a direct bond.
[0091] More preferably Z is --O--, --NH-- or --S--.
[0092] Particularly Z is --O-- or --S--, especially --O--.
[0093] Advantageously X.sup.10 represents a direct bond, --O--,
--S--, --NR.sup.57C(O)--, --NR.sup.60SO.sub.2-- or --NR.sup.61--
(wherein R.sup.57, R.sup.60 and R.sup.61 each independently
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0094] Preferably X.sup.10 represents a direct bond, --O--, --S--,
--NR.sup.57C(O)--, --NR.sup.60SO.sub.2-- (wherein R.sup.57 and
R.sup.60 each independently represents hydrogen or C.sub.1-2alkyl)
or NH.
[0095] More preferably X.sup.10 represents --O--, --S--,
--NR.sup.57C(O)-- (wherein R.sup.57 represents hydrogen or
C.sub.1-2alkyl) or NH.
[0096] Particularly X.sup.10 represents --O-- or --NR.sup.57C(O)--
(wherein R.sup.57 represents hydrogen or C.sub.1-2alkyl), more
particularly --O-- or --NHC(O)--, especially --O--.
[0097] According to another aspect of the present invention
X.sup.10 represents --O-- or a direct bond.
[0098] Advantageously X.sup.12 represents --O--, --S--, --SO--,
--SO.sub.2--, --NR.sup.68C(O)--, --NR.sup.71SO.sub.2-- or
--NR.sup.72-- (wherein R.sup.68, R.sup.71 and R.sup.72 each
independently represents hydrogen, C.sub.1-2alkyl or
C.sub.1-2alkoxyethyl).
[0099] Preferably X.sup.12 represents --O--, --S--, --SO--,
--SO.sub.2-- or --NR.sup.72-- (wherein R.sup.72 represents
hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0100] More preferably X.sup.12 represents --O-- or --NR.sup.72--
(wherein R.sup.72 represents hydrogen or C.sub.1-2alkyl).
[0101] According to another aspect of the present invention
X.sup.12 represents --O--, --SO.sub.2--, --NR.sup.71SO.sub.2-- or
--NR.sup.72-- (wherein R.sup.71 and R.sup.72 each independently
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0102] Advantageously X.sup.18 represents --O--, --S-- or
--NR.sup.104l -- (wherein R.sup.104 represents hydrogen,
C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0103] Preferably X.sup.18 represents --O-- or --NR.sup.104--
(wherein R.sup.104 represents hydrogen or C.sub.1-2alkyl).
[0104] According to another aspect of the present invention
X.sup.18 represents --O--, --CONR.sup.101-- or --NR.sup.104--
(wherein R.sup.101 and R.sup.104 each independently represents
hydrogen or C.sub.1-2alkyl).
[0105] Advantageously R.sup.67 represents a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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 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.1-3alkyl).
[0106] Preferably R.sup.67 is pyrrolidinyl, piperazinyl,
piperidinyl, imidazolidinyl, azetidinyl, morpholino or
thiomorpholino which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1
3alkyl, C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0107] More preferably R.sup.67 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1or 2 substituents selected from oxo, hydroxy, halogeno,
cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0108] Particularly R.sup.67 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0109] Preferably R.sup.79 is pyrrolidinyl, piperazinyl,
piperidinyl, imidazolidinyl, azetidinyl, morpholino or
thiomorpholino which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0110] More preferably R.sup.79 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,
cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl1,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0111] Particularly R.sup.79 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0112] Advantageously R.sup.105 and R.sup.106 are each
independently a 5-6-membered saturated heterocyclic group with 1-2
heteroatoms, selected independently from O, S and N, which cyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl,
C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.sub.1-3alkyl, C.sub.1-3alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino, C,
.alkylaminoC.sub.1-3alkyl, di(C.sub.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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 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.1-3alkyl).
[0113] Preferably R.sup.105 and R.sup.106 are each independently
selected from pyrrolidinyl, piperazinyl, piperidinyl,
imidazolidinyl, azetidinyl, morpholino and thiomorpholino which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl,
C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl, C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0114] More preferably R.sup.105 and R.sup.106 are each
independently selected from pyrrolidinyl, piperazinyl, piperidinyl,
azetidinyl, morpholino and thiomorpholino which group may bear 1 or
2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0115] Particularly R.sup.105 and R.sup.106 are each independently
selected from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino which group may bear 1 or 2
substituents selected from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0116] Advantageously R.sup.1 represents 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 is as defined hereinbefore and
R.sup.56 is selected from one of the following nine groups: [0117]
1) C.sub.1-5alkylX.sup.12R.sup.67 (wherein X.sup.12 and R.sup.67
are as defined hereinbefore); [0118] 2) R.sup.79 (wherein R.sup.79
is as defined hereinbefore); [0119] 3) C.sub.1-5alkylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); [0120] 4)
C.sub.2-5alkenylR.sup.79 (wherein R.sup.79 is as defined
hereinbefore); [0121] 5) C.sub.2-5alkynylR.sup.79 (wherein R.sup.79
is as defined hereinbefore); [0122] 6)
C.sub.1-3alkylX.sup.18C.sub.1-3alkylR.sup.79 (wherein X.sup.18 and
R.sup.79 are as defined hereinbefore); [0123] 7)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); [0124] 8)
C.sub.2-5alkynylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); and [0125] 9)
C.sub.1-3alkylR.sup.105(C.sub.1-3alkyl).sub.x(X.sup.18).sub.yR.sup.106
(wherein X.sup.18, x, y, R.sup.105 and R.sup.106 are as defined
hereinbefore; and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
may bear one or more substituents selected from hydroxy, halogeno
and amino, with the proviso that when X.sup.10 is a direct bond
R.sup.56 is not R.sup.79).
[0126] Preferably R.sup.1 represents oxo, halogeno, hydroxy,
C.sub.1-2alkoxy, C.sub.1-2alkyl, C.sub.1-2alkoxymethyl,
C.sub.2-3alkanoyl, C.sub.1-2haloalkyl, cyano, amino,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.2-3alkanoyloxy, nitro,
C.sub.2-3alkanoylamino, C.sub.1-2alkoxycarbonyl,
C.sub.1-2alkylsulphanyl, C.sub.1-2alkylsulphinyl,
C.sub.1-2alkylsulphonyl, carbamoyl, N--C.sub.1-2alkylcarbamoyl,
N,N-di(C.sub.1-2alkyl)carbamoyl, aminosulphonyl,
N--C.sub.1-2alkylaminosulphonyl,
N,N-di(C.sub.1-2alkyl)aminosulphonyl,
N--(C.sub.1-2alkylsulphonyl)amino,
N--(C.sub.1-2alkylsulphonyl)--N--(C.sub.1-2alkyl)amino or a
C.sub.3-7alkylene chain joined to two ring C carbon atoms.
[0127] More preferably 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.
[0128] Particularly R.sup.1 represents methyl, ethyl,
trifluoromethyl or halogeno.
[0129] Especially R.sup.1 represents methyl, fluoro, chloro or
bromo, more especially methyl or fluoro.
[0130] Preferably n is an integer from 0 to 3.
[0131] More preferably n is 0, 1 or 2.
[0132] Preferably m is an integer from 0 to 2, more preferably 1 or
2, most preferably 2.
[0133] Advantageously 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.1-2alkyl or C.sub.1-2alkoxyethyl).
[0134] Preferably 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.
[0135] More preferably X.sup.1 represents --O--, --S--,
--NR.sup.6C(O)-- (wherein R.sup.6 represents hydrogen or
C.sub.1-2alkyl) or NH.
[0136] Particularly X.sup.1 represents --O-- or --NR.sup.6C(O)--
(wherein R.sup.6 represents hydrogen or C.sub.1-2alkyl), more
particularly --O-- or --NHC(O)--, especially --O--.
[0137] According to another aspect of the present invention X.sup.1
represents --O-- or a direct bond.
[0138] Advantageously X.sup.2 represents --O-- or NR.sup.12
(wherein R.sup.12 represents hydrogen, C.sub.1-3alkyl or
C.sub.1-2alkoxyethyl).
[0139] Advantageously X.sup.3 represents --O--, --S--, --SO--,
--SO.sub.2--, --NR.sup.17C(O)--, --NR.sup.20SO.sub.2-- or
--NR.sup.21-- (wherein R.sup.17, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-2alkyl or
C.sub.1-2alkoxyethyl).
[0140] Preferably X.sup.3 represents --O--, --S--, --SO--,
--SO.sub.2-- or --NR.sup.21-- (wherein R.sup.21 represents
hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0141] More preferably X.sup.3 represents --O-- or --NR.sup.21--
(wherein R.sup.21 represents hydrogen or C.sub.1-2alkyl).
[0142] According to another aspect of the present invention X.sup.3
represents --O--, --SO.sub.2--, --NR.sup.20SO.sub.2-- or
--NR.sup.21-- (wherein R.sup.20 and R.sup.21 each independently
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0143] Advantageously X.sup.4 and X.sup.5 which may be the same or
different each represents --O--, --S--, --SO--, --SO.sub.2-- or
--NR.sup.27-- (wherein R.sup.27 represents hydrogen, C.sub.1-3alkyl
or C.sub.1-2alkoxyethyl).
[0144] Preferably 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).
[0145] More preferably X.sup.4 and X.sup.5 which may be the same or
different each represents --O-- or --NH--.
[0146] Advantageously 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).
[0147] Preferably X represents --O-- or --NR.sup.38-- (wherein
R.sup.38 represents hydrogen or C.sub.1-2alkyl).
[0148] Advantageously 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).
[0149] Preferably X.sup.7 represents --O-- or --NR.sup.43--
(wherein R.sup.43 represents hydrogen or C.sub.1-2alkyl).
[0150] Advantageously 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).
[0151] Preferably X.sup.8 represents --O-- or --NR.sup.48 --
(wherein R.sup.48 represents hydrogen or C.sub.1-2alkyl).
[0152] Advantageously 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).
[0153] Preferably X.sup.9 represents --O-- or --NR.sup.53--
(wherein R.sup.53 represents hydrogen or C.sub.1-2alkyl).
[0154] According to another aspect of the present invention X.sup.9
represents --O--, --CONR.sup.50-- or --NR.sup.53-- (wherein
R.sup.50 and R.sup.53 each independently represents hydrogen or
C.sub.1-2alkyl).
[0155] Conveniently R.sup.28 is pyrrolidinyl, piperazinyl,
piperidinyl, imidazolidinyl, azetidinyl, morpholino or
thiomorpholino which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0156] Advantageously R.sup.28 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,
cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0157] In one embodiment of the present invention R.sup.28 is
pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino or
thiomorpholino which group may bear 1 or 2 substituents selected
from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0158] Particularly R.sup.28 is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,
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.1-3alkyl.
[0159] According to another aspect of the present invention,
preferably R.sup.28 is pyrrolidinyl, piperazinyl, piperidinyl,
morpholino or thiomorpholino which group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, 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.1-3alkyl.
[0160] Where R.sup.29 is a 5-6-membered aromatic heterocyclic
group, it preferably has 1 or 2 heteroatoms, selected from O, N and
S, of which more preferably one is N, and may be substituted as
hereinbefore defined.
[0161] R.sup.29 is particularly a pyridone, phenyl, pyridyl,
imidazolyl, thiazolyl, thienyl, triazolyl or pyridazinyl group
which group may be substituted as hereinbefore defined, more
particularly a pyridone, pyridyl, imidazolyl, thiazolyl or
triazolyl group, especially a pyridone, pyridyl, imidazolyl or
triazolyl group which group may be substituted as hereinbefore
defined.
[0162] In one embodiment of the invention R.sup.29 represents a
pyridone, phenyl or 5-6-membered aromatic heterocyclic group with 1
to 3 heteroatoms selected from O, N and S, which group may
preferably carry up to 2 substituents, more preferably up to one
substituent, selected from the group of substituents as
hereinbefore defined.
[0163] In the definition of R.sup.29, conveniently substituents are
selected from halogeno, C.sub.1-4alkyl, C.sub.1-4alkoxy, cyano 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0164] In the definition of R.sup.29, more conveniently
substituents are selected from chloro, fluoro, methyl, ethyl 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0165] According to another embodiment of the present invention in
the definition of R.sup.29, conveniently substituents are selected
from halogeno, C.sub.1-4alkyl, C.sub.1-4alkoxy and cyano, more
conveniently substituents are selected from chloro, fluoro, methyl
and ethyl.
[0166] Advantageously R.sup.54 and R.sup.55 are each independently
a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which cyclic group may bear
1 or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
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 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.1-3allyl).
[0167] Preferably R.sup.54 and R.sup.55 are each selected from
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl,
morpholino and thiomorpholino which group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0168] More preferably R.sup.54 and R.sup.55 are each selected from
pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and
thiomorpholino which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0169] Particularly R.sup.54 and R.sup.55 are each selected from
pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and
thiomorpholino which group may bear 1 or 2 substituents selected
from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0170] More particularly R.sup.54 and R.sup.55 are each selected
from pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino
and thiomorpholino which group is unsubstituted.
[0171] Conveniently R.sup.2 represents hydroxy, halogeno, cyano,
nitro, trifluoromethyl, C.sub.1-3alkyl, amino or R.sup.5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following twenty-two groups: [0172] 1)
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
fluoro, chloro and bromo, or C.sub.2-5alkyl which may be
unsubstituted or substituted with one or more groups selected from
hydroxy and amino; [0173] 2) C.sub.2-3alkylX.sup.2C(O)R.sup.11
(wherein X.sup.2 is as hereinbefore defined 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
are each C.sub.1-4alkyl or C.sub.1-2alkoxyethyl)); [0174] 3)
C.sub.2-4alkyl X.sup.3R.sup.16 (wherein X.sup.3 is as hereinbefore
defined 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.1-3alkoxy 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.1-4alkylamino, 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)); [0175] 4)
C.sub.2-3alkylX.sup.4C.sub.2-3alkylX.sup.3R.sup.22 (wherein X.sup.4
and X.sup.5 are as hereinbefore defined and R.sup.22 represents
hydrogen or C.sub.1-3alkyl); [0176] 5) R.sup.28 (wherein R.sup.28
is as defined hereinbefore); [0177] 6) C.sub.1-5alkylR.sup.107
(wherein R.sup.107 is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
heterocyclic group is linked to C.sub.1-5alkyl through a carbon
atom and 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.1-4alkylamino, 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)) or C.sub.2-5alkylR.sup.108 (wherein R.sup.108 is a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms, of
which one is N and the other may be selected independently from O,
S and N, which heterocyclic group is linked to C.sub.2-5alkyl
through a nitrogen atom and 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.1-4alkylamino, 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)); [0178] 7) C.sub.3-4alkenylR.sup.109 (wherein
R.sup.109 represents R.sup.108 or R.sup.108 as defined
hereinbefore); [0179] 8) C.sub.3-4alkynylR.sup.109 (wherein
R.sup.109 represents R.sup.107 or R.sup.108 as defined
hereinbefore); [0180] 9) R.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0181] 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29
is as defined hereinbefore); [0182] 11) C.sub.3-5alkenylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); [0183] 12)
C.sub.3-5alkynylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0184] 13) C.sub.1-5alkylX.sup.6R.sup.29 (wherein
X.sup.6 and R.sup.29 are as defined hereinbefore); [0185] 14)
C.sub.4-5alkenylX.sup.7R.sup.29 (wherein X.sup.7 and R.sup.29 are
as defined hereinbefore); [0186] 15)
C.sub.4-5alkynylX.sup.8R.sup.29 (wherein X.sup.8 and R.sup.29 are
as defined hereinbefore); [0187] 16)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.29 (wherein X.sup.9 and
R.sup.29 are as defined hereinbefore); [0188] 17)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0189] 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; [0190] 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; [0191] 20)
C.sub.2-5alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0192] 21)
C.sub.2-5alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0193] 22)
C.sub.1-3alkylR.sup.54(C.sub.1-3alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9, q, r, R.sup.54 and R.sup.55 are as defined
hereinbefore); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1-- may
bear one or more substituents selected from hydroxy, halogeno and
amino].
[0194] Advantageously R.sup.2 represents hydroxy, halogeno, cyano,
nitro, trifluoromethyl, C.sub.1-3alkyl, amino or R.sup.5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following twenty-two groups: [0195] 1)
C.sub.1-4alkyl which may be unsubstituted or which may be
substituted with one or more groups selected from fluoro, chloro
and bromo, or C.sub.2-5alkyl which may be unsubstituted or
substituted with one or more groups selected from hydroxy and
amino; [0196] 2) C.sub.2-3alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2
is as hereinbefore defined and R.sup.11 represents
--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 are each C.sub.1-4alkyl
or C.sub.1-2alkoxyethyl)); [0197] 3) C.sub.2-1alkylX.sup.3R.sup.16
(wherein X.sup.3 is as hereinbefore defined and R.sup.16 is a group
selected from C.sub.1-3alkyl, cyclopentyl, cyclohexyl,
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl, azetidinyl
and tetrahydropyranyl, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl,
piperazinyl, piperidinyl, imidazolidinyl, azetidinyl or
tetrahydropyranyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl,
C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3allyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl)); [0198] 4)
C.sub.2-3alkylX.sup.4C.sub.2-3alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 are as hereinbefore defined and R.sup.22 represents
hydrogen or C.sub.1-3alkyl); [0199] 5) R.sup.28 (wherein R.sup.28
is as defined hereinbefore); [0200] 6) C.sub.1-4alkylR.sup.110
(wherein R.sup.110 is a group selected from pyrrolidinyl,
piperazinyl, piperidinyl, imidazolidin-1-yl, azetidinyl,
1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and
1,3-dithian-2-yl, which group is linked to C.sub.1-4alkyl through a
carbon atom and which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl)) or
C.sub.2-4alkylR.sup.111 (wherein R.sup.111 is a group selected from
morpholino, thiomorpholino, azetidin-1-yl, pyrrolidin-1-yl,
piperazin-1-yl and piperidino which group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-3cyanoalkyl, C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl,
C.sub.1-3alkoxy, C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.sub.1-3alkyl, C.sub.1-3alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino,
C.sub.1-3alkylaminoC,-.sub.3alkyl,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl)); [0201] 7)
C.sub.3-4alkenylR.sup.112 (wherein R.sup.112 represents R.sup.110
or R.sup.111 as defined hereinbefore); [0202] 8)
C.sub.3-4alkynylR.sup.112 (wherein R.sup.112 represents R.sup.110
or R.sup.111 as defined hereinbefore); [0203] 9) R.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0204] 10)
C.sub.1-4akylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0205] 11) 1-R.sup.29prop-1-en-3-yl or
1-R.sup.29but-2-en-4-yl (wherein R.sup.29 is as defined
hereinbefore with the proviso that when R.sup.5 is
1-R.sup.29prop-1-en-3-yl, R.sup.29 is linked to the alkenyl group
via a carbon atom); [0206] 12) 1-R.sup.29prop-1-yn-3-yl or
1-R.sup.29but-2-yn-4-yl (wherein R.sup.29 is as defined
hereinbefore with the proviso that when R.sup.5 is
1-R.sup.29prop-1-yn-3-yl, R.sup.29 is linked to the alkynyl group
via a carbon atom); [0207] 13) C.sub.1-5alkylX.sup.6R.sup.29
(wherein X.sup.6 and R.sup.29 are as defined hereinbefore); [0208]
14) 1-(R.sup.29X.sup.7)but-2-en-4-yl (wherein X.sup.7 and R.sup.29
are as defined hereinbefore); [0209] 15)
1-(R.sup.29X.sup.8)but-2-yn-4-yl (wherein X.sup.8 and R.sup.29 are
as defined hereinbefore); [0210] 16)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.29 (wherein X.sup.9 and
R.sup.29 are as defined hereinbefore); [0211] 17)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0212] 18) C.sub.2-5alkenyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two 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; [0213] 19) C.sub.2-5alkynyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two 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; [0214] 20)
C.sub.2-4alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0215] 21)
C.sub.2-4alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0216] 22)
C.sub.1-3alkylR.sup.54(C.sub.1-3alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9, q, r, R.sup.54 and R.sup.55 are as defined
hereinbefore); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1-- may
bear one or more substituents selected from hydroxy, halogeno and
amino].
[0217] Preferably R.sup.2 represents hydroxy, halogeno, nitro,
trifluoromethyl, C.sub.1-3alkyl, cyano, amino or R5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following twenty groups: [0218] 1) C.sub.1-3alkyl
which may be unsubstituted or which may be substituted with one or
more groups selected from fluoro, chloro and bromo, or
C.sub.2-3alkyl which may be unsubstituted or substituted with one
or more groups selected from hydroxy and amino; [0219] 2)
2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,
2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,
3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,
3-(N,N-dimethylcarbamoyloxy)propyl, 2-N-methylcarbamoyloxy)ethyl,
3-N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,
3-(carbamoyloxy)propyl, or
2-N-methyl-N-(butoxycarbonyl)amino)ethyl; [0220] 3)
C.sub.2-3alkylX.sup.3R.sup.16 (wherein X.sup.3 is as hereinbefore
defined and R.sup.16 is a group selected from C.sub.1-3alkyl,
cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl,
azetidinyl, imidazolidinyl and tetrahydropyranyl which group is
linked to X.sup.3 through a carbon atom and which C.sub.1-3alkyl
group may bear 1 or 2 substituents selected from hydroxy, halogeno
and C.sub.1-2alkoxy and which cyclopentyl, cyclohexyl,
pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, imidazolidinyl
or tetrahydropyranyl group may bear one substituent selected from
oxo, hydroxy, halogeno, cyano, C.sub.1-2cyanoalkyl, C.sub.1-2alkyl,
C.sub.1-2hydroxyalkyl, C.sub.1-2alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.sub.1-3alkyl, C.sub.1-2alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino,
C.sub.1-3alkylaminoC.sub.1-3alkyl,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino)); [0221] 4)
C.sub.2-3alkylX.sup.4C.sub.2-3alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 are as hereinbefore defined and R.sup.22 represents
hydrogen or C.sub.1-2alkyl); [0222] 5) R.sup.28 (wherein R.sup.28
is as defined hereinbefore); [0223] 6) C.sub.1-3alkylR.sup.110
(wherein R.sup.110 is a group selected from pyrrolidinyl,
piperazinyl, piperidinyl, azetidinyl, imidazolidinyl,
1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and
1,3-dithian-2-yl, which group is linked to C.sub.1-3alkyl through a
carbon atom and which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-2cyanoalkyl,
C.sub.1-2alkyl, C.sub.1-2hydroxyalkyl, C.sub.1-2alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.sub.1-3alkyl, C.sub.1-2alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino,
C.sub.1-3alkylaminoC.sub.1-3alkyl,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino)) or C.sub.2-3alkylR.sup.111 (wherein
R.sup.111 is a group selected from morpholino, thiomorpholino,
azetidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl and piperidino which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, cyano, C.sub.1-2cyanoalkyl, C.sub.1-2alkyl,
C.sub.1-2hydroxyalkyl, C.sub.1-2alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.sub.1-3alkyl, C.sub.1-2alkoxycarbonyl,
C.sub.1-3alkylamino, di(C.sub.1-3alkyl)amino,
C.sub.1-3alkylaminoC.sub.1-3alkyl,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino)); [0224] 7) R.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0225] 8)
C.sub.1-4alkylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0226] 9) 1-R.sup.29but-2-en-4-yl (wherein R.sup.29
is as defined hereinbefore); [0227] 10) 1-R.sup.29but-2-yn-4-yl
(wherein R.sup.29 is as defined hereinbefore); [0228] 11)
C.sub.1-3alkylX.sup.6R.sup.29 (wherein X.sup.6 and R.sup.29 are as
defined hereinbefore); [0229] 12) 1-(R.sup.29X.sup.7)but-2-en-4-yl
(wherein X.sup.7 and R.sup.29 are as defined hereinbefore); [0230]
13) 1-(R.sup.29X.sup.8)but-2-yn-4-yl (wherein X.sup.8 and R.sup.29
are as defined hereinbefore); [0231] 14)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.29 (wherein X.sup.9 and
R.sup.29 are as defined hereinbefore); [0232] 15)
C.sub.2-3alkylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0233] 16) C.sub.2-5alkenyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two 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; [0234] 17) C.sub.2-5alkynyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two 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; [0235] 18)
C.sub.2-3alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0236] 19)
C.sub.2-3alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0237] 20)
C.sub.1-3alkylR.sup.54(C.sub.1-3alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9, q, r, R.sup.54 and R.sup.55 are as defined
hereinbefore); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1-- may
bear one or more substituents selected from hydroxy, halogeno and
amino].
[0238] More preferably R.sup.2 represents 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, 3-(methylamino)propyl,
2-(ethylamino)ethyl, 3-(ethylamino)propyl,
2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,
2-(N,N-diethylamino)ethyl, 3-(N,N-diethylamino)propyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,
2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,
2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, 2-(piperidin-2-yl)ethyl,
3-(piperidin-2-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidin-4-yl)ethyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperdine-4yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidin-4-yl)propyl,
(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,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-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, 3-(piperazin-1-yl)propyl,
(pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl,
3-(pyrrolidin-1-yl)propyl,
(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-acetamnidothiazol-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-(4-methylpiperazin-1-yl)propyl,
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,
2-((N-methyl-N-4-pyridyl)amino)ethyl, 3-(4oxidomorpholino)propyl,
2-(2-4-methylpiperazin-1-yl)ethoxymethyl,
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-pyrrolidinylethyl)piperidin-4-ylmethyl,
1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,
1-(2-piperidinylethyl)piperidin-4-ylmethyl,
1-(3-piperidinylpropyl)piperidin-4-ylmethyl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(3-morpholinopropyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,
1-(2-azetidinylethyl)piperidin-4-ylmethyl or
1-(3-azetidinylpropyl)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-pyrrolidin-1-yl-2-hydroxypropyl,
(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,
(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
3-((N,N-diethylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,
(2S)-3-((N,N-diethylamino)-2-hydroxypropyl,
3-(isopropylamino)-2-hydroxypropyl,
(2R)-3-(isopropylamino)-2-hydroxypropyl,
(2S)-3-(isopropylamino)-2-hydroxypropyl,
3-(N,N-diisopropylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or
(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].
[0239] Particularly R.sup.2 represents C.sub.1-3alkyl, amino or
R.sup.5X.sup.1-- [wherein X.sup.1 is as hereinbefore defined and
R.sup.5 represents 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, 3-(methylamino)propyl, 2-(ethylamino)ethyl,
3-(ethylamino)propyl, 2-(N,N-dimethylamino)ethyl,
3-(N,N-dimethylamino)propyl, 2-(N,N-diethylamino)ethyl,
3-(N,N-diethylamino)propyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,
2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,
2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-(2-methylsulphonyl)ethylpiperidino)ethyl,
3-(2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-piperidin-4yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, 2-(piperidin-2-yl)ethyl,
3-(piperidin-2-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidin-4-yl)ethyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidin-4-yl)propyl,
(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,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-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, 3-(piperazin-1-yl)propyl,
(pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl,
3-(pyrrolidin-1-yl)propyl,
(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-metliyltliazol-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-(4-methylpiperazin-1-yl)propyl,
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,
2-((N-methyl-N-4-pyridyl)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-pyrrolidinylethyl)piperidin-4-ylmethyl,
1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,
1-(2-piperidinylethyl)piperidin-4-ylmethyl,
1-(3-piperidinylpropyl)piperidin-4-ylmethyl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(3-morpholinopropyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,
1-(2-azetidinylethyl)piperidin-4-ylmethyl or
1-(3-azetidinylpropyl)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-pyrrolidin-1-yl-2-hydroxypropyl,
(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,
(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
3-(N,N-diethylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,
(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,
3-(isopropylamino)-2-hydroxypropyl,
(2R)-3-(isopropylamino)-2-hydroxypropyl,
(2S)-3-(isopropylamino)-2-hydroxypropyl,
3-(N,N-diisopropylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or
(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].
[0240] More particularly R.sup.2 represents C.sub.1-3alkyl, amino
or R.sup.5X.sup.1-- [wherein X.sup.1 is as hereinbefore defined and
R.sup.5 represents ethyl, 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, 3-methylamino)propyl,
2-(ethylamino)ethyl, 3-(ethylamino)propyl,
2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,
2-(N,N-diethylamino)ethyl, 3-(N,N-diethylamino)propyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,
2-(methylpiperidino)ethyl, 3-(methylpiperidino)propyl,
2-(ethylpiperidino)ethyl, 3-(ethylpiperidino)propyl,
2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, 2-(piperidin-2-yl)ethyl,
3-(piperidin-2-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidin-4-yl)ethyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidin-4-yl)propyl,
(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,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-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, 3-(piperazin-1-yl)propyl,
(pyrrolidin-2-yl)methyl, 2-(pyrrolidin-1-yl)ethyl,
3-(pyrrolidin-1-yl)propyl,
(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-(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-(4-methylpiperazin-1-yl)propyl,
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-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
2-((N-methyl-N-4-pyridyl)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-pyrrolidinylethyl)piperidin-4-ylmethyl,
1-(3-pyrrolidinylpropyl)piperidin-4-ylmethyl,
1-(2-piperidinylethyl)piperidin-ylmethyl,
1-(3-piperidinylpropyl)piperidin-4-ylmethyl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(3-morpholinopropyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
1-(3-thiomorpholinopropyl)piperidin-4-ylmethyl,
1-(2-azetidinylethyl)piperidin-4-ylmethyl or
1-(3-azetidinylpropyl)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-pyrrolidin-1-yl-2-hydroxypropyl,
(2R)-3-pyrrolidin-1-yl-2-hydroxypropyl,
(2S)-3-pyrrolidin-1-yl-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
3-(N,N-diethylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diethylamino)-2-hydroxypropyl,
(2S)-3-(N,N-diethylamino)-2-hydroxypropyl,
3-(isopropylamino)-2-hydroxypropyl,
(2R)-3-(isopropylamino)-2-hydroxypropyl,
(2S)-3-(isopropylamino)-2-hydroxypropyl,
3-(N,N-diisopropylamino)-2-hydroxypropyl,
(2R)-3-(N,N-diisopropylamino)-2-hydroxypropyl or
(2S)-3-(N,N-diisopropylamino)-2-hydroxypropyl].
[0241] In another aspect R.sup.2 represents ethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy,
3-hydroxypropoxy, 2-methoxyethoxy, 3-methoxypropoxy,
2-(methylsulphinyl)ethoxy, 2-(methylsulphonyl)ethoxy,
2-(ethylsulphinyl)ethoxy, 2-(ethylsulphonyl)ethoxy,
2(N,N-dimethylsulphamoyl)ethoxy, 2-(N-methylsulphamoyl)ethoxy,
2-sulphamoylethoxy, 2-(methylamino)ethoxy, 3-(methylamino)propoxy,
2-(ethylamino)ethoxy, 3-(ethylamino)propoxy,
2-(N,N-dimethylamino)ethoxy, 3(N,N-dimethylamino)propoxy,
2-(N,N-diethylamino)ethoxy, 3-(N,N-diethylamino)propoxy,
2-(N-methyl-N-methylsulphonylamino)ethoxy,
3-(N-methyl-N-methylsulphonylamino)propoxy, 2-morpholinoethoxy,
3-morpholinopropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,
2-(methylpiperidino)ethoxy, 3-(methylpiperidino)propoxy,
2-(ethylpiperidino)ethoxy, 3-(ethylpiperidino)propoxy,
2-((2-methoxyethyl)piperidino)ethoxy,
3-((2-methoxyethyl)piperidino)propoxy,
2-((2-methylsulphonyl)ethylpiperidino)ethoxy,
3-((2-methylsulphonyl)ethylpiperidino)propoxy,
piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
2-(piperidin-3-yl)ethoxy, 2-(piperidin-4-yl)ethoxy,
3-(piperidin-3-yl)propoxy, 3-(piperidin-4-yl)propoxy,
2-(piperidin-2-yl)ethoxy, 3-(piperidin-2-yl)propoxy,
(1-methylpiperidin-3-yl)methoxy, (1-methylpiperidin-4-yl)methoxy,
(1-cyanomethylpiperidin-3-yl)methoxy,
(1-cyanomethylpiperidin-4-yl)methoxy,
2-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4-yl)ethoxy,
2-(1-cyanomethylpiperidin-3-yl)ethoxy,
2-(1-cyanomethylpiperidin-4-yl)ethoxy,
3-(methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)propoxy,
3-(1-cyanomethylpiperidin-3-yl)propoxy,
3-(1-cyanomethylpiperidin-4-yl)propoxy,
2-(ethylpiperidin-3-yl)ethoxy, 2-(ethylpiperidin-4-yl)ethoxy,
3-(ethylpiperidin-3-yl)propoxy, 3-(ethylpiperidin-4-yl)propoxy,
((2-methoxyethyl)piperidin-3-yl)methoxy,
((2-methoxyethyl)piperidin-4-yl)methoxy,
2-((2-methoxyethyl)piperidin-3-yl)ethoxy,
2-((2-methoxyethyl)piperidin-4-yl)ethoxy,
3-((2-methoxyethyl)piperidin-3-yl)propoxy,
3-((2-methoxyethyl)piperidin-4-yl)propoxy,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methoxy,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,
3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,
3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,
1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,
1-isopropylpiperidin-4-ylmethoxy,
2-(1-isopropylpiperidin-2-yl)ethoxy,
2-(1-isopropylpiperidin-3-yl)ethoxy,
2-(1-isopropylpiperidin-4-yl)ethoxy,
3-(1-isopropylpiperidin-2-yl)propoxy,
3-(1-isopropylpiperidin-3-yl)propoxy,
3-(1-isopropylpiperidin-4-yl)propoxy, 2-(piperidin-4-yloxy)ethoxy,
3-(piperidin-4-yloxy)propoxy,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethoxy,
3-(1-(cyanomethyl)piperidin-4-yloxy)propoxy,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propoxy,
2-(piperazin-1-yl)ethoxy, 3-(piperazin-1-yl)propoxy,
(pyrrolidin-2-yl)methoxy, 2-(pyrrolidin-1-yl)ethoxy,
3-(pyrrolidin-1-yl)propoxy,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,
(1,3-dioxolan-2-yl)methoxy, 2-(1,3-dioxolan-2-yl)ethoxy,
2-(2-methoxyethylamino)ethoxy,
2-(N-(2-methoxyethyl)-N-methylamino)ethoxy,
2-(2-hydroxyethylamino)ethoxy, 3-(2-methoxyethylamino)propoxy,
3-(N-(2-methoxyethyl)-N-methylamino)propoxy,
3-(2-hydroxyethylamino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy,
2-(1,2,3-triazol-2-yl)ethoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
2-(1,2,4-triazol-4-yl)ethoxy, 4-pyridylmethoxy,
2-(4-pyridyl)ethoxy, 3-(4-pyridyl)propoxy, 2-(4-pyridyloxy)ethoxy,
2-(4-pyridylamino)ethoxy, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy,
2-(2-oxo-imidazolidin-1-yl)ethoxy,
3-(2-oxo-imidazolidin-1-yl)propoxy, 2-thiomorpholinoethoxy,
3-thiomorpholinopropoxy, 2-(1,1-dioxothiomorpholino)ethoxy,
3-(1,1-dioxothiomorpholino)propoxy, 2-(2-methoxyethoxy)ethoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy, 3-(methylsulphinyl)propoxy,
3-(methylsulphonyl)propoxy, 3-(ethylsulphinyl)propoxy,
3-(ethylsulphonyl)propoxy, 2-(5-methyl-1,2,4-triazol-1-yl)ethoxy,
2-((N-(3-morpholinopropylsulphonyl)N-methyl)amino)ethoxy,
2-((N-methyl-N-4-pyridyl)amino)ethoxy,
3-(4-oxidomorpholino)propoxy,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propoxy,
2-(2-morpholinoethoxy)ethoxy, 3-(2-morpholinoethoxy)propoxy,
2-(tetrahydropyran-4-yloxy)ethoxy,
3-(tetrahydropyran-4-yloxy)propoxy,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yloxy,
1-(2-pyrrolidinylethyl)piperidin-4-ylmethoxy,
1-(3-pyrrolidinylpropyl)piperidin-4-ylmethoxy,
1-(2-piperidinylethyl)piperidin-4-ylmethoxy,
1-(3-piperidinylpropyl)piperidin-4-ylmethoxy,
1-(2-morpholinoethyl)piperidin-4-ylmethoxy,
1-(3-morpholinopropyl)piperidin-4-ylmethoxy,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethoxy,
1-(3-thiomorpholinopropyl)piperidin-4-ylmethoxy,
1-(2-azetidinylethyl)piperidin-4-ylmethoxy or
1-(3-azetidinylpropyl)piperidin-4-ylmethoxy,
3-morpholino-2-hydroxypropoxy, (2R)-3-morpholino-2-hydroxypropoxy,
(2S)-3-morpholino-2-hydroxypropoxy, 3-piperidino-2-hydroxypropoxy,
(2R)-3-piperidino-2-hydroxypropoxy,
(2S)-3-piperidino-2-hydroxypropoxy,
3-pyrrolidin-1-yl-2-hydroxypropoxy,
(2R)-3-pyrrolidin-1-yl-2-hydroxypropoxy,
(2S)-3-pyrrolidin-1-yl-2-hydroxypropoxy,
3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropoxy,
(2S)-3-1(-methylpiperazin-4-yl)-2-hydroxypropoxy,
3-(N,N-diethylamino)-2-hydroxypropoxy,
(2R)-3-(N,N-diethylamino)-2-hydroxypropoxy,
(2S)-3-(N,N-diethylamino)-2-hydroxypropoxy,
3-(isopropylamino)-2-hydroxypropoxy,
(2R)-3-(isopropylamino)-2-hydroxypropoxy,
(2S)-3-(isopropylamino)2-hydroxypropoxy,
3-(N,N-diisopropylamino)-2-hydroxypropoxy,
(2R)-3-(N,N-diisopropylamino)-2-hydroxypropoxy or
(2S)-3-(N,N-diisopropylamino)-2-hydroxypropoxy.
[0242] According to another aspect of the present invention
conveniently R.sup.2 represents hydroxy, halogeno, nitro,
trifluoromethyl, C.sub.1-3alkyl, cyano, amino or R.sup.5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following twenty-one groups: [0243] 1)
C.sub.1-5alkyl which may be unsubstituted or substituted with one
or more fluorine atoms, or C.sub.2-5alkyl which may be
unsubstituted or substituted with one or more groups selected from
hydroxy and amino; [0244] 2) C.sub.2-3alkylX.sup.2C(O)R.sup.11
(wherein X.sup.2 is as hereinbefore defined 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
are each C.sub.1-2alkyl or C.sub.1-2alkoxyethyl)); [0245] 3)
C.sub.2-4alkylX.sup.3R.sup.16 (wherein X.sup.3 is as hereinbefore
defined 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.1-3alkoxy and which cyclic
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and
C.sub.1-4alkoxy); [0246] 4)
C.sub.2-3alkylX.sup.4C.sub.2-3alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 are as hereinbefore define and R.sup.22 represents
hydrogen or C.sub.1-3alkyl); [0247] 5) C.sub.1-5alkylR.sup.129
(wherein R.sup.129 is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
heterocyclic group is linked to C.sub.1-5alkyl through a carbon
atom and 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 and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl) or C.sub.2-5alkylR.sup.130
(wherein R.sup.130 is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms of which one is N and the other is selected
independently from O, S and N, which heterocyclic group is linked
to C.sub.2-5alkyl through a nitrogen atom and 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 and
C.sub.1-4alkylsulphonylC.sub.1-4alkyl); [0248] 6)
C.sub.3-4alkenylR.sup.131 (wherein R.sup.131 represents R.sup.129
or R.sup.130 as defined hereinbefore); [0249] 7)
C.sub.3-4alkynylR.sup.131 (wherein R.sup.131 represents R.sup.129
or R.sup.130 as defined hereinbefore); [0250] 8) R.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0251] 9)
C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0252] 10) C.sub.3-5alkenylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0253] 11)
C.sub.3-5alkynylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0254] 12) C.sub.1-5alkylX.sup.6X.sup.29 (wherein
X.sup.6 and R.sup.29 are as defined hereinbefore); [0255] 13)
C.sub.4-5alkenylX.sup.7R.sup.29 (wherein X.sup.7 and R.sup.29 are
as defined hereinbefore); [0256] 14)
C.sub.4-5alkynylX.sup.8R.sup.29 (wherein X.sup.8 and R.sup.29 are
as defined hereinbefore); [0257] 15)
C.sub.2-3alkylX.sup.9C.sub.1-2alkylR.sup.29 (wherein X.sup.9 and
R.sup.29 are as defined hereinbefore); [0258] 16) R.sup.28 (wherein
R.sup.28 is as defined hereinbefore); [0259] 17)
C.sub.2-3alkylX.sup.9C.sub.1-2alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0260] 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; [0261] 19) C.sub.2-5alkynyl
which may be unsubstituited 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; [0262] 20)
C.sub.2-5alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0263] 21)
C.sub.2-5alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore)].
[0264] According to another aspect of the present invention
advantageously R.sup.2 represents hydroxy, halogeno, nitro,
trifluoromethyl, C.sub.1-3alkyl, cyano, amino or R.sup.5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following twenty-one groups: [0265] 1)
C.sub.1-4alkyl which may be unsubstituted or substituted with one
or more fluorine atoms, or C.sub.2-4alkyl which may be
unsubstituted or substituted with 1 or 2 groups selected from
hydroxy and amino; [0266] 2) C.sub.2-3alkylX.sup.2C(O)R.sup.11
(wherein X.sup.2 is as hereinbefore defined and R.sup.11 represents
--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 are each C.sub.1-2alkyl
or C.sub.1-2alkoxyethyl)); [0267] 3) C.sub.2-4alkylX.sup.3R.sup.16
(wherein X.sup.3 is as hereinbefore defined and R.sup.16 is a group
selected from C.sub.1-3alkyl, cyclopentyl, cyclohexyl,
pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is
linked to X.sup.3 through a carbon atom and which C.sub.1-3alkyl
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno and C.sub.1-2alkoxy and which cyclopentyl, cyclohexyl,
pyrrolidinyl or piperidinyl group may carry one substituent
selected from oxo, hydroxy, halogeno, C.sub.1-2alkyl,
C.sub.1-2hydroxyalkyl and C.sub.1-2alkoxy); [0268] 4)
C.sub.2-3alkylX.sup.4 C.sub.2-3alkylX.sup.5R.sup.22 (wherein
X.sup.4 and X.sup.5 are as hereinbefore defined and R.sup.22
represents hydrogen or C.sub.1-3alkyl); [0269] 5)
C.sub.1-4alkylR.sup.132 (wherein R.sup.132 is a group selected from
pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl,
1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which
group is linked to C.sub.1-4alkyl through a carbon atom and which
group may carry 1 or 2 substituents selected from oxo, hydroxy,
halogeno, 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.1-3alkyl) or C.sub.2-4alkylR.sup.133
(wherein R.sup.133 is a group selected from morpholino,
thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino
which group may carry 1 or 2 substituents selected from oxo,
hydroxy, halogeno, 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.1-3alkyl); [0270] 6)
C.sub.3-4alkenylR.sup.134 (wherein R.sup.134 represents R.sup.132
or R.sup.133 as defined hereinbefore); [0271] 7)
C.sub.3-4alkynylR.sup.134 (wherein R.sup.134 represents R.sup.132
or R.sup.133 as defined hereinbefore); [0272] 8) R.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0273] 9)
C.sub.1-4alkylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0274] 10) 1-R.sup.29prop-1-en-3-yl or
1-R.sup.29but-2-en-4-yl (wherein R.sup.29 is as defined
hereinbefore with the proviso that when R.sup.5 is
1-R.sup.29prop-1-en-3-yl, R.sup.29 is linked to the alkenyl group
via a carbon atom); [0275] 11) 1-R.sup.29prop-1-yn-3-yl or
1-R.sup.29but-2-yn-4-yl (wherein R.sup.29 is as defined
hereinbefore with the proviso that when R.sup.5 is
1-R.sup.29prop-1-yn-3-yl, R.sup.29 is linked to the alkynyl group
via a carbon atom); [0276] 12) C.sub.1-5alkylX.sup.6R.sup.29
(wherein X.sup.6 and R.sup.29 are as defined hereinbefore); [0277]
13) 1-(R.sup.29X.sup.7)but-2-en-4-yl (wherein X.sup.7 and R.sup.29
are as defined hereinbefore); [0278] 14)
1-(R.sup.29X.sup.8)but-2-yn-4-yl (wherein X.sup.8 and R.sup.29 are
as defined hereinbefore); [0279] 15)
C.sub.2-3alkylX.sup.9C.sub.1-2alkylR.sup.29 (wherein X.sup.9 and
R.sup.29 are as defined hereinbefore); [0280] 16) R.sup.28 (wherein
R.sup.28 is as defined hereinbefore); [0281] 17)
C.sub.2-3alkylX.sup.9C.sub.1-2alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0282] 18) C.sub.2-5alkenyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two groups selected from
hydroxy, 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; [0283] 19) C.sub.2-5alkynyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two groups selected from
hydroxy, 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; [0284] 20)
C.sub.2-4alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0285] 21)
C.sub.2-4alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore)].
[0286] According to another aspect of the present invention
preferably R.sup.2 represents hydroxy, halogeno, nitro,
trifluoromethyl, C.sub.1-3alkyl, cyano, amino or R.sup.5X.sup.1--
[wherein X.sup.1 is as hereinbefore defined and R.sup.5 is selected
from one of the following nineteen groups: [0287] 1) C.sub.1-3alkyl
which may be unsubstituted or substituted with one or more fluorine
atoms, or C.sub.2-3alkyl which may be unsubstituted or substituted
with 1 or 2 groups selected from hydroxy and amino; [0288] 2)
2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,
2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,
3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,
3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,
3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,
3-(carbamoyloxy)propyl; [0289] 3) C.sub.2-3alkylX.sup.3R.sup.16
(wherein X.sup.3 is as defined hereinbefore and R.sup.16 is a group
selected from C.sub.1-2alkyl, cyclopentyl, cyclohexyl,
pyrrolidinyl, piperidinyl and tetrahydropyranyl which group is
linked to X.sup.3 through a carbon atom and which C.sub.1-2alkyl
group may bear 1 or 2 substituents selected from hydroxy, halogeno
and C.sub.1-2alkoxy and which cyclopentyl, cyclohexyl, pyrrolidinyl
or piperidinyl group may carry one substituent selected from oxo,
hydroxy, halogeno, C.sub.1-2alkyl, C.sub.1-2hydroxyalkyl and
C.sub.1-2alkoxy); [0290] 4)
C.sub.2-3alkylX.sup.4C.sub.2-3alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 are as hereinbefore defined and R.sup.22 represents
hydrogen or C.sub.1-2alkyl); [0291] 5) C.sub.1-2alkylR.sup.132
(wherein R.sup.132 is a group selected from pyrrolidinyl,
piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,
1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to
C.sub.1-2alkyl through a carbon atom and which group may carry one
substituent selected from oxo, hydroxy, halogeno, 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.1-3alkyl) or C.sub.2-3alkylR.sup.133
(wherein R.sup.133 is a group selected from morpholino,
thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl
which group may carry one or two substituents selected from oxo,
hydroxy, halogeno, 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.1-3alkyl); [0292] 6) R.sup.29 (wherein
R.sup.29 is as defined hereinbefore); [0293] 7)
C.sub.1-4alkylR.sup.29 (wherein R.sup.29 is as defined
hereinbefore); [0294] 8) 1-R.sup.29but-2-en-4-yl (wherein R.sup.29
is as defined hereinbefore); [0295] 9) 1-R.sup.29but-2-yn-4-yl
(wherein R.sup.29 is as defined hereinbefore); [0296] 10)
C.sub.1-5alkylX.sup.6R.sup.29 (wherein X.sup.6 and R.sup.29 are as
defined hereinbefore); [0297] 11) 1-R.sup.29X.sup.7)but-2-en-4-yl
(wherein X.sup.7 and R.sup.29 are as defined hereinbefore); [0298]
12) 1-(R.sup.29X.sup.8)but-2-yn-4-yl (wherein X.sup.8 and R.sup.29
are as defined hereinbefore); [0299] 13) ethylX.sup.9methylR.sup.29
(wherein X.sup.9 and R.sup.29 are as defined hereinbefore); [0300]
14) R.sup.28 (wherein R.sup.28 is as defined hereinbefore); [0301]
15) ethylX.sup.9C.sub.1-2alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); [0302] 16) C.sub.2-5alkenyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two groups selected from
hydroxy, 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; [0303] 17) C.sub.2-5alkynyl
which may be unsubstituted or which may be substituted with one or
more fluorine atoms or with one or two groups selected from
hydroxy, 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; [0304] 18)
C.sub.2-3alkenylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and [0305] 19)
C.sub.2-3alkynylX.sup.9C.sub.1-3alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore)].
[0306] According to another aspect of the present invention more
preferably R.sup.2 represents 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-(N,N-dimethylsulphamoyl)ethyl,
2-N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,
2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,
2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,
3-piperidinopropyl, 2-methylpiperidino)ethyl,
3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,
3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-(2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidinyl)ethyl, 2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidinyl)propyl,
(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)piperidinyl)propyl,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,
3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,
2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,
(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-acetamidothiazolylmethyl, 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-thiomorpholinoethyl, 3-thiomorpholinopropyl,
2-1,1-dioxothiomorpholino)ethyl, 3-(1,1-dioxothiomorpholino)propyl,
2-(2-methoxyethoxy)ethyl, 2-(4-methylpiperazin-1-yl)ethyl,
3-4-methylpiperazin-1-yl)propyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)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,
2-((N-methyl-N-4-pyridyl)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 or
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].
[0307] According to another aspect of the present invention
particularly R.sup.2 represents C.sub.1-3alkyl, amino or
R.sup.5X.sup.1-- [wherein X.sup.1 is as hereinbefore defined and
R.sup.5 represents ethyl, benzyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,
2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,
2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,
2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,
2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,
3-piperidinopropyl, 2-(methylpiperidino)ethyl,
3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,
3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidin-4-yl)ethyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl, yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidin-4yl)propyl,
(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-4yl)propyl,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,
3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,
2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,
(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-thiomorpholinoethyl, 3-thiomorpholinopropyl,
2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,
3-(methylsulphinyl)propyl, 3-(methylsulphonyl)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,
2-((N-methyl-N-4-pyridyl)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 or
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].
[0308] According to another aspect of the present invention more
particularly R.sup.2 represents C.sub.1-3alkyl, amino or
R.sup.5X.sup.1-- [wherein X.sup.1 is as hereinbefore defined and
R.sup.5 represents ethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,
2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,
2-(N,N-dimethylsulpharnoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,
2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,
3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,
2-piperidinoethyl, 3-piperidinopropyl, 2-(methylpiperidino)ethyl,
3-(methylpiperidino)propyl, 2-(ethylpiperidino)ethyl,
3-(ethylpiperidino)propyl, 2-((2-methoxyethyl)piperidino)ethyl,
3-((2-methoxyethyl)piperidino)propyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl, piperidin-3-ylmethyl,
piperidin-4-ylmethyl, 2-(piperidin-3-yl)ethyl,
2-(piperidin-4-yl)ethyl, 3-(piperidin-3-yl)propyl,
3-(piperidin-4-yl)propyl, (1-methylpiperidin-3-yl)methyl,
(1-methylpiperidin-4-yl)methyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl, 2-(methylpiperidin-3-yl)ethyl,
2-(methylpiperidin-4-yl)ethyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(methylpiperidin-3-yl)propyl, 3-(methylpiperidin-4-yl)propyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
2-(ethylpiperidin-3-yl)ethyl, 2-(ethylpiperidin-4-yl)ethyl,
3-(ethylpiperidin-3-yl)propyl, 3-(ethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
2-((2-methoxyethyl)piperidin-3-yl)ethyl,
2-((2-methoxyethyl)piperidin-4-yl)ethyl,
3-((2-methoxyethyl)piperidin-3-yl)propyl,
3-((2-methoxyethyl)piperidin-4-yl)propyl,
(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)piperidinyl)propyl,
1-isopropylpiperidin-2-ylmethyl, 1-isopropylpiperidin-3-ylmethyl,
1-isopropylpiperidin-4-ylmethyl,
2-(1-isopropylpiperidin-2-yl)ethyl,
2-(1-isopropylpiperidin-3-yl)ethyl,
2-(1-isopropylpiperidin-4-yl)ethyl,
3-(1-isopropylpiperidin-2-yl)propyl,
3-(1-isopropylpiperidin-3-yl)propyl,
3-(1-isopropylpiperidin-4-yl)propyl, 2-(piperazin-1-yl)ethyl,
3-(piperazin-1-yl)propyl, (pyrrolidin-2-yl)methyl,
2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,
(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-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,
3-(methylsulphinyl)propyl, 3-(methylsulphonyl)propyl, morpholino,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
2-((N-methyl-N-4-pyridyl)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 or
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl].
[0309] According to another embodiment of the present invention in
another aspect R.sup.2 represents methoxy, 2-methoxyethoxy,
2-(2-methoxyethoxy)ethoxy, 3-methoxypropoxy,
2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, benzyloxy,
2-(tetrahydropyran-4-yloxy)ethoxy,
3-(tetrahydropyran-4-yloxy)propoxy,
2-(4-methylpiperazin-1-yl)ethoxy,
3-(4-methylpiperazin-1-yl)propoxy, 2-morpholinoethoxy,
3-morpholinopropoxy, 2-(imidazol-1-yl)ethoxy,
3-(imidazol-1-yl)propoxy 2-(1,1-dioxothiomorpholino)ethoxy,
3-(1,1-dioxothiomorpholino)propoxy, 2-(1,2,3-triazol-1-yl)ethoxy,
3-(1,2,3-triazol-1-yl)propoxy, 2-(1,2,4-triazol-1-yl)ethoxy,
2-((N-methyl-N-4-pyridyl)amino)ethoxy, 2-(N,N-dimethylamino)ethoxy,
3-(N,N-dimethylamino)propoxy,
2-(N-methoxyacetyl-N-methylamino)ethoxy,
3-(N-methoxyacetyl-N-methylamino)propoxy,
1-methylpiperidin-3-ylmethoxy, 1-methylpiperidin-4-ylmethoxy,
(1-cyanomethylpiperidin-3-yl)methoxy,
(1-cyanomethylpiperidin-4-yl)methoxy,
2-(1-cyanomethylpiperidin-3-yl)ethoxy,
2-(1-cyanomethylpiperidin-4-yl)ethoxy,
3-(1-cyanomethylpiperidin-3-yl)propoxy,
3-(1-cyanomethylpiperidin-4-yl)propoxy,
((2-methoxyethyl)piperidin-3-yl)methoxy,
((2-methoxyethyl)piperidin-4-yl)methoxy,
2-(N-(2-methoxyethyl)-N-methylamino)ethoxy,
4-(pyrrolidin-1-yl)but-2-en-yloxy, 2-(2-oxopyrrolidin-1-yl)ethoxy,
3-(2-oxopyrrolidin-1-yl)propoxy, (pyrrolidin-2-yl)methoxy,
2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,
2-(2-(pyrrolidin-1-yl)ethoxy)ethoxy,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 2-piperidinoethoxy,
3-piperidinopropoxy, 2-(methylpiperidino)ethoxy,
3-(methylpiperidino)propoxy, 2-(ethylpiperidino)ethoxy,
3-(ethylpiperidino)propoxy, 2-((2-methoxyethyl)piperidino)ethoxy,
3-((2-methoxyethyl)piperidino)propoxy,
1-(2-methylsulphonylethyl)piperidin-3-ylmethoxy,
1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy,
2-(2-methylsulphonyl)ethylpiperidino)ethoxy,
3-((2-methylsulphonyl)ethylpiperidino)propoxy,
piperidin-3-ylmethoxy, piperidin-4-ylmethoxy,
2-piperidin-3-yl)ethoxy, 2-(piperidin-4-yl)ethoxy,
3-(piperidin-3-yl)propoxy, 3-(piperidin-4-yl)propoxy,
2-(methylpiperidin-3-yl)ethoxy, 2-(methylpiperidin-4-yl)ethoxy,
3-(methylpiperidin-3-yl)propoxy, 3-(methylpiperidin-4-yl)propoxy,
2-(ethylpiperidin-3-yl)ethoxy, 2-(ethylpiperidin-4-yl)ethoxy,
3-(ethylpiperidin-3-yl)propoxy, 3-(ethylpiperidin-4-yl)propoxy,
2-((2-methoxyethyl)piperidin-3-yl)ethoxy,
2-((2-methoxyethyl)piperidin-4-yl)ethoxy,
3-((2-methoxyethyl)piperidin-3-yl)propoxy,
3-((2-methoxyethyl)piperidin-4-yl)propoxy,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethoxy,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethoxy,
3-((2-methylsulphonylethyl)piperidin-3-yl)propoxy,
3-((2-methylsulphonylethyl)piperidin-4-yl)propoxy,
1-isopropylpiperidin-2-ylmethoxy, 1-isopropylpiperidin-3-ylmethoxy,
1-isopropylpiperidin-4-ylmethoxy,
2-(1-isopropylpiperidin-2-yl)ethoxy,
2-(1-isopropylpiperidin-3-yl)ethoxy,
2-(1-isopropylpiperidin-4-yl)ethoxy,
3-(1-isopropylpiperidin-2-yl)propoxy,
3-(1-isopropylpiperidin-3-yl)propoxy,
3-(1-isopropylpiperidin-4-yl)propoxy,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethoxy, 3-(2-(4-
methylpiperazin-1-yl)ethoxy)propoxy, 2-(2-morpholinoethoxy)ethoxy,
3-(2-morpholinoethoxy)propoxy,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl or
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl.
[0310] Where one of the R.sup.2 substituents is R.sup.5X.sup.1--
the substituent R.sup.5X.sup.1-- is preferably at the 6- or
7-position of the quinazoline ring, more preferably at the
7-position of the quinazoline ring.
[0311] When one of the R.sup.2 substituents is at the 6-position of
the quinazoline ring it is preferably hydrogen, halogeno,
C.sub.1-3alkyl, trifluoromethyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl or --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4 are as defined hereinbefore).
[0312] When one of the R.sup.2 substituents is at the 6-position of
the quinazoline ring it is more preferably C.sub.1-3alkoxy,
especially methoxy.
[0313] In another aspect of the present invention there is provided
the use of compounds of the formula Ia: ##STR4## [wherein: [0314]
ring C, R.sup.1, R.sup.2, n and Z are as defined hereinbefore with
the provisos that R.sup.2 is not hydrogen and that Z is not
CH.sub.2 or a direct bond; and [0315] R.sup.2a represents hydrogen,
halogeno, C.sub.1-3alkyl, trifluoromethyl, 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), or R.sup.5a(CH.sub.2).sub.zaX.sup.1a
(wherein R.sup.5a is a 5- or 6-membered saturated heterocyclic
group 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, ,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.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C,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.1alkyl), za is an integer from 0 to 4 and X.sup.1a represents
a direct bond, --O--, --CH.sub.2--, --S--, --SO--, --SO.sub.2--,
--NR.sup.6aC(O)--, --C(O)NR.sup.7a--, --SO.sub.2NR.sup.8a--,
--NR.sup.9aSO.sub.2-- or --NR.sup.10a-- (wherein R.sup.6a,
R.sup.7a, R.sup.8a, R.sup.9a and R.sup.10a each independently
represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); and salts thereof, and prodrugs
thereof for example esters and amides, 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.
[0316] In another aspect of the present invention there is provided
the use of compounds of the formula Ia: ##STR5## [wherein: [0317]
ring C, R.sup.1, R.sup.2, n and Z are as defined hereinbefore with
the provisos that R.sup.2 is not hydrogen and that Z is not
CH.sub.2 or a direct bond; and [0318] R.sup.2a represents hydrogen,
halogeno, C.sub.1-3alkyl, trifluoromethyl, 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), or R.sup.5a(CH.sub.2).sub.zaX.sup.1a
(wherein R.sup.5a is a 5- or 6-membered saturated heterocyclic
group 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, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl and
C.sub.1-4alkoxy, za is an integer from 0 to 4 and X.sup.1a
represents a direct bond, --O--, --CH.sub.2--, --S--, --SO--,
--SO.sub.2--, --NR.sup.6aC(O)--, --C(O)NR.sup.7a--,
--SO.sub.2NR.sup.8a, --NR.sup.9aSO.sub.2-- or --NR.sup.10a--
(wherein R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a and R.sup.10a each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, 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.
[0319] Advantageously X.sup.1a represents --O--, --S--,
--NR.sup.6aC(O)--, --NR.sup.9aSO.sub.2-- or --NR.sup.10a-- (wherein
R.sup.6a, R.sup.9a and R.sup.10a each independently represents
hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0320] Preferably X.sup.1a represents --O--, --S--,
--NR.sup.6aCO--, --NR.sup.9aSO.sub.2-- (wherein R.sup.6a and
R.sup.9a each independently represents hydrogen or C.sub.1-2alkyl)
or NH.
[0321] More preferably X.sup.1a represents --O--, --S--,
--NR.sup.6aCO-- (wherein R.sup.6a represents hydrogen or
C.sub.1-2alkyl) or NH.
[0322] Particularly X.sup.1a represents --O-- or --NR.sup.6aCO--
(wherein R.sup.6a represents hydrogen or C.sub.1-2alkyl), more
particularly --O-- or --NHCO--, especially --O--.
[0323] Preferably za is an integer from 1 to 3.
[0324] Preferably R.sup.5a is a group selected from pyrrolidinyl,
piperazinyl, piperidinyl, imidazolidinyl, azetidinyl, morpholino
and thiomorpholino which group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, azetidinyl,
morpholino and thiomorpholino, which cyclic group may bear one or
more substituents selected from C.sub.1-3alkyl).
[0325] More preferably R.sup.5a is a group selected from
pyrrolidinyl, piperazinyl, piperidinyl, azetidinyl, morpholino and
thiomorpholino which group may bear 1 or 2 substituents selected
from oxo, hydroxy, halogeno, cyano, C.sub.1-3cyanoalkyl,
C.sub.1-3alkyl, C.sub.1-3hydroxyalkyl, C.sub.1-3alkoxy,
C.sub.1-2alkoxyC.sub.1-3alkyl,
C.sub.1-2alkylsulphonylC.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.1-3alkyl)aminoC.sub.1-3alkyl,
C.sub.1-3alkylaminoC.sub.1-3alkoxy,
di(C.sub.1-3alkyl)aminoC.sub.1-3alkoxy 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0326] Particularly R.sup.5a is pyrrolidinyl, piperazinyl,
piperidinyl, azetidinyl, morpholino or thiomorpholino which group
may bear 1 or 2 substituents selected from 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, methylpiperazinyl, piperidinyl, azetidinyl,
morpholino and thiomorpholino).
[0327] According to another aspect of the present invention
preferably R.sup.5a is a group selected from pyrrolidinyl,
piperazinyl, piperidinyl, morpholino and thiomorpholino which group
may carry 1 or 2 substituents selected from oxo, hydroxy, halogeno,
C.sub.1-2alkyl, C.sub.1-2hydroxyalkyl and C.sub.1-2alkoxy.
[0328] Advantageously R.sup.2a represents C.sub.1-3alkyl,
C.sub.1-3alkoxy, amino or R.sup.5a(CH.sub.2).sub.zaX.sup.1a
(wherein R.sup.5a, X.sup.1a and za are as defined hereinbefore).
Another advantageous value of R.sup.2a is hydrogen.
[0329] Preferably R.sup.2a is methyl, ethyl, methoxy, ethoxy or
R.sup.5a(CH.sub.2).sub.zaX.sup.1a (wherein R.sup.5a, X.sup.1a and
za are as defined hereinbefore). Another preferred value of
R.sup.2a is hydrogen.
[0330] More preferably R.sup.2a is methyl, ethyl, methoxy, ethoxy
or R.sup.5a(CH.sub.2).sub.zaX.sup.1a (wherein R.sup.5a is a group
selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholino
and thiomorpholino which group may carry 1 or 2 substituents
selected from oxo, hydroxy, halogeno, C.sub.1-2alkyl,
C.sub.1-2hydroxyalkyl and C.sub.1-2alkoxy, X.sup.1a is --O--,
--S--, --NR.sup.6aC(O)--, --NR.sup.9aSO.sub.2-- (wherein R.sup.6a
and R.sup.9a each independently represents hydrogen or
C.sub.1-2alkyl) or NH, and za is an integer from 1 to 3).
[0331] Particularly R.sup.2a represents methyl, methoxy or
R.sup.5a(CH.sub.2).sub.zaX.sup.1a (wherein R.sup.5a, X.sup.1a and
za are as defined hereinbefore).
[0332] More particularly R.sup.2a represents methoxy.
[0333] In a further aspect of the present invention there is
provided the use of compounds of the formula Ib: ##STR6## [wherein:
[0334] ring C, R.sup.1, R.sup.2, R.sup.2a and n are as defined
hereinbefore with the proviso that R.sup.2 is not hydrogen; and
[0335] Zb is --O-- or --S--; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides, 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.
[0336] Preferably Zb is --O--.
[0337] According to another aspect of the present invention there
are provided compounds of the formula II: ##STR7## [wherein: [0338]
ring C, R.sup.1, R.sup.2, R.sup.2a, Zb and n are as defined
hereinbefore with the proviso that R.sup.2 is not hydrogen and
excluding the compounds: [0339]
6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline,
6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline,
6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and
6,7-dimethoxy-4-(2-naphthyloxy)quinazoline; and salts thereof, and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0340] According to another aspect of the present invention there
are provided compounds of the formula IIa: ##STR8## [wherein:
[0341] ring C, R.sup.1, R.sup.2, R.sup.2a, Zb and n are as defined
hereinbefore with the proviso that R.sup.2 does not have any of the
following values: hydrogen, substituted or unsubstituted
C.sub.1-5alkyl, halogeno or phenoxy and excluding the compounds:
[0342] 6,7-dimethoxy-4-(1-naphthylsulphanyl)quinazoline,
6,7-dimethoxy-4-(2-naphthylsulphanyl)quinazoline,
6,7-dimethoxy-4-(1-naphthyloxy)quinazoline and
6,7-dimethoxy-4-(2-naphthyloxy)quinazoline; and salts thereof, and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0343] According to another aspect of the present invention there
are provided compounds of the formula IIb: ##STR9## [wherein:
[0344] ring C, R.sup.1, R.sup.2, R.sup.2a, Zb and n are as defined
hereinbefore with the proviso that R.sup.2 does not have any of the
following values: hydrogen, substituted or unsubstituted
C.sub.1-5alkyl, halogeno, C.sub.1-5alkoxy, C.sub.2-5alkenyl,
phenoxy or phenylC.sub.1-5alkoxy; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0345] Preferred compounds of the present invention include [0346]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazolin-
e, [0347]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line, [0348]
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quin-
azoline, [0349]
6-methoxy-7-(3-4-methylpiperazin-1-yl)propoxy)4-(quinolin-7-yloxy)quinazo-
line, [0350]
6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line, [0351]
4-4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
[0352]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinoli-
n-7-yloxy)quinazoline, [0353]
6-methoxy-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinaz-
oline, [0354]
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,
[0355]
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-
-(quinolin-7-yloxy)quinazoline, [0356]
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-
quinazoline, [0357]
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quina-
zoline, [0358]
6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-y-
loxy)quinazoline, [0359]
6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)-
quinazoline, [0360]
(R,S)-4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)m-
ethoxy)quinazoline, [0361]
4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
[0362]
7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline, [0363]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quina-
zoline, [0364]
7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazo-
line, [0365]
6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline,
[0366]
4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
[0367]
4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoline-
, [0368]
4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)qu-
inazoline, [0369]
6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quina-
zoline, [0370]
7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazoline,
[0371]
7-(3-(N,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6--
methoxyquinazoline, [0372]
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)-
quinazoline, [0373]
7-(2-(N,N-diethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
[0374]
4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoli-
ne, [0375]
4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline,
[0376]
4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
[0377]
7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)-
quinazoline. [0378]
6-methoxy4-3-methylindol-5-yloxy)-7-3-piperidinopropoxy)quinazoline,
[0379]
7-(2-hydroxy-3-piperidinopropoxy)-methoxy-4-(2-methylindol-5-ylox-
y)quinazole, [0380]
7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindo-
l-5-yloxy)quinazoline, [0381]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazolin-
e, and [0382]
7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-ylox-
y)quinazoline, and salts thereof especially hydrochloride salts
thereof and prodrugs thereof for example esters and amides.
[0383] Especially preferred compounds of the present invention
include [0384]
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline-
, [0385]
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)-
methoxy)quinazoline, [0386]
4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline,
[0387]
4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazol-
ine, [0388]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoli-
ne, [0389]
7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-ylo-
xy)quinazoline, [0390]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,
[0391]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)qu-
inazoline, [0392]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quin-
azoline, [0393]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline,
[0394]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)a-
mino)ethoxy)quinazoline, [0395]
6-methoxy-4-2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
[0396]
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)-
quinazoline, [0397]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)qu-
inazoline, [0398]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethox-
y)ethoxy)quinazoline, [0399]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline,
[0400]
4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
[0401]
6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methyl-
indol-5-yloxy)quinazoline, [0402]
6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamo-
yl)vinyl)quinazoline, [0403]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-4-methypiperazin-1-yl)propoxy)qu-
inazoline, [0404]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
[0405]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)etho-
xy)quinazoline, [0406]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-N-methyl-N-5
methylsulphonylamino)ethoxy)quinazoline, [0407]
7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindo-
l-5-yloxy)quinazoline, [0408]
4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline,
[0409]
4-(2-methylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)q-
uinazoline, [0410]
4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
[0411]
4-(indol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline,
[0412]
7-(3-(N,N-dimethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquina-
zoline, [0413]
7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline,
[0414]
7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methox-
yquinazoline, [0415]
4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline,
[0416]
4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
[0417]
7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yl-
oxy)quinazoline, [0418]
7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quin-
azoline, [0419]
7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-
-5-yloxy)quinazoline, [0420]
7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline, [0421]
7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy4-(2-methylindol-5-ylo-
xy)quinazoline, [0422]
7-3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)-
quinazoline, [0423]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline-
, [0424]
4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
[0425]
(2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperi-
dinopropoxy)quinazoline, [0426]
(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmetho-
xy)quinazoline, [0427]
4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
[0428]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethy-
l)-piperidin-4-ylmethoxy)quinazoline. [0429]
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)4-(indol-5-yloxy)-6-methoxyq-
uinazoline, [0430]
(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line, [0431]
(2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line, [0432]
(2S)-7-(2-hydroxy-3-(N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-5
methoxyquinazoline, [0433]
(2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line, [0434]
(2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy4-(3-methylindol-5-yloxy)-
quinazoline, [0435]
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol--
5-yloxy)quinazoline, [0436]
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol--
5-yloxy)quinazoline, [0437]
(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy-6-methoxy-4-(2-methyl-
indol-5-yloxy)quinazoline, [0438]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-y-
lmethoxy)quinazoline, [0439]
4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazolin-
e, [0440]
4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)qui-
nazoline, [0441]
6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)quinazoline, [0442]
(2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropo-
xy)quinazoline, and [0443]
4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propox-
y)quinazoline, and salts thereof especially hydrochloride salts
thereof and prodrugs thereof for example esters and amides.
[0444] More especially preferred compounds of the present invention
include [0445]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line, [0446]
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quin-
azoline, [0447]
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-
quinazoline, [0448]
4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line, [0449]
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line, [0450]
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline,
[0451]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-y-
l)propoxy)quinazoline, [0452]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quina-
zoline, [0453]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)m-
ethoxy)quinazoline, [0454]
4-(4-fluoro-2-methylindol-5-yloxy)6-methoxy-7-(3-(4-methylpiperazin-1-yl)-
propoxy)quinazoline, [0455]
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)q-
uinazoline, [0456]
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-
-yloxy)-6-methoxyquinazoline, and [0457]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(I
-methylpiperidin-4-yl)ethoxy)quinazoline, and salts thereof
especially hydrochloride salts thereof and prodrugs thereof for
example esters and amides.
[0458] Thus preferred compounds of the present invention include
those, the preparation of which is described in Examples 23, 10, 5,
176, 7, 22, 13, 15, 177, 12, 35, 47, 44, 45, 157, 52, 62, 66, 75,
159, 87, 88, 89, 167, 83, 97, 101, 108, 113, 114, 121, 124, 178,
162, 165, 150 and 166, and salts thereof especially hydrochloride
salts thereof and prodrugs thereof for example esters and
amides.
[0459] Thus especially preferred compounds of the present invention
include those, the preparation of which is described in Examples 2,
11, 34, 36, 186, 151, 57, 54, 55, 58, 56, 60, 61, 64, 65, 67, 68,
71, 72, 74, 70, 77, 79, 80, 82, 86, 122, 107, 110, 112, 117, 118,
119, 123, 161, 147, 163, 164, 63, 78, 115, 320, 318, 290, 252, 292,
293, 294, 301, 299, 279, 280, 305, 269, 246, 266, 267, 182, 321 and
250,
and salts thereof especially hydrochloride salts thereof and
prodrugs thereof for example esters and amides.
[0460] Thus more especially preferred compounds of the present
invention include those, the preparation of which is described in
Examples 9, 243, 251, 245, 247, 249, 240, 238, 237, 239, 241, 258
and 322,
and salts thereof especially hydrochloride salts thereof and
prodrugs thereof for example esters and amides.
[0461] In another embodiment, preferred compounds of the present
invention include [0462]
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline,
[0463]
(S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-y-
loxy)quinazoline. [0464]
6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline,
[0465]
4-(1H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
[0466] 6,7-dimethoxyA(quinolin-7-yloxy)quinazoline, [0467]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihy-
droquinolin-6-yloxy)quinazoline, [0468]
6-methoxy-7-((2-piperidin-1-yl)ethoxy)-4-(quinolin-7-yloxy)quinazoline,
[0469]
6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropox-
y)quinazoline, [0470]
6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-(2-methylsulphonylethyl)pipe-
ridin-4-yl)methoxy)quinazoline, [0471]
6-methoxy-4-(2-methylquinolin-7-yloxy)-7-((1-methylpiperidin-4-yl)methoxy-
)quinazoline, [0472]
4-(2-chloro-1H-benzimidazol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl-
)methoxy)quinazoline, [0473]
4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)met-
hoxy)quinazoline, [0474]
4-(1H-indazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
[0475]
4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)q-
uinazoline, [0476]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxaz-
in-6-yloxy)quinazoline, [0477]
7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline, [0478]
6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-methylsulphonylpropo-
xy)quinazoline, [0479]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(tetrahydropyran-4-yloxy)ethoxy)-
quinazoline, [0480]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(1,2-cycloheptanebenzimid-
azol-5-yloxy)quinazoline, [0481]
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)quinazoline,
[0482]
6-methoxy-7-(3-morpholinopropoxy)-4-(3-oxo-1,2-dihydro-3H-indazol-
-1-yl)quinazoline, [0483]
4-(2,3-dihydro-1H-indan-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quina-
zoline, [0484]
6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((1-methylpiperidin-4-y-
l)methoxy)quinazoline, [0485]
6-methoxy-4-(4-methyl-4H-1,4-benzoxazin-6-yloxy)-7-((1-methylpiperidin-4--
yl)methoxy)quinazoline, [0486]
6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-((3-pyrrolidin-1-yl)pro-
poxy)quinazoline, [0487]
6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6yloxy)-7-3-pyrrolidi-
n-1-ylpropoxy)quinazoline, [0488]
7-benzyloxy-6-methoxy-4-quinolin-7-yloxy)quinazoline, [0489]
4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)qu-
inazoline, [0490]
6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)-
quinazoline, [0491]
6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-methylsulphonylpropoxy)quinaz-
oline, [0492]
6-methoxy-7-(3-morpholinopropoxy)-4-(quinazolin-7-yloxy)quinazoline,
[0493]
6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(3-oxo-2H4H-1,4-benzoxaz-
in-6-yloxy)quinazoline, [0494]
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline, [0495]
6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)quinazoline, and
salts thereof especially hydrochloride salts thereof and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0496] In another embodiment more preferred compounds of the
present invention include [0497]
6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline-
, [0498]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-ylo-
xy)quinazoline, [0499]
6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-morpholinopropoxy)qu-
inazoline, [0500]
(R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)qui-
nazoline, [0501]
6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2,2,4-trimethyl-1,2-dihydroquin-
olin-6-yloxy)quinazoline, [0502]
6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline,
[0503]
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperi-
din-4-yl)methoxy)quinazoline, [0504]
6-methoxy-4-(2-methylindol-5-ylamino)-7-((1-methylpiperidin-4-yl)methoxy)-
quinazoline, [0505]
6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazo-
line, [0506]
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsuiphonylpropoxy)quinaz-
oline, [0507]
4-(7-hydroxy-2-naphthyloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazo-
line, [0508]
6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)-
quinazoline, [0509]
7-(2-N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazo-
line, [0510]
6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-
-5-yloxy)quinazoline, [0511]
4-(2,3dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-yl)methox-
y)quinazoline, [0512]
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)qui-
nazoline, [0513]
(S)-6-methoxy-7-((2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methoxy)-4-(quinoli-
n-7-yloxy)quinazoline, and salts thereof especially hydrochloride
salts thereof and prodrugs thereof for example esters, amides and
sulphides, preferably esters and amides.
[0514] In another embodiment especially preferred compounds of the
present invention include [0515]
6-methoxy-4(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-
e, [0516]
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quina-
zoline, [0517]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsulphonylpropoxy)quinazoli-
ne, [0518]
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-3-yl)methoxy)qu-
inazoline, [0519]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1-yl)ethoxy)quinazoli-
ne, [0520]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line, [0521]
6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line, [0522]
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)qu-
inazoline, [0523]
4-(indol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-
e, [0524]
4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline,
[0525]
6-methoxy-7-(3-methylsulphonylpropoxy)-4-(quinolin-7-yloxy)quinaz-
oline, [0526]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(pyrrolidin-1-yl)ethoxy)quinazol-
ine, [0527]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amino)eth-
oxy)quinazoline, [0528]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline,
[0529]
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline-
, [0530]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)-
quinazoline, [0531]
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quin-
azoline, [0532]
6-methoxy-7-(3-(1-methylpiperazin-4-yl)propoxy)-4-(quinolin-7-yloxy)quina-
zoline, [0533]
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline-
, [0534]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)4-(4-methylquinoli-
n-7-yloxy)quinazoline, [0535]
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline,
[0536]
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-
-(quinolin-7-yloxy)-quinazoline, [0537]
7-((1-cyanomethylpiperidin-4-yl)methoxy)-6-methoxy4-2-methylindol-5-yloxy-
)quinazoline, [0538]
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-trifluoromethylindol-5-
-yloxy)quinazoline, [0539]
4-(3-fluoroquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy-
)quinazoline, [0540]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline,
[0541]
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)-
quinazoline, [0542]
7-(3-(N,N-dimethylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quina-
zoline, [0543]
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline, [0544]
6-methoxy-4(2-methylindol-5-yloxy)-7-(2-(2-(1-methylpiperazin-4-yl)ethoxy-
)ethoxy)quinazoline, [0545] 6-methoxy
4(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxybethoxy)quinazoline,
[0546]
6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropox-
y)quinazoline, [0547]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1,2,4-triazol-1-yl)ethoxy)quina-
zoline, [0548]
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methox-
y)quinazoline, [0549]
4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
and salts thereof especially hydrochloride salts thereof and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0550] In another aspect of the present invention preferred
compounds include [0551]
6-methoxy-7-((1-(2-methoxyethyl)piperidin-4-yl)methoxy)-4-(2-methylindol--
5-yloxy)quinazoline, [0552]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(pyrrolidin-1-yl)ethylcarbamo-
yl)vinyl)quinazoline, [0553]
4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-
quinazoline, [0554]
6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(4-trifluoromethylquinoli-
n-7-yloxy)quinazoline, [0555]
6-methoxy-4-(2-methyl-1H-benzimidazol-5-yloxy)-7-((1-methylpiperidin-4-yl-
)methoxy)quinazoline, [0556]
4-(3-carbamoylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)meth-
oxy)quinazoline, [0557]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(1-methylpiperazin-4-yl)propoxy)-
quinazoline, [0558]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
and salts thereof especially hydrochloride salts thereof and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0559] An especially preferred compound of the present invention is
[0560]
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)q-
uinazoline and salts thereof especially hydrochloride salts thereof
and prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0561] 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.
[0562] 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 halogeno, 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. 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.
[0563] For the avoidance of any doubt, where R.sup.2 has a value of
substituted or unsubstituted C.sub.1-5alkyl, R.sup.2 has been
selected from C.sub.1-3alkyl or from a group R.sup.5X.sup.1 wherein
X.sup.1 is a direct bond or --CH.sub.2-- and R.sup.5 is
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.
[0564] 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.
[0565] 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.
[0566] 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.
[0567] 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.
[0568] 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.
[0569] 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.
[0570] 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.
[0571] 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.
[0572] 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.
[0573] A compound of the formula I, or salt thereof, and other
compounds of the invention (as hereinafter 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 European Patent Applications Publication Nos.
0520722, OS66226, 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.
[0574] Thus, the following processes (a) to (f) and (i) to (vi)
constitute further features of the present invention.
Synthesis of Compounds of Formula I
[0575] (a) Compounds of the formula I and salts thereof may be
prepared by the reaction of a compound of the formula III:
##STR10## (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: ##STR11## (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.
[0576] 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, 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-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.
[0577] 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.
[0578] (b) Production of those compounds of formula I and salts
thereof wherein at least one R.sup.2 is R.sup.5X.sup.1 wherein
R.sup.5 is 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: ##STR12## (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 a compound of formula VI: R.sup.5-L.sup.1
(VI) (wherein R.sup.5 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.
[0579] (c) Compounds of the formula I and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 wherein R.sup.5 is 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: ##STR13## with a compound of the
formula VIII: R.sup.5--X.sup.1--H (VIII) (wherein L.sup.1, R.sup.1,
R.sup.2, R.sup.5, 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.
[0580] (d) Compounds of the formula I and salts thereof wherein at
least one R.sup.2 is R.sup.5X.sup.1 wherein X.sup.1 is as defined
hereinbefore and R.sup.5 is C.sub.1-5alkylR.sup.113, wherein
R.sup.113 is selected from one of the following six groups: [0581]
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); [0582] 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); [0583] 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 hereinbefore); [0584] 4)
R.sup.28 (wherein R.sup.28 is as defined hereinbefore); [0585] 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 [0586] 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); and additionally R.sup.113 may be selected from the
following three groups: [0587] 7) R.sup.29 (wherein R.sup.29 is as
defined hereinbefore); [0588] 8) X.sup.22C.sub.1-4alkylR.sup.28
(wherein X.sup.22 and R.sup.28 are as defined hereinbefore); and
[0589] 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); may be prepared by reacting a compound of the
formula IX: ##STR14## (wherein L.sup.1, X.sup.1, R.sup.1, R.sup.2,
ring C, Z, n and s are as hereinbefore defined) with a compound of
the formula X: R.sup.113--H (X) (wherein R.sup.113 is 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.
[0590] Processes (a) and (b) are preferred over processes (c) and
(d).
[0591] Process (a) is preferred over processes (b), (c) and
(d).
[0592] (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).
[0593] (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
[0594] (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: ##STR15## wherein R.sup.2 and m are as
hereinbefore defined).
[0595] 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.
[0596] The compounds of formula XI and salts thereof may, for
example, be prepared by reacting a compound of the formula XII:
##STR16## (wherein R.sup.2, s and L.sup.1 are as hereinbefore
defined) with a compound of the formula VIII 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.
[0597] Compounds of formula XI and salts thereof wherein at least
one R.sup.2 is R.sup.5X.sup.1 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: ##STR17## (wherein
R.sup.2 and s are as hereinbefore defined and X.sup.1 is as
hereinbefore defined in this section) with a compound of the
formula VI 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.
[0598] The compounds of formula XI and salts thereof may also be
prepared by cyclising a compound of the formula XIV: ##STR18##
(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.
[0599] 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: ##STR19## (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.
[0600] Compounds of the formula XV and salts thereof may for
example be prepared by the reaction of a compound of the formula
XVI: ##STR20## (wherein R.sup.2, s, L.sup.1 and A.sup.1 are as
hereinbefore defined) with a compound of the formula VIII as
hereinbefore defined to give a compound of the formula XV. The
reaction of the compounds of formulae XVI and VIII is conveniently
effected under conditions as described for process (c)
hereinbefore.
[0601] Compounds of formula XV and salts thereof wherein at least
one R.sup.2 is R.sup.5X.sup.1 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: ##STR21## (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 a compound of the
formula VI as hereinbefore defined to yield a compound of formula
XV as hereinbefore defined. The reaction of the compounds of
formulae XVII and VI is conveniently effected under conditions as
described for process (b) hereinbefore.
[0602] 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 XIII
(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.
[0603] 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.
[0604] 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.
[0605] 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 --O--,
--S--, --SO.sub.2--, --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: ##STR22## (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 a compound of the formula VI
as hereinbefore defined, whereby to obtain a compound of formula
III in which L.sup.1 is represented by L.sup.2.
[0606] 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.
[0607] The compounds of formula XVIII and salts thereof may for
example be prepared by deprotecting a compound of the formula XIX
##STR23## (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.
[0608] 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.
[0609] (ii) Compounds of formula IV and salts thereof in which ring
C is an 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.
[0610] Examples of the preparation of indoles are given in the
Examples hereinafter, such as Examples 48, 237, 242, 250 and
291.
[0611] Compounds of formula IV and salts thereof in which ring C is
a 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.
[0612] (iii) Compounds of formula V as hereinbefore defined and
salts thereof may be made by deprotecting the compound of formula
XX: ##STR24## (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.
[0613] Compounds of the formula XX and salts thereof may be made by
reacting compounds of the formulae XIX and IV as hereinbefore
defined, under the conditions described in (a) hereinbefore, to
give a compound of the formula XX or salt thereof
[0614] (iv) Compounds of the formula VII and salts thereof may be
made by reacting a compound of the formula XXI: ##STR25## (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.
[0615] (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.
[0616] (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.
[0617] 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.
[0618] Many of the intermediates defined herein, for example, those
of the formulae V, VII, IX and XX 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.
[0619] The identification of compounds which potently inhibit the
tyrosine kinase activity associated with VEGF receptors such as Flt
and/or KDR and which inhibit angiogenesis and/or increased vascular
permeability is desirable and is the subject of the present
invention. These properties may be assessed, for example, using one
or more of the procedures set out below:
(a) In Vitro Receiptor Tyrosine Kinase Inhibition Test
[0620] 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 (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.
[0621] For expression of cFlt tyrosine kinase activity, Sf21 cells
were infected with plaque-pure cFlt 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 50 .mu.l of dilute enzyme is used for each assay
well.
[0622] 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.
[0623] 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.
[0624] 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.
[0625] 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 room 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 room
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 room 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 room 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%
inhibtion of enzyme activity.
(b) In Vitro HUVEC Proliferation Assay
[0626] This assay determines the ability of a test compound to
inhibit the growth factor-stimulated proliferation of human
umbilical vein endothelial cells (HUVEC).
[0627] 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
[0628] This test measures the capacity of compounds to inhibit
solid tumour growth.
[0629] 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.
[0630] 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.
[0631] 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.
[0632] 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.
[0633] 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.
[0634] 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.
[0635] 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.
[0636] 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.
[0637] 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.
[0638] 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 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 ractitioner who is treating any
particular patient.
[0639] 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 he 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: [0640] (i) other
antiangiogenic agents 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 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)); [0641]
(ii) cytostatic agents such as antioestrogens (for example
tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene),
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), inhibitors of
testosterone 5.alpha.-dihydroreductase (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, tyrosine kinase
inhibitors and serine/threonine kinase inhibitors); and [0642]
(iii) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as antimetabolites (for
example antifolates like methotrexate, fluoropyrimidines like
5-fluorouracil, purine and adenosine analogues, cytosine
arabinoside); antitumour antibiotics (for example anthracyclines
like 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 and taxoids
like taxol, taxotere); topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan, and also irinotecan); also enzymes (for example
asparaginase); and thymidylate synthase inhibitors (for example
raltitrexed); and additional types of chemotherapeutic agent
include: [0643] (iv) biological response modifiers (for example
interferon); and [0644] (v) antibodies (for example
edrecolomab).
[0645] 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).
[0646] 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, 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. 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 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.
[0647] 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.
[0648] It is to be understood that where the term "ether" is used
anywhere in this specification it refers to diethyl ether.
[0649] The invention will now be illustrated in the following
non-limiting Examples in which, unless otherwise stated:-
[0650] (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;
[0651] (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;
[0652] (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;
[0653] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0654] (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.
[0655] (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, quin, quintet;
[0656] (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;
[0657] (viii) HPLC were run under 2 different conditions: [0658] 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; [0659] 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.
[0660] (ix) petroleum ether refers to that fraction boiling between
40-60.degree. C.
[0661] (x) the following abbreviations have been used:- [0662] DMF
N,N-dimethylformamide [0663] DMSO dimethylsulphoxide [0664] TFA
trifluoroacetic acid [0665] NMP 1-methyl-2-pyrrolidinone [0666] THF
tetrahydrofuran [0667] HMDS 1,1,1,3,3,3-hexamethyldisilazane.
[0668] HPLC RT HPLC retention time [0669] DEAD diethyl
azodicarboxylate [0670] DMA dimethylacetamide [0671] DMAP
4-dimethylaminopyridine
EXAMPLE 1
[0672] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), potassium carbonate (106 mg, 0.77 mmol) and
6-hydroxyquinoline (112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred
at 100.degree. C. for 5 hours and allowed to cool to ambient
temperature. The reaction mixture was treated with 1M aqueous
sodium hydroxide solution (40 ml) and stirred at ambient
temperature for a few minutes. The crude solid was collected by
filtration and washed with water. The resultant solid was dissolved
in dichloromethane (2 ml) and filtered through phase separating
paper. The filtrate was evaporated under vacuum and the residue was
triturated with ether, collected by filtration and dried to give
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-6-yloxy)quinazoline
(163 mg, 55%).
[0673] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98(m, 2H); 2.40(m,
4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s,
1H); 7.58(m, 1H); 7.62(s, 1H); 7.74(dd, 1H); 7.92(d, 1H); 8.10(d,
1H); 8.38(d, 1H); 8.55(s, 1H); 8.92(m, 1H)
[0674] MS (ESI): 447 (MH).sup.+ TABLE-US-00001 Elemental analysis:
Found C 65.9 H 5.7 N 12.4 C.sub.25H.sub.26N.sub.4O.sub.40.5H.sub.2O
Requires C 65.9 H 6.0 N 12.3%
[0675] The starting material was prepared as follows:
[0676] 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 (7.4g, 0.05 mol) in dioxane (100 ml) was stirred and heated
at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and
acetic acid (1.65 ml, 0.029 mol) 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%).
[0677] 7-Benzyloxy-6-methoxy-3,4-dihydroquinazolinone (35 g, 124
mmol) was suspended in thionyl chloride (440 ml) and DMF (1.75 ml)
and heated at reflux for 4 hours. The thionyl chloride was
evaporated under vacuum and the residue azeotroped with toluene
three times. The residue was dissolved in NMP (250 ml) to give a
solution of 7-benzyloxychloro-6-methoxyquinazoline.
[0678] Phenol (29.05 g, 309 mmol) was dissolved in NMP (210 ml),
sodium hydride (11.025 g, 60% dispersion in mineral oil) was added
in portions with cooling and the mixture was stirred for 3 hours.
The viscous suspension was diluted with NMP (180 ml) and stirred
overnight. The solution of
7-benzyloxy-4-chloro-6-methoxyquinazoline was added and the
suspension stirred at 100.degree. C. for 2.5 hours. The suspension
was allowed to cool to ambient temperature and poured into water
(1.5l) with vigorous stirring. The precipitate was collected by
filtration, washed with water and dried under vacuum. The residue
was dissolved in dichloromethane, washed with brine and filtered
through phase separating paper. The filtrate was evaporated under
vacuum then triturated with ether to give
7-benzyloxy-6-methoxy-4-phenoxyquinazoline (87.8 g, 83%) as a pale
cream solid.
[0679] .sup.1H NMR Spectrum: (CDCl.sub.3) 4.09(s, 3H); 5.34(s, 2H);
7.42(m, 12H); 7.63(s, 1H)
[0680] MS (ESI): 359 (MH).sup.+
[0681] 7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (36.95 g, 105.5
mmol) was suspended in TFA (420 ml) and heated at reflux for 3
hours. The reaction mixture was allowed to cool and evaporated
under vacuum. The residue was stirred mechanically in water then
basified with saturated aqueous sodium hydrogen carbonate solution
and stirred overnight. The water was decanted and the solid
suspended in acetone. After stirring the white solid was collected
by filtration, washed with acetone and dried to give
7-hydroxy-6-methoxy-4-phenoxyquinazoline (26.61 g, 96%).
[0682] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.97(s, 3H); 7.22(s,
1H); 7.30(m, 3H); 7.47(t, 2H); 7.56(s, 1H); 8.47(s, 1H); 10.70(s,
1H)
[0683] MS (ESI): 269 (MH).sup.+
[0684] Morpholine (52.2 ml, 600 mmol) and 1-bromo-3-chloropropane
(30 ml, 300 mmol) were dissolved in dry toluene (180 ml) and heated
to 70.degree. C. for 3 hours. The solid was removed by filtration
and the filtrate evaporated under vacuum. The resulting oil was
decanted from the additional solid residue and the oil was vacuum
distilled to yield 1-chloro-3-morpholinopropane (37.91 g, 77%) as
an oil.
[0685] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.85(m, 2H); 2.30(t,
4H); 2.38(t, 2H); 3.53(t, 4H); 3.65(t, 2H)
[0686] MS (ESI): 164 (MH).sup.+
[0687] 7-Hydroxy-6-methoxyphenoxyquinazoline (25.27 g, 0.1 mol) and
1-chloro-3-morpholinopropane (18.48 g, 0.11 mol) were taken up in
DMF (750 ml) and potassium carbonate (39.1 g, 0.33 mol) was added.
The suspension was heated at 90.degree. C. for 3 hours then allowed
to cool. The suspension was filtered and the volatiles were removed
by evaporation. The residue was triturated with ethyl acetate and
6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (31.4 g,
84%) was collected by filtration as a yellow crystalline solid.
[0688] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.97(m, 2H); 2.39(t,
4H); 2.47(t, 2H); 3.58(t, 4H); 3.95(s, 3H); 4.23(t, 2H); 7.31(m,
3H); 7.36(s, 1H); 7.49(t, 2H); 7.55(s, 1H); 8.52(s, 1H)
[0689] MS (ESI): 396 (MH).sup.+
[0690] 6-Methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline
(33.08 g, 84 mmol) was dissolved in 6M aqueous hydrochloric acid
(800 ml) and heated at reflux for 1.5 hours. The reaction mixture
was decanted and concentrated to 250 ml then basified (pH9) with
saturated aqueous sodium hydrogen carbonate solution. The aqueous
layer was extracted with dichloromethane (4.times.400 ml), the
organic layer was separated and filtered through phase separating
paper. The solid was triturated with ethyl acetate to give
6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9
g, 89%) as a white solid.
[0691] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.91(m, 2H); 2.34(t,
4H); 2.42(t, 2H); 3.56(t, 4H); 3.85(s, 3H); 4.12(t, 2H); 7.11(s,
1H); 7.42(s, 1H); 7.96(s, 1H); 12.01(s, 1H)
[0692] MS (ESI): 320 (MH).sup.+
[0693]
6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (23.9
g, 75 mmol) was suspended in thionyl chloride (210 ml) and DMF (1.8
ml) then heated at reflux for 1.5 hours. The thionyl chloride was
removed by evaporation under vacuum and the residue azeotroped with
toluene three times. The residue was taken up in water and basified
(pH8) with saturated aqueous sodium hydrogen carbonate solution.
The aqueous layer was extracted with dichloromethane (4.times.400
ml), the organic layer was washed with water and brine then dried
(MgSO.sub.4). After filtration the organic layer was concentrated
under vacuum to give a yellow solid which was triturated with ethyl
acetate to give
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (17.39 g,
52%) as a pale cream solid.
[0694] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.10-2.16(m, 2H); 2.48(br
s, 4H); 2.57(t, 2H); 3.73(t, 4H); 4.05(s, 3H); 4.29(t, 2H); 7.36(s,
1H); 7.39(s, 1H); 8.86(s, 1H)
[0695] MS-ESI: 337[MH].sup.+
EXAMPLE 2
[0696] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxyquinoline
(112 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100.degree. C.
for 5 hours and allowed to cool to ambient temperature. The
reaction mixture was treated with 1M aqueous sodium hydroxide
solution (40 ml) and stirred at ambient temperature for a few
minutes. The crude solid was collected by filtration washing with
water. The resultant solid was dissolved in dichloromethane (2 ml)
and filtered through phase separating paper. The filtrate was
evaporated under vacuum to give a solid residue which was
triturated with ether, filtered and dried to give
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-7-yloxy)quinazoline
(116 mg, 39%).
[0697] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98(m, 2H); 2.39(m,
4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.25(t, 2H); 7.40(s,
1H); 7.58(m, 2H); 7.62(s, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.44(d,
1H); 8.55(s, 1H); 8.92(m, 1H)
[0698] MS (ESI): 447 (MH).sup.+ TABLE-US-00002 Elemental analysis:
Found C 66.6 H 5.7 N 12.4
C.sub.25H.sub.26N.sub.4O.sub.40.25H.sub.2O Requires C 66.6 H 5.9 N
12.4%
EXAMPLE 3
[0699] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (106 mg, 0.77 mmol) and 1-naphthol (111 mg,
0.77 mmol) in DMF (7.5 ml) was stirred at 100.degree. C. for 5
hours then allowed to cool to ambient temperature. The reaction
mixture was treated with 1M aqueous sodium hydroxide solution (40
ml) and stirred at ambient temperature for a few minutes. The
reaction mixture was extracted with ethyl acetate and the organic
extracts were washed with water. The organic extracts were dried
(MgSO.sub.4) and the solvent removed by evaporation. The residue
was purified by column chromatography eluting with methylene
chloride/methanol (95/5) to give a solid which was triturated with
ether, filtered and dried to give
6-methoxy-7-(3-morpholinopropoxy)-4-(1-naphthyloxy)quinazoline (194
mg, 65%).
[0700] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98(m, 2H); 2.39(m,
4H); 2.48(t, 2H); 3.59(m, 4H); 4.00(s, 3H); 4.26(t, 2H); 7.40(s,
1H); 7.48(m, 2H); 7.58(m, 2H); 7.74(s, 1H); 7.75(d, 1H); 7.92(d,
1H); 8.03(d, 1H); 8.42(s, 1H)
[0701] MS (ESI): 446 (MH).sup.+ TABLE-US-00003 Elemental analysis:
Found C 69.9 H 6.2 N 9.4 C.sub.26H.sub.27N.sub.3O.sub.4 Requires C
70.1 H 6.1 N 9.4%
EXAMPLE 4
[0702] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (106 mg, 0.77 mmol) and
7-hydroxy4-methylquinoline (122 mg, 0.77 mmol), (Chem. Berich.
1967, 100, 2077), in DMF (7.5 ml) was stirred at 100.degree. C. for
5 hours then allowed to cool to ambient temperature. The reaction
mixture was treated with 1M aqueous sodium hydroxide solution (40
ml) and stirred at ambient temperature for a few minutes. The crude
solid was collected by filtration washing with water. The resultant
solid was dissolved in dichloromethane (2 ml) and was filtered
through phase separating paper. The filtrate was evaporated under
vacuum to give a solid residue which was triturated with ether,
filtered and dried to give
6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline
(175 mg, 57%).
[0703] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98(m, 2H); 2.39(m,
4H); 2.48(t, 2H); 2.71(s, 3H); 3.59(m, 4H); 4.00(s, 3H); 4.26(t,
2H); 7.40(s, 1H); 7.41(m, 1H); 7.61(dd, 1H); 7.62(s, 1H); 7.90(d,
1H); 8.20(d, 1H); 8.52(s, 1H); 8.78(d, 1H)
[0704] MS (ESI): 461 (MH).sup.+ TABLE-US-00004 Elemental analysis:
Found C 67.1 H 5.9 N 12.1 C.sub.26H.sub.28N.sub.4O.sub.40.2H.sub.2O
Requires C 67.3 H 6.2 N 12.1%
EXAMPLE 5
[0705] A mixture of
4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline
(220 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and
7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred
at 100.degree. C. for 5 hours then allowed to cool to ambient
temperature. The reaction mixture was treated with 1M aqueous
sodium hydroxide solution (40 ml) and stirred at ambient
temperature for a few minutes. The crude solid was collected by
filtration washing with water. The resultant solid was dissolved in
dichloromethane (2 ml) and was filtered through phase separating
paper. The filtrate was evaporated under vacuum to give a solid
residue which was triturated with ether, filtered and dried to give
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(quinolin-7-yloxy)quin-
azoline (205 mg, 73%).
[0706] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98(m, 2H); 2.65(t,
2H); 2.92(m, 4H); 3.10(m, 4H); 4.00(s, 3H); 4.28(t, 2H); 7.42(s,
1H); 7.58(m, 2H); 7.64(s, 1H); 7.92(d, 1H); 8.10(d, 1H); 8.44(d,
1H); 8.55(s, 1H); 8.92(m, 1H)
[0707] MS (ESI): 495 (MH).sup.+ TABLE-US-00005 Elemental analysis:
Found C 60.0 H 5.0 N 11.1
C.sub.25H.sub.26N.sub.4O.sub.5S0.25H.sub.2O Requires C 60.2 H 5.4 N
11.2%
[0708] The starting material was prepared as follows:
[0709] 7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.3 g,
124 mmol), (prepared as described for the starting material in
Example 1), was taken up in thionyl chloride (440 ml) and DMF (1.75
ml) then heated at reflux for 4 hours. The thionyl chloride was
evaporated under vacuum and the residue azeotroped with toluene
three times to give 7-benzyloxy-4-chloro-6-methoxyquinazoline.
[0710] A mixture of the crude
7-benzyloxy-4-chloro-6-methoxyquinazoline, potassium carbonate (50
g, 362 mmol) and 4-chloro-2-fluorophenol (8.8 ml, 83 mmol) in DMF
(500 ml) was stirred at 100.degree. C. for 5 hours then allowed to
cool to ambient temperature overnight. The reaction mixture was
poured into water (2l) and was stirred at ambient temperature for a
few minutes. The crude solid was collected by filtration washing
with water. The resultant solid was dissolved in dichloromethane
and filtered through diatomaceous earth. The filtrate was treated
with decolourising charcoal, boiled for a few minutes then filtered
through diatomaceous earth. The filtrate was filtered through phase
separating paper and then evaporated under vacuum to give a solid
residue which was triturated with ether, filtered and dried to give
7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2
g, 76%).
[0711] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.98(s, 3H); 5.34(s,
2H); 7.42(m, 9H); 7.69(dd, 1H); 8.55(s, 1H)
[0712] MS (ESI): 411 (MH).sup.+
[0713]
7-Benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (1.4
g, 3.4 mmol) was suspended in TFA (15 ml) and heated at reflux for
3 hours. The reaction mixture was allowed to cool, toluene was
added and the volatiles were removed by evaporation under vacuum.
The residue was triturated with ether and then acetone. The
precipitate was collected by filtration and dried to give
4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (21.8
g). This was used without further purification in the next
step.
[0714] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.97(s, 3H); 7.22(s,
1H); 7.39(d, 1H); 7.53(m, 2H); 7.67(dd, 1H); 8.46(s, 1H)
[0715] MS (ESI): 321 (MH).sup.+
[0716] A mixture of 3-amino-1-propanol (650 .mu.l, 8.4 mmol) and
vinyl sulphone (1 g, 8.4 mmol) was heated at 110.degree. C. for 45
minutes. The mixture was allowed to cool and was purified by column
chromatography eluting with methylene chloride/methanol (95/5) to
give 3-(1,1-dioxothiomorpholino)-1-propanol (800 mg, 90%).
[0717] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.7-1.8(m, 2H); 2.73(t,
2H); 3.06(br s, 8H); 3.25(s, 1H); 3.78(t, 2H)
[0718] MS-ESI: 194 [MH].sup.+
[0719] 4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline
(5.0 g, 15.6 mmol) was suspended in dichloromethane (150 ml) and
tributylphosphine (11.1 ml, 44.6 mmol) was added followed by
stirring at ambient temperature for 30 minutes. To this mixture was
added 3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol)
followed by the addition of 1,1'-(azodicarbonyl)dipiperidine (11.7
g, 46.4 mmol) in portions. The mixture was stirred at ambient
temperature overnight then diluted with ether (300 ml) and the
precipitate was removed by filtration. The residue was
chromatographed on silica eluting with dichloromethane and methanol
(95/5). The relevant fractions were combined and evaporated to give
a solid which was triturated with ethyl acetate filtered and dried
to give
4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-met-
hoxyquinazoline (5.4 g, 70%). This was used without further
purification in the next step.
[0720] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.86(m, 2H); 2.65(t,
2H); 2.92(m, 4H); 3.08(m, 4H); 3.97(s, 3H); 4.26(t, 2H); 7.40(m,
1H); 7.42(s, 1H); 7.56(m, 2H); 7.68(dd, 1H); 8.54(s, 1H)
[0721] MS (ESI): 496 (MH).sup.+ TABLE-US-00006 Elemental analysis:
Found C 52.7 H 4.4 N 8.3
C.sub.22H.sub.23N.sub.3ClFO.sub.5S0.25H.sub.2O Requires C 52.8 H
4.7 N 8.4%
[0722]
4-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy-
)-6-methoxyquinazoline (3.5 g, 7 mmol) was dissolved in 2M aqueous
hydrochloric acid (56 ml) and heated at 95.degree. C. for 2 hours.
The cooled reaction mixture was treated with solid sodium hydrogen
carbonate solution to give a thick paste which was diluted with
water and filtered. The solid was transferred to a flask and
azeotroped with toluene twice to give a dry solid. The solid was
flash chromatographed on silica eluting with dichloromethane and
methanol (95/5). The relevant fractions were combined and
evaporated to give
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4--
one (2.26 g, 87%) as a white solid.
[0723] MS (ESI): 368 (MH).sup.+.
[0724]
7-(3-(1,1-Dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinaz-
olin-4-one (4.2 g, 11.4 mmol) was suspended in thionyl chloride (45
ml) and DMF (0.1 ml) then heated at reflux for 2.5 hours. The
residue was diluted with toluene, the thionyl chloride was
evaporated under vacuum, the residue was then azeotroped with
toluene three times. The residue was taken up in water and basified
(pH8) with saturated aqueous sodium hydrogen carbonate solution.
The aqueous layer was extracted with dichloromethane (.times.4),
the organic layer was washed with water and brine then filtered
through phase separating paper. The organic layer was concentrated
under vacuum to give an orange solid. The solid was flash
chromatographed on silica eluting with dichloromethane and methanol
(95/5). The relevant fractions were combined and evaporated to give
a solid which was triturated with ether then filtered and dried to
give
4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline
(2.27 g, 52%).
[0725] MS (ESI): 386 (MH).sup.+.
Example 6
[0726] 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (290 mg, 1.4 mmol)
was suspended in thionyl chloride (5 ml) and DMF (2 drops) and
heated at reflux for 2 hours. The thionyl chloride was evaporated
under vacuum and the residue azeotroped with toluene three times to
give 4-chloro-6,7-dimethoxyquinazoline. A mixture of the crude
4-chloro-6,7-dimethoxyquinazoline, potassium carbonate (970 mg, 7
mmol) and 7-hydroxyquinoline (235 mg, 1.62 mmol) in DMF (10 ml) was
stirred at 100.degree. C. for 5 hours and allowed to cool to
ambient temperature overnight. The reaction mixture was treated
with 1M aqueous sodium hydroxide solution and stirred at ambient
temperature for a few minutes. The reaction mixture was extracted
with ethyl acetate (.times.4) and the organic extracts washed with
water and brine. The organic extracts were dried (MgSO.sub.4),
filtered and the solvent removed under vacuum. The residue was
triturated with ethyl acetate and then recrystallised from hot
ethyl acetate to give 6,7-dimethoxy-4-(quinolin-7-yloxy)quinazoline
(110 mg, 24%) as a white solid.
[0727] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.00(s, 3H); 4.00(s,
3H); 7.40(s, 1H); 7.59(m, 3H); 7.92(d, 1H); 8.08(d, 1H); 8.42(d,
1H); 8.55(s, 1H); 8.92(dd, 1H)
[0728] MS (ESI): 334 (MH).sup.+ TABLE-US-00007 Elemental analysis:
Found C 68.2 H 4.3 N 12.5 C.sub.19H.sub.15N.sub.3O.sub.3 Requires C
68.5 H 4.5 N 12.6%
[0729] The starting material was prepared as follows:
[0730] A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and
formamide (10 ml) was stirred and heated at 190.degree. C. for 5
hours. The mixture was allowed to cool to approximately 80.degree.
C. and water (50 ml) was added. The mixture was then allowed to
stand at ambient temperature for 3 hours. The precipitate was
collected by filtration, washed with water and tried to give
6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).
EXAMPLE 7
[0731] A mixture of
(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline
(183 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and
7-hydroxyquinoline (111 mg, 0.77 mmol) in DMF (7 ml) was stirred at
100.degree. C. for 5 hours and allowed to cool to ambient
temperature. The reaction mixture was treated with 1M aqueous
sodium hydroxide solution (30 ml) and stirred for 10 minutes. The
crude solid was collected by filtration washing with water. The
resultant solid was dissolved in dichloromethane (2 ml) and
filtered through phase separating paper. The filtrate was
evaporated under vacuum to give a solid residue which was
triturated with ether, filtered and dried to give a scalemic
mixture of
6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line (149 mg, 61%).
[0732] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.10(m, 1H); 1.51(m,
1H); 1.64(m, 1H); 1.85(m, 3H); 2.09(m, 1H); 2.15(s, 3H); 2.62(m,
1H); 2.82(m, 1H); 3.99(s, 3H); 4.09(d, 2H); 7.38(s, 1H); 7.55(m,
2H); 7.63(s, 1H); 7.91(d, 1H); 8.10(d, 1H); 8.44(d, 1H); 8.54(s,
1H); 8.93(d, 1H)
[0733] MS (ESI): 431 (MH).sup.+ TABLE-US-00008 Elemental analysis:
Found C 68.7 H 5.7 N 12.8 C.sub.25H.sub.26N.sub.4O.sub.30.3H.sub.2O
Requires C 68.9 H 6.2 N 12.8%
[0734] The starting material was prepared as follows:
[0735] (R)-Ethyl nipecotate (5.7 g 365 mmol), (prepared by
resolution of ethyl nipecotate by treatment with L(+)-tartaric acid
as described in J. Org. Chem. 1991, (56), 1168), was dissolved in
38.5% aqueous formaldehyde solution (45 ml) and formic acid (90 ml)
and the mixture heated at reflux for 18 hours. The mixture was
allowed to cool and added dropwise to cooled saturated aqueous
sodium hydrogen carbonate solution. The mixture was adjusted to
pH12 by addition of sodium hydroxide and the mixture was extracted
with methylene chloride. The organic extract was washed with brine,
dried (MgSO.sub.4) and the solvent removed by evaporation to give
(R)-ethyl 1-methylpiperidine-3-carboxylate (4.51 g, 73%) as a
colourless oil.
[0736] MS-ESI: 172 [MH].sup.+.
[0737] A solution of (R)-ethyl 1-methylpiperidine-3-carboxylate
(5.69 g, 33 mmol) in ether (20 ml) was added dropwise to a stirred
solution of lithium aluminium hydride (36.6 ml of a 1M solution in
THF, 36.6 mmol) in ether (85 ml) cooled to maintain a reaction
temperature of 20.degree. C. The mixture was stirred for 1.5 hours
at ambient temperature and then water (1.4 ml), 15% aqueous sodium
hydroxide solution (1.4 ml) and then water (4.3 ml) were added. The
insolubles were removed by filtration and the volatiles removed
from the filtrate by evaporation to give
(R)-(1-methylpiperidin-3-yl)methanol (4.02 g, 94%) as a colourless
oil.
[0738] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.06(q, 1H);
1.51-1.94(m, 5H); 2.04(s, 3H); 2.34(br s, 1H); 2.62(m, 1H); 2.78(d,
1H); 3.49(m, 1H); 3.59(m, 1H)
[0739] MS-ESI: 130 [MH].sup.+
[0740] 4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline
(12.1 g, 3 8 mmol), (prepared as described for the starting
material in Example 5), was suspended in dichloromethane (375 ml)
and treated with triphenylphosphine (29.6 g, 113 mmol) then stirred
at ambient temperature for 30 minutes.
(1-Methylpiperidin-3-yl)methanol (8.25 g, 63.8 mmol) and
(R)-(1-methylpiperidin-3-yl)methanol (1.46 g, 11.3 mmol), (CAS
20519411-2), giving R:S (57.5:42.5 by chiral HPLC) (9.7 g, 75 mmol)
were dissolved in dichloromethane (75 ml) and added to the
suspension. Diethyl azodicarboxylate (17.7 ml, 75 mmol) was added
in portions using a syringe pump and the mixture was then allowed
to warm to ambient temperature and stirred overnight. The residue
was concentrated under vacuum then chromatographed on silica
eluting with dichloromethane followed by
dichloromethane/methanol/ammonia (93/6/1). The relevant fractions
were combined and evaporated to give an oil. The residue was
triturated with ether, filtered and dried to give
(R,S)-4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-3-yl)m-
ethoxy)quinazoline (8.7 g, 53%).
[0741] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.11(m, 1H); 1.50(m,
1H); 1.58-1.98(m, 4H); 2.09(m, 1H); 2.15(s, 3H); 2.62(d, 1H);
2.81(d, 1H); 3.95(s, 3H); 4.09(d, 2H); 7.39(m, 2H); 7.55(m, 2H);
7.67(d, 1H); 8.53(s, 1H)
[0742] MS (ESI): 432 (MH).sup.+
[0743]
(R,S)-4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-((1-methylpiperidin-
-3-yl)methoxy)quinazoline (8.7 g, 20 mmol) was dissolved in 2M
aqueous hydrochloric acid (150 ml) and heated at reflux for 1.5
hours. The reaction mixture was concentrated then basified (pH9)
with saturated aqueous ammonia solution (0.88). The aqueous layer
was extracted with dichloromethane (4.times.400 ml) and the organic
extracts filtered through phase separating paper then evaporated
under vacuum. The solid was triturated with ether to give
(R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroquinazolin-
-4-one (4.05 g, 66%) as a white solid.
[0744] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.05(m, 1H);
1.40-1.95(m, 5H); 2.02(m, 1H); 2.14(s, 3H); 2.59(d, 1H); 2.78(d,
1H); 3.85(s, 3H); 3.95(d, 2H); 7.09(s, 1H); 7.42(s, 1H); 7.95(s,
1H); 12.00(s, 1H)
[0745] MS (ESI): 304 (MH).sup.+
[0746]
(R,S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-3,4-dihydroqui-
nazolin-4-one (2.72 g, 8.9 mmol) was suspended in thionyl chloride
(90 ml) and DMF (0.5 ml) and heated at reflux for 45 minutes. The
thionyl chloride was evaporated under vacuum and the residue
azeotroped with toluene three times. The residue was taken up in
water and basified (pH8) with saturated aqueous sodium hydrogen
carbonate solution. The aqueous layer was extracted with ethyl
acetate (4.times.400 ml). The organic extracts were washed with
saturated aqueous sodium hydrogen carbonate solution, water and
brine then dried (MgSO.sub.4). After filtration the organic
extracts were concentrated under vacuum then dried overnight at
40.degree. C. under vacuum to give
(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline
(2.62 g, 91%) as a solid.
[0747] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.10(m, 1H);
1.42-1.96(m, 5H); 2.09(m, 1H); 2.15(s, 3H); 2.60(d, 1H); 2.80(d,
1H); 3.98(s, 3H); 4.10(d, 2H); 7.35(s, 1H); 7.42(s, 1H); 8.84(s,
1H)
[0748] MS (ESI): 322 (MH).sup.+
EXAMPLE 8
[0749]
(R,S)-6-Methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7--
yloxy)quinazoline, (prepared as described in Example 7), was
chromatographed on Chiral CEL OD (250 mm.times.4.6 mm), (trade mark
of Daicel Chemical Industries Ltd), in
isohexane/ethanol/triethylamine/TFA (80/20/0.5/0.25). The relevant
fractions for S (RT 12.55) and R (RT 15.88) enantiomers were each
combined separately and worked up as follows.
[0750] The solution was evaporated under vacuum to give a liquid.
This was treated with 5M aqueous sodium hydroxide solution (15 ml)
and extracted with ethyl acetate. The organic extracts were washed
with water then brine and filtered through phase separating paper.
The filtrate was evaporated to give
(S)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)qui-
nazoline (50 mg). The same method was used to give
(R)-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(quinolin-7-yloxy)qui-
nazoline (71 mg).
EXAMPLE 9
[0751] A suspension of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13
g, 0.4 mmol), 5-hydroxy-2-methylindole (74 mg, 0.5 mmol) and
potassium carbonate (83 mg, 0.6mmol) in DMF (1.5 ml) was stirred at
100.degree. C. for 2 hours. After cooling to ambient temperature,
water (20 ml) was added. The precipitate was collected by
filtration, washed with water and dried under vacuum at 60.degree.
C. to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (80 mg, 46%).
[0752] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.9-2.0(m, 2H); 2.05-2.2(m, 2H); 2.25-2.4(m, 2H); 2.43(s, 3H);
3.05-3.2(m, 2H); 3.35-3.5(m, 2H); 3.65-3.75(m, 2H); 4.12(s, 3H);
4.35-4.5(t, 2H); 7.0(dd, 1H); 7.35(d, 1H); 7.42(d, 1H); 7.6(s, 1H);
7.85(s, 1H); 9.15(s, 1H)
[0753] MS (ESI): 433 (MH).sup.+
[0754] The starting material was prepared as follows:
[0755] A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g, 50
mmol), 3-(pyrrolidin-1-yl)propyl chloride (14.75 g, 0.1 mol), (J.
Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (13.8 g, 0.1
mol) and potassium iodide (1.66 g, 10 mmol) in DMF (150 ml) was
stirred and heated at 100.degree. C. for 3 hours. The mixture was
allowed to cool and the insolubles were removed by filtration and
the volatiles were removed from the filtrate by evaporation. The
residue was dissolved in ethanol (75 ml), 2M aqueous sodium
hydroxide (75 ml) was added and the mixture was heated at
90.degree. C. for 2 hours. The mixture was concentrated by
evaporation, acidified with concentrated hydrochloric acid, washed
with ether and then subjected to purification on a Diaion (trade
mark of Mitsubishi) HP20SS resin column, eluting with water and
then with a gradient of methanol (0 to 25%) in dilute hydrochloric
acid (pH2.2). The methanol was removed by evaporation and the
aqueous residue was freeze dried to give
3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride
(12.2 g, 77%).
[0756] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
2.2(m, 2H); 3.15(t, 2H); 3.3(t, 2H); 3.5(d, 2H); 3.7(t, 2H);
3.82(s, 3H); 4.05(d, 2H); 4.15(t, 2H); 7.07(d, 1H); 7.48(s, 1H);
7.59(d, 1H)
[0757] MS-EI: 279 [M.sup.-].sup.+
[0758] Fuming nitric acid (2.4 ml, 57.9 mmol) was added slowly at
0.degree. C. to a solution of
3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride
(12.1 g, 38.17 mmol) in TFA (40 ml). The cooling bath was removed
and the reaction mixture stirred at ambient temperature for 1 hour.
The TFA was removed by evaporation and ice/water was added to the
residue and the solvent removed by evaporation. The solid residue
was dissolved in dilute hydrochloric acid (pH2.2), poured onto a
Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted
with methanol (gradient 0 to 50%) in water. Concentration of the
fractions by evaporation gave a precipitate which was collected by
filtration and dried under vacuum over phosphorus pentoxide to give
5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid
hydrochloride (12.1 g, 90%).
[0759] .sup.1H NMR Spectrum: (DMSOd.sub.6, TFA) 1.8-1.9 (m, 2H);
2.0-2.1(m, 2H); 2.1-2.2(m, 2H); 3.0-3.1(m, 2H); 3.3(t, 2H);
3.6-3.7(m, 2H); 3.95(s, 3H); 4.25(t, 2H); 7.35(s, 1H); 7.62(s,
1H)
[0760] A solution of
5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid
hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20 ml) and DMF
(50 .mu.l) was heated at 45.degree. C. for 1.5 hours. The excess
thionyl chloride was removed by evaporation and by azeotroping with
toluene (.times.2). The resulting solid was suspended in THF (250
ml) and methylene chloride (100 ml) and ammonia was bubbled though
the mixture for 30 minutes and the mixture stirred for a further
1.5 hours at ambient temperature. The volatiles were removed by
evaporation, the residue was dissolved in water and applied to a
Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted
with water/methanol (100/0 to 95/5). The solvent was removed by
evaporation from the fractions containing product and the residue
was dissolved in a minimum of methanol and the solution was diluted
with ether. The resulting precipitate was collected by filtration,
washed with ether and dried under vacuum to give
5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g,
73%).
[0761] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.85-1.95(m, 2H); 2-2.1(m, 2H); 2.15-2.25(m, 2H); 3.0-3.1(m, 2H);
3.31(t, 2H); 3.62(t, 2H); 3.93(s, 3H); 4.2(t, 2H); 7.16(s, 1H);
7.60(s, 1H)
[0762] MS-EI: 323 [M.sup.-].sup.+
[0763] Concentrated hydrochloric acid (5 ml) was added to a
suspension of
5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzamide (1.5 g,
4.64 mmol) in methanol (20 ml) and the mixture was heated at
50.degree. C. to give a solution. Iron powder (1.3 g, 23.2 mmol)
was added in portions and the reaction mixture was then heated at
reflux for 1 hour. The mixture was allowed to cool, the insolubles
were removed by filtration through diatomaceous earth and the
volatiles were removed from the filtrate by evaporation. The
residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS
resin column, eluting with water anti then with dilute hydrochloric
acid (pH2). The fractions containing product were concentrated by
evaporation and the resulting precipitate was collected by
filtration and dried under vacuum over phosphorus pentoxide to give
2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide
hydrochloride (1.44 g, 85%).
[0764] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.9(br s, 2H); 2.05(br s, 2H); 2.2(br s, 2H); 3.05(br s, 2H);
3.3(t, 2H); 3.61(br s, 2H); 3.8(s, 3H); 4.11(t, 2H); 7.05(s, 1H);
7.53(s, 1H)
[0765] MS-EI: 293 [M.sup.-].sup.+
[0766] A mixture of
2-amino-5-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzamide
hydrochloride (5.92 g, 16.2 mmol) and Gold's reagent (3.5 g, 21.4
mmol) in dioxane (50 ml) was heated at reflux for 5 hours. Acetic
acid (0.7 ml) and sodium acetate (1.33 g) were added to the
reaction mixture which was heated at reflux for a further 5 hours.
The mixture was allowed to cool and the volatiles were removed by
evaporation. The residue was dissolved in water, adjusted to pH8
with 2M aqueous sodium hydroxide solution and purified on a Diaion
(trademark of Mitsubishi) HP20SS resin column eluting with methanol
(gradient 0-50%) in water. The fractions containing product were
concentrated by evaporation and then freeze dried to give
4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (4.55
g, 83%).
[0767] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.9(m, 2H); 2.0-2.1(m, 2H); 2.2-2.3(m, 2H); 3.05(m, 2H); 3.34(t,
2H); 3.6-3.7(br s, 2H); 3.94(s, 3H); 4.27(t, 2H); 7.31(s, 1H);
7.55(s, 1H); 9.02(s, 1H)
[0768] A mixture of
4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7
g, 5 mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was
heated at reflux for 3 hours. Excess thionyl chloride was removed
by evaporation and by azeotroping with toluene (.times.2). The
residue was suspended in ether and 10% aqueous solution of sodium
hydrogen carbonate was added to the mixture. The organic layer was
separated, dried (MgSO.sub.4) and the solvent removed by
evaporation to give
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94
g, quantitative).
[0769] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.8(br s, 4H); 2.17(m,
2H); 2.6(br s, 4H); 2.7(t, 2H); 4.05(s, 3H); 4.3(t, 2H); 7.35(s,
1H); 7.38(s, 1H); 8.86(s, 1H)
[0770] MS-ESI: 322 [MH].sup.+
EXAMPLE 10
[0771] A suspension of
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(74 mg, 0.23 mmol), potassium carbonate (48 mg, 0.35 mmol) and
7-hydroxyquinoline (40.6 mg, 0.28 mmol) in DMF (1.5 ml) was heated
at 100.degree. C. for 3 hours. After cooling, the mixture was
stirred for 10 hours at ambient temperature and then overnight at
5.degree. C. After dilution with methylene chloride (5 ml), the
mixture was poured onto a column of silica and was eluted with an
increasing gradient of methanol/methylene chloride (10/90, 20/80)
followed by ammonia/methanol (5%) in methylene chloride (25/75) to
give, after removal of the volatiles by evaporation and drying
under vacuum,
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-7-yloxy)quinazo-
line (82 mg, 88%).
[0772] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5(m, 2H);
1.75-1.9(m, 3H); 1.9-2.05(m, 2H); 2.12(s, 3H); 2.8-2.9(d, 2H);
4.5(s, 3H); 4.1(d, 2H); 7.4(s, 1H); 7.6(dd, 1H); 7.62(dd, 1H)
[0773] MS (ESI): 431 [MH].sup.+
[0774] The starting material was prepared as follows:
[0775] To a solution of ethyl 4-piperidinecarboxylate (30 g, 0.19
mol) in ethyl acetate (150 ml) cooled at 5.degree. C. was added
dropwise a solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol)
in ethyl acetate (75 ml) while maintaining the temperature in the
range 0-5.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), 0.1M 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-butyloxycarbonylpiperidine)carboxylate (48 g, 98%).
[0776] .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)
[0777] To a solution of ethyl
4-(1-tert-butyloxycarbonylpiperidine)carboxylate (48 g, 0.19 mol)
in dry THF (180 ml) cooled at 0.degree. C. was added dropwise a
solution of 1M lithium aluminium hydride in THF (133 ml, 0.133
mol). After stirring at 0.degree. C. for 2 hours, water (30 ml) was
added followed by 2M sodium hydroxide (10 ml). The precipitate was
filtered through diatomaceous earth and washed with ethyl acetate.
The filtrate was washed with water, brine, dried (MgSO.sub.4) and
evaporated to give
4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (36.3 g,
89%).
[0778] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.05-1.2(m, 2H);
1.35-1.55(m, 10H); 1.6-1.8(m, 2H); 2.6-2.8(t, 2H); 3.4-3.6(t, 2H);
4.0-4.2(br s, 2H)
[0779] MS (EI): 215 [M.]+
[0780] To a solution of
4-hydroxymethyl-1-tert-butyloxycarbonylpiperidine (52.5 g, 0.244
mol) in tert-butyl methyl ether (525 ml) was added
1,4-diazabicyclo[2.2.2]octane (42.4 g, 0.378 mol). After stirring
for 15 minutes at ambient temperature, the mixture was cooled to
5.degree. C. and a solution of toluene sulphonyl chloride (62.8 g,
0.33 mmol) in tert-butyl methyl ether (525 ml) was added dropwise
over 2 hours while maintaining the temperature at 0.degree. C.
After stirring for 1 hour at ambient temperature, petroleum ether
(1l) was added. The precipitate was removed by filtration. The
filtrate was evaporated to give a solid. The solid was dissolved in
ether and washed successively with 0.5M aqueous hydrochloric acid
(2.times.500 ml), water, saturated sodium hydrogen carbonate and
brine, dried (MgSO.sub.4) and evaporated to give
4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine
(76.7 g, 85%).
[0781] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.0-1.2(m, 2H); 1.45(s,
9H); 1.65(d, 2H); 1.75-1.9(m, 2H); 2.45(s, 3H); 2.55-2.75(m, 2H);
3.85(d, 1H); 4.0-4.2(br s, 2H); 7.35(d, 2H); 7.8(d, 2H)
[0782] MS (ESI): 392 [MNa].sup.+
[0783] To a suspension of ethyl 3-methoxy-4-hydroxybenzoate (19.6
g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200
ml) was added
4-(4-methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperid-
ine (40 g, 0.11 mol). After stirring at 95.degree. C. for 2.5
hours, the mixture was cooled to ambient temperature and
partitioned between water and ethyl acetate/ether. The organic
layer was washed with water, brine, dried (MgSO.sub.4) and
evaporated. The resulting oil was crystallised from petroleum ether
and the suspension was stored overnight (at 5.degree. C.). The
solid was collected by filtration, washed with petroleum ether and
dried under vacuum to give ethyl
3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate
(35 g, 89%).
[0784] m.p. 81-83.degree. C.
[0785] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2-1.35(m, 2H); 1.4(t,
3H); 1.48(s, 9H); 1.8-1.9(d, 2H); 2.0-2.15(m, 2H); 2.75(t, 2H);
3.9(d, 2H); 3.95(s, 3H); 4.05-4.25(br s, 2H); 4.35(q, 2H); 6.85(d,
1H); 7.55(s, 1H); 7.65(d, 1H)
[0786] MS (ESI): 416 [MNa].sup.+ TABLE-US-00009 Elemental analysis:
Found C 63.4 H 8.0 N 3.5 C.sub.21H.sub.31NO.sub.60.3H.sub.2O
Requires C 63.2 H 8.0 N 3.5%
[0787] To a solution of ethyl
3-methoxy-4-(1-tert-butyloxycarbonylpiperidin-4-ylmethoxy)benzoate
(35 g, 89 mmol) in formic acid (35 ml) was added formaldehyde (12M,
37% in water, 35 ml, 420 mmol). After stirring at 95.degree. C. for
3 hours, the volatiles were removed by evaporation. The residue was
dissolved in methylene chloride and 3M hydrogen chloride in ether
(40 ml, 120 mmol) was added. After dilution with ether, the mixture
was triturated until a solid was formed. The solid was collected by
filtration, washed with ether and dried under vacuum overnight at
50.degree. C. to give ethyl
3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g,
quant.).
[0788] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.29(t, 3H); 1.5-1.7(m,
2H); 1.95(d, 2H); 2.0-2.15(br s, 1H); 2.72(s, 3H); 2.9-3.1(m, 2H);
3.35-3.5(br s, 2H); 3.85(s, 3H); 3.9-4.05(br s, 2H); 4.3(q, 2H);
7.1(d, 1H); 7.48(s, 1H); 7.6(d, 1H)
[0789] MS (ESI): 308 [MH].sup.+
[0790] A solution of ethyl
3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (30.6 g, 89
mmol) in methylene chloride (75 ml) was cooled to 0-5.degree. C.
TFA (37.5 ml) was added followed by the dropwise addition over 15
minutes of a solution of fuming 24M nitric acid (7.42 ml, 178 mmol)
in methylene chloride (15 ml). After completion of the addition,
the solution was allowed to warm up and stirred at ambient
temperature for 2 hours. The volatiles were removed under vacuum
and the residue was dissolved in methylene chloride (50 ml). The
solution was cooled to 0-5.degree. C. and ether was added. The
precipitate was collected by filtration, and dried under vacuum at
50.degree. C. The solid was dissolved in methylene chloride (500
ml) and 3M hydrogen chloride in ether (30 ml) was added followed by
ether (500 ml). The solid was collected by filtration and dried
under vacuum at 50.degree. C. to give ethyl
3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (28.4
g, 82%).
[0791] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3(t, 3H); 1.45-1.65(m,
2H); 1.75-2.1(m, 3H); 2.75(s, 3H); 2.9-3.05(m, 2H); 3.4-3.5(d, 2H);
3.95(s, 3H); 4.05(d, 2H); 4.3(q, 2H); 7.32(s, 1H); 7.66(s, 1H)
[0792] MS (ESI): 353 [MH].sup.+
[0793] A suspension of ethyl
3-methoxy4-(1-methylpiperidin-4-ylmethoxy)-6-nitrobenzoate (3.89 g,
10 mmol) in methanol (80 ml) containing 10% platinum on activated
carbon (50% wet) (389 mg) was hydrogenated at 1.8 atmospheres
pressure until uptake of hydrogen ceased. The mixture was filtered
and the filtrate was evaporated. The residue was dissolved in water
(30 ml) and adjusted to pH10 with a saturated solution of sodium
hydrogen carbonate. The mixture was diluted with ethyl
acetate/ether (1/1) and the organic layer was separated. The
aqueous layer was further extracted with ethyl acetate/ether and
the organic layers were combined. The organic layers were washed
with water, brine, dried (MgSO.sub.4), filtered and evaporated. The
resulting solid was triturated in a mixture of ether/petroleum
ether, filtered, washed with petroleum ether and dried under vacuum
at 60.degree. C. to give ethyl
6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (2.58
g, 80%).
[0794] m.p. 111-112.degree. C.
[0795] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.35(t, 3H); 1.4-1.5(m,
2H); 1.85(m, 3H); 1.95(t, 2H); 2.29(s, 3H); 2.9(d, 2H); 3.8(s, 3H);
3.85(d, 2H); 4.3(q, 2H); 5.55(br s, 2H); 6.13(s, 1H); 7.33(s,
1H)
[0796] MS (ESI): 323 [MH].sup.+ TABLE-US-00010 Elemental analysis:
Found C 62.8 H 8.5 N 8.3 C.sub.17H.sub.26N.sub.2O.sub.40.2H.sub.2O
Requires C 62.6 H 8.2 N 8.6%
[0797] A solution of ethyl
6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1
g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine
acetate (5.2 g, 50mmol) was heated at 115.degree. C. for 2 hours.
Formamidine acetate (10.4 g, 100 mmol) was added in portions every
30 minutes during 4 hours. Heating was prolonged for 30 minutes
after the last addition. After cooling, the volatiles were removed
under vacuum. The solid was dissolved in ethanol (100 ml) and
methylene chloride (50 ml). The precipitate was removed by
filtration-and the filtrate was concentrated to a final volume of
100 ml. The suspension was cooled to 5.degree. C. and the solid was
collected by filtration, washed with cold ethanol followed by ether
and dried under vacuum overnight at 60.degree. C. to give
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one
(12.7 g, 70%).
[0798] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25-1.4(m, 2H); 1.75(d,
2H); 1.9(t, 1H); 1.9(s, 3H); 2.16(s, 2H); 2.8(d, 2H); 3.9(s, 3H);
4.0(d, 2H); 7.11(s, 1H); 7.44(s, 1H); 7.97(s, 1H)
[0799] MS (ESI): 304 [MH].sup.+
[0800] A solution of
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one
(2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing DMF (280
.mu.l) was refluxed at 85.degree. C. for 1 hour. After cooling, the
volatiles were removed by evaporation. The precipitate was
triturated with ether, filtered, washed with ether and dried under
vacuum. The solid was dissolved in methylene chloride and saturated
aqueous sodium hydrogen carbonate was added. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated to give
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(2.9 g, 98%).
[0801] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5(m, 2H);
1.75-1.9(m, 3H); 2.0(t, 1H); 2.25(s, 3H); 2.85(d, 2H); 4.02(s, 3H);
4.12(d, 2H); 7.41(s, 1H); 7.46(s, 1H); 8.9(t, 1H)
[0802] MS (ESI): 322 [MH].sup.+
EXAMPLE 11
[0803] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(0.13 g, 0.4 mmol), (prepared as described for the starting
material in Example 10), was reacted with 5-hydroxy-2-methylindole
(74 mg, 0.5 mol) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)qu-
inazoline (137 mg, 79%).
[0804] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45(m, 2H);
1.7-1.95(m, 5H); 2.15(s, 3H); 2.4(s, 3H); 2.8(d, 2H); 3.98(s, 3H);
4.05(d, 2H); 6.14(s, 1H); 6.88(d, 1H); 7.29(s, 1H); 7.32(d, 1H);
7.35(s, 1H); 7.6(s, 1H); 8.45(s, 1H)
[0805] MS (ESI): 433 [MH].sup.+
EXAMPLE 12
[0806] To a solution of
4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)q-
uinazoline (115 mg, 0.28 mmol) and 7-hydroxyquinoline (50 mg, 0.33
mmol) in DMF (1.5. ml) was added potassium carbonate (60 mg, 0.42
mmol). The mixture was stirred for 2 hours at 100.degree. C. After
cooling, and removal of the volatiles by evaporation, the residue
was partitioned between ethyl acetate and water. The organic layer
was washed with water, brine, dried (MgSO.sub.4) and evaporated.
The residue was purified by column chromatography eluting with
ethylacetate/methylene chloride/methanol (1/1/0 followed by
40/50/10 and 0/9/1). After removal of the volatiles by evaporation,
the residue was triturated with pentane, filtered and dried under
vacuum to give
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-4-(quinol-
in-7-yloxy)quinazoline (110 mg, 76%).
[0807] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45(m, 2H);
1.75-1.9(m, 3H); 2.05(t, 2H); 2.72(t, 2H); 2.95(d, 2H); 3.05(s,
3H); 3.35-3.45(m, 2H); 4.00(s, 3H); 4.1(d, 2H); 7.41(s, 1H);
7.57(dd, 1H); 7.62(dd, 1H); 7.65(s, 1H); 7.93(s, 1H); 8.12(d, 1H);
8.45(d, 1H); 8.55(s, 1H); 8.95(d, 1H)
[0808] MS (ESI): 523 [MH].sup.+ TABLE-US-00011 Elemental analysis:
Found C 61.3 H 6.0 N 10.6
C.sub.27H.sub.30N.sub.4O.sub.5S0.4H.sub.2O Requires C 61.2 H 5.9 N
10.6%
[0809] The starting material was prepared as follows:
[0810] 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), (prepared as described for the starting material in Example
1), 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 (MgSO.sub.4) 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%).
[0811] .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)
[0812] 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%).
[0813] .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)
[0814] A suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(6.12 g, 20 mmol) potassium carbonate (5.52 g, 40 mmol) in DMF (60
ml) was stirred at ambient temperature for 30 minutes.
4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine
(8.86 g, 24 mmol), (prepared as described for the starting material
in Example 10), was added and the mixture was stirred at
100.degree. C. for 2 hours. After cooling, the mixture was poured
onto water/ice (400 ml, 1/1) containing 2M hydrochloric acid (10
ml). The precipitate was collected by filtration, washed with water
and dried under vacuum over phophorus pentoxide. The solid was
triturated in a mixture of ether/pentane (1/1), collected by
filtration and dried to give
6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4--
yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 78.5%).
[0815] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.1(s, 9H); 1.1-1.3(m,
2H); 1.42(s, 9H); 1.73(d, 2H); 1.93-2.1(br s, 1H); 2.65-2.9(br s,
2H); 3.9(s, 3H); 3.9-4.1(m, 4H); 5.9(s, 2H); 7.2(s, 1H); 7.5(s,
1H); 8.35(s, 1H)
[0816] MS (ESI): 526 [MNa]+
[0817] A solution of
6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4--
yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 16 mmol) in
methylene chloride (80 ml) containing 5.5M hydrogen chloride in
isopropanol (80 ml) was stirred for 1 hour at ambient temperature.
Ether was added and the solid was collected by filtration, washed
with ether and dried under vacuum at 60.degree. C. to give
6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydro-
quinazolin one hydrochloride (6.9 g, 100%).
[0818] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.15(s, 9H); 1.5-1.7(m, 2H); 2.0(d, 2H); 2.2-2.3(br s, 1H); 3.0(t,
2H); 3.4(d, 2H); 3.94(s, 3H); 4.15(d, 2H); 5.97(s, 2H); 7.3(s, 1H);
7.6(s, 1H); 8.65(s, 1H)
[0819] MS (ESI): 404 [MH].sup.+
[0820] To a solution of
6-methoxy-7-((piperidinyl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroqui-
nazolin-4-one hydrochloride (0.88 g, 2 mmol) and triethylamine (0.3
ml, 2.1 mmol) in methanol (10 ml) and methylene chloride (10 ml)
was added potassium carbonate (280 mg, 2 mmol) and methyl vinyl
sulfone (0.4 ml, 2.1 mmol). After stirring for 2 hours at ambient
temperature, the volatiles were removed under vacuum. The residue
was partitioned between ethyl acetate and water. The organic layer
was washed with brine, dried (MgSO.sub.4) and evaporated to give
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pival-
oyloxy)methyl)-3,4-dihydroquinazolin-4-one (0.55 g, 54%).
[0821] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.09(s, 9H); 1.25-1.4(m,
2H); 1.7-1.9(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.95(d, 2H); 3.02(s,
3H); 3.25-3.45(m, 2H); 3.9(s, 3H); 4.0(d, 2H); 5.9(s, 2H); 7.15(s,
1H); 7.49(s, 1H); 8.35(s, 1H)
[0822] MS (ESI): 510 [MH].sup.+
[0823] To a suspension of
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pival-
oyloxy)methyl)-3,4-dihydroquinazolin-4-one (90 mg, 0.18 mmol) in
methanol (3 ml) was added 2M aqueous sodium hydroxide (180 .mu.l,
0.35 mmol). After stirring for 2 hours at ambient temperature, the
mixture was adjusted to pH 10 with 2M hydrochloric acid. The
volatiles were removed under vacuum and the residue was suspended
in water, filtered, washed with water followed by ether and dried
under vacuum at 60.degree. C. to give
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4--
dihydroquinazolin-4-one (55 mg, 79%).
[0824] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.2-1.4(m, 2H);
1.7-1.85(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.9(d, 2H); 3.02(s, 3H);
3.3-3.5(m, 2H); 3.9(s, 3H); 4.0(d, 2H); 7.11(s, 1H); 7.45(s, 1H);
7.97(s, 1H)
[0825] MS (ESI): 396 [MH].sup.+
[0826] A solution of
6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3,4-dihyd-
roquinazolin-4-one (335 mg, 0.85 mmol) in thionyl chloride (5 ml)
containing DMF (50 .mu.l) was refluxed for 1 hour. After cooling,
the volatiles were removed under vacuum and the residue was
triturated with ether and filtered. The solid was suspended in
methylene chloride and sodium hydrogen carbonate was added. The
organic layer was washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was triturated with ether, filtered and
dried under vacuum to give
4chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)qui-
nazoline (335 mg, 95%).
[0827] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25-1.45(m, 2H);
1.75-1.90(m, 3H); 2.0(t, 2H); 2.7(t, 2H); 2.92(d, 2H); 3.03(s, 3H);
3.2-3.35(m, 2H); 4.0(s, 3H); 4.1(d, 2H); 7.40(s, 1H); 7.45(s, 1H);
8.9(s, 1H)
[0828] MS (ESI): 414 [MH].sup.+
EXAMPLE 13
[0829] Using a procedure analogous to that described for Example
10,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(130 mg, 0.4 mmol), (prepared as described for the starting
material in Example 10), was reacted with
4-methyl-7-hydroxyquinoline (80 mg, 0.5 mol), (Chem. Ber. 1967,
100, 2077), to give
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(4-methylquinolin-7-yloxy-
)quinazoline (160 mg, 90%).
[0830] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5(m, 2H);
1.7-1.95(m, 3H); 1.9(t, 2H); 2.17(s, 3H); 2.74(s, 3H); 2.8(d, 2H);
4.07(s, 3H); 4.1(d, 2H); 7.4(m, 2H); 7.65(dd, 1H); 7.9(s, 1H);
8.21(d, 1H); 8.54(s, 1H); 8.78(d, 1H)
[0831] MS (ESI): 445 [MH].sup.+
EXAMPLE 14
[0832] A solution of
4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)q-
uinazoline (115 mg, 0.28 mmol), (prepared as described for the
starting material in Example 12), 5-hydroxy-2-methylindole (50 mg,
0.33 mmol) and potassium carbonate (60 mg, 0.42mmol) in DMF (1.5
ml) was stirred at 100.degree. C. for 2 hours. After cooling, the
mixture was partitioned between ethyl acetate and water. The
organic layer was washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by chromatography eluting with
ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl
acetate/methylene chloride (1/4/5 and 1/0/9) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl-
)piperidin-4-yl)methoxy)quinazoline (60 mg, 41%).
[0833] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45(m, 2H);
1.75-1.92(m, 3H); 2.02(t, 2H); 2.4(s, 3H); 2.7(t, 2H); 2.95(d, 2H);
3.05(s, 3H); 4.0(s, 3H); 4.05(d, 2H); 6.15(s, 1H); 6.85(dd, 1H);
7.25(s, 1H); 7.3(d, 1H); 7.38(s, 1H); 7.6(s, 1H); 8.45(s, 1H)
[0834] MS (ESI): 525 [MH].sup.+ TABLE-US-00012 Elemental analysis:
Found C 60.7 H 6.2 N 10.5 C.sub.27H.sub.32O.sub.5S0.5H.sub.2O
Requires C 60.8 H 6.2 N 10.5%
EXAMPLE 15
[0835] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13
g, 0.4 mol), (prepared as described for the starting material in
Example 9), was reacted with 7-hydroxy-4-methylquinoline (80 mg,
0.5 mol), (Chem. Berich. 1967, 100, 2077), to give
6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quin-
azoline (155 mg, 87%).
[0836] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7(br s, 4H); 2.05(m,
2H); 2.5(br s, 4H); 2.6(t, 2H); 2.75(s, 3H); 4.02(s, 3H); 4.3(t,
2H); 7.41 (s, 1H); 7.45(d, 1H); 7.65(s, 1H); 7.65(d, 1H); 7.95(s,
1H); 8.25(d, 1H); 8.55(s, 1H); 8.8(d, 1H)
[0837] MS (ESI): 445 [MH].sup.+
EXAMPLE 16
[0838] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13
g, 0.4 mol), (prepared as described for the starting material in
Example 9), was reacted with
2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV.
ACAD. NAVK. SSSR. Ser. Khim. 1981, 9,2008), to give
6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroqu-
inolin-6-yloxy)quinazoline (90 mg, 47%).
[0839] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.23(s, 6H); 1.7(br s,
4H); 1.85(s, 3H); 2.0(m, 2H); 2.45(br s, 4H); 2.57(t, 2H); 3.95(s,
3H); 4.25(t, 2H); 5.35(s, 1H); 5.9(s, 1H); 6.5(d, 1H); 6.8(dd, 1H);
6.85(s, 1H); 7.32(s, 1H); 7.52(s, 1H); 8.5(s, 1H)
[0840] MS (ESI): 475 [MH].sup.+
EXAMPLE 17
[0841] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(0.13 g, 0.4 mmol), (prepared as described for the starting
material in Example 10), was reacted with
2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV.
ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give
6-methoxy-7-(1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihyd-
roquinolin-6-yloxy)quinazoline (140 mg, 74%).
[0842] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.15(s, 6H); 1.3-1.45(m,
2H); 1.7-2.0(m, 8H); 2.16(s, 3H); 2.65-2.85(d, 2H); 4.0(s, 3H);
4.05(d, 2H); 5.35(s, 1H); 5.9(s, 1H); 6.5(d, 1H); 6.80(d, 1H);
6.82(s, 1H); 7.33(s, 1H); 7.5(s, 1H); 8.52(s, 1H)
[0843] MS (ESI): 475 [MH].sup.+
EXAMPLE 18
[0844] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(0.13 g, 0.4 mol), (prepared as described for the starting material
in Example 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline
(87 mg, 0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give
4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)met-
hoxy)quinazoline (61 mg, 33%).
[0845] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5(m, 2H);
1.7-1.95(m, 5H); 2.2(s, 3H); 2.65(s, 3H); 2.7(s, 3H); 2.75-2.9(br
d, 2H); 4.05(s, 3H); 4.1(d, 2H); 7.3(s, 1H); 7.4(s, 1H); 7.52(d,
1H); 7.65(s, 1H); 7.8(s, 1H); 8.15(d, 1H); 8.55(s, 1H)
[0846] MS (ESI): 459 [MH].sup.+
EXAMPLE 19
[0847] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(0.13 g, 0.4 mol), (prepared as described for the starting material
in Example 10), was reacted with
6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mol), (J. Chem.
Soc. C, 1971, 2696), to give
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxaz-
in-6-yloxy)quinazoline (158 mg, 88%).
[0848] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25-1.45(m, 2H); 1.8(d,
2H); 1.7-1.9(m, 1H); 1.9(t, 2H); 2.2(s, 3H); 2.8(d, 2H); 3.97(s,
3H); 4.05(d, 2H); 4.65(s, 2H); 6.8(s, 1H); 6.85(d, 1H); 7.05(d,
1H); 7.35(s, 1H); 7.52(s, 1H); 8.55(s, 1H)
[0849] MS (ESI): 451 [MH].sup.+
EXAMPLE 20
[0850] Using a procedure analogous to that described for Example 9,
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13
g, 0.4 mol), (prepared as described for the starting material in
Example 9), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one
(83 mg, 0.5 mol), (J. Chem. Soc. C, 1971, 2696), to give
6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6--
yloxy)quinazoline (170 mg, 94%).
[0851] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3CO.sub.2D)
1.8-2.0(m, 2H); 2.0-2.15(m, 2H); 2.2-2.35(m, 2H); 3.0-3.2(m, 2H);
3.4(t, 2H); 3.6-3.75(m, 2H); 4.05(s, 3H); 4.35(t, 2H); 4.65(s, 2H);
6.85(s, 1H); 6.9(d, 1H); 7.1(d, 1H); 7.5(s, 1H); 7.7(s, 1H); 8.9(s,
1H)
[0852] MS (ESI): 451 [MH].sup.+
EXAMPLE 21
[0853] Using a procedure analogous to that described for Example
10,
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(74 mg, 0.23 mmol), (prepared as described for the starting
material in Example 10), was reacted with 6-hydroxyquinoline (41
mg, 0.28 mol) to give
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(quinolin-6-yloxy)quinazo-
line (89 mg, 94%).
[0854] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5(m, 2H); 1.8(d,
2H); 1.9(t, 2H); 1.8-1.9(m, 1H); 2.2(s, 3H); 2.82(d, 2H); 4.02(s,
3H); 4.1(d, 2H); 7.4(s, 1H); 7.6(dd, 1H); 7.65(s, 1H); 7.75(d, 1H);
7.95(s, 1H); 8.15(d, 1H); 8.4(d, 1H); 8.55(s, 1H); 8.95(d, 1H)
[0855] MS (ESI): 431 [MH].sup.+
EXAMPLE 22
[0856] To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(250 mg, 0.74 mmol), (prepared as described for the starting
material in Example 1), in suspension in DMF (4 ml) were
successively added 4-chloro-7-hydroxyquinoline (133 mg, 0.74 mmol)
and potassium carbonate (153 mg, 1 mmol) and the reaction mixture
heated to 100.degree. C. More 4-chloro-7-hydroxyquinoline (27 mg,
0.15 mmol) was added after one hour and heating was continued for a
further 30 minutes. The product precipitated upon cooling to
ambient temperature. The reaction mixture was diluted with water,
the product was collected by filtration and washed with more water.
The dried solid was triturated with ether and filtered to give
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(166 mg, 47%). .sup.1H NMR Spectrum: (DMSOd.sub.6,
CF.sub.3CO.sub.2D) 2.3(m, 2H); 3.2(m, 2H); 3.4(m, 2H); 3.5(m, 2H);
3.7(m, 2H); 4.0(m, 2H); 4.1(s, 3H); 4.4(m, 2H); 7.55(s, 1H);
7.75(s, 1H); 7.90(dd, 1H); 7.95(d, 1H);.8.15(d, 1H); 8.45 (d, 1H);
8.80(s, 1H); 9.05(d, 1H)
[0857] MS-ESI: 481 [MH].sup.+ TABLE-US-00013 Elemental analysis:
Found C 61.8 H 5.1 N 11.5 C.sub.25H.sub.25ClN.sub.4O.sub.4 Requires
C 62.4 H 5.2 N 11.7%
[0858] The starting material was prepared as follows:
[0859] A solution of 7-benzyloxy-4-chloroquinoline (17 g, 56 mmol),
(Konishi et al. WO 96/11187), in TFA (170 ml) was heated at reflux
for 2 hours. The solvent was removed under vacuum and the residue
was triturated with ether, filtered and washed with ether. The
solid was suspended in an aqueous solution of sodium hydrogen
carbonate (5.5 g, 65 mmol in 200ml of water) and stirred at ambient
temperature for 30 minutes. The solid was collected by filtration,
washed with water and dried overnight under vacuum and over
phosphorus pentoxide to give 4-chloro-7-hydroxyquinoline (9.85 g,
98%).
[0860] .sup.1H NMR Spectrum: (DMSOd.sub.6) 7.37(s, 1H); 7.39(d,
1H); 7.62(d, 1H); 8.15(d, 1H); 8.8(d, 1H);
[0861] MS-EI: m/z 179 [M.]+
EXAMPLE 23
[0862] A solution of
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(74 mg, 0.23 mmol), (prepared as described for the starting
material in Example 10), and 2-hydroxynaphthalene (40 mg, 0.28
mmol) in DMF (1.5 ml) containing potassium carbonate (48 mg, 0.35
mmol) was stirred at 100.degree. C. for 3.5 hours. After cooling,
methylene chloride (4.5 ml) was added and the mixture was poured
onto a column of silica (SiO2 Isolute.RTM.) and eluted with,
successively, methylene chloride, methylene chloride/methanol
(9/1), methylene chloride/methanol/3M ammonia in methanol
(75/20/5). The fractions containing the product were evaporated
under vacuum. The residues was triturated with ether, filtered and
dried under vacuum to give
6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2-naphthyloxy)quinazolin-
e (80 mg, 83%).
[0863] MS-ESI: 430 [MH]+
[0864] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.45 (m, 2H), 1.8
(d, 2H), 2.0 (t, 1H), 2.2 (s, 3H). 2.85 (d, 2H), 3.3-3.4 (m, 2H),
4.02 (s, 3H), 4.1 (d, 2H), 7.4 (s, 1H), 7.5 (dd, 1H), 7.55 (m, 2H),
7.65 (s, 1H), 7.88 (s, 1H), 7.98 (d, 1H), 8.0 (d, 1H), 8.1 (d, 1H),
8.55 (s, 1H)
EXAMPLE 24
[0865] A solution of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg, 0.23
mmol), (prepared as described for the starting material in Example
1), and 3,4-(methylenedioxy)aniline (53 mg, 0.24 mmol) in a
solution of isopropanol (3.5 ml) containing 5.5M hydrogen chloride
in isopropanol (42 .mu.l) was heated for 3 hours. After cooling to
ambient temperature, the reaction mixture was cooled to 0.degree.
C. and maintained at this temperature overnight. The precipitate
was collected by filtration, washed with ethyl acetate and dried
under vacuum to give
4-(1,3-benzodioxol-5-ylamino)-6methoxy-7-(3-morpholinopropoxy)quinazoline
(82 mg, 76%).
[0866] MS-ESI: 439 [MH].sup.+
[0867] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3-2.4 (m, 2H),
3.05-3.2 (m,2H), 3.25-3.35 (m, 2H), 3.5 (d, 2H), 3.82 (t, 2H), 4.0
(d, 2H), 4.05 (s, 3H), 4.32 (t, 2H), 6.1 (s, 2H), 7.02 (d, 1H), 7.1
(dd, 1H), 7.3 (s, 1H), 7.4 (s, 1H), 8.32 (s, 1H), 8.8 (s, 1H)
EXAMPLES 25-29
[0868] Using an analogous procedure to that described in Example
24, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline,
(prepared as described for the starting material in Example 1), was
used in the synthesis of the compounds described in Table I
hereinafter as detailed in the notes a)-e) to Table I.
TABLE-US-00014 TABLE I ##STR26## Example Weight yield MS-ESI No.
(mg) % [MH]+ note R 25 104 90 435.1 a 1-H-indazol-6-yl 26 102 89
435.1 b 1-H-indazol-5-yl 27 99 84 452 c 1,3-benzothiazol-6-yl 28
108 91 466 d 2-methyl-1,3-benzothiazol- 5-yl 29 102 95 435.1 e
2,3-dihydro-1H-inden-5-yl Notes a)
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was
reacted with 6-aminoindazole (32 mg) to give
4-(1-H-indazoI-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3-2.4 (m, 2H), 3.05-3.2 (m,
2H), 3.2-3.3 (m, 2H), 3.52 (d, 2H), 3.85 (t, 2H), 4.0 (d, 2H), 4.05
(s, 3H), 4.32 (t, 2H), 7.42 (s, 1H), 7.45 (d, 1H), 7.85 (d, 1H),
7.98 (s, 1H), 8.1 (s, 1H), 8.42 (s, 1H), 8.85 (s, 1H) b)
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was
reacted with 5-aminoindazole (32 mg) to give
4-(1-H-indazol-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.4) 2.3-2.4 (m, 2H), 3.05-3.2 (m,
2H), 3.25-3.3 (m, 2H), 3.45-3.55 (m, 2H), 3.8-3.9 (m, 2H), 3.9-4.02
(m, 2H), 4.05 (s, 3H), 4.32 (t, 2H), 7.42 (s, 1H), 7.65 (m, 2H),
8.05 (s, 1H), 8.15 (s, 1H), 8.4 (s, 1H), 8.75 (s, 1H) c)
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was
reacted with 6-aminothiazole (36 mg) to give
4-(1,3-benzothiazol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoli-
ne. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3-2.4 (m, 2H), 3.05-3.2
(m, 2H), 3.2-3.3 (m, 2H), 3.55 (d, 2H), 3.8 (t, 2H), 4.0 (d, 2H),
4.08 (s, 3H), 4.32 (t, 2H), 7.4 (s, 1H), 7.88 (dd, 1H), 8.2 (d,
1H), 8.4 (s, 1H), 8.55 (s, 1H), 8.85 (s, 1H), 9.42 (s, 1H) d)
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74 mg) was
reacted with 6-amino-2-methylthiazole (57 mg) to give
6-methoxy-4-(2-methyl-1,3-benzothiazol-5-ylamino)-7-(3-morpholinopropoxy)-
quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.4) 2.3-2.4 (m, 2H),
2.85 (s, 3H), 3.05-3.2 (m, 2H), 3.3 (t, 2H), 3.4-3.5 (m, 2H), 3.85
(t, 2H), 4.0 (d, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.42 (s, 1H),
7.75 (dd, 1H), 8.15 (d, 1H), 8.3 (s, 1H), 8.42 (s, 1H), 8.85 (s,
1H) e) 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (74
mg) was reacted with 5-aminoindan (32 mg) to give
4-(2,3-dihydro-1H-inden-5-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quina-
zoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.08 (m, 2H), 2.3-2.4
(m, 2H), 2.9 (m, 4H), 3.05-3.2 (m, 2H), 3.2-3.3 (m, 2H), 3.5 (d,
2H), 3.82 (t, 2H), 4.0 (d, 2H), 4.05 (s, 3H), 4.3 (t, 2H), 7.32 (d,
1H), 7.4 (m, 2H), 7.55 (s, 1H), 8.32 (s, 1H), 8.8 (s, 1H)
EXAMPLE 30
[0869] A suspension of
4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(130 mg, 0.4 mmol), (prepared as described for the starting
material in Example 10), 7-hydroxy-2-methylchromone (88 mg, 0.5
mmol), (Bull Soc. Chim. Fr. 1995, 132, 233), and potassium
carbonate (83 mg, 0.6 mmol) was heated at 100.degree. C. for 1.5
hours. After cooling, the mixture was partioned between water and
ethyl acetate. The organic layer was washed with water, brine,
dried (MgSO.sub.4), and the volatiles were removed by evaporation.
The residue was triturated with ether, collected by filtration,
washed with ether and dried under vacuum to give
6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(1-methylpiperidin-4-yl-
methoxy)quinazoline (170 mg, 92%).
[0870] MS-ESI: 462 [MH]+
[0871] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5 (m, 2H);
1.75-1.95 (m, 5H); 2.2 (s, 3H); 2.42 (s, 3H); 4.0 (s, 3H); 4.1 (d,
2H); 6.3 (s, 2H); 7.4 (s, 1H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.7 (s,
1H); 8.15 (d, 1H); 8.61 (s, 1H)
EXAMPLES 31-33
[0872] Using an analogous procedure to that described in Example
30, the compounds described in Table II hereinafter and detailed in
the notes a)-c) to Table II, were made. TABLE-US-00015 TABLE II
##STR27## Example Weight yield MS-ESI No. (mg) % [MH]+ note Q R 31
180 85 451 a 1-methylpiperidin- 4-methyl-3,4-dihydro-2H-
4-ylmethoxy 1,4-benzoxazin-6-yloxy 32 160 87 462 b 3-pyrrolidin-1-
2-methyl-4-oxo-4H- ylpropoxy chromen-7-yloxy 33 100 56 451 c
3-pyrrolidin-1- 4-methyl-3,4-dihydro-2H- ylpropoxy
1,4-benzoxazin-6-yloxy a)
4-Chloro-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline (130
mg), (prepared as described for the starting material in Example
10), was reacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol
(83 mg), (J. Org. Chem. 1971, 36 (1)), to give
6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(1-methylp-
iperidin-4-ylmethoxy)quinazoline .sup.1H NMR Spectrum:
(DMSOd.sub.6) 1.6-1.75 (m, 2H); 1.9-2.3 (m, 5H); 2.8 (s, 311); 2.9
(s, 3H); 3.0-3.15 (m,2H); 3.3 (br s, 211); 3.5-3.6 (d, 211); 4.1
(s, 3H); 4.2 (d, 2H); 4.3 (t, 2H); 6.55 (m, 111); 6.75 (s, 1H); 6.8
(d, 1H); 7.6 (s, 1H); 7.75 (s, 1H); 9.15 (s, 1H) b)
4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130
mg), (prepared as described for the starting material in Example
9), was reacted with 7-hydroxy-2-methylchromone (88 mg), (Bull Soc.
Chim Fr. 1995, 132, 233). After cooling, water was added (20 ml)
and the precipitate was collected by filtration and dried under
vacuum over phosphorus pentoxide at 60.degree. C. to give
6-methoxy-4-(2-methyl-4-oxo-4H-chromen-7-yloxy)-7-(3-pyrrolidin-1-ylpropo-
xy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD)
1.8-2.0 (m, 2H); 2.0-2.15 (m, 2H); 2.2-2.3 (m, 2H); 2.4 (s, 3H);
3.05-3.15 (m, 2H); 3.3-3.4 (m, 2H); 3.6-3.7 (m, 2H); 4.05 (s, 3H);
4.35 (t, 2H); 6.3 (s, 1H); 7.45 (d, 1H); 7.5 (s, 1H); 7.65 (s, 1H);
7.72 (s, 1H); 8.15 (d, 1H); 8.75 (s, 1H) c)
4-Chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (130
mg), (prepared as described for the starting material in Example
9), was reacted with 3,4-dihydro-4-methyl-2H-1,4-benzoxazin-6-ol
(83 mg), (J. Org. Chem. 1971, 36 (1)), to give
6-methoxy-4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yloxy)-7-(3-pyrroli-
din-1-ylpropoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
1.85-2.0 (m, 2H); 2.0-2.15 (m, 2H); 2.25-2.35 (m, 2H); 2.83 (s,
3H); 3.05-3.15 (m, 2H); 3.3 (t, 2H); 3.4 (t, 2H); 3.7 (br m, 2H);
4.1 (s, 3H); 4.3 (t, 2H); 4.4 (t, 2H); 6.52 (d, 1H); 6.7 (s, 1H);
6.8 (d, 1H); 7.55 (s, 1H); 7.75 (s, 1H); 9.1 (s, 1H)
EXAMPLE 34
[0873] A solution of
4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(110 mg, 0.34mmol), (prepared as described for the starting
material in Example 10), and 5-hydroxyindole (55 mg, 0.41 mmol) in
DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was
heated at 100.degree. C. for 2 hours. After cooling, water was
added and the precipitate was collected by filtration, washed with
water followed by ether, and dried under vacuum over phosphorus
pentoxide to give
4-(indol-5yloxy)-6methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(90 mg, 64%).
[0874] MS-ESI: 419 [MH]+
[0875] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.5 (m, 2H); 1.8
(d, 2H); 1.95 (t, 2H); 1.7-2.0 (m, 1H); 2.2 (s, 3H); 2.85 (d, 2H);
4.02 (s, 3H); 4.1 (d, 2H); 6.45 (s, 1H); 7.0 (d, 1H); 7.35 (s, 1H);
7.4-7.5 (m, 3H); 7.6 (s, 1H); 8.5 (s, 1H) TABLE-US-00016 Elemental
analysis: Found C 67.4 H 6.5 N 13.1
C.sub.24H.sub.26N.sub.4O.sub.30.5H.sub.2O Requires C 67.4 H 6.4 N
13.1%
EXAMPLE 35
[0876] Using an analogous procedure to that described in Example
34, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(110 mg, 0.34 mmol), (prepared as described for the starting
material in Example 10), was reacted with
2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm.
1972, 305, 159). The crude product was purified by column
chromatography eluting with methanol/methylene chloride (1/9)
followed by 3M ammonia in methanol/methanol/methylene chloride
(5/15/80) to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-
quinazoline (60 mg, 40%).
[0877] MS-ESI: 447 [MH]+
[0878] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.2-1.4 (m, 2H); 1.7 (d,
2H); 1.8 (t, 2H); 1.7-1.9 (m, 1H); 2.05 (s, 3H); 2.12 (s, 3H); 2.25
(s, 3H); 2.75 (d, 2H); 3.9 (s, 3H); 4.0 (d, 2H); 6.8 (d, 1H); 7.15
(s, 1H); 7.2 (d, 1H); 7.3 (s, 1H); 7.52 (s, 1H); 8.45 (s, 1H)
TABLE-US-00017 Elemental analysis: Found C 68.6 H 6.9 N 12.5
C.sub.26H.sub.30N.sub.4O.sub.30.4H.sub.2O Requires C 68.8 H 6.8 N
12.4%
EXAMPLE 36
[0879] Using an analogous procedure to that described in Example
34, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (110
mg, 0.34 mmol), (prepared as described for the starting material in
Example 9), was reacted with 5-hydroxyindole (55 mg, 0.41 mmol).
The crude product was purified by chromatography on alumina,
eluting with methanol/ethyl acetate/methylene chloride (5/45/50) to
give
4-(indol-5-yloxy)-6methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline
(70 mg, 50%).
[0880] MS-ESI 419 [MH]+
[0881] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.9-2.0
(m, 2H); 2.1 (m, 2H); 2.3 (t, 2H); 3.0-3.15 (m, 2H); 3.4 (t, 2H);
3.6-3.75 (m, 2H); 4.1 (s, 3H); 4.4 (t, 2H); 6.5 (s, 1H); 7.05 (d,
1H); 7.5 (s, 1H); 7.5-7.6 (m, 2H); 7.85 (s, 1H); 9.11 (s, 1H)
TABLE-US-00018 Elemental analysis: Found C 63.7 H 6.4 N 12.1
C.sub.24H.sub.26N.sub.4O.sub.31.9H.sub.2O Requires C 63.7 H 6.6 N
12.4%
EXAMPLE 37
[0882] A suspension of
4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(100 mg, 0.31 mmol), (prepared as described for the starting
material in Example 10), and 5-amino-2,3-dimethylindole (55 mg,
0.34 mmol) in isopropanol (6 ml) containing 5.5M hydrogen chloride
in isopropanol (60 .mu.L) was heated for 30 minutes at 70.degree.
C. After cooling, the solid was collected by filtration, washed
with isopropanol, followed by ether and dried under vacuum to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethox-
y)quinazoline hydrochloride (118 mg, 74%).
[0883] MS-ESI: 446 [MH]+
[0884] .sup.1H NMR Spectrum: (DMSOd.sub.6): 1.8-1.9 (m, 2H); 2.0
(d, 2H); 2.1-2.2 (m, 1H); 2.16 (s, 3H); 2.33 (s, 3H); 2.75 (br s,
3H); 2.95-3.05 (m, 2H); 3.5 (d, 2H); 4.0 (s, 3H); 4.07 (d, 2H);
7.25 (d, 1H); 7.4 (d, 1H); 7.42 (s, 1H); 7.52 (s, 1H); 8.25 (s,
1H); 8.75 (s, 1H); 10.0 (br s. 1H); 10.9 (s, 1H); 11.25 (br s, 1H)
TABLE-US-00019 Elemental analysis: Found C 58.5 H 6.8 N 12.9
C.sub.26H.sub.31N.sub.5O.sub.21H.sub.2O1.9HCl Requires C 58.6 H 6.6
N 13.1%
EXAMPLE 38
[0885] Using an analogous procedure to that described in Example
37, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100
mg, 0.31 mmol), (prepared as described for the starting material in
Example 9), was reacted with 5-amino-2,3-dimethylindole (55 mg,
0.34 mmol) to give
4-(2,3-dimethylindol-5ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quin-
azoline hydrochloride (114 mg, 72%).
[0886] MS-ESI: 446 [MH]+
[0887] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.85-2.0
(m, 2H); 2.05-2.15 (m, 2H); 2.1 (s, 3H); 2.2 (s, 3H); 2.25-2.35 (m,
2H); 2.35 (s, 3H); 3.0-3.15 (m, 2H); 3.32-3.42 (m, 2H); 3.6-3.7 (m,
2H); 4.05 (s, 3H); 4.3 (t, 2H); 7.2 (d, 1H); 7.3 (s, 1H); 7.35 (d,
1H); 7.57 (s, 1H); 8.2 (s, 1H); 8.8 (s, 1H) TABLE-US-00020
Elemental analysis: Found C 58.8 H 7.0 N 12.5
C.sub.26H.sub.31N.sub.5O1.9H.sub.2O1.9HCl 0.1isopropanol Requires C
58.6 H 7.1 N 12.9%
EXAMPLE 39
[0888] Using an analogous procedure to that described in Example
38, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100
mg, 0.31 mmol), (prepared as described for the starting material in
Example 9), was reacted with 5-amino-2-methylindole (50 mg, 0.34
mmol) to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-pyrrolidin-1-ylpropoxy)quinazo-
line hydrochloride (138 mg, 89%).
[0889] MS-ESI: 432 [MH]+
[0890] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.8-1.9 (m, 2H); 2.0-2.1
(m, 2H); 2.15-2.35 (m, 2H); 2.4 (s, 3H); 3.0-3.1 (m, 2H); 3.2-3.3
(m, 2H); 3.5-3.6 (m, 2H); 4.0 (s, 3H); 4.32 (t, 2H); 6.2 (s, 1H);
7.2 (d, 1H); 7.3 (m, 2H); 7.65 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H);
10.75 (br s, 1H); 11.15 (s, 1H); 11.25 (br s, 1H) TABLE-US-00021
Elemental analysis: Found C 58.9 H 6.6 N 13.5
C.sub.25H.sub.29N.sub.5O.sub.22.2HCl 0.1isopropanol Re- C 58.7 H
6.2 N 13.5% quires
EXAMPLE 40
[0891] A mixture of
4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg,
0.31 mmol), (prepared as described for the starting material in
Example 9), and 7-hydroxy-2,4-dimethylquinoline (64 mg, 0.36 mmol),
(Chem. Berichte, 1903, 36, 4016), in DMF (3 ml) containing
potassium carbonate (86 mg, 0.62 mmol) was heated at 90.degree. C.
for 3 hours. After cooling, the mixture was poured onto a column of
silica and eluted with 2.5M ammonia in methanol/methylene chloride
(5/95) to give
4-(2,4-dimethylquinolin-7-yloxy)-6methoxy-7-(3-pyrrolidin-1-ylpropoxy)qui-
nazoline (50 mg, 35%).
[0892] MS-ESI: 459 [MH]+
[0893] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.8 (br s, 4H); 2.2 (m,
4H); 2.55 (br s, 4H); 2.7 (2s, 6H); 2.68 (m, 2H); 4.05 (s, 3H); 4.3
(t, 2H); 7.15 (s, 1H); 7.35 (s, 1H); 7.45 (d, 1H); 7.6 (s, 1H); 7.9
(s, 1H); 8.05 (d, 1H); 8.6 (s, 1H) TABLE-US-00022 Elemental
analysis: Found C 70.4 H 7.1 N 12.1 C.sub.27H.sub.30N.sub.4O.sub.3
0.2ether Requires C 70.5 H 6.8 N 11.8%
EXAMPLE 41
[0894] Using an analogous procedure to that described in Example
37, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(50 mg, 0.155 mmol), (prepared as described for the starting
material in Example 10), was reacted with 5-amino-2-methylindole
(0.171 mmol) to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(1-methylpiperidin-4-ylmethoxy)qu-
inazoline hydrochloride (72 mg, quant.).
[0895] MS-ESI: 432 [MH]+
[0896] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.5-1.7
(m, 2H); 2.05 (d, 2H); 2.1-2.2 (m, 1H); 2.45 (s, 3H); 2.8 (s, 3H);
3.05 (t, 2H); 3.5 (d, 2H); 4.0 (s, 3H); 4.1 (d, 2H); 6.2 (s, 1H);
7.2 (d, 1H); 7.32 (d, 1H); 7.4 (d, 1H); 7.6 (s, 1H); 8.2 (s, 1H);
8.85 (s, 1H) TABLE-US-00023 Elemental analysis: Found C 53.9 H 6.8
N 12.4 C.sub.25H.sub.29N.sub.5O.sub.22.6H.sub.2O2.07HCl Requires C
54.2 H 6.6 N 12.6%
EXAMPLE 42
[0897] A suspension of
4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg,
0.31 mmol), (prepared as described for the starting material in
Example 9), and 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J.
Med. Chem. 1998, 41, 4062), in DMF (3 ml) containing potassium
carbonate (86 mg, 0.62 mmol) was heated at 90.degree. C. for 2
hours. After cooling, the mixture was partitioned between ethyl
acetate and water. The organic layer was separated, washed with
water, brine, dried and the volatiles were removed by evaporation.
The residue was triturated with minimal ether, collected by
filtration and dried under vacuum to give
6-methoxy-4-(2-methylquinolin-7-yloxy)-7-(3-pyrrolidin-1-ylpropoxy)quinaz-
oline (95 mg, 69%).
[0898] MS-ESI: 445 [MH]+
[0899] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.8 (br s, 4H); 2.2 (m,
2H); 2.5 (br s, 4H); 2.7 (t, 2H); 2.8 (s, 3H); 4.1 (s, 3H); 4.3 (t,
2H); 7.3 (d, 1H); 7.35 (s, 1H); 7.45 (dd, 1H); 7.6 (s, 1H); 7.85
(d, 1H); 7.9 (s, 1H); 8.1 (d, 1H); 8.6 (s, 1H)
EXAMPLE 43
[0900] Using an analogous procedure to that described in Example
42,
4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)qui-
nazoline (156 mg, 0.38 mmol), (prepared as described for the
starting material in Example 12), was reacted with
7-hydroxy-2-methylquinoline (66 mg, 0.4 mmol), (J. Med. Chem. 1998,
41, 4062), to give
6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)-4-(2-methyl-
quinolin-7-yloxy)quinazoline (166 mg, 82%).
[0901] MS-ESI: 537 [MH]+
[0902] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5 (m, 2H);
1.75-1.95 (m, 3H); 1.95-2.15 (m, 2H); 2.7 (s, 3H); 2.7-2.8 (m, 2H);
2.9-3.0 (m, 2H); 3.05 (s, 3H); 3.2-3.35 (m, 2H, 4.02 (s, 3H); 4.1
(d, 2H); 7.4 (s, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.65 (s, 1H); 7.8
(s, 1H); 8.05 (d, 1H); 8.35 (d, 1H); 8.55 (s, 1H) TABLE-US-00024
Elemental analysis: Found C 62.2 H 6.3 N 10.4
C.sub.28H.sub.32N.sub.4O.sub.5S 0.35ether 0.2DMF Re- C 62.4 H 6.4 N
10.2% quires
EXAMPLE 44
[0903] A suspension of
4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50
mg, 0.155 mmol), (prepared as described for the starting material
in Example 10), and 5-hydroxy-2-trifluoromethylindole (34 mg, 0.17
mmol) in DMF (1.5 ml) containing potassium carbonate (43 mg, 0.31
mmol) was heated at 90.degree. C. for 2 hours. After cooling, the
mixture was partitioned between ethyl acetate and water. The
organic layer was separated, washed with brine, dried (MgSO.sub.4)
and the volatiles were removed by evaporation. The residue was
purified by column chromatography eluting with methanol/ethyl
acetate/methylene chloride (10/50/40) followed by 2.5M ammonia in
methanol/ethyl acetate/methylene chloride (10/50140) to give
6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindo-
l-5-yloxy)quinazoline (35 mg, 48%).
[0904] MS-ESI: 487 [MH]+
[0905] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25-1.4 (m, 2H); 1.75
(d, 2H); 1.8 (t, 2H); 1.7-2.0 (m, 1H); 2.2 (s, 3H); 2.75 (d, 2H);
4.0 (s, 3H); 4.1 (d, 2H); 7.0 (s, 1H); 7.25 (d, 1H); 7.4 (s, 1H);
7.6 (d, 1H); 7.8 (s, 1H); 8.5 (s, 1H); 12.5 (s, 1H) TABLE-US-00025
Elemental analysis: Found C 60.2 H 5.8 N 10.9
C.sub.25H.sub.25F.sub.3N.sub.4O.sub.30.7H.sub.2O 0.2ether Requires
C 60.3 H 5.6 N 10.9%
[0906] The starting material was prepared as follows:
[0907] A solution of (4-methoxy-2-methylphenyl)-carbamic
acid-1,1-dimethylethyl ester (2 g, 8.43 mmol), (J. Med. Chem. 1996,
39, 5119), in dry THF (25 ml) was cooled to -40.degree. C. and
sec-butyllithium (15 ml, 19.5 mmol) was added. After stirring for
15 minutes at this temperature,
N-methyl-N-methoxytrifluoroacetamide (1.32 g, 8.43 mmol) in THF (20
ml) was added in portions. Stirring was continued for 1 hour at
-40.degree. C. and then the mixture was allowed to warm to ambient
temperature. The mixture was poured onto ether/1M hydrochloric
acid. The organic layer was separated, washed with water, brine,
dried (MgSO.sub.4) and the volatiles were removed by
evaporation.
[0908] The crude residue (1.4 g) was dissolved in methylene
chloride (8 ml) and TEA was added (1.5 ml). After stirring for 3
hours at ambient temperature, the volatiles were removed under
vacuum. The crude product was partitioned between methylene
chloride and water. The organic layer was separated, washed with
water, brine, dried (MgSO.sub.4) and the volatiles were removed by
evaporation. The residue was purified by column chromatography,
eluting with ether/petroleum ether (1/9) to give
5-methoxy-2-trifluoromethylindole (845 mg, 47% over 2 steps).
[0909] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.83 (s, 3H), 6.82 (s,
1H), 7.0 (dd, 1H), 7.1 (s, 1H), 7.3 (d, 1H), 8.15 (br s, 1H)
[0910] A solution of 5-methoxy-2-trifluoromethylindole (800 mg, 3.7
mmol) in methylene chloride (6 ml) was cooled to -15.degree. C. and
a solution of 1M boron tribromide in methylene chloride (7.44 ml,
7.4 mmol) was added in portions. The mixture was allowed to warm to
ambient temperature and was stirred for 45 minutes. After cooling
to 0.degree. C., saturated aqueous sodium hydrogen carbonate (25
ml) was added. The mixture was extracted with ethyl acetate. The
organic layer was dried (MgSO.sub.4) and the volatiles were removed
by evaporation. The residue was purified by column chromatography
eluting with ethyl acetate/petroleum ether. After removal of the
volatiles by evaporation, the solid was triturated with pentane,
collected by filtration and dried under vacuum to give
5-hydroxy-2-trifluoromethylindole (290 mg, 39%).
[0911] MS-EI: 201 [M.]+
[0912] .sup.1H NMR Spectrum: (CDCl.sub.3) 4.64 (s, 1H), 6.8 (s,
1H), 6.92 (dd, 1H), 7.1 (s, 1H), 7.3 (d, 1H), 8.3 (br s, 1H)
TABLE-US-00026 Elemental analysis: Found C 53.3 H 2.9 N 6.8
C.sub.9H.sub.6F.sub.3NO0.1H.sub.2O Requires C 53.3 H 3.1 N 6.9%
EXAMPLE 45
[0913] Using an analogous procedure to that described in Example
44, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100
mg, 0.3 mmol), (prepared as described for the starting material in
Example 9), was reacted with 5-hydroxy-2-trifluoromethylindole (75
mg, 0.37 mmol), (prepared as described for the starting material in
Example 44), to give
6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)-
quinazoline (105 mg, 70%).
[0914] MS-ESI: 487 [MH]+
[0915] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.8 (m, 4H); 2.1-2.3 (m,
2H); 2.55 (br s, 4H); 2.7 (t, 2H); 4.1 (s, 3H); 4.3 (t, 2H); 6.95
(s, 1H); 7.2 (dd, 1H); 7.35 (s, 1H); 7.5 (d, 1H); 7.55 (s, 1H); 7.6
(s, 1H); 8.6 (s, 1H); 8.8 (s, 1H) TABLE-US-00027 Elemental
analysis: Found C 61.7 H 5.5 N 11.5
C.sub.25H.sub.25F.sub.3N.sub.4O.sub.3 Requires C 61.7 H 5.2 N
11.5%
EXAMPLE 46
[0916] Using an analogous procedure to that described in Example
42, 4-chloro-6-methoxy-7-1-methylpiperidin-4-ylmethoxy)quinazoline
(100 mg, 0.31 mmol), (prepared as described for the starting
material in Example 10), was reacted with
7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem.
1998, 41, 4062), to give
6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)q-
uinazoline (86 mg, 63%).
[0917] MS-ESI: 445 [MH]+
[0918] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.4-1.6 (m, 2H); 1.95 (d,
2H); 2.05 (t, 2H); 1.9-2.1 (m, 1H); 2.35 (s, 3H); 2.8 (s, 3H); 2.95
(d, 2H); 4.1 (s, 3H); 4.15 (d, 2H); 7.3 (m, 2H); 7.45 (dd, 1H); 7.6
(s, 1H); 7.9 (d, 1H); 7.95 (s, 1H); 8.1 (d, 1H); 8.6 (s, 1H)
TABLE-US-00028 Elemental analysis: Found C 69.7 H 6.5 N 12.8
C.sub.26H.sub.28N.sub.4O.sub.30.2H.sub.2O Requires C 69.7 H 6.4 N
12.5%
EXAMPLE 47
[0919] A suspension of
4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (110 mg,
0.34 mmol), (prepared as described for the starting material in
Example 9), and 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol),
(Arch. Pharm. 1972, 305, 159), in DMF (1.5 ml) containing potassium
carbonate (70 mg, 0.51 mmol) was heated at 100.degree. C. for 2
hours. After cooling, the residue was purified by chromatography,
eluting with methanol/methylene chloride (1/9) followed by 2.5M
ammonia in methanol/methanol/methylene chloride (5/10/85) to give
4-(2,3-dimethylindol-5yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinaz-
oline (50 mg, 33%).
[0920] MS-ESI: 447 [MH]+
[0921] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.9-2.0
(m, 2H); 2.05-2.15 (m, 2H); 2.15 (s, 3H); 2.3-2.4 (m, 2H); 2.4 (s,
3H), 3.05-3.15 (m, 2H); 3.35-3.45 (t, 2H); 3.7 (br s, 2H); 4.1 (s,
3H); 4.4 (t, 2H); 6.95 (d, 1H); 7.3 (s, 1H); 7.35 (d, 1H); 7.55 (s,
1H); 7.85 (s, 1H); 9.15 (s, 1H) TABLE-US-00029 Elemental analysis:
Found C 67.7 H 6.8 N 12.2 C.sub.26H.sub.30N.sub.4O.sub.30.8H.sub.2O
Requires C 67.8 H 6.9 N 12.2%
EXAMPLE 48
[0922] Using an analogous procedure to that described in Example
32, 7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol),
(prepared as described for the starting material in Example 1), was
reacted with 5-hydroxy-2-methylindole (0.59 g, 4 mmol) to give
7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.25 g,
91%).
[0923] MS-ESI: 412 [MH]+
[0924] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H); 4.0 (s,
3H); 5.35 (s. 2H); 6.15 (s, 1H); 6.85 (s, 1H); 7.2-7.6 (m, 9H); 8.5
(s, 1H) TABLE-US-00030 Elemental analysis: Found C 72.2 H 5.1 N
10.2 C.sub.25H.sub.21N.sub.3O.sub.30.2H.sub.2O Requires C 72.3 H
5.2 N 10.1%
[0925] The starting material may be prepared as follows:
[0926] A solution of boron tribromide (32.5 ml, 341 mmol) in
methylene chloride (60 ml) was added in portions to a solution of
5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride
(250 ml) cooled at -45.degree. C. After stirring for 15 minutes at
-30.degree. C., the mixture was warmed up to ambient temperature
and stirred for 1 hour. Methylene chloride (300 ml) was added in
portions and the mixture was cooled to 0.degree. C. Water was added
in portions and the mixture was adjusted to pH6 with 4N sodium
hydroxide. The organic layer was separated. The aqueous layer was
extracted with methylene chloride and the organic layers were
combined, washed with water, brine, dried (MgSO.sub.4) and the
volatiles were removed by evaporation. The residue was purified by
column chromatography eluting with ethyl acetate/methylene chloride
(1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g,
93%).
[0927] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H); 5.95 (s,
1H); 6.5 (dd, 1H) ; 6.7 (s, 1H); 7.05 (d, 1H); 8.5 (s, 1H)
EXAMPLE 49
[0928] A solution of
7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (0.2 g,
0.5 mmol), (prepared as described in Example 48), in a mixture of
methylene chloride (5 ml) and DMF (2 ml) containing 10%
palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8
atmospheres pressure for 2 hours. The suspension was filtered and
the catalyst was washed with methanol followed by methylene
chloride. The volatiles were removed from the filtrate by
evaporation. The residue was triturated with water. The resulting
solid was washed with water and dried under vacuum over phosphorus
pentoxide at 60.degree. C. to give
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg,
89%).
[0929] MS-ESI: 322 [MH]+
[0930] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H); 4.0 (s,
3H); 6.15 (s, 1H); 6.9 (d, 1H); 7.2 (s, 1H); 7.25 (s, 1H); 7.3 (d,
1H); 7.6 (s, 1H); 8.4 (s, 1H)
EXAMPLE 50
[0931] A suspension of
4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg,
0.45 mmol) and 5-hydroxy-2-trifluoromethylindole (109 mg, 0.54
mmol), (prepared as described for the starting material in Example
44), in DMF (1.5 ml) containing potassium carbonate (94 mg, 0.67
mmol) was heated at 100.degree. C. for 1 hour. After cooling, the
precipitate was collected by filtration, washed with ether, and
dried under vacuum to give
6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-trifluoromethylindol-5yloxy)q-
uinazoline (195 mg, 87%).
[0932] MS-ESI: 496 [MH]+
[0933] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.25-2.4
(m, 2H), 3.1 (s, 3H), 3.35 (t, 2H), 4.1 (s, 3H), 4.4 (t, 2H), 7.1
(s, 1H), 7.3 (d, 1H), 7.5 (s, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.78
(s, 1H), 8.9 (s, 1H)
[0934] The starting material was prepared as follows:
[0935] A solution of 3-(methylthio)-1-propanol (5.3 g, 50 mmol) in
methanol (500 ml) was added to a solution of OXONE, (trade mark of
E.I. du Pont de Nemours & Co., Inc), (30 g) in water (150 ml)
and the mixture stirred at ambient temperature for 24 hours. The
precipitated solid was removed by filtration and the methanol
removed from the filtrate by evaporation. The aqueous residue was
saturated with sodium chloride and extracted with methylene
chloride (4.times.25 ml). The aqueous residue was then saturated
with ammonium chloride and extracted with ethyl acetate (4.times.25
ml). The extracts were combined, dried (MgSO.sub.4) and the solvent
removed by evaporation to give 3-(methylsulphonyl)-1-propanol (610
mg, 9%) as an oil.
[0936] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.10(m, 2H); 2.96(s, 3H);
3.20(t, 2H); 3.80(t, 2H)
[0937] MS-ESI: 139 [MH].sup.+
[0938] Alternatively the 3-(methylsulphonyl)-1-propanol may be
prepared as follows:
[0939] m-Chloroperoxybenzoic acid (67%, 25 g, 97.2 mmol) was added
in portions to 3-(methylthio)-1-propanol (5 ml, 48.6 mmol) in
solution in dichloromethane. Some m-chlorobenzoic acid precipitated
out and was removed by filtration. The filtrate was evaporated and
the residue was purified over alumina using first dichloromethane
(100%) then dichloromethane/methanol (95/5) to give
3-(methylsulphonyl)-1-propanol (4.18 g, 62%) as an oil.
[0940] Triphenylphosphine (8.9 g, 35.2 mmol) was added to a
suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(6 g, 19.6 mmol), (prepared as described for the starting material
in Example 12), in methylene chloride (150 ml). This was followed
by the addition of 3-(methylsulphonyl)-1-propanol (3.5 g, 25.4
mmol) and diethyl azodicarboxylate (5.55 ml, 35.2 mmol) in
portions. The reaction was complete once the reaction became
homogeneous. Silica was added and the volatiles were removed by
evaporation. The free flowing powder was placed on the top of a
flash chromatography column pre-equilibrated with ethyl acetate
(100%). Elution was done using ethyl acetate (100%) followed by
methylene chloride/ethyl acetate/methanol (60/35/5). The volatiles
were removed by evaporation to give
6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydr-
oquinazolin-4-one (7.58 g, 91%) as a white solid.
[0941] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2(s, 9H); 2.4-2.5(m,
2H); 3.0(s, 3H); 3.25-3.35(t, 2H); 5.95(s, 1H); 7.1(s, 1H); 7.65(s,
1H); 8.2(s, 1H)
[0942]
6-Methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-
-dihydroquinazolin-4-one (7 g, 17 mmol) was suspended in methanol
and 2M sodium hydroxide (3.3 ml, 6.6 mmol) was added with
continuous stirring. The reaction mixture became homogeneous after
15 minutes. After a further 45 minutes water was added (7 ml) and
the reaction mixture was adjusted to pH10 with 2M hydrochloric
acid. The precipitate (a white solid) was collected by filtration,
washed with water and dried over phosphorus pentoxide under vacuum
to give
6-methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one
(5 g, 90%).
[0943] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2-2.3(m, 2H); 3.05(s,
3H); 3.35(t, 2H); 3.9(s, 3H); 4.25(t, 2H); 7.15(s, 1H); 7.5(s, 1H);
8.0(s, 1H)
[0944]
6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one
(3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF
(1.8 ml) was added under argon and the mixture was heated at reflux
for 1.5 hours. The thionyl chloride was eliminated by several
azeotropic distillations using toluene. The solid residue was
suspended in ice/water and a saturated solution of sodium hydrogen
carbonate was added to adjust the mixture to pH7. The solid was
collected by filtration, washed with water and dried in a vacuum
dessicator over phosphorus pentoxide to give
4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g,
88%).
EXAMPLES 51-52
[0945] Using an analogous procedure to that described in Example
50, 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline,
(prepared as described for the starting material in Example 50),
was reacted with the appropriate phenol to give the compounds
described in Table III: TABLE-US-00031 TABLE III ##STR28## Example
Weight Yield MS-ESI No. (mg) % [MH].sup.+ Ar Note 51 189 92 454
2-methylquinolin-7-yl a 52 175 90 428 indol-5-yl b a)
4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg,
0.45 mmol) was reacted with 7-hydroxy-2-methylquinoline (86.6 mg,
0.54 mmol), (J. Med. Chem. 1998, 41, 4062). After cooling, water
was added and the precipitate was collected by filtration, washed
with water, followed by ether and dried under vacuum to give
6-methoxy-7-(3-methylsulphonylpropoxy)-4-(2-methylquinolin-7-yloxy)quinaz-
oline. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.2-2.35
(m, 2H), 2.95 (s, 3H), 3.1 (s, 3H), 3.35 (m, 2H), 4.05 (s, 3H), 4.4
(t, 2H), 7.5 (s, 1H), 7.7 (s, 1H), 7.95 (dd, 1H), 8.02 (d,; 1H),
8.2 (s, 1H), 8.48 (d, 1H), 8.7 (s, 1H), 9.12 (d, 1H) b) Using an
analogous procedure to that described in note a),
4-chloro-6-methoxy-7-(3-(methylsulphonyl)propoxy)quinazoline (150
mg, 0.45 mmol) was reacted with 5-hydroxyindole (72.4 mg, 0.54
mmol) to give
4-(indol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2-2.35 (m, 2H), 3.1 (s, 3H),
3.3-3.4 (t, 2H), 4.0 (s, 3H), 4.4 (t, 2H), 6.5 (s, 1H), 7.0 (dd,
1H), 7.4 (s, 1H), 7.4-7.5 (m, 3H), 7.6 (s, 1H), 8.5 (s, 1H), 11.25
(s, 1H)
EXAMPLE 53
[0946] 0.5M Triphenylphosphine in methylene chloride and
diisopropyl azodicarboxylate (150 .mu.l, 0.75 mmol) were added in
portions to a suspension of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (112 mg,
0.35 mmol), (prepared as described in Example 49), and
N,N-dimethylethanolamine (62 mg, 0.7 mmol) in methylene chloride (2
ml). After stirring for 2 hours at ambient temperature, the
reaction mixture was poured onto an isolute.RTM. column (10 g of
silica) and eluted with ethyl acetate/methylene chloride (1/1)
followed by methanol/ethyl acetate/methylene chloride (10/40/50),
methanol/methylene chloride (10/90), and 3M ammonia in
methanol/methanol/methylene chloride (5/15/80). After removal of
the volatiles by evaporation, the residue was dissolved in the
minimum amount of methylene chloride (about 3 ml) and ether and
petroleum ether (about 10 ml) was added. The resulting precipitate
was collected by filtration and dried under vacuum to give
7-(2-(N,N-dimethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinaz-
oline (52 mg, 38%).
[0947] MS-ESI: 393 [MH].sup.+
[0948] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.25 (s, 6H), 2.4 (s,
3H), 2.75 (t, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15 (s, 1H), 6.87 (d,
1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.5 (s,
1H)
EXAMPLES 54-56
[0949] Using an analogous procedure to that described in Example
53, the appropriate alcohols were reacted with
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared
as described in Example 49), in analogous proportions to give the
compounds described in Table IV: TABLE-US-00032 TABLE IV ##STR29##
Example Weight Yield MS-ESI No. (mg) % [MH].sup.+ R Note 54 25 17
419 2-pyrrolidin-1-ylethoxy a 55 112 74 433
1-methylpiperidin-3-ylmethoxy b 56 115 72 456
2-(N-methyl-N-(4-pyridyl)amino)ethoxy c a)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 1-(2-hydroxyethyl)pyrrolidine (81 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-pyrrolidin-1-ylethoxy)quinazolin-
e. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65-1.8 (m, 4H), 2.4 (s,
3H), 2.6 (br s, 4H), 2.9 (t, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.15
(s, 1H), 6.9 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6
(s, 1H), 8.5 (s, 1H) b)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 1-methyl-3-piperidinemethanol (90 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methylpiperidin-3-ylmethoxy)quin-
azoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.45-2.2 (m, 7H), 2.18
(s, 3H), 2.4 (s, 3H), 2.6 (br d, 1H), 2.85 (br d, 1H), 4.0 (s, 3H),
4.1 (d, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.25 (d, 1H), 7.3 (d, 1H),
7.35 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H) c)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 2-(N-methyl-N-(4-pyridyl)amino)ethanol (106 mg), (EP
0359389), to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-(4-pyridyl)amin-
o)ethoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s,
3H), 3.1 (s, 3H), 3.9 (t, 2H), 3.97 (s, 3H), 4.4 (t, 2H), 6.15 (s,
1H), 6.75 (d, 2H), 6.87 (dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.35
(s, 1H), 7.6 (s, 1H), 8.15 (d, 2H), 8.5 (s, 1H)
EXAMPLES 57-66
[0950] Using an analogous procedure to that described in Example
53, except that ammonia in methanol was not necessary during the
column chromatography, the appropriate alcohols were reacted with
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared
as described in Example 49), in analogous proportions to give the
compounds described in Table V: TABLE-US-00033 TABLE V ##STR30##
Example Weight Yield MS-ESI No. (mg) % [MH].sup.+ R Note 57 115 76
435 2-morpholinoethoxy a 58 64 42 433 2-piperidinoethoxy b 59 66 43
437 2-(N-(2-methoxyethyl)-N- c methylamino)ethoxy 60 118 75 449
3-morpholinopropoxy d 61 101 68 424 2-(2-methoxyethoxy)ethoxy e 62
81 57 407 3-(N,N-dimethylamino)propoxy f 63 160 92 497
3-(1,1-dioxothiomorpholino)propoxy g 64 121 83 417
2-(1H-1,2,4-triazol-1-yl)ethoxy h 65 38 22 492
2-(2-(4-methylpiperazin-1- i yl)ethoxy)ethoxy 66 80 48 479
2-(2-morpholinoethoxy)ethoxy j a)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 4-(2-hydroxyethyl)morpholine (92 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H). 2.5-2.7 (m, 4H),
2.8 (t, 2H), 3.6 (t, 4H), 4.0 (s, 3H), 4.35 (t, 2H), 6.15 (s, 1H),
6.87 (dd, 1H), 7.25 (s, 1H), 7.32 (d, 1H), 7.4 (s, 1H), 7.6 (s,
1H), 8.5 (s, 1H) b)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 1-(2-hydroxyethyl)piperidine (90 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45 (m, 2H), 1.4-1.6 (m,
4H), 2.4 (s, 3H), 2.4-2.5 (m, 4H), 2.75 (t, 2H), 3.97 (s, 3H), 4.3
(t, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4
(s, 1H), 7.6 (s, 1H), 8.5 (s, 1H) c)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-xyloxy)quinazoline was
reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (93 mg) to
give
6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy)-4-(2-methylindol-
-5-yloxy)quinazoline .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s,
3H), 2.4 (s, 3H), 2.65 (t, 2H), 2.85 (t, 2H), 3.25 (s, 3H), 3.45
(t, 2H), 3.97 (s, 3H), 4.25 (t, 2H), 6.15 (s, 1H), 6.9 (dd, 1H),
7.25 (s, 1H), 7.32 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)
The starting material was prepared as follows: A mixture of
2-(methylamino)ethanol (5.4 g, 72 mmol), 2-bromoethyl methyl ether
(10 g, 72 mmol) and triethylamine (10 ml, 72 mmol) in acetonitrile
(70 ml) was refluxed overnight. After cooling, the solid was
filtered and the filtrate was evaporated. The residue was
triturated with ether. The ether layer was separated and evaporated
to give 2-(N-(2-methoxyethyl)-N-Methylamino)ethanol (3 g, 31%).
MS-EI: 134 [MH]+ .sup.1H NMR Spectrum: (CDCl.sub.3) 2.35 (s, 3H);
2.6 (t, 2H); 2.65 (t, 2H); 3.35 (s, 3H); 3.5 (t, 2H); 3.6 (t,2H) d)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 4-(3-hydroxypropyl)morpholine (102 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.1 (m, 2H), 2.4 (s, 3H),
2.45 (t, 2H), 2.45-2.6 (s, 4H), 3.6 (t, 4H), 4.0 (s, 3H), 4.25 (t,
2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.38 (s,
1H), 7.6 (s, 1H), 8.5 (s, 1H) The starting material was prepared as
follows: Morpholine (94 g, 1.08 mol) was added dropwise to a
solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml)
and the reaction then heated at 80.degree. C. for 4 hours. The
mixture was allowed to cool to ambient temperature and the
precipitated solid was removed by filtration. The volatiles were
removed from the filtrate and the resulting yellow oil was purified
by distillation at 0.4-0.7 mmHg to give
4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil. b.p.
68-70.degree. C. (.about.0.5 mmHg) .sup.1H NMR Spectrum:
(DMSOd.sub.6) 1.65-l.78 (m, 2H); 2.50 (t, 4H); 2.60 (t, 2H); 3.68
(t, 4H); 3.78 (t, 2H); 4.90 (br d, 1H) e)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 2-(2-methoxyethoxy)ethanol (84 mg) to give
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-yloxy)quinazol-
ine. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.42 (s, 3H), 3.27 (s,
3H), 3.5 (t, 2H), 3.65 (t, 2H), 3.85 (t, 2H), 4.0 (s, 3H), 4.32 (t,
2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.4 (s,
1H), 7.6 (s, 1H), 8.5 (s, 1H) f)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 3-(N,N-dimethylamino)propanol (72 mg) to give
7-(3-N,N-dimethylaminopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazo-
lioe. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.0 (m, 2H), 2.17 (s,
6H), 2.4 (s, 3H), 3.98 (s, 3H), 4.22 (t, 2H), 6.14 (s, 1H), 6.88
(dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.35 (s, 1H), 7.6 (s, 1H),
8.47 (s, 1H) g)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (135 mg),
(prepared as described for the starting material in Example 5), to
give
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.0 (m, 2H),
2.38 (s, 3H), 2.65 (t, 2H), 2.9 (hr s, 4H), 3.1 (br s, 4H), 3.96
(s, 3H), 4.25 (t, 2H), 6.12 (s, 1H), 6.85 (dd, 1H), 7.25 (s, 1H),
7.3 (d, 1H), 7.37 (s, 1H), 7.56 (s, 1H), 8.46 (s, 1H) h)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 2-(1H-1,2,4-triazol-l-yl)ethanol (79 mg), (Ann. Phar.
Fr. 1977, 35, 503-508), to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)qu-
inazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.42 (s, 3H), 3.96
(s, 3H), 4.62 (m, 2H), 4.75 (m, 2H), 6.15 (s, 1H), 6.9 (dd, 1H),
7.27 (s, 1H), 7.32 (d, 1H), 7.47 (s, 1H), 7.63 (s, 1H), 8.03 (s,
1H), 8.51 (s, 1H), 8.60 (s, 1H) i)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 2-(2-(4-methylpiperazin-1-yl)ethoxy)ethanol (132 mg),
(Arzneim. Forsch. 1966, 16, 1557-1560), to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-(4-methylpiperazin-1-yl)ethox-
y)ethoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s,
3H), 2.2-2.6 (m, 10H), 2.4 (s, 3H), 3.65 (t, 2H), 3.85 (t, 2H),
4.03 (s, 3H), 4.35 (m, 2H), 6.16 (s, 1H), 6.9 (dd, 1H), 7.3 (s,
1H), 7.35 (d, 1H), 7.4 (s, 1H), 7.61 (s, 1H), 8.5 (s, 1H) j)
7-HYdroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline was
reacted with 2-(2-morpholinoethoxy)ethanol (123 mg) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(2-morpholinoethoxy)ethoxy)quina-
zoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.4-2.5
(m, 4H), 2.4-2.6 (m, 2H), 3.55 (t, 4H), 3.6 (t, 2H), 3.85 (t, 2H),
3.97 (br s, 3H), 4.15 (br s, 2H), 6.15 (s, 1H), 6.9 (d, 1H), 7.25
(s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.48 (s, 1H)
[0951] The starting material was prepared as follows:
[0952] 2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a
mixture of morpholine (2.58 g, 30 mmol) and potassium carbonate
(5.5 g, 40 mmol) in acetonitrile (50 ml). The mixture was heated at
reflux for 6 hours and then stirred for 18 hours at ambient
temperature. The insolubles were removed by filtration and the
volatiles were removed from the filtrate by evaporation. The
residue was purified by column chromatography eluting with
methylene chloride/methanol (95/5 followed by 90/10 and then 80/20)
to give 2-(2-morpholinoethoxy)ethanol (600 mg, 34%).
[0953] MS-(El): 175 [M.].sup.+
[0954] .sup.1H NMR Spectrum: (CDCO.sub.3) 2.5(br s, 4H); 2.59(t,
2H); 3.6-3.85(m, 10H)
EXAMPLE 67
[0955] A solution of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg, 0.29
mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (prepared as
described for the starting material in Example 48), and potassium
carbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85.degree.
C. for 3 hours, followed by heating at 95.degree. C. for 2 hours.
After cooling, ice/water (15 ml) was added and the precipitate was
collected by filtration and dried under vacuum. The solid was
purified by column chromatography eluting with methylene
chloride/methanol (95/5) followed by methylene chloride/methanol/3M
ammonia in methanol (95/3/2) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline
(71 mg, 54%).
[0956] MS-ESI: 447 [MH].sup.+
[0957] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.4 (m, 2H),
1.45-1.55 (m, 4H), 1.92-2.0 (m, 2H), 2.3-2.4 (m, 4H), 2.40 (s, 3H),
2.4-2.5 (m, 2H), 3.97 (s, 3H), 4.22 (t, 2H), 6.15 (s, 1H), 6.9 (d,
1H), 7.27 (s, 1H), 7.8 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.48
(s, 1H)
[0958] The starting material was prepared as follows:
[0959] Diethyl azodicarboxylate (3.9 ml, 24.5 mmol) was added in
portions to a suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(5 g, 16.3 mmol), (prepared as described for the starting material
in Example 12), 3-bromo-1-propanol (2.21 ml, 24.5 mmol) and
triphenylphosphine (6.42 g, 24.5 mmol) in methylene chloride (50
ml). After stirring for 2 hours at ambient temperature, the
volatiles were removed under vacuum and the residue was purified by
column chromatography eluting with methylene chloride followed by
methylene chloride/methanol (95/5) to give
7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazoli-
n-4-one (6 g, 86%).
[0960] MS-ESI: 427-429 [MH].sup.+
[0961] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.12 (s, 9H), 2.32 (t,
2H), 3.7 (t, 2H), 3.9 (s, 3H), 4.25 (t, 2H), 5.9 (s, 2H), 7.20 (s,
1H), 7.51 (s, 1H), 8.36 (s, 1H) TABLE-US-00034 Elemental analysis:
Found C 50.1 H 5.4 N 6.4
C.sub.18H.sub.23BrN.sub.2O.sub.50.2H.sub.2O Requires C 50.2 H 5.5 N
6.5%
[0962] A solution of
7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazoli-
n-4-one (2.89 g, 6.78 mmol) in piperidine (10 ml) was heated at
100.degree. C. for 1 hour. After cooling, the volatiles were
removed under vacuum. The residue was dissolved in methylene
chloride, and washed with saturated ammonium chloride and brine.
The organic layer was dried (MgSO.sub.4) and the volatiles were
removed by evaporation. The residue was dried under vacuum to give
6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquin-
azolin-4-one (2.4 g, 83%).
[0963] MS-ESI: 432 [MH].sup.+
[0964] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.15 (s, 9H), 1.35-1.5
(m, 1H), 1.6-1.8 (m, 3H), 1.8-1.9 (d, 2H), 2.2-2.3 (m, 2H), 2.95
(t, 2H), 3.25 (t, 2H), 3.55 (d, 2H), 3.95 (s, 3H), 4.25 (t, 2H),
5.94 (s, 2H), 7.24 (s, 1H), 7.56 (s, 1H), 8.46 (s, 1H)
[0965] A solution of
6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquin-
azolin-4-one (2.35 g, 5.45 mmol) in 7M ammonia in methanol (50 ml)
was stirred overnight at ambient temperature. The volatiles were
removed under vacuum and the residue was triturated with ether,
filtered and washed with ether followed by ether/methylene chloride
(1/1) and dried under vacuum to give
6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.65
g, 95%).
[0966] MS-ESI: 318 [MH].sup.+
[0967] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.4 (m, 2H),
1.4-1.55 (m, 4H), 1.85-1.95 (m, 2H), 2.35 (br s, 4H), 2.4 (t, 2H),
3.9 (s, 3H), 4.15 (t, 2H), 7.11 (s, 1H), 7.44 (s, 1H), 7.9 (s, 1H)
TABLE-US-00035 Elemental analysis: Found C 63.5 H 7.4 N 13.1
C.sub.17H.sub.23N.sub.3O.sub.30.2H.sub.2O Requires C 63.6 H 7.4 N
13.0%
[0968] A solution of
6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.5
g, 4.7 mmol) in thionyl chloride (15 ml) containing DMF (1.5 ml)
was heated at reflux for 3 hours. After cooling, the volatiles were
removed under vacuum. The residue was azeotroped with toluene. The
solid was partitioned between methylene chloride and sodium
hydrogen carbonate. The aqueous layer was adjusted to pH10 with 6M
aqueous sodium hydroxide. The organic layer was separated, washed
with brine, dried (MgSO.sub.4) and the volatiles were removed by
evaporation. The residue was purified by column chromatography to
give 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.21 g,
76%).
[0969] MS-ESI: 336 [MH].sup.+
[0970] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.45 (m, 2H),
1.5-1.6 (m, 4H), 1.9-2.05 (m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H),
4.0 (s, 3H), 4.29 (t, 2H), 7.41 (s, 1H), 7.46 (s, 1H), 8.9 (s,
1H)
EXAMPLE 68
[0971] Using an analogous procedure to that described in Example
67, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg),
(prepared as described for the starting material in Example 67),
was reacted with 5-hydroxyindole (48 mg, 0.36 mmol) to give
4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (57
mg, 45%).
[0972] MS-ESI: 433 [MH].sup.+
[0973] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4 (br s, 2H), 1.45-1.6
(br s, 4H), 1.9-2.1 (m, 2H), 2.4 (br s, 4H), 2.45 (t, 2H), 4.0 (s,
3H), 4.25 (t, 2H), 6.47 (s, 1H), 7.0 (d, 1H), 7.35 (s, 1H), 7.45
(s, 2H), 7.47 (d, 1H), 7.61 (s, 1H), 8.49 (s, 1H)
EXAMPLE 69
[0974] A solution of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (161 mg,
0.5 mmol), (prepared as described in Example 49),
4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine
(222 mg, 0.6 mmol), (prepared as described for the starting
material in Example 10), and potassium carbonate (188 mg, 1 mol) in
DMF (1.6 ml) was heated at 100.degree. C. for 2 hours. After
cooling, water was added. The precipitate was collected by
filtration, washed with water, and dried under vacuum over
phosphorus pentoxide at 60.degree. C. The solid was triturated with
petroleum ether, collected by filtration, washed with a mixture of
ether/petroleum ether (1/1) and dried under vacuum to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-y-
lmethoxy)quinazoline (200 mg, 77%).
[0975] MS-ESI: 541 [MNa].sup.+
[0976] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.1-1.3 (m, 2H), 1.4 (s,
9H), 1.8 (d, 2H), 1.95-2.1 (m, 1H), 2.4 (s, 1H), 2.7-2.85 (br s,
2H), 3.95 (s, 3H), 4.05 (d, 2H), 6.12 (s, 1H), 6.85 (d, 1H), 7.25
(s, 1H), 7.3 (d, 1H), 7.35 (s, 1H), 7.55 (s, 1H), 8.45 (s, 1H)
EXAMPLE 70
[0977] A solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-y-
lmethoxy)quinazoline (155 mg, 0.3 mmol), (prepared as described in
Example 69), in methylene chloride (5 ml) containing TFA (1 ml) was
stirred at ambient temperature for 30 minutes. The volatiles were
removed under vacuum and the residue was treated with water and
adjusted to pH12 with 2M sodium hydroxide. The mixture was
extracted with methylene chloride. The organic layer was dried
(MgSO.sub.4), and the volatiles were removed by evaporation. The
residue was purified by column chromatography eluting with
methylene chloride/ethyl acetate/methanol (5/4/1) followed by
methylene chloride/methanol (9/1) and by 3M ammonia in
methanol/methanol/methylene chloride (5/15/80). After removal of
the solvent by evaporation, the residue was dissolved in the
minimum of methylene chloride, ether was added followed by
petroleum ether. The precipitate was collected by filtration,
washed with ether and dried under vacuum to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(120 mg, 96%).
[0978] MS-ESI: 419 [MH].sup.+
[0979] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.5-1.7
(m, 2H), 2.05 (br d, 2H), 2.3-2.4 (m, 1H), 2.4 (s, 3H), 3.05 (t,
2H), 3.4 (d, 2H), 4.09 (s, 3H), 4.25 (d, 2H), 6.95 (dd, 1H), 7.35
(s, 1H), 7.4 (d, 1H), 7.6 (s, 1H), 7.85 (s, 1H), 9.15 (s, 1H)
EXAMPLE 71
[0980] Methoxyacetaldehyde (368 mg, 3.47 mol) (freshly distilled)
followed by sodium triacetoxyborohydride (552 mg, 2.6 mol) were
added to a solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(726 mg, 1.74 mmol), (prepared as described in Example 70), in a
mixture of methylene chloride (15 ml) and methanol (15 ml). After
stirring for 1.5 hours at ambient temperature, saturated sodium
hydrogen carbonate was added. The volatiles were removed under
vacuum and the residue was partitioned between methylene chloride
and water. The organic layer, was separated, washed with water,
brine, dried (MgSO.sub.4) and the volatiles were removed by
evaporation. The residue was purified by column chromatography
eluting with methylene chloride/methanol (80/20). After removal of
the solvent, the residue was triturated with ether, collected by
filtration, washed with ether and dried under vacuum at 60.degree.
C. to give
6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methyl-
indol-5-yloxy)quinazoline (392 mg, 47%).
[0981] MS-ESI 477 [MH].sup.+
[0982] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.6-1.8
(m, 2H), 2.05 (br d, 2H), 2.15-2.3 (m, 1H), 2.4 (s, 3H), 3.05 (t,
2H), 3.3 (br s, 2H), 3.32 (s, 3H), 3.58 (d, 2H), 3.65 (br s, 2H),
4.05 (s, 3H), 4.18 (d, 2H), 6.2 (s, 0.5 H (partly exchanged)), 6.92
(dd, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H),
9.15 (s, 1H) TABLE-US-00036 Elemental analysis: Found C 68.0 H 6.8
N 11.8 C.sub.27H.sub.32N.sub.4O.sub.4 Requires C 68.1 H 6.8 N
11.8%
[0983] The starting material was prepared as follows:
[0984] A solution of 1,1,2-trimethoxyethane (90 g, 750 mmol) in
water (570 ml) containing 12 N hydrochloric acid (3.75 ml) was
stirred at 40.degree. C. for 1.5 hours. After cooling, solid sodium
chloride was added and the mixture was extracted with ether. The
organic layer was dried (MgSO.sub.4). The organic layer was
distilled and the fraction from 70-90.degree. C. was collected to
give methoxyacetaldehyde (20.3 g) which was used directly in the
next step.
EXAMPLE 72
[0985] Diphenylphosphoryl azide (83 mg, 0.3 mmol) was added in
portions to a solution of
7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(75 mg, 0.2 mmol), triethylamine (40 mg, 0.4 mmol) and
1-(2-aminoethyl)pyrrolidine (46 mg, 0.4mmol) in DMF (1.5 ml). After
stirring for 5 hours at ambient temperature, the mixture was
partitioned between ethyl acetate and water. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and the
volatiles were removed by evaporation. The residue was purified by
column chromatography eluting with methylene chloride/methanol
(9/1) followed by methylene chloride/3M ammonia in methanol (9/1).
After removal of the solvent, the solid was triturated with ether,
collected by filtration, washed with ether and dried under vacuum
to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-((2-(2-pyrrolidin-1-ylethyl)carbamo-
yl)vinyl)quinazoline (25 mg, 26%).
[0986] MS-ESI: 472 [MH].sup.+
[0987] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.8-1.95
(m, 2H), 1.95-2.1 (m, 2H), 2.48 (s, 3H), 3.0-3.2 (m, 2H), 3.35 (t,
2H), 3.6 (t, 2H), 3.65 (br s, 2H), 4.11 (s, 3H), 6.18 (s, 0.5H,
partially exchanged), 6.95 (dd, 1H), 7.05 (d, 1H), 7.35 (s, 1H),
7.37 (d, 1H), 7.8 (s, 1H), 7.86 (d, 1H), 8.2 (s, 1H), 8.76 (s,
1H)
[0988] The starting material was prepared as follows:
[0989] Trifluoromethanesulphonic anhydride (338 mg, 1.2 mmol) was
added to a suspension of
4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320
mg, 1 mmol), (prepared as described for the starting material in
Example 5), in methylene chloride (2 ml) containing pyridine (2 ml)
cooled at 5.degree. C. When the addition was complete, the mixture
was left to warm to ambient temperature and stirred for 1 hour.
After removal of the volatiles by evaporation, the residue was
partitioned between ethyl acetate/ether and water. The organic
layer was separated, washed with 0.5M hydrochloric acid, followed
by water, brine, dried (MgSO.sub.4) and evaporated to give
4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)qui-
nazoline (400 mg, 88%).
[0990] MS-ESI: 453-455 [MH].sup.+
[0991] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.15 (s, 3H), 7.5 (d,
1H), 7.62 (t, 1H), 7.78 (d, 1H), 8.02 (s, 1H), 8.27 (s, 1H), 8.77
(s, 1H)
[0992] Triethylamine (33 mg, 0.33mmol) and tert-butyl acrylate (77
mg, 0.6 mmol) followed by diphenylpropylphosphine (3.4 mg, 0.008
mmol) and palladium(II) acetate (1.7 mg, 0.0075 mmol) were added to
a solution of
4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(trifluoromethylsulphonyloxy)qui-
nazoline (136 mg, 0.3 mmol) in DMF (1.5 ml) under argon. When the
addition was complete the reaction flask was purged with argon. The
mixture was stirred at 80-85.degree. C. for 6 hours. After cooling,
the mixture was partitioned between ethyl acetate and water. The
aqueous layer was adjusted to pH6 with 2M hydrochloric acid. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with methylene chloride followed by
methylene chloride/ether (95/5). After removal of the solvent under
vacuum, the solid was triturated with pentane/ether, collected by
filtration and dried under vacuum to give
4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)qu-
inazoline (63 mg, 49%).
[0993] MS-ESI: 431 [MH].sup.+
[0994] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.51 (s, 9H), 4.07 (s,
3H), 6.87 (d, 1H), 7.45 (d, 1H), 7.6 (t, 1H), 7.7 (s, 1H), 7.75 (d,
1H), 7.91 (d, 1H), 8.39 (s, 1H), 8.65 (s, 1H) TABLE-US-00037
Elemental analysis: Found C 61.1 H 4.8 N 6.6
C.sub.22H.sub.20ClFN.sub.2O.sub.3 Requires C 61.3 H 4.7 N 6.5%
[0995] A solution of
4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(2-(tert-butoxycarbonyl)vinyl)qu-
inazoline (581 mg, 1.31 mmol) in a mixture of methylene
chloride/TFA (2.5 ml/2.5 ml) was stirred at ambient temperature for
1.5 hours. After removal of the volatiles under vacuum, the residue
was partitioned between ethyl acetate and water. The aqueous layer
was adjusted to pH3 with 0.5M sodium hydroxide. The organic layer
was separated and the aqueous layer was further extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried (MgSO.sub.4) and evaporated to give
7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazol-
ine (430 mg, 85%).
[0996] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.08 (s, 3H), 6.9 (d,
1H), 7.45 (s, 1H), 7.6 (t, 1H), 7.70 (s, 1H), 7.73 (d, 1H), 7.95
(d, 1H), 8.39 (s, 1H), 8.66 (s, 1H)
[0997] 1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a
suspension of
7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline
(105 mg, 0.28 mmol) and 5-hydroxy-2-methylindole (82 mg, 0.56
mmol), (prepared as described for the starting material in Example
48), in DMSO (1.5 ml). After stirring for 2 hours at ambient
temperature, the mixture was partitioned between ethyl acetate and
water. The aqueous layer was adjusted to pH3 with 2M hydrochloric
acid. The organic layer was washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with methylene chloride/methanol (95/5
followed by 90/10 and 70/30) to give
7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(75 mg, 71%).
[0998] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 4.06 (s,
3H), 6.15 (s, 1H), 6.82 (d, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35
(d, 1H), 7.68 (s, 1H), 7.84 (d, 1H), 8.25 (s, 1H), 8.55 (s, 1H)
EXAMPLE 73
[0999] A suspension of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1
mmol), (prepared as described in Example 49),
1-bromo-3-chloropropane (120 .mu.l, 1.2 mmol) and potassium
carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient
temperature overnight. After addition of water, the precipitate was
collected by filtration, washed with water and dried over
phosphorus pentoxide at 60.degree. C. to give
7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(280 mg, 70%).
[1000] MS-ESI: 398 [MH].sup.+
[1001] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2-2.35 (m, 2H), 2.4
(s, 3H), 3.85 (t, 2H), 4.0 (s, 3H), 4.32 (d, 2H), 6.15 (s, 1H),
6.88 (d, 1H), 7.27 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H),
8.5 (s, 1H)
EXAMPLE 74
[1002] A solution of
7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(150 mg, 0.38 mmol), (prepared as described in Example 73), in
1-methylpiperazine (2 ml) was heated at 100.degree. C. for 2 hours.
After cooling, the mixture was partitioned between ethyl acetate
and aqueous 5% sodium hydrogen carbonate. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography on an
isolute column eluting with methanol/ethyl acetate/methylene
chloride (1/4/5 followed by 1/9/0) and 3M ammonia in
methanol/methanol/methylene chloride (5/10/80). After removal of
the solvent under vacuum, the solid was dissolved in the minimum of
methylene chloride and ether/petroleum ether was added. The
precipitate was collected by filtration, and dried under vacuum to
give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)-
quinazoline (55 mg, 32%).
[1003] MS-ESI: 462 [MH].sup.+
[1004] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD, 60.degree.
C.) 2.2-2.3 (m, 2H), 2.4 (s, 3H), 2.9 (s, 3H), 3.4-3.5 (m, 4H),
3.5-3.8 (m, 6H), 4.07 (s, 3H), 4.4 (t, 2H), 6.95 (d, 1H), 7.35 (s,
1H), 7.4 (d, 1H), 7.55 (s, 1H), 7.8 (s, 1H), 8.95 (s, 1H)
EXAMPLE 75
[1005] Triphenylphosphine (262 mg, 1 mmol) and
N,N-diethylethanolamine (88 mg, 0.75 mmol) were added to a
suspension of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (160 mg,
0.5 mmol), (prepared as described in Example 49), in methylene
chloride (5 ml), followed by the addition, in portions, of diethyl
azodicarboxylate (165 .mu.l, 1 mmol). After stirring for 1 hour at
ambient temperature, the volatiles were removed under vacuum. The
residue was purified by column chromatography eluting with
methylene chloride/methanol (95/5) followed by methylene
chloride/3M ammonia in methanol (90/10) to give
7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazo-
line (147 mg, 70%).
[1006] MS-ESI 421 [MH].sup.+
[1007] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.0 (t, 6H),2.41 (s,
3H), 2.6 (q, 4H), 2.89 (t, 2H), 3.97 (s, 3H), 4.24 (t, 2H), 6.14
(s, 1H), 6.89 (dd, 1H), 7.25 (s, 1H), 7.32 (d, 1H), 7.38 (s, 1H),
7.58 (s, 1H), 8.48 (s, 1H) TABLE-US-00038 Elemental analysis: Found
C 66.2 H 6.9 N 13.1 C.sub.24H.sub.28N.sub.4O.sub.30.8H.sub.2O
Requires C 66.3 H 6.9 N 12.9%
EXAMPLE 76
[1008] Using an analogous procedure to that described in Example
75, 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321
mg, 1 mmol), (prepared as described in Example 49), was reacted
with 2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (294 mg,
1.2 mmol) to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((1-tertbutoxycarbonyl)pipe-
ridin-4-yloxy)ethoxy)quinazoline (420 mg, 76%).
[1009] MS-ESI: 549 [MH].sup.+
[1010] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4 (s, 9H), 1.3-1.5 (m,
2H), 1.7-1.9 (m, 2H), 2.38 (s, 3H), 3.0 (br t, 2H), 3.5-3.7 (m,
3H), 3.85 (m, 2H), 3.98 (s, 3H), 4.3 (t, 2H), 6.12 (s, 1H), 6.85
(d, 1H), 7.22 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.55 (s, 1H), 8.48
(s, 1H)
[1011] The starting material was prepared as follows:
[1012] tert-Butoxycarbonyl anhydride (1.52 g, 7 mmol) in acetone
(3.5 ml) was added to a solution of 4,4-(ethylenedioxy)piperidine
(1 g, 7 mmol) in acetone/trichloromethane (3.5 ml/3.5 ml) cooled at
0.degree. C. After stirring for 4 hours at ambient temperature, the
volatiles were removed under vacuum. The residue was dissolved in
ether and the ether solution was washed with water, brine, dried
(MgSO.sub.4) and evaporated to give
4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (1.7 g,
quant.).
[1013] .sup.1H NMR Spectrum: (CDCl.sub.3): 1.46 (s, 9H), 1.65 (t,
4H), 3.5 (t, 4H), 3.97 (s, 4H)
[1014] Freshly distilled boron trifluoride etherate (52 .mu.l, 0.41
mmol), followed by sodium cyanoborohydride (38 mg, 0.6 mmol) were
added to a solution of
4,4-(ethylenedioxy)-1-tertbutoxycarbonylpiperidine (100 mg, 0.41
mmol) in THF (1.4 ml) cooled at 0.degree. C. After stirring for 6
hours at ambient temperature, boron trifluoride etherate (52 .mu.l)
and sodium cyanoborohydride (26 mg, 0.41mmol) were added. After
stirring overnight at ambient temperature, the mixture was
partitioned between ethyl acetate and 2M sodium hydroxide. The
organic layer was washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography
eluting with methylene chloride/methanol (95/5) followed by
methylene chloride/methanol/3M ammonia in methanol (80/15/5) to
give 2-((1-tertbutoxycarbonyl)piperidin-4-yloxy)ethanol (42 mg,
42%).
[1015] MS-ESI: 268 [MNa].sup.+
[1016] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.48 (s, 9H), 1.5-1.6 (m,
2H), 1.8-1.9 (m, 2H), 2.0 (t, 1H), 3.05-3.15 (m, 2H), 3.5 (m, 1H),
3.57 (t, 2H), 3.7-3.9 (m, 4H)
EXAMPLE 77
[1017] A solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-((1-tertbutoxycarbonyl)piperidin-
-4-yloxy)ethoxy)quinazoline (379 mg, 0.69 mmol), (prepared as
described in Example 76), in methylene chloride (7 ml) containing
TFA (2.5 ml) was stirred for 1.5 hours at ambient temperature.
After removal of the volatiles under vacuum, the residue was
partitioned between ethyl acetate and water. Solid sodium hydrogen
carbonate and 2N sodium hydroxide were added to adjust the aqueous
layer to about pH10. The organic layer was washed with water,
followed by brine, dried (MgSO.sub.4) and evaporated. The residue
was triturated with ether, filtered, washed with ether and dried
under vacuum to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinaz-
oline (164 mg, 53%).
[1018] .sup.1HNMR Spectrum: (DMSOd.sub.6) 1.2-1.4 (m, 2H), 1.8-1.9
(m, 2H), 2.47 (s, 3H), 2.4-2.5 (m, 2H), 2.9-3.0 (d, 2H), 3.3-3.5
(m, 1H), 3.95 (s, 2H), 4.0 (s, 3H), 4.35 (s, 2H), 6.15 (s, 1H), 6.9
(dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.41 (s, 1H), 7.60 (s, 1H),
8.49 (s, 1H)
[1019] MS-ESI: 448 [M.].sup.+
EXAMPLE 78
[1020] A solution of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (193 mg,
0.6 mmol), (prepared as described in Example 49),
4-(2-hydroxyethoxy)pyridine (166 mg, 1.2 mmol), (J. Chem. Soc.
Perkin II, 1987, 1867), in methylene chloride (5 ml) containing
triphenylphosphine (330 mg, 1.26 mmol) and diisopropyl
azodicarboxylate (255 mg, 1.26 mmol) was stirred at ambient
temperature for 2 hours. The precipitate was filtered, triturated
with ether followed by ethyl acetate, and dried under vacuum to
give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(4-pyridyloxy)ethoxy)quinazoline
(142 mg, 54%).
[1021] .sup.1HNMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 3.97 (s,
3H), 4.52 (t, 2H), 4.58 (t, 2H), 6.14 (s, 1H), 6.89 (dd, 1H), 7.07
(d, 2H), 7.26 (s, 1H), 7.31 (d, 1H), 7.46 (s, 1H), 7.61 (s, 1H),
8.41 (s, 2H), 8.5 (s, 1H)
[1022] MS-ESI: 443 [MH].sup.+ TABLE-US-00039 Elemental analysis
Found C 66.6 H 5.0 N 12.5
C.sub.25H.sub.22N.sub.4O.sub.40.12CH.sub.2Cl.sub.2 Requires C 66.9
H 5.0 N 12.4%
EXAMPLE 79
[1023] A suspension of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonyla-
mino)ethoxy)quinazoline (148 mg, 0.31 mmol), (prepared as described
in Example 149), in methylene chloride (4 ml) containing TFA (1 ml)
was stirred for 1 hour. After removing the volatiles under vacuum,
the residue was azeotroped with toluene. The residue was dissolved
in methylene chloride (3 ml) and triethylamine (215 .mu.l, 1.5
mmol) was added followed by methanesulphonyl chloride (48 .mu.l,
0.62 mmol). After stirring for 1 hour at ambient temperature, the
mixture was partitioned between methylene chloride and water. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with ethylacetate/methanol (99/1 followed by
97/3). After evaporation of the solvent, the solid was triturated
with ether, filtered, washed with ether and dried under vacuum to
give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-methylsulpho-
nylamino)ethoxy)quinazoline (54 mg, 38%).
[1024] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 2.93 (s,
3H), 3.0 (s, 3H), 3.62 (t, 2H), 4.0 (s, 3H), 4.38 (t, 2H), 6.14 (s,
1H), 6.88 (dd, 1H), 7.26 (s, 1H), 7.3 (d, 1H), 7.43 (s, 1H), 7.61
(s, 1H), 8.49 (s, 1H)
[1025] MS-ESI: 457 [MH].sup.+
EXAMPLE 80
[1026] A solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yloxy)ethoxy)quinaz-
oline (76 mg, 0.17 mmol), (prepared as described in Example 77), in
acrylonitrile (0.5 ml), methylene chloride (1 ml) and methanol (1
ml) was stirred overnight at ambient temperature. After removal of
the volatiles under vacuum the residue was purified by column
chromatography eluting with methylene chloride/methanol (98/2
followed by 95/5 and 90/10). The residue was triturated with ethyl
acetate and ether. The resulting solid was filtered and dried under
vacuum to give
7-(2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethoxy)-6-methoxy-4-(2-methylindo-
l-5yloxy)quinazoline (73 mg, 86%).
[1027] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4-1.55 (m, 2H),
1.8-1.9 (m, 2H), 2.15 (t, 2H), 2.4 (s, 3H), 2.55 (t, 2H), 2.65 (t,
2H), 2.7-2.8 (m, 2H), 3.4-3.5 (m, 1H), 3.85 (m, 2H), 4.0 (s, 3H),
4.3 (t, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H),
7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)
[1028] MS-ESI: 502 [MH].sup.+ TABLE-US-00040 Elemental analysis
Found C 67.0 H 6.2 N 14.0 C.sub.28H.sub.31N.sub.5O.sub.4 Requires C
67.1 H 6.2 N 14.0%
EXAMPLE 81
[1029] A solution of
4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg,
0.31 mmol), (prepared as described for the starting material in
Example 9), 6-hydroxyindole (50 mg, 0.37 mmol) and potassium
carbonate (64 mg, 0.466 mmol) in DMF (1 ml) was heated at
95.degree. C. for 4 hours. After cooling, the mixture was diluted
with methylene chloride and poured onto a silica column. The
product was eluted with methylene chloride, followed by methylene
chloride/methanol (80/20 followed by 70/30 and 50/50). After
removal of the solvent by evaporation, the precipitate was
triturated with ether, filtered and dried under vacuum to give
6-methoxy-4-(indol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
(90 mg, 69%).
[1030] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.85 (br s, 4H),
2.15-2.25 (m, 2H), 2.85-3.15 (m, 6H), 4.01 (s, 3H), 4.32 (t, 2H),
6.5 (s, 1H), 6.95 (dd, 1H), 7.32 (s, 1H), 7.4 (s, 2H), 7.6 (d, 1H),
7.65 (s, 1H). 8.52 (s, 1H)
[1031] MS-ESI: 419 [MH].sup.+
EXAMPLE 82
[1032] Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added
to a solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.34 mmol), triphenyl phosphine (189 mg, 0.72 mol), and
3-pyrrolidinopropan-1-ol (89 mg, 0.686 mmol), (J. Org. Chem. 1988,
53, 3164), in methylene chloride (2.5 ml). After stirring overnight
at ambient temperature, the solid was filtered. The filtrate was
purified by column chromatography eluting with ethyl
acetate/methylene chloride (1/1) followed by ethyl
acetate/methylene chloride/methanol (4/5/1), methylene
chloride/methanol (9/1) and 3N ammonia in methanol/methylene
chloride (1/9). After removal of the solvent, the residue was
triturated with ether, filtered, and dried under vacuum to give
4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline
(49 mg, 35%).
[1033] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.8-2.0 (m, 2H),
2.0-2.15 (m, 2H), 2.2-2.32 (m, 2H), 2.41 (s, 3H), 3.0-3.2 (m, 2H),
3.4 (t, 2H), 3.6-3.7 (m, 2H), 4.35 (t, 2H), 6.2 (s, 1H), 6.95 (dd,
1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.5 (s, 1H), 7.57 (dd, 1H), 8.5 (d,
1H), 9.15 (s, 1H)
[1034] MS-ESI: 403 [MH].sup.+
[1035] The starting material was prepared as follows:
[1036] Sodium (368 mg, 16 mmol) was added to benzyl alcohol (10 ml,
96 mmol) and the mixture was heated at 148.degree. C. for 30
minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (656 mg, 4 mmol), (J.
Chem. Soc. section B 1967, 449), was added and the mixture
maintained at 148.degree. C. for 24 hours. The reaction mixture was
allowed to cool, the solution was poured on to water 170 ml) and
the aqueous mixture adjusted to pH3 with concentrated hydrochloric
acid. The precipitate was collected by filtration, washed with
water, ether and dried under vacuum to give
7-benzyloxy-3,4-dihydroquinazolin-4-one (890 mg, 89%) as a white
solid.
[1037] m.p. 267-269.degree. C.
[1038] .sup.1H NMR Spectrum: (DMSOd.sub.6; CF.sub.3COOD) 5.32(s,
2H); 7.25(d, 1H); 7.32-7.52(m, 6H); 8.12(d, 1H); 8.99(s, 1H)
[1039] MS-ESI: 252 [MH].sup.+ TABLE-US-00041 Elemental analysis:
Found C 71.4 H 4.9 N 10.7
C.sub.15H.sub.12N.sub.2O.sub.20.04H.sub.2O Requires C 71.2 H 4.8 N
11.1%
[1040] A mixture of 7-benzyloxy-3,4-dihydroquinazolin-4-one (11 g,
43.6 mmol) and DMF (1 ml) in thionyl chloride (100 ml) was heated
at reflux for 1.5 hours. Excess thionyl chloride was removed by
evaporation and the residue azeotroped with toluene. The residue
was partitioned between methylene chloride and water and saturated
aqueous sodium hydrogen carbonate was added until the aqueous layer
was at about pH9. The organic layer was separated, washed with
water, brine, dried (MgSO.sub.4) and evaporated to give
7-benzyloxy-4-chloroquinazoline (10.5 g, 89%).
[1041] .sup.1H NMR Spectrum: (DMSOd.sub.6) 5.4 (s, 2H); 7.35-7.65
(m, 6H); 8.2 (d, 1H); 9.0 (s, 1H)
[1042] MS-ESI: 270 [MH].sup.+
[1043] A solution of 7-benzyloxy-4-chloroquinazoline (2 g, 7.4
mmol), 5-hydroxy-2-methylindole (1.3 g, 8.9 mmol), (prepared as
described for the starting material in Example 48), in DMF (20 ml)
containing potassium carbonate (1.53 g, 11.1 mmol) was stirred at
80.degree. C. for 3 hours. After cooling, the mixture was poured in
portions into ice/water. The precipitate was filtered and washed
with water and dried under vacuum. The solid was dissolved in
methylene chloride and was purified by column chromatography
eluting with ethyl acetate and methylene chloride (1/1) to give
7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (2.28 g, 81%).
[1044] MS-ESI: 382 [MH].sup.+
[1045] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.41 (s, 3H), 5.4 (s,
2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.4 (d,
1H), 7.4-7.5 (m, 4H), 7.55 (d, 2H), 8.32 (d, 1H), 8.6 (s, 1H).
[1046] 10% Palladium on charcoal (200 mg) followed by ammonium
formate (4.34 g, 69 mmol) were added to a solution of
7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (1.75 g, 4.58
mmol) in DMF (60 ml). After stirring for 1 hour at ambient
temperature, the mixture was filtered. The filtrate was evaporated.
The residue was triturated with water, filtered, washed with ethyl
acetate, and dried under vacuum to give
7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (1.24 g, 93%).
[1047] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 6.14 (s,
1H), 6.88 (dd, 1H), 7.17 (s, 1H), 7.25-7.3 (m, 2H), 7.30 (d, 1H),
8.24 (d, 1H), 8.5 (s, 1H)
EXAMPLES 83-89
[1048] Using an analogous procedure to that described in Example
82, the appropriate alcohols were reacted with
7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline, (prepared as
described for the starting material in Example 82), to give the
compounds described in Table VI below. TABLE-US-00042 TABLE VI
##STR31## Example Weight number (mg) Yield % MS-ESI [MH].sup.+ R
Note 83 34 24 412 ##STR32## a 84 45 32 405 ##STR33## b 85 5 3 417
##STR34## c 86 56 35 467 ##STR35## d 87 63 44 419 ##STR36## e 88 24
17 403 ##STR37## f 89 84 63 387 ##STR38## g a)
7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted
with 3- sulphonyl)-1-propanol (95 mg), (prepared as described for
the starting material in (methyl- Example 50), to give
7-(3-(methylsulphonyl)propoxy)-4-(2-methylindol-5-yloxy)quinazo-
line. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.2-2.3 (m,
2H), 2.4 (s, 3H), 3.05 (s, 3H), 3.3-3.45 (m, 2H), 4.4 (t, 2H), 6.2
(s, 1H), 6.95 (dd, 1H), 7.38 (s, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.6
(dd, 1H), 8.5 (d, 1H), 9.2 (s, 1H) Elemental analysis Found C 60.2
H 5.3 N 10.6 C.sub.21H.sub.21N.sub.3O.sub.4S 0.4 DMF Requires C
60.5 H 5.4 N 10.8% b)
7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted
with 4-(2- hydroxyethyl)morpholine (90 mg) to give
4-(2-methylindol-5-yloxy)-7-(2-morpholino- ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.4 (s, 3H),
3.1-3.3 (m, 2H), 3.62 (d, 2H), 3.7-3.9 (m, 4H), 4.05 (d, 2H), 4.7
(t, 2H), 6.2 (s, 0.5 H, partially exchanged), 6.95 (dd, 1H), 7.35
(s, 1H), 7.39 (d, 1H), 7.6 (s, 1H), 7.65 (dd, 1H), 8.55 (d, 1H),
9.15 (s, 1H) Elemental analysis Found C 67.2 H 6.0 N 13.5
C.sub.23H.sub.24N.sub.4O.sub.3 0.3 H.sub.2O Requires C 67.4 H 6.1 N
13.7% c) 7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg)
was reacted with 1-(3- hydroxypropyl)piperidine (98 mg) to give
4-(2-methylindol-5-yloxy)-7-(3-(piperidin-1-
yl)propoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6,
CF.sub.3COOD) 1.2-1.5 (m, 2H), 1.6-1.8 (m, 2H), 1.8-1.9 (m, 2H),
2.25-2.35 (m, 2H), 2.45 (s, 3H), 2.95 (t, 2H), 3.25-3.3 (m, 2H),
3.55 (d, 2H), 4.4 (t, 2H), 6.95 (dd, 1H), 7.4 (s, 1H), 7.45 (d,
1H), 7.5 (s, 1H), 7.6 (d, 1H), 8.55 (d, 1H), 9.15 (s, 1H) d)
7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted
with 3-(1,1- dioxothiomorpholino)-1-propanol (133 mg), (prepared as
described for the starting material in Example 5), to give
4-(2-methylindol-5-yloxy)-7-(1,1-dioxothiomorpholino)pro-
poxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.0 (m,
2H), 2.4 (s, 3H), 1.6-1.7 (m, 2H), 2.9 (br s, 4H), 3.1 (br s, 4H),
4.25 (t, 2H), 6.12 (s, 1H), 6.85 (d, 1H), 7.22 (s, 1H), 7.3 (d,
1H), 7.3-7.4 (m, 2H), 8.25 (d, 1H), 8.55 (s, 1H) e)
7-Hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg) was reacted
with 4-(3-hydro- xypropyl)morpholine (100 mg), (prepared as
described for the starting material in Example 60), to give
4-(2-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m, 2H), 2.42 (s,
3H), 2.5 (t, 2H), 2.55 (t, 4H), 3.6 (t, 4H), 4.3 (t, 2H), 6.18 (s,
1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H), 7.3-7.4 (m, 2H), 8.3
(d, 1H), 8.6 (s, 1H) Elemental analysis Found C 66.5 H 6.2 N 12.7
C.sub.24H.sub.26N.sub.4O.sub.3 0.14 CH.sub.2Cl.sub.2 0.7 H.sub.2O
Requires C 66.7 H 6.4 N 13.0% f)
7-Hydroxy-4-(2-methylindol-s-yloxy)quinazoline (100 mg) was reacted
with 1-(2-hydro- xyethyl)piperidine (89 mg) to give
4-(2-methylindol-5-yloxy)-7-(2-(piperidin-1- yl)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4-1.5 (br s, 2H), 1.5-1.7 (br
s, 4H), 2.42 (s, 3H), 2.5-2.7 (br s, 4H), 2.8-3.0 (br a, 2H), 4.35
(br a, 2H), 6.18 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H),
7.4 (d, 1H), 7.42 (s, 1H), 8.3 (d, 1H), 8.6 (s, 1H) Elemental
analysis Found C 69.0 H 6.6 N 13.4 C.sub.24H.sub.26N.sub.4O.sub.2
0.8 H.sub.2O Requires C 69.1 H 6.7 N 13.4% g)
7-Hydroxy-4-(2-methylindol-s-yloxy)quinazoline (100 mg) was reacted
with 2-(1H- 1,2,4-triazol-1-yl)ethanol (78 mg), (Ann. Phar. Fr.
1977, 35, 503-508), to give 4-(2-
methylindol-5-yloxy)-7-(2-(1H-1,2,4-triazol-1-yl)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 4.6 (m, 2H), 4.7
(m, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.28 (s, 1H), 7.3 (d, 2H), 7.4
(s, 1H), 8.02 (s, 1H), 8.3 (d, 1H), 8.6 (s, 1H), 8.65 (s, 1H)
Elemental analysis Found C 63.7 H 4.8 N 21.5
C.sub.21H.sub.18N.sub.6O.sub.2 0.5 H.sub.2O Requires C 63.8 H 4.8 N
21.3%
EXAMPLE 90
[1049] A solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline
(423 mg, 1.45 mol), (prepared as described for the starting
material in Example 82), triphenylphosphine (685 mg, 2.61 mmol),
4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (500 mg, 2.32
mmol), (prepared as described for the starting material in Example
10), and diisopropyl azodicarboxylate (528 mg, 2.61 mmol) in
methylene chloride (18 ml) was stirred overnight at ambient
temperature. The mixture was then poured onto a column of silica
and eluted with ethyl acetate. After evaporation of the solvent,
the residue was triturated with ether, filtered, and dried under
vacuum to give
7-(1-tert-butoxycarbonylpiperidinylmethoxy)-4-(2-methylindol-5-yloxy)quin-
azoline (478 mg, 68%).
[1050] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.4 (m, 2H), 1.42
(s, 9H), 1.85 (d, 2H), 2.0-2.1 (m, 1H), 2.42 (s, 3H), 2.7-2.9 (br
s, 2H), 3.95-4.05 (m, 2H), 4.1 (d, 2H), 6.15 (s, 1H), 6.9 (dd, 1H),
7.3 (s, 1H), 7.33 (d, 1H), 7.38 (s, 1H), 7.35-7.4 (m, 1H), 8.3 (d,
1H), 8.6 (s, 1H)
[1051] MS-ESI: 489 [MH].sup.+ TABLE-US-00043 Elemental analysis
Found C 68.7 H 6.7 N 11.3 C.sub.28H.sub.32N.sub.4O.sub.4 Requires C
68.8 H 6.6 N 11.5%
EXAMPLE 91
[1052] To a suspension of
4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124
mg, 0.32 mmol) in methylene chloride (2.5 ml) was added
triphenylphosphine (179 mg, 0.628 mmol),
1-(2-hydroxyethyl)pyrrolidine (75 mg, 0.65 mmol) followed by
diisopropyl azodicarboxylate (134 .mu.l, 0.68 mmol) in portions.
After stirring overnight at ambient temperature the mixture was
poured onto a column of silica and eluted with ethyl
acetate/methylene chloride (1/1) followed by ethyl
acetate/methylene chloride/methanol (4/5/1) followed by methylene
chloride/methanol (9/1). After removal of the solvent, the solid
was triturated with ether, filtered, washed with ether and dried
under vacuum to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quin-
azoline (51 mg, 37%).
[1053] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.6-1.75 (m, 4H), 2.12
(s, 3H), 2.28 (s, 3H), 2.52 (br s, 4H), 3.85 (t, 2H), 3.93 (s, 3H),
4.25 (t, 2H), 6.8 (d, 1H), 7.17 (s, 1H), 7.22 (d, 1H), 7.33 (s,
1H), 7.54 (s, 1H), 8.43 (s, 1H)
[1054] The starting material was prepared as follows:
[1055] To a solution of 2,3-dimethyl-5-methoxyindole (175 mg, 1
mmol), (J. Chem. Soc. 1957, 3175-3180) in methylene (5 ml) cooled
at -60.degree. C. was added boron tribromide (210 .mu.l, 2.2 mmol)
dropwise. After completion of addition, the mixture was left to
warm up to ambient temperature and was stirred for 1 hour. Water
was added and the pH was adjusted to 6 with 2N sodium hydroxide.
The mixture was extracted with ethyl acetate and the organic layer
was separated, washed with brine, dried (MgSO.sub.4) and evaporated
to give 2,3-dimethyl-5-hydroxyindole (124 mg, 77%).
[1056] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.1 (s, 3H); 2.3 (s,
3H); 6.5 (dd, 1H); 6.65 (d, 1H); 7.0 (d, 1H); 8.45 (s, 1H)
[1057] Under nitrogen, to a solution of
2,3-dimethyl-5-hydroxyindole (643 mg, 4 mmol), in DMF (10 ml) was
added potassium carbonate (690 mg, 5 mmol). After stirring for 15
minutes at ambient temperature,
7-benzyloxy-4-chloro-6-methoxyquinazoline (1 g, 3.33 mmol),
(prepared as described for the starting material in Example 1), was
added. The mixture was heated at 90.degree. C. for 2 hours followed
by 30 minutes at 95.degree. C. After cooling, the mixture was
poured onto water (100 ml) cooled at 5.degree. C. The precipitate
was filtered, washed with water, followed by ether and dried under
vacuum to give
7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (1.4
g, 95%).
[1058] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H); 2.35 (s,
3H); 4.02 (s, 3H) 5.4 (s, 2H); 6.9 (dd, 1H); 7.22 (d, 1H); 7.3 (d,
1H); 7.35-7.6 (m, 6H); 7.65 (s, 1H); 8.5 (s, 1H)
[1059] A solution of
7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (2
g, 4.7 mmol) in DMF (120 ml) containing ammonium formate (11 gr,
174 mmol) and 10% palladium on charcoal (200 mg) was stirred for
2.5 hours at ambient temperature. The mixture was filtered, and the
filtrate was evaporated under vacuum. The residue was triturated
with ether and the solid was filtered, washed with water followed
by ether and dried under vacuum at 50.degree. C. to give
4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1.1
g, 69%).
[1060] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.1 (s, 3H); 2.32 (s,
3H); 3.97 (s, 3H); 7.85 (dd, 1H); 7.2 (bs, 2H); 7.25 (d, 1H); 7.58
(s, 1H); 8.4 (s, 1H)
EXAMPLES 92-106
[1061] Using an analogous procedure to that described in Example
91, the appropriate alcohol was reacted with
4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline,
(prepared as described for the starting material in Example 91), to
give the compounds described in the Table VII below. TABLE-US-00044
TABLE VII ##STR39## Example Weight Yield MS-ESI HPLC* number (mg) %
[MH].sup.+ R RT (min) Note 92 91 65 431 ##STR40## -- a 93 78 55 438
##STR41## -- b 94 34 27 435 ##STR42## -- c 95 39 33 407 ##STR43##
-- d 96 58 44 449 ##STR44## -- e 97 58 47 421 ##STR45## -- f 98 85
66 447 ##STR46## -- g 99 24 18 447 ##STR47## -- h 100 110 82 461
##STR48## -- i 101 9 7 447 ##STR49## -- j 102 81 62 463 ##STR50##
3.4 k 103 75 57 451 ##STR51## -- l 104 96 65 511 ##STR52## -- m 105
103 78 457 ##STR53## -- n 106 64 49 456 ##STR54## -- o *HPLC
conditions 2) as described hereinbefore. a)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124
mg) was reacted with 2-(1H-1,2,4-triazol-1-yl)ethanol (74 mg),
(Ann. Phar. Fr. 1977, 35, 503-508), to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(1H-1,2,4-triazol-1-yl)ethox-
y)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.10 (s, 3H),
2.30 (s, 3H), 3.93 (s, 3H), 4.52 (m, 2H), 4.55-4.65 (m, 2H), 6.85
(d, 1H), 7.2 (s, 1H), 7.25 (d, 1H), 7.4 (d, 1H), 7.58 (s, 1H), 8.0
(s, 1H), 8.48 (s, 1H), 8.58 (s, 1H) b)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124
mg) was reacted with 2-(2-methoxyethoxy)ethanol (78 mg) to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quin-
azoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.14 (s, 3H), 2.35 (s,
3H), 3.3 (s, 3H), 3.5 (t, 2H), 3.65 (t, 2H), 3.85 (t, 2H), 4.0 (s,
3H), 4.32 (t, 2H), 6.9 (d, 1H), 7.25 (d, 1H), 7.28 (d, 1H), 7.4 (s,
1H), 7.6 (s, 1H), 8.5 (s, 1H) c)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with N,N-diethylethanolamine (68 mg) to give
7-(2-(N,N-diethylamino)ethoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyqui-
nazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.05 (t, 6H), 2.15
(s, 3H), 2.35 (s, 3H), 2.6-2.7 (m, 4H), 2.92 (br s, 2H), 4.0 (s,
3H), 4.25 (t, 2H), 6.9 (dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s,
1H), 7.6 (s, 1H), 8.5 (s, 1H) d)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with N,N-dimethylethanolamine (52 mg) to give
7-(2-(N,N-dimethylamino)ethoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyqu-
inazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H), 2.35
(s, 9H), 2.85 (br s, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.87 (dd, 1H),
7.22 (s, 1H), 7.3 (d, 1H), 7.42 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H)
e) 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 4-(2-hydroxyethyl)morpholine (59 mg) to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-morpholinoethoxy)quinazoline-
. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H), 2.35 (s, 3H),
3.25-3.4 (m, 2H), 3.65 (d, 2H), 3.7-3.8 (m, 4H), 4.0-4.1 (m, 2H),
4.1 (s, 3H), 4.7 (t, 2H), 6.95 (dd, 1H), 7.3 (s, 1H), 7.35 (d, 1H),
7.6 (s, 1H), 7.8 (s, 1H), 9.0 (s, 1H) f)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 3-(N,N-dimethylamino)propan-1-ol (60 mg) to
give
7-(3-(N,N-dimethylamino)propoxy)-4-(2,3-dimethylindol-5-yloxy)-6-methoxyq-
uinazoline .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m, 2H),
2.15 (s, 3H), 2.2 (s, 6H), 2.35 (s, 3H), 2.45 (t, 2H), 4.0 (s, 3H),
4.25 (t, 2H), 6.9 (dd, 1H), 7.22 (d, 1H), 7.3 (d, 1H), 7.37 (s,
1H), 7.6 (s, 1H), 8.5 (s, 1H) g)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 1-(2-hydroxyethyl)-2-pyrrolidinone (75 mg) to
give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(2-oxopyrrolidin-1-yl)ethoxy-
)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.05 (m, 4H),
2.15 (s, 3H), 2.25 (t, 2H), 2.35 (s, 3H), 3.65 (t, 2H), 4.0 (s,
3H), 4.35 (t, 2H), 6.9 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.45 (s,
1H), 7.62 (s, 1H), 8.5 (s, 1H) h)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 2-(2-hydroxyethyl)piperidine (75 mg) to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quina-
zoline. .sup.1HMR Spectrum: (DMSOd.sub.6) 1.0-1.15 (m, 1H),
1.25-1.4 (m, 2H), 1.5 (br s, 1H), 1.65 (d, 1H), 1.7-1.8 (m, 1H),
1.8-1.9 (m, 2H), 2.15 (s, 3H), 2.35 (s, 3H), 2.5 (d, 1H), 2.6-2.7
(m, 1H), 2.9-3.0 (m, 1H), 4.0 (s, 3H), 4.2-4.35 (m, 2H), 6.88 (dd,
1H), 7.2 (s, 1H), 7.27 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s,
1H) i) 4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(97 mg) was reacted with 1-(2-hydroxyethyl)pyrrolidin-2,5-dione (83
mg) to give
4-(2,3-dimethylindol-5-yloxy)-7-(2-(2,5-dioxopyrrolidin-1-yl)ethoxy)-6-me-
thoxyquinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.12 (s, 3H),
2.35 (s, 3H), 2.68 (s, 4H), 3.85 (t, 2H), 3.95 (s, 3H), 4.35 (t,
2H), 6.88 (dd, 1H), 7.22 (s, 1H), 7.25 (d, 1H), 7.4 (s, 1H), 7.6
(s, 1H), 8.5 (s, 1H) j)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 1-methyl-3-piperidinemethanol (75 mg) to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)-
quinazoline. k)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 4-(3-hydroxypropyl)morpholine (75 mg),
(prepared as described for the starting material in Example 60), to
give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazolin-
e. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m, 2H), 2.15 (s,
3H), 2.35 (s, 3H), 2.42 (br s, 4H), 2.5 (t, 2H), 3.6 (m, 4H), 4.0
(s, 3H), 4.25 (t, 2H), 6.85 (dd, 1H), 7.25 (d, lH), 7.3 (d, 1H),
7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H). l)
4-(2,3-Dimethylindol-S-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol
(77 mg), (prepared as described for the starting material in
Example 59), to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methyl-
amino)ethoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15
(s, 3H), 2.35 (s, 6H), 2.65 (t, 2H), 2.9 (t, 2H), 3.25 (s, 3H),
3.45 (t, 2H), 4.0 (s, 3H), 4.3 (t, 2H), 6.9 (dd, 1H), 7.22 (s, 1H),
7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s, 1H) m)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (112
mg), (prepared as described for the starting material in Example
5), to give
4-(2,3-dimethylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-me-
thoxyquinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m,
2H), 2.15 (s, 3H), 2.35 (s, 3H), 2.7 (t, 2H), 2.95 (br s, 4H), 3.15
(br s, 4H), 4.0 (s, 3H), 4.29 (t, 2H), 6.9 (dd, 1H), 7.25 (s, 1H),
7.3 (d, 1H), 7.4 (s, 1H), 7.61 (s, 1H), 8.5 (s, 1H) n)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 2-(4-pyridyloxy)ethanol (81 mg), ( J. Chem.
Soc. Perkin Trans 2, 1987, 12, 1867), to give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazo-
line. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H), 2.35 (s,
3H), 4.0 (s, 3H), 4.55 (m, 2H), 4.6 (m, 2H), 6.88 (dd, 1H), 7.08
(d, 2H), 7.22 (s, 1H), 7.28 (d, 1H), 7.48 (s, 1H), 7.6 (s, 1H),
8.42 (d, 2H), 8.5 (s, 1H), 10.78 (s, 1H) o)
4-(2,3-Dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (97
mg) was reacted with 3-(methylsulphonyl)-1-propanol (80 mg),
(prepared as described for the starting material in Example 50), to
give
4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quina-
zoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.8-1.9 (m, 2H), 2.15
(s, 3H), 2.25-2.35 (m, 2H), 2.35 (s, 3H), 3.0 (s, 3H), 4.02 (s,
3H), 4.35 (t, 2H), 6.9 (dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s,
1H), 7.7 (s, 1H), 8.52 (s, 1H)
EXAMPLE 107
[1062] Using an analogous procedure to that described in Example
91, 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 2-(2-methoxyethoxy)ethanol (70 mg) to give
4-(indol-5-yloxy)-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline
(50 mg, 42%).
[1063] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.3 (s, 3H), 3.5 (m,
2H), 3.65 (m, 2H), 3.85 (n, 2H), 4.02 (s, 3H), 4.35 (t, 2H), 6.58
(s, 1H), 7.0 (dd, 1H), 7.4 (s, 1H), 7.45 (br s, 2H), 7.47 (d, 1H),
7.61 (s, 1H), 8.5 (s, 1H)
[1064] MS-ESI: 410 [MH]+
[1065] The starting material was prepared as follows:
[1066] A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (3 g,
10 mmol), (prepared as described for the starting material in
Example 1), 5-hydroxyindole (1.46 g, 11 mmol) in DMF (30 ml)
containing potassium carbonate (2.75 g, 20 mmol) was heated at
95.degree. C. for 2 hours. After cooling the mixture was poured
onto water (100 ml). The precipitate was filtered, washed with
water and dried under vacuum at 50.degree. C. over phosphorus
pentoxide. The solid was triturated with ether, filtered, washed
with ether and dried under vacuum to give
7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.5 g,
88%).
[1067] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.02 (s, 3H), 5.4 (s,
2H), 6.5 (s, 1H), 7.0 (dd, 1H), 7.4-7.5 (s, 9H), 7.65 (s, 1H), 8.5
(s, 1H), 11.23 (s, 1H)
[1068] MS-ESI: 398 [MH]+
[1069] A solution of
7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (8 g, 20 mmol)
in DMF (50 ml) and methylene chloride (100 ml) containing 10%
palladium on charcoal (2 g) was hydrogenated at 1.8 atmospheres
pressure until uptake of hydrogen had ceased. The solution was
filtered, the catalyst was washed with DMF and the filtrate was
evaporated. The residue was purified by column chromatography
eluting with methylene chloride, followed by methylene
chloride/methanol (95/5 and 90/10). After evaporation of the
solvent, the residue was triturated with ether, filtered and dried
under vacuum to give
7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (2.7 g; 44%).
[1070] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.0 (s, 3H), 6.46 (s,
1H), 7.01 (dd, 1H), 7.2 (s, 1H), 7.4-7.5 (m, 3H), 7.6 (s, 1H), 8.41
(s, 1H)
EXAMPLES 108-118
[1071] Using an analogous procedure to that described in Example
107, the appropriate alcohol was reacted with
7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline, (prepared as
described for the starting material in Example 107), to give the
compounds described in the Table VIII below. TABLE-US-00045 TABLE
VIII ##STR55## Example Weight Yield MS-ESI number (mg) % [MH].sup.+
R Note 108 58 49 407 ##STR56## r 109 14 13 379 ##STR57## s 110 55
48 393 ##STR58## t 111 27 23 405 ##STR59## u 112 58 47 421
##STR60## v 113 63 52 419 ##STR61## w 114 64 53 419 ##STR62## x 115
106 84 435 ##STR63## y 116 76 62 423 ##STR64## z 117 113 81 483
##STR65## aa 118 24 19 429 ##STR66## bb r)
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with N,N-diethylethanolamine (68 mg) to give
7-(2-(N,N-diethylamino)ethoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline.
s) 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg was
reacted with N,N-dimethylethanolamine (52 mg) to give
7-(2-(N,N-dimethylamino)ethoxy)A-(indol-5-yloxy)-6-methoxyquinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3 (s, 6H), 2.8 (t, 2H), 4.0
(s, 3H), 4.3 (t, 2H), 6.45 (s, 1H), 7.0 (dd, 1H), 7.4-7.5 (m, 4H),
7.6 (s, 1H), 8.5 (s, 1H) t)
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 3-(N,N-dimethylamino)propan-1-ol (60 mg) to give
7-(3-(N,N-dimethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.05 (m, 2H), 2.21 (s, 6H),
2.45 (t, 2H), 4.02 (s, 3H), 4.25 (t, 2H), 6.47 (s, 1H), 7.0 (dd,
1H), 7.38 (s, 1H), 7.35-7.4 (m, 2H), 7.45 (d, 1H), 7.6 (s, 1H), 8.5
(s, 1H) u) 7-Hydroxy-4-(indol-s-yloxy)-6-methoxyquinoline (89 mg)
was reacted with (2S)-2-(hydroxymethyl)-1 -methylpyrrolidine (67
mg) to give
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(1-methylpyrrolidin-2-yl)quinazoline
v) 7-Hydroxy-4-(indol-s-yloxy)-6-methoxyquinoline (89 mg) was
reacted with 3-(N,N-diethylamino)-1-propanol (76 mg) to give
7-(3-(N,N-diethylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline
.sup.1H NMR Spectrum: (DMSOd.sub.6) 0.95 (t, 6H), 1.9-2.0 (m, 2H),
2.5 (m, 4H), 2.6 (t, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.48 (s, 1H),
7.0 (dd, 1H), 7.38 (s, 1H), 7.42-7.5 (m, 3H), 7.6 (s, 1H), 8.5 (s,
1H) w) 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 2-(2-hydroxyethyl)piperidine (75 mg) to give
4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-2-yl)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.45-1.75 (m, 3H), 1.75-1.85
(m, 2H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1R), 2.25-2.35 (m, 1H), 2.95
(t, 1H), 3.3-3.4 (m, 2H), 4.1 (s, 3H), 4.4-4.5 (m, 2H), 6.5 (S,
1H), 7.05 (dd, 1H), 7.45-7.6 (m, 4H), 7.75 (s, 1H), 9.0 (s, 1H) x)
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 1-(2-hydroxyethyl)piperidine (75 mg) to give
4-(indol-5-yloxy)-6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.1-1.3 (m, 1H), 1.35-1.5 (m,
1H), 1.65-1.8 (m, 2H), 1.8-1.9 (m, 2H), 3.1 (t, 2H), 3.6 (d, 2H),
3.65 (t, 2H), 4.1 (s, 3H), 4.7 (t, 2H), 6.5 (d, 1H), 7.05 (dd, 1H),
7.45 (s, 1H), 7.5-7.55 (m, 2H), 7.61 (s, 1H), 7.8 (s, 1H), 9.0 (m,
1H) y) 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 4-(3-hydroxypropyl)morpholine (84 mg), (prepared as
described for the starting material in Example 60), to give
4-(indol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.9-2.1 (m, 2H), 2.4 (br s,
4H), 2.5 (t, 2H), 3.6 (t, 4H), 4.0 (s, 3H), 4.25 (t, 2H), 6.45 (s,
1H), 7.0 (dd, 1H), 7.4 (s, 1H), 7.4-7.45 (m, 2H), 7.47 (d, 1H), 7.6
(s, 1H), 8.5 (s, 1H) z)
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (77 mg),
(prepared as described for the starting material in Example 59), to
give
4-(indol-5-yloxy)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)ethoxy-
)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H),
2.65 (t, 2H), 2.9 (t, 2H), 3.25 (s, 3H), 3.45 (t, 2H), 4.0 (s, 3H),
4.3 (t, 2H), 6.45 (s, 1H), 7.05 (dd, 1H), 7.4-7.5 (m, 4H), 7.6 (s,
1H), 8.5 (s, 1H) aa)
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg) was
reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (112 mg),
(prepared as described for the starting material in Example 5), to
give
7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0 (m, 2H), 2.65 (m,
2H), 2.9 (br s, 4H), 3.15 (br s, 4H), 4.0 (s, 3H), 4.25 (t, 2H),
6.5 (s, 1H), 7.0 (dd, 1H), 7.35-7.5 (m, 4H), 7.65 (s, 1H), 8.5 (s,
1H) bb) 7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (89 mg)
was reacted with 2-(4-pyridyloxy)ethanol (81 mg), (J. Chem. Soc.
Perkin Trans 2, 1987, 12, 1867), to give
4-(indol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline
EXAMPLE 119
[1072] A solution of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.59
mmol), (prepared as described for the starting material in Example
67), 6-hydroxyindole (96 mg, 0.715 mmol) in DMF (3 ml) containing
cesium carbonate (291 mg, 0.894 mmol) was heated at 90.degree. C.
for 4 hours. After cooling, the mixture was diluted with water, the
precipitate was filtered, washed with water and dried under vacuum.
The solid was purified by column chromatography eluting with
methylene chloride/methanol (90/10 increasing to 50/50) to give
4(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (240
mg, 93%).
[1073] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.45 (m, 2H),
1.45-1.55 (m, 4H), 1.9-2.05 (m, 2H), 2.3-2.4 (m, 4H), 2.45 (t, 2H),
4.0 (s, 3H), 4.22 (t, 2H), 6.5 (s, 1H), 6.9 (dd, 1H), 7.3 (s, 1H),
7.35-7.40 (m, 2H), 7.55-7.65 (m, 2H), 8.5 (s, 1H)
[1074] MS-ESI: 433 [MH].sup.+ TABLE-US-00046 Elemental analysis
Found C 68.4 H 6.4 N 12.8 C.sub.25H.sub.28N.sub.4O.sub.30.4H.sub.2O
Requires C 68.3 H 6.6 N 12.7%
EXAMPLE 120
[1075] A solution of
4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (200 mg,
0.6 mmol), (prepared as described for the starting material in
Example 50), and 6-hydroxyindole (97 mg, 0.73 mmol) in DMF (3 ml)
containing potassium carbonate (125 mg, 0.91 mmol) was heated at
90.degree. C. for 2.5 hours. After cooling, water was added. The
precipitate was filtered, washed with water and dried under vacuum.
The residue was triturated with ether, filtered, washed with ether
and dried under vacuum to give
4-(indol-6-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline
(130 mg, 50%).
[1076] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2-2.35 (m, 2H), 3.05
(s, 3H), 3.3 (m, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.48 (s, 1H), 6.9
(dd, 1H), 7.3 (s, 1H), 7.4 (2s, 2H), 7.6 (d, 1H), 7.65 (s, 1H), 7.9
(s, 1H)
[1077] MS-ESI: 428 [MH].sup.+ TABLE-US-00047 Elemental analysis
Found C 56.2 H 4.9 N 9.3 C.sub.21H.sub.21N.sub.3O.sub.5S1.1H.sub.2O
Requires C 56.4 H 5.2 N 9.4%
EXAMPLE 121
[1078] Using an analogous procedure to that described for Example
120, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg,
0.59 mmol), (prepared as described for the starting material in
Example 1), was reacted with 6-hydroxyindole (95 mg, 0.71 mmol) to
give 4-(indol-6-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(155 mg, 60%).
[1079] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m, 2H), 2.4
(br s, 4H), 2.48 (t, 2H), 3.6 (t, 4H), 4.0 (s, 3H), 4.27 (t, 2H),
6.5 (s, 1H), 6.93 (dd, 1H), 7.3 (s, 1H), 7.4 (br s, 2H), 7.6 (d,
1H), 7.61 (s, 1H), 8.5 (s, 1H)
[1080] MS-ESI: 435 [MH].sup.+ TABLE-US-00048 Elemental analysis
Found C 62.0 H 6.2 N 12.1 C.sub.24H.sub.26N.sub.4O.sub.41.6H.sub.2O
Requires C 62.2 H 6.4 N 12.1%
EXAMPLE 122
[1081] A suspension of
7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)q-
uinazoline (150 mg, 0.31 mmol), (prepared as described in Example
90), in methylene chloride (2 ml) and TFA (1.5 ml) was stirred for
1 hour at ambient temperature. After removal of the volatiles under
vacuum the residue was azeotroped with toluene. The residue was
partitioned between methylene chloride and water and the aqueous
layer was adjusted to pH11. The organic layer was separated, washed
with brine, dried (MgSO.sub.4), and evaporated. The residue was
triturated with ether, filtered, washed with ether and dried under
vacuum to give
4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (80
mg, 67%).
[1082] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.5-1.65
(m, 2H), 2.0 (d, 2H), 2.15-2.3 (m, 1H), 2.4 (s, 3H), 2.95 (t, 2H),
3.38 (d, 2H), 4.2 (d, 2H), 6.2 (s, 0.5H, partially exchanged), 6.9
(dd, 1H), 7.35 (s, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 7.58 (dd, 1H),
8.5 (d, 1H), 9.1 (s, 1H)
[1083] MS-ESI: 389 [MH].sup.+ TABLE-US-00049 Elemental analysis
Found C 68.9 H 6.2 N 13.7
C.sub.23H.sub.24N.sub.4O.sub.20.2H.sub.2O0.12CH.sub.2Cl.sub.2
Requires C 69.0 H 6.2 N 13.9%
EXAMPLE 123
[1084] Using an analogous procedure to that described for Example
71, 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(150 mg, 0.386 mmol), (prepared as described in Example 122), was
reacted with methoxyacetaldehyde (83 mg, 0.772 mmol), (prepared as
described for the starting material in Example 71), to give
7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quin-
azoline (80 mg, 46%).
[1085] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.42 (m, 2H),
1.7-1.9 (m, 3H), 2.0 (t, 2H), 2.4 (s, 3H), 2.48 (t, 2H), 2.92 (d,
2H), 3.22 (s, 3H), 3.42 (t, 2H), 4.05 (d, 2H), 6.15 (s, 1H), 6.88
(dd, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.35 (s, 1H), 7.37 (d, 1H),
8.28 (d, 1H), 8.6 (s, 1H)
[1086] MS-ESI: 447 [MH].sup.+ TABLE-US-00050 Elemental analysis
Found C 68.4 H 6.7 N 12.2 C.sub.26H.sub.30N.sub.4O.sub.30.5H.sub.2O
Requires C 68.6 H 6.9 N 12.3%
EXAMPLE 124
[1087] Diethyl azodicarboxylate (117 mg, 0.67 mmol) was added in
portions to a solution of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (120 mg,
0.37 mmol), (prepared as described in Example 49), and
3-(ethylsulphonyl)-1-propanol (74 mg, 0.48 mmol) in methylene
chloride (3.5 ml) and triphenylphosphine (176 mg, 0.67 mmol). After
stirring for 2 hours at ambient temperature, the residue was poured
onto a column of silica and eluted with ethyl acetate/methylene
chloride (1/1) followed by methylene chloride/methanol (97/3
followed by 95/5). After removal of the solvent under vacuum, the
residue was triturated with ether, filtered and dried under vacuum
to give
7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazol-
ine (93 mg, 55%).
[1088] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25 (t, 3H), 2.2-2.3
(m, 2H), 2.4 (s, 3H), 3.2 (q, 2H), 3.3 (t, 2H), 4.0 (s, 3H), 4.35
(t, 2H), 6.15 (s, 1H), 6.9 (dd, 1H), 7.28 (s, 1H), 7.32 (d, 1H),
7.4 (s, 1H), 7.62 (s, 1H), 8.5 (s, 1H)
[1089] MS-ESI: 456 [MH].sup.+ TABLE-US-00051 Elemental analysis
Found C 60.3 H 5.6 N 9.2 C.sub.23H.sub.25N.sub.3O.sub.5S Requires C
60.6 H 5.5 N 9.2%
[1090] The starting material was prepared as follows:
[1091] A solution of ethylthiopropanol (1.2 g, 10 mmol) in
methylene chloride (30 ml) containing 3-chloroperoxybenzoic acid (5
g, 20 mmol) was stirred at ambient temperature for 30 minutes. The
precipitate was filtered, washed with methylene chloride and the
filtrate was poured onto a column of aluminium oxide and eluted
with methylene chloride, followed by methylene chloride/methanol
(95/5 and 90/10). After removal of the solvent, the residue was
dissolved in methylene chloride, dried (MgSO.sub.4) and evaporated
to give 3-(ethylsulphonyl)-1-propanol (1.05 g, 69%).
[1092] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25 (t, 3H), 1.75-1.9
(m, 2H), 3.0-3.2 (m, 4H), 3.5 (q, 2H), 4.7 (t, 1H)
[1093] MS-ESI: 153 [MH].sup.+
EXAMPLE 125
[1094] Using an analogous procedure to that described for Example
124, 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(120 mg, 0.36 mol), (prepared as described for the starting
material in Example 91), was reacted with 3-(ethylsulphonyl
)-1-propanol (71 mg, 0.46 mol), (prepared as described for the
starting material in Example 124), to give
4-(2,3-dimethylindol-5-yloxy)-7-(3-ethylsulphonylpropoxy)-6-methoxyquinaz-
oline (96 mg, 57%).
[1095] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25 (t, 3H), 2.15 (s,
3H), 2.2-2.3 (m, 2H), 2.35 (s, 3H), 3.2 (q, 2H), 3.3 (t, 2H), 4.02
(s, 3H), 4.35 (t, 2H), 6.9 (dd, 1H), 7.22 (s, 1H), 7.3 (d, 1H), 7.4
(s, 1), 7.63 (s, 1H), 8.51 (s, 1H)
[1096] MS-ESI: 470 [MH].sup.+ TABLE-US-00052 Elemental analysis
Found C 60.6 H 6.0 N 8.8 C.sub.24H.sub.27N.sub.3O.sub.5S0.4H.sub.2O
Requires C 60.5 H 5.9 N 8.8%
EXAMPLE 126
[1097] Using an analogous procedure to that described for Example
124, 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (128
mg, 0.4 mmol), (prepared as described in Example 49), was reacted
with 4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine (119 mg,
0.52 mmol) overnight to give
7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylin-
dol-5-yloxy)quinazoline (34 mg, 16%).
[1098] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.05-1.2 (m, 2H), 1.42
(s, 9H), 1.62-1.85 (m, 5H), 2.42 (s, 3H), 2.62-2.82 (m, 2H),
3.9-4.0 (m, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.17 (s, 1H), 6.9 (dd,
1H), 7.3 (d, 1H), 7.32 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s,
1H)
[1099] MS-ESI: 533 [MH].sup.+ TABLE-US-00053 Elemental analysis
Found C 67.8 H 6.9 N 10.5 C.sub.30H.sub.36N.sub.4O.sub.5 Requires C
67.7 H 6.8 N 10.5%
[1100] The starting material was prepared as follows:
[1101] A solution of 4-(2-hydroxyethyl)pyridine (1.8 g, 14.6 mol)
in acetic acid (15 ml) containing platinum oxide (200 mg) was
hydrogenated for 20 hours at 3.3-4 atmospheres pressure. After
filtration, the filtrate was evaporated and azeotroped twice with
toluene. The residue was triturated with 2N sodium hydroxide and
solid sodium hydroxide was added to adjust the pH to 13. The
volatiles were removed under vacuum and the residue was triturated
with ether, filtered, washed with methylene chloride, and dried
under vacuum to give 2-(piperidin-4-yl)-1-ethanol (860 mg,
46%).
[1102] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.3-1.5
(m, 4H), 1.6-1.7 (m, 1H), 1.7-1.9 (d, 2H), 1.75 (t, 2H), 3.25 (d,
2H), 3.55 (t, 2H)
[1103] A solution of 2-(piperidin-4-yl)-1-ethanol (830 mg, 6.4
mmol) in DMF (5 ml) containing tertbutyl dicarbonate anhydride (1.4
g, 6.4 mol) was stirred at ambient temperature for 48 hours. After
removal of the volatiles under vacuum, the residue was partitioned
between ether and water. The organic layer was separated, washed
with water, brine, dried (MgSO.sub.4) and evaporated to give
4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine (1 g,
68%).
[1104] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.9-1.1 (m, 2H), 1.3-1.6
(m, 3H), 1.4 (s, 9H), 1.6 (d, 2H), 2.5-2.8 (br s, 2H), 3.45 (dd,
2H), 3.9 (d, 2H), 4.35 (t, 1H)
EXAMPLE 127
[1105] Using an analogous procedure to that described for Example
121, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg,
0.47 mol), (prepared as described for the starting material in
Example 1), was reacted with 6-hydroxy-2-methylindole (84 mg, 0.57
mol), (Eur. J. Med. Chem. 1975, 10, 187), to give
6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-morpholinopropoxy)quinazoline
(157 mg, 73%).
[1106] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.25-2.35
(m, 2H), 2.38 (s, 3H), 3.15 (t, 2H), 3.35 (t, 2H), 3.5 (d, 2H),
3.68 (t, 2H), 4.0 (d, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.18 (s,
1H), 6.9 (d, 1H), 7.22 (s, 1H), 7.45 (d, 1H), 7.52 (s, 1H), 7.8 (s,
1H), 9.05 (s, 1H) MS-ESI: 449 [MH].sup.+ TABLE-US-00054 Elemental
analysis Found C 66.4 H 6.4 N 12.4
C.sub.25H.sub.28N.sub.4O.sub.40.2H.sub.2O Requires C 66.4 H 6.3 N
12.4%
EXAMPLE 128
[1107] Using an analogous procedure to that described for the
synthesis of
4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline,
(prepared as described in Example 122),
7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylin-
dol-5-yloxy)quinazoline (400 mg, 0.75 mmol), (prepared as described
in Example 126), was used to give
6-methoxy-4-(2-methylindol-5yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazolin-
e (284 mg, 87%).
[1108] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.3-1.5
(m, 2H), 1.8-2.0 (m, 5H), 2.4 (s, 3H), 2.9 (t, 2H), 3.3 (d, 2H),
4.05 (s, 3H), 4.35 (t, 2H), 6.2 (s, 1H), 6.95 (dd, 1H), 7.35 (s,
1H), 7.37 (d, 1H), 7.52 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H)
[1109] MS-ESI: 433 [MH].sup.+
EXAMPLE 129
[1110] Diethyl azodicarboxylate (65 .mu.l, 0.4 mmol) was added in
portions to a suspension of
4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol), triphenylphosphine (107 mg, 0.4 mmol),
(E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (40 mg, 0.28 mmol) in DMF (0.4
ml) and dichloromethane (1.5 ml) cooled at 0.degree. C. The
reaction mixture was left to warm up to ambient temperature and was
stirred overnight. The mixture was poured onto a column of silica
and was eluted with methylene chloride followed by methylene
chloride/methanol (98/2), followed by methylene chloride/3N ammonia
in methanol (95/5 and 90/10) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((E)4-(pyrrolidin-1-yl)but-2--
en-1-yloxy)quinazoline (51 mg, 55%).
[1111] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.6-1.7 (m, 4H), 2.15
(s, 3H), 2.3 (s, 3H), 2.4 (br s, 4H), 3.1 (d, 2H), 3.97 (s, 3H),
4.7 (d, 2H), 5.8-6.0 (m, 2H), 7.15 (s, 1H), 7.22 (d, 1H), 7.3 (d,
1H), 7.55 (s, 1H), 7.87 (s, 1H), 8.3 (s, 1H), 9.4 (s, 1H), 10.62
(s, 1H) MS-ESI: 458 [MH].sup.+
[1112] The starting material was prepared as follows:
[1113] Thionyl chloride (9.3 ml, 128 mmol) was added in portions to
a stirred solution of 2-butyne-1,4-diol (10 g, 116 mmol) in toluene
(15 ml) and pyridine (10.3 ml) cooled at 0.degree. C. The mixture
was stirred for 3.5 hours at ambient temperature and then poured
onto ice water. The mixture was extracted with ether, the organic
layer was washed with saturated aqueous sodium hydrogen carbonate
solution and then brine, dried (MgSO.sub.4) and the volatiles
removed by evaporation. The residue was purified by column
chromatography eluting with petroleum ether/ether (7/3) to give
4-chlorobut-2-yn-1-ol (4.74 g, 39%).
[1114] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.68(t, 1H); 4.18(d, 2H);
4.33(d, 2H)
[1115] Pyrrolidine (7.8 ml, 94 mmol) was added dropwise to a
solution of 4-chlorobut-2-yn-1-ol (4.74 g, 45 mmol) in toluene (40
ml) and the mixture stirred and heated at 60.degree. C. for 1 hour.
The volatiles were removed by evaporation and the residue was
purified by chromatography eluting with methylene chloride/methanol
(96/4) to give 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%).
[1116] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.82(t, 4H); 2.63(t, 4H);
3.44(t, 2H), 4.29(t, 2H)
[1117] A solution of 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 31
mmol) in THF (20 ml) was added dropwise to a suspension of lithium
aluminium hydride (2.35 g, 62 mmol) in anhydrous THF (8 ml) and the
mixture stirred and heated at 60.degree. C. for 2 hours. The
mixture was cooled to 5.degree. C. and 2M aqueous sodium hydroxide
solution (28 ml) was added dropwise. The resulting suspension was
filtered and the volatiles removed from the filtrate by
evaporation. The residue was dissolved in a mixture of methylene
chloride/ethyl acetate, dried (MgSO.sub.4) and the solvent removed
by evaporation. The residue was purified by column chromatography
on aluminum oxide eluting with methylene chloride/methanol (97/3)
to give (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.09 g, 70%).
[1118] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.82(m, 4H); 2.61(m, 4H);
3.17(m, 2H); 4.13(s, 2H); 5.84(m, 2H)
[1119] A solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (7
g, 23 mmol), (prepared as described for the starting material in
Example 1), and 5-amino-2,3-dimethylindole (4.5 g, 28 mmol) in
isopropanol (90 ml) containing 6.2 N hydrogen chloride in
isopropanol (380 .mu.l) was heated at relux for 3 hours and stirred
overnight at ambient temperature. The mixture was triturated with
ether and the solid was filtered, washed with ether and dried under
vacuum to give
7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline
(10.5 g, quant.).
[1120] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.16 (s, 3H), 2.33 (s,
3H), 4.0 (s, 3H), 5.34 (s, 2H), 7.2 (d, 1H), 7.32 (d, 1H),
7.35-7.55 (m, 7H), 8.2 (s, 1H), 8.7 (s, 1H), 10.9 (s, 1H), 11.15
(s, 1H),
[1121] MS-ESI: 425 [MH].sup.+
[1122] Ammonium formate (20 g, 326 mmol) and 10% palladium on
carbon (1 g) were added to a solution of
7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline
(10 g, 22 mmol) in DMF (100 ml) and methanol (300 ml). After
stirring for 3 hours at ambient temperature, aqueous ammonia (120
ml) was added. The precipitate was filtered, washed with water and
dried under vacuum. The residue was triturated with ethyl acetate
and ether and was filtered, dried under vacuum and purified by
column chromatography eluting with methanol/methylene chloride
(5/95 followed by 10/90) to give
4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (5.5
g, 75%).
[1123] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2 (s, 3H), 2.35 (s,
3H), 3.97 (s, 3H), 7.0 (s, 1H), 7.22 (d, 1H), 7.3 (d, 1H), 7.55 (s,
1H), 7.85 (s, 1H), 8.28 (s, 1H), 9.35 (s, 1H), 10.2 (br s, 1H),
10.62 (s, 1H)
[1124] MS-ESI: 335 [MH].sup.+
EXAMPLES 130-145
[1125] Using an analogous procedure to that described in Example
129 4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline
(68 mg, 0.2 mmol), (prepared as described for the starting material
in Example 129), was reacted with the appropriate alcohol to give
the compounds described in Table IX. TABLE-US-00055 TABLE IX
##STR67## Ex- am- ple MS- num- Weight Yield ESI ber (mg) % [MH] R
Note 130 10 11 458 ##STR68## a 131 63 69 450 ##STR69## b 132 5 6
443 ##STR70## c 133 35 36 475 ##STR71## d 134 53 51 510 ##STR72## e
135 56 58 469 ##STR73## f 136 4 4.6 415 ##STR74## g 137 29 35 406
##STR75## h 138 49 56 432 ##STR76## i 139 8 8.6 481 ##STR77## j 140
15 15 477 ##STR78## k 141 38 42 446 ##STR79## l 142 69 72 470
##STR80## m 143 21 21 492 ##STR81## n 144 36 40 440 ##STR82## o 145
31 33 460 ##STR83## p a)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with
3-(5-methyl-[1,2,4]-triazol-1-yl)propan-1-ol (40 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(5-methyl-1H-[1,2,4]-triaz-
ol-1-yl)propoxy)quinazoline. The starting material was prepared as
follows: Under argon, 1,2,4-triazole (13.8 g, 200 mmol) was added
to a solution of sodium ethoxide (freshly prepared from sodium (4.6
g) and ethanol (250 ml)). After complete dissolution,
3-bromopropan-1-ol (18 ml, 200 mmol) was added dropwise. The
mixture was refluxed for 18 hours and the solid was filtered and
washed with ethanol. The filtrate was evaporated and the residue
was purified by column chromatography eluting with methylene
chloride/methanol (9/1) to give 3-(1,2,4-triazol-1-yl)propan-1-ol
(22.8 g, 90%). .sup.1H NMR Spectrum: (CDCl.sub.3): 2.12(m, 2H) ;
2.6(br s, 1H); 3.65 (t, 2H); 4.35(t, 2H); 7.95(s, 1H); 8.1(s,1H) To
a solution of 3-(1,2,4-triazol-1-yl)propan-1-ol (7 g, 55 mmol) in
DMF (70 ml) was added tertbutyldimethylsilyl chloride (9.1 g, 60
mmol) followed by DMAP (336 mg, 2.7 mmol) followed by imidazole
(4.5 gr, 66 mmol). After stirring overnight at ambient temperature,
the volatiles were removed under vacuum and the residue was
partitioned between water and ethyl acetate/ether. The organic
layer was separated, washed with water, brine, dried (MgSO4) and
evaporated. The residue was purified by column chromatography
eluting with methylene chloride/ether (6/4) to give
3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (11.1
gr, 84%). MS-EI: 242 [MH]+ .sup.1H NMR Spectrum: (CDCl.sub.3)
0.25(s, 6H); 0.9(s, 9H); 2.05(m, 2H); 3.52(t, 2H); 4.25(t, 2H);
7.9(s, 1H); 8.02(s, 1H) To a solution of
3-(tertbutyldimethylsilyloxy)-1-(1,2,4-triazol-1-yl)propane (7 g,
29 mmol) in DMF (100 ml) cooled at -700.degree. C. was added 2.5 M
n-butyllithium (17.4 ml) over 45 minutes. After stirring for 90
minutes at -70.degree. C., methyl iodide (3.6 ml, 58 mmol) was
added. After stirring for 2 hours at ambient temperature, the
mixture was poured onto saturated ammonium chloride. The mixture
was then diluted with ether and ethyl acetate. The organic layer
was separated, washed with aqueous sodium thiosulphate followed by
brine, dried (MgSO.sub.4) and evaporated to give
3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)pr-
opane (7.3 g, 98%). MS-EI: 256 [MH]+ .sup.1H NMR Spectrum:
(CDCl.sub.3) 0.25(s, 6H); 0.85(s, 9H); 2.0(, 2H); 2.4(s, 3H);
3.52(t, 2H); 4.15(t, 2H); 7.72(s, 1H) To a solution of ammonium
fluoride (10.4 g, 280 mmol) in methanol (110 ml) was added a
solution of
3-(tertbutyldimethylsilyloxy)-1-(5-methyl-[1,2,4]-triazol-1-yl)propane
(7.2 g, 28 mmol) in methanol (30 ml). The mixture was refluxed for
4.5 hours. After cooling, silica (100 g) was added and the
volatiles were removed under vacuum. The residue was added onto a
column of silica and eluted with a mixture of methylene
chloride/ethyl acetate (1/1) followed by methylene
chloride/methanol (9/1) to give
3-(5-methyl-[1,2,4]-triazol-1-yl)propan-1-ol (3.65 g, 92%). MS-EI:
142 [MH]+ .sup.1H NMR Spectrum: (CDCl.sub.3) 2.05(m, 2H); 2.5(s,
3H); 3.62(t, 2H); 425(t, 2H); 7.8(s, 1H) b)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with
2-(N-(2-methoxyethyl)-N-methylainino)ethanol (38 mg), (prepared as
described for the starting material in Example 59), to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-(2-methoxyethyl-
)-N-methylamino)ethoxy)quinazoline. .sup.1H NMR Spectrum:
(DMSOd.sub.6) 2.15(s, 3H), 2.35(s, 6H), 2.65(t, 2H), 2.85(t, 2H),
3.25(s, 3H), 3.45(t, 2H), 3.95(s, 3H), 4.2(t, 2H), 7.15(s, 1H),
7.22(s, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H),
9.4(s, 1H), 10.62(s, 1H) c)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 2-(1-methylimidazol-2-yl)ethanol (36
mg), (EP 06751112 A1), to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)eth-
oxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15(s, 3H),
2.32(s, 3H), 3.2(t, 2H), 3.7(s, 3H), 3.95(s, 3H), 4.45(t, 2H),
6.8(s, 1H), 7.05(s, 1H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H),
7.55(s, 1H), 7.88(s, 1H), 8.32(s, 1H), 9.4(s, 1H), 10.62(s, 1H) d)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with
1-(3-hydroxypropyl)-4-methylpiperazine (45 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(4-methylpiperazin-
-1-yl)propoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
1.9-2.0(m, 2H), 2.15(2s, 6H), 2.0-2.9(m, 8H), 2.32(s, 3H), 2.45(t,
2H), 3.95(s, 3H), 4.2(t, 2H), 7.1(s, 1H), 7.22(d, 1H), 7.3(dd, 1H),
7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 9.4(s, 1H), 10.62(s, 1H) The
starting material was prepared as follows: 3-Bromopropan-1-ol (20
ml, 20 mmol) was added dropwise to a solution of 1-methylpiperazine
(29 ml, 26 mmol) in ethanol (200 ml). Potasium carbonate (83 gr, 60
mmol) was added and the mixture was refluxed for 20 hours. After
cooling, the solid was filtered and the filtrate was evaporated.
The residue was triturated with ether, filtrate and evaporated. The
residue was distilled at about 60-70.degree. C. under about 0.2 mm
Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g, 53%).
.sup.1H NMR Spectrum: (CDCl.sub.3) 1.72(m, 2H); 2.3(s, 3H);
2.2-2.8(m, 8H); 2.6(t, 2H); 3.8(t, 2H); 5.3(br s, 1H) e)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with
3-(1,1-dioxothiomorpholino)-1-propanol (55 mg), (prepared as
described for the starting material in Example 5), to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(1,1-dioxothiomorphol-
ino)propoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
1.9-2.0(m, 2H), 2.5(s, 9H), 2.65(t, 2H), 2.9(br s, 4H), 3.15(br s,
4H), 3.95(s, 3H), 4.25(t, 2H), 7.2(s, 1H), 7.85(s, 1H), 8.0(dd,
1H), 8.15(d, 1H), 8.2(s, 1H), 8.45(s, 1H), 9.6(s, 1H), 10.95(s, 1H)
f) 4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazolifle
(68 mg, 0.2 mmol) was reacted with
2-(N-methyl-N-(4-pyridyl)amino)ethanol (43 mg), (EP 0359389), to
give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridyl)ami-
no)ethoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15(s,
3H), 2.35(s, 3H), 3.07(s, 3H), 3.85(t, 2H), 3.95(s, 3H), 4.3(t,
2H), 6.7(d, 2H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s,
1H), 7.85(s, 1H), 8.15(d, 2H), 8.3(s, 1H), 9.4(s, 1H), 10.65(s, 1H)
g) 4-(2-3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline
(68 mg, 0.2 mmol) was reacted with 2-furanmethanol (28 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-furylmethoxy)quinazoline.
h) 4-(2-3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline
(68 mg, 0.2 mmol) was reacted with 2-N,N-dimethylethanolamine (25
mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-N,N-dimehtylamino)ethoxy)q-
uinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15(s, 3H),
2.25(s, 6H), 2.32(s, 3H), 2.72(t, 2H), 3.95(s, 3H), 4.2(t, 2H),
7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H),
8.32(s, 1H), 9.4(s, 1H), 10.6(s, 1H) i)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 1-(2-hydroxyethyl)pyrrolidine (33
mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)qu-
inazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65-1.75(m, 4H),
2.15(s, 3H), 2.35(s, 3H), 2.55-2.65(m, 4H), 2.9(t, 2H), 3.95(s,
3H), 4.25(t, 2H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s,
1H), 7.85(s, 1H), 8.32(s, 1H), 9.4(s, 1H), 10.62(s, 1H) j)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with triethylene glycol monomethyl ether
(47 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(2-(2-methoxyethoxy)e-
thoxy)ethoxy)quinazoline. k)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 5,5-dimethyl-1,3-dioxane-2-ethanol
(46 mg) to give
7-(2-(5,5-dimethyl-1,3-dioxan-2-yl)ethoxy)-4-(2,3-dimethylindol-5-yl-
amino)-6-methoxyquinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
0.7(s, 3H), 1.15(s, 3H), 2.05-2.1(m, 2H), 2.1(s, 3H), 2.6(s, 3H),
3.42(d, 2H), 3.57(d, 2H), 4.0(s, 3H), 4.22(t, 2H), 4.7(t, 1H),
7.2(s, 1H), 7.82(s, 1H), 8.0(dd, 1H), 8.17(a, 1H), 8.3(s, 1H),
8.45(s, 1H), 9.6(s, 1H), 10.95(s, 1H) l)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 1-(2-hydroxyethyl)piperidine (37 mg)
to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoli-
ne. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45(m, 2H),
1.45-1.6(m, 4H), 2.15(s, 3H), 2.35(s, 3H), 2.45(br s, 4H), 2.75(t,
2H), 3.95(s, 3H), 4.25(t, 2H), 7.15(s, 1H), 7.22(d, 1H), 7.3(dd,
1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 9.4(s, 1H), 10.62(s, 1H)
m) 4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline
(68 mg, 0.2 mmol) was reacted with
2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (44 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-y-
l)amino)ethoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
2.15(s, 3H), 2.32(s, 3H), 3.1(s, 3H), 3.9(s, 3H), 3.95(t, 2H),
4.35(t, 2H), 6.85(dd, 1H), 7.15(s, 1H), 7.20(d, 1H), 7.28(dd, 1H),
7.55(s, 1H), 7.85(s, 1H), 8.3(s, 1H), 8.58(d, 1H), 8.9(d, 1H),
9.4(s, 1H), 10.62(s, 1H) The starting material was prepared as
follows: A solution of 4-bromo-3,6-dichloro-pyridazine (1.11 g, 5
mmol), (J. Chem. Soc., Perkin Trans I, 1974, 696), and
2-(methylamino)ethanol (0.75 g, 10 mmol) in isopropanol (10 ml) was
heated at reflux for 30 minutes. The solvent was removed by
evaporation, the residue was partitioned between methylene chloride
and water and the aqueous layer was adjusted to pH9 with solid
potassium carbonate. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and the solvent removed by evaporation.
The residue was triturated with ether, collected by filtration and
dried under vacuum to give
2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (1 g, 90%).
.sup.1H NMR Spectrum: (CDCl.sub.3) 2.1(br s, 1H); 3.09(s, 3H);
3.71(t, 2H); 3.93(t, 2H); 6.8(s, 1H) MS-ESI: 221 [MH].sup.+ A
mixture of 2-W-(3 ,6-dichloropyridazin-4-yl)-N-methylamino)ethanol
(444 mg, 2 mmol) and 10% palladium-on-charcoal catalyst (150 mg) in
ethanol (15 ml), methanol (15 ml), methanol (5 ml) and aqueous
ammonia (15 ml) was stirred under hydrogen at 3 atmospheres
pressure for 4 hours. The catalyst was removed by filtration and
the solvent removed from the filtrate by evaporation. The residue
was dissolved in methylene chloride, the insoluble material was
removed by filtration and the solvent was removed from the filtrate
by evaporation. The residue was purified by column chromatography
on neutral aluminum oxide eluting with methylene chloride/methanol
(95/5 followed by 90/10). The purified product was triturated with
petroleum ether, the solid product was collected by filtration and
dried under vacuum to give
2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg, 91%). .sup.1H
NMR Spectrum: (CDCl.sub.3) 3.06(s, 3H); 3.57(t, 2H); 3.89(t, 2H);
6.52(dd, 1H); 8.48(d, 1H); 8.54(d, 1H) MS-ESI: 153 [MH].sup.+ n)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 2-(2-morpholinoethoxy)ethanol (50
mg) to give
4-(2,3-dimetbylindol-5-ylamino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy-
)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.18(s, 3H),
2.35(s, 3H), 2.35-2.45(m, 4H), 2.45-2.5(m, 2H), 3.5-3.55(m, 4H),
3.65(t, 2H), 3.8-3.85(m, 2H), 3.95(s, 1H), 4.25(m, 2H), 7.15(s,
1H), 7.22(d, 1H), 7.3(dd, 1H), 7.55(s, 1H), 7.85(s, 1H), 8.3(s,
1H), 9.4(s, 1H), 10.62(s, 1H) The starting material was prepared as
follows:
2-(2-Chloroethoxy)ethanol (1.25 g, 10 mmol) was added to a mixture
of morpholine (2.58 g, 30 mmol) and potassium carbonate (5.5 g, 40
mmol) in acetonitrile (50 ml). The mixture was heated at reflux for
6 hours and then stirred for 18 hours at ambient temperature. The
insolubles were removed by filtration and the volatiles were
removed from the filtrate by evaporation. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(95/5 followed by 90/10 and then 80/20) to give
2-(2-morpholinoethoxy)ethanol (600 mg, 34%). .sup.1H NMR Spectrum:
(CDCl.sub.3) 2.5(br s, 4H); 2.59(t, 2H); 3.6-3.85(m, 10 H) MS-ESI:
175 [MH].sup.+ o)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 3-(2-hydroxyethyl)pyridine (35 mg)
to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(2-(3-pyridyl)ethoxy)quinazol-
ine. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15(s, 3H), 2.32(s, 3H),
3.15(t, 2H), 3.95(s, 3H), 4.4(t, 2H), 7.2(s, 1H), 7.22(d, 1H),
7.3(dd, 1H), 7.35(dd, 1H), 7.55(s, 1H), 7.8(d, 1H), 7.85(s, 1H),
8.32(s, 1H), 8.45(dd, 1H), 8.6(s, 1H), 9.4(s, 1H), 10.68(s, 1H) p)
4-(2,3-Dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68
mg, 0.2 mmol) was reacted with 1-(3-hydroxypropyl)pyrrolidin-2-one
(41 mg) to give
4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl-
)propoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
1.9-2.05(m, 4H), 2.12(s, 3H), 2.15-2.3(m, 2H), 2.6(s, 3H),
3.3-3.45(m, 4H), 4.0(s, 3H), 4.15(t, 2H), 7.15(s, 1H), 7.82(s, 1H),
8.0(dd, 1H), 8.17(d, 1H), 8.3(s, 1H), 8.45(s, 1H), 9.6(s, 1H),
10.95(s, 1H)
EXAMPLE 146
[1126] Using an analogous procedure to that described for Example
121, 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150
mg, 0.47 mmol), (prepared as described for the starting material in
Example 9), was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56
mol), (Eur. J. Med. Chem. 1975, 10, 187), to give
6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (170 mg, 85%).
[1127] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65-1.8 (m, 4H),
1.95-2.05 (m, 2H), 2.42 (s, 3H), 2.5 (br s, 1H), 2.6 (t, 2H), 4.0
(s, 3H), 4.27 (t, 2H), 6.2 (s, 1H), 6.85 (dd, 1H), 7.2 (s, 1H), 7.4
(s, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 8.5 (s, 1H)
[1128] MS-ESI: 433 [MH].sup.+ TABLE-US-00056 Elemental analysis
Found C 68.3 H 6.4 N 12.8 C.sub.25H.sub.28N.sub.4O.sub.30.4H.sub.2O
Requires C 68.3 H 6.6 N 12.7%
EXAMPLE 147
[1129] Using an analogous procedure to that described in Example
123,
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoli-
ne (120 mg, 0.28 mmol) was used to give
7-(2-(1-(2-methoxyethyl)piperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-
-5-yloxy)quinazoline (55 mg, 40%).
[1130] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.15-1.3 (m, 2H),
1.4-1.55 (m, 1H), 1.65-1.8 (m, 4H), 1.95 (t, 2H), 2.4 (s, 3H), 2.42
(t, 2H), 2.85 (d, 2H), 3.25 (s, 3H), 3.42 (t, 2H), 4.0 (s, 3H),
4.22 (t, 2H), 6.15 (s, 1H), 6.85 (dd, 1H), 7.25 (s, 1H), 7.3 (d,
1H), 7.38 (s, 1H), 7.59 (s, 1H), 8.5 (s, 1).
[1131] MS-ESI: 491 [MH].sup.+ TABLE-US-00057 Elemental analysis
Found C 65.3 H 7.1 N 10.9 C.sub.28H.sub.34N.sub.4O.sub.41.3H.sub.2O
Requires C 65.4 H 7.2 N 10.9%
EXAMPLE 148
[1132] Using an analogous procedure to that described in Example
120 OR 121 PER PP, 4-
chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (160 mg, 0.48
mmol), (prepared as described for the starting material in Example
1), was reacted with 1,2-dimethyl-5-hydroxyindole (92 mg, 0.57
mol), (Tetrahedron 1994, 50, 13433), to give
4-(1,2-dimethylindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazolin-
e (163 mg, 74%).
[1133] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.1 (m, 2H), 2.4
(br s, 4H), 2.45 (s, 3H), 2.5 (t, 2H), 3.65 (t, 4H), 3.75 (s, 3H),
4.0 (s,3H), 4.25 (t, 2H), 6.25 (s, 1H), 6.95 (dd, 1H), 7.3 ) s,
1H), 7.38 (s, 1H), 7.45 (d, 1H), 7.6 (s, 1H), 8.5 (s, 1H) MS-ESI:
463 [MH].sup.+ TABLE-US-00058 Elemental analysis Found C 67.2 H 6.5
N 12.1 C.sub.26H.sub.30N.sub.4O.sub.4 Requires C 67.5 H 6.5 N
12.1%
EXAMPLE 149
[1134] Using an analogous procedure to that described in Example
124, 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (2.3
g, 7.16 mmol), (prepared as described in Example 49), was reacted
with (N-methyl-N-tert-butoxycarbonyl)ethanolamine (1.51 g, 8.6
mmol) to give
6-methoxy-4-(2-methylindol-5yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylam-
ino)ethoxy)quinazoline (1.93 g, 56%).
[1135] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4 (s, 9H), 2.4 (s,
3H), 2.90 (s, 3H), 3.65 (t, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.15
(s, 1H), 6.8 (dd, 1H), 7.28 (s, 1H), 7.35 (d, 1H), 7.42 (s, 1H),
7.6 (s, 1H), 8.5 (s, 1H);
[1136] MS-ESI: 479 [MH].sup.+ TABLE-US-00059 Elemental analysis
Found C 65.0 H 6.4 N 11.7 C.sub.26H.sub.30N.sub.4O.sub.5S Requires
C 65.3 H 6.3 N 11.7%
EXAMPLE 150
[1137] A solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonyla-
mino)ethoxy)quinazoline (550 mg, 1.15 mmol), (prepared as described
in Example 149), in methylene chloride (10 ml) containing TFA (12
ml) was stirred for 3 hours at ambient temperature. After removal
of the volatiles under vacuum, the residue was partitioned between
methylene chloride and sodium hydrogen carbonate. The pH of the
aqueous layer was adjusted to 11 with 2N sodium hydroxide. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was triturated with ether,
filtered and dried under vacuum to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazolin-
e (356 mg, 82%).
[1138] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 2.5 (s,
3H), 2.9 (t, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.25 (s, 1H), 6.9 (dd,
1H), 7.25 (s, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 8.5 (s,
1), 11.0 (s, 1H)
[1139] MS-ESI: 379 [MH].sup.+ TABLE-US-00060 Elemental analysis
Found C 64.6 H 5.8 N 14.2 C.sub.21H.sub.22N.sub.4O.sub.30.7H.sub.2O
Requires C 64.5 H 6.0 N 14.3%
EXAMPLE 151
[1140] A mixture of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(419 mg, 1 mmol), (prepared as described in Example 70), in DMF (6
ml) containing chloroacetonitrile (114 mg, 1.5 mmol), potassium
carbonate (346 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol)
was stirred at ambient temperature overnight. The mixture was
poured into water and the precipitate was filtered, washed with
water and dried under vacuum. The residue was purified by column
chromatography, eluting with methylene chloride, followed by
methylene chloride/methanol (98/2 and 95/5). After removal of the
solvent under vacuum, the residue was triturated with ether,
filtered, washed with ether and dried under vacuum to give
7-((1-cyanomethyl)piperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5-ylo-
xy)quinazoline (304 mg, 66%).
[1141] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.6-1.8
(m, 2H), 2.05-2.2 (d, 2H), 2.2-2.3 (m, 1H), 2.45 (s, 3H), 3.2 (t,
2H), 3.65 (d, 2H), 4.1 (s, 3H), 4.22 (d, 2H), 4.6 (s, 2H), 6.2 (s,
0.5H, partially exchanged), 6.9 (dd, 1H), 7.35 (s, 1H), 7.4 (d,
1H), 7.55 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H)
[1142] MS-ESI: 458 [MH].sup.+ TABLE-US-00061 Elemental analysis
Found C 67.6 H 6.1 N 15.2 C.sub.26H.sub.27N.sub.5O.sub.30.2H.sub.2O
Requires C 67.7 H 6.0 N 15.2%
EXAMPLE 152
[1143] A mixture of
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (360 mg, 1.00 mmol), potassium carbonate (215 mg, 1.56 mmol)
and 5-hydroxyindole (147 mg, 1.10 mmol) in DMF (8.0 ml) was stirred
at 100.degree. C. for 5 hours and allowed to cool to ambient
temperature. The solvent was removed by evaporation and the residue
purified by silica column chromatography eluting with methanol (2.5
to 5%) in dichloromethane. The resulting solid was recrystallised
from ethyl acetate, filtered and washed with diethyl ether to give
4-(indol-5-yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy-
)quinazoline (77 mg, 17%).
[1144] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.07 (m, 2H), 2.78 (s,
3H), 2.87 (s, 3H), 3.25 (t, 2H), 3.97 (s, 3H), 4.23 (t, 2H), 6.43
(br s, 1H), 6.96 (dd, 1H), 7.32 (s, 1H), 7.41 (m, 3H), 7.59 (d,
1H), 8.48 (s, 1H) and 11.17 (s, 1H)
[1145] MS (ESI): 457 (MH).sup.+ TABLE-US-00062 Elemental analysis
Found C 57.5 H 5.3 N 12.0 C.sub.22H.sub.24N.sub.4O.sub.5S Requires
C 57.9 H 5.3 N 12.3%
[1146] The starting material was prepared as follows:
[1147] Using an analogous procedure to that described for the
synthesis of the starting material in Example 5,
4-(4-bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline was made
in a similar way to
4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline using
4-bromo-2-fluorophenol instead of 4-chloro-2-fluorophenol.
[1148] A mixture of
4-(4-bromo-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (9.64 g,
26.4 mmol) and triphenylphosphine (20.9 g, 79.8 mmol) in
dichloromethane (240 ml) was stirred under nitrogen, at ambient
temperature for 30 minutes. 3-(N-tertButoxycarbonyl)-propanolamine
(6.26 g, 35.8 mmol) was added followed by diethyl azodicarboxylate
(12.4 ml, 13.7 g, 78.7 mmol). The reaction mixture was stirred for
2 hours. The solvent was then removed by evaporation and the
residue taken up in acetonitrile (250 ml). The solution was
concentrated to half the original volume and cooled. The resulting
crystalline solid was filtered, washed with ether and dried to give
4-4bromo-2-fluorophenoxy)-7-(3-(N-tertbutoxycarbonylamino)propoxy)-6-
-methoxyquinazoline (10.0 g, 73%).
[1149] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.37 (s, 9H), 1.94 (t,
2H), 3.13 (q, 2H), 3.97 (s, 3H), 4.21 (t, 2H), 6.89 (br s, 1H),
7.38 (s, 1H), 7.43-7.53 (m, 2H), 7.57 (s, 1H), 7.78 (dd, 1H) and
8.55 (s, 1H) MS (ESI): 522 (MH).sup.+ TABLE-US-00063 Elemental
analysis Found C 52.1 H 4.7 N 7.9 C.sub.23H.sub.25N.sub.3BrFO.sub.5
Requires C 52.3 H 4.9 N 8.0%
[1150]
4-(4-Bromo-2-fluorophenoxy)-7-(3-(N-tertbutoxycarbonylamino)propox-
y)-6-methoxyquinazoline (5.46 g, 10.5 mmol) was taken up in
trifluoroacetic acid (75 ml) and heated at 85.degree. C. for 1.5
hours. The solution was allowed to cool and the excess
trifluoroacetic acid removed by evaporation. The residue was then
treated with aqueous ammonia (0.88) solution, extracted with
dichloromethane (3.times.150 ml) and filtered through phase
separating paper. The solvent was removed by evaporation to give
7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline
(4.42 g, 100%).
[1151] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.87 (m, 2H), 2.73 (t,
2H), 3.98 (s, 3H), 4.26 (t, 2H), 7.40 (s, 1H), 7.50 (m, 2H), 7.55
(s, 1H), 7.78 (dd, 1H) and 8.55 (s, 1H) MS (ESI): 422
(MH).sup.+
[1152] A solution of
7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline
(2.71 g, 6.4 mmol) and triethylamine (1.1 ml 0.80 g, 7.9 mmol) in
dichloromethane (15 ml) was treated with a solution of
methanesulphonyl chloride (0.53 ml, 0.79 g, 6.9 mmol) in
dichloromethane (10 ml) and stirred at ambient temperature, under
nitrogen for 18 hours. The dichloromethane was then removed by
evaporation and THF (4 ml) added. The resulting solution was
treated with saturated aqueous sodium hydrogen carbonate solution
(to pH 8), stirred vigorously for 30 minutes and the precipitate
filtered, washed with water and dried to give
4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propox-
y)quinazoline (2.98 g, 93%).
[1153] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.01 (m, 2H), 2.90 (s,
3H), 3.15 (t, 2H), 3.96 (s, 3H), 4.25 (t, 2H), 7.06 (s, 1H), 7.40
(s, 1H), 7.49 (m, 2H), 7.56 (s, 1H), 7.78 (dd, 1H) and 8.54 (s, 1H)
MS (ESI): 500/502 (MH).sup.+
[1154]
4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino-
)propoxy)quinazoline (1.0 g, 2 mmol) was taken up in DMF (10 ml),
treated with sodium hydride (60% dispersion in mineral oil, 0.11 g,
2.7 mmol) and stirred, under nitrogen for 30 minutes. Methyl iodide
(0.16 ml, 2.6 mmol) was added and the mixture stirred for 18 hours.
The solvent was removed by evaporation and the residue taken up in
water and extracted with dichloromethane (3.times.30 ml). The
organic solution was then washed with water, brine, dried
(MgSO.sub.4) and evaporated to dryness. The crude product was
purified by silica column chromatography eluting with methanol (2.5
to 5%) in dichloromethane to give
4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methyl
N-methylsulphonylamino) propoxy)quinazoline (0.86 g, 83%).
[1155] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.06 (m, 2H), 2.78 (s,
3H), 2.87 (s, 3H), 3.24 (t, 2H), 3.97 (s, 3H), 4.23 (t, 2H), 7.39
(s, 1H), 7.48 (m, 2H), 7.55 (s, 1H), 7.78 (dd, 1H) and 8.54 (s, 1H)
MS (ESI): 514/516 (MH).sup.+
[1156] 4-(4-Bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methyl
N-methylsulphonylamino)propoxy)quinazoline (4.70 g, 9.1 mmol) was
dissolved in 2N aqueous hydrochloric acid solution (85 ml) and
heated at reflux for 1 hour. After cooling, the solution was
carefully poured into saturated aqueous sodium hydrogen carbonate
solution (to pH8) and stirred vigorously for 30 minutes. The
resulting precipitate was filtered and dried. The filter cake was
then taken up as a suspension in acetone, filtered, washed with
diethyl ether and dried to give
.sup.6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-4-
-one (3.23 g, 88%).
[1157] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.02 (m, 2H), 2.77 (s,
3H), 2.86 (s, 3H), 3.22 (t, 2H), 3.86 (s, 3H), 4.13 (t, 2H), 7.09
(s, 1H), 7.42 (s, 1H), 7.95 (s, 1H) and 12.02 (s, 1H)
[1158] MS (ESI): 342 (MH).sup.+
[1159]
6-Methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazolin-
-4-one (2.24 g, 6.6 mmol) was taken up in thionyl chloride (25 ml)
and treated with DMF (5 drops). The resulting solution was then
heated at reflux for 1 hour followed by cooling to ambient
temperature. The excess thionyl chloride was removed by evaporation
followed by azeotroping with toluene (3.times.). The residue was
basified with saturated aqueous sodium hydrogen carbonate solution
(to pH8) and extracted twice with ethyl acetate. The organic
solution was washed with water, brine, dried (MgSO.sub.4) and
evaporated to dryness to give
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (1.90 g, 80%).
[1160] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.08 (m, 2H), 2.78 (s,
3H), 2.88 (s, 3H), 3.24 (t, 2H), 3.99 (s, 3H), 4.26 (t, 2H), 7.37
(s, 1H), 7.42 (s, 1H) and 8.86 (s, 1H)
[1161] MS (ESI): 360(MH).sup.+
EXAMPLE 153
[1162] A mixture of
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (360 mg, 1.00 mmol), (prepared as described for the starting
material in Example 152), potassium carbonate (215 mg, 1.56 mmol)
and 5-hydroxy-2-methylindole (162 mg, 1.10 mmol) in DMF (8.0 ml)
was stirred at 100.degree. C. for 5 hours and allowed to cool to
ambient temperature. The solvent was removed by evaporation and the
residue was purified by silica column chromatography eluting with
methanol (2.5 to 5%) in dichloromethane . The resulting solid was
recrystallised from ethyl acetate, filtered and washed with diethyl
ether to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino-
)propoxy)quinazoline (166 mg, 35%).
[1163] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.06 (m, 2H), 2.38 (s,
3H), 2.79 (s, 3H), 2.89 (s, 3H), 3.24 (t, 2H), 3.96 (s, 3H), 4.21
(t, 2H), 6.11 (br s, 1H), 6.87 (dd, 1H), 7.23 (d, 1H), 7.30 (d,
1H), 7.35 (s, 1H), 7.57 (s, 1H), 8.46 (s, 1H) and 10.98 (s, 1H)
[1164] MS (ESI): 471 (MH).sup.+ TABLE-US-00064 Elemental analysis
Found C 58.3 H 5.6 N 11.7 C.sub.23H.sub.26N.sub.4O.sub.5S Requires
C 58.7 H 5.6 N 11.9%
EXAMPLE 154
[1165] A mixture of
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (150 mg, 0.42 mmol), (prepared as described for the starting
material in Example 152), potassium carbonate (90 mg, 0.63 mmol)
and 7-hydroxyquinoline (67 mg, 0.46 mmol) in DMF (5.0 ml) was
stirred at 100.degree. C. for 2 hours and allowed to cool to
ambient temperature. The solvent was removed by evaporation and the
residue taken up in 2N. aqueous sodium hydroxide solution. The
precipitate was filtered off, dried, taken up in dichloromethane
and the solution filtered through phase separating paper. The
filtrate was then evaporated to dryness. The resulting solid was
recrystallised from acetonitrile, filtered and washed with diethyl
ether to give
6-methoxy-7-(3-(N-methyl-Nmethylsulphonylamino)propoxy)-4-(quinolin-7-ylo-
xy)quinazoline (122 mg, 63%).
[1166] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.09 (m, 2H), 2.79 (s,
3H), 2.90 (s, 3H), 3.26 (t, 2H), 3.99 (s, 3H), 4.26 (t, 2H), 7.39
(s, 1H), 7.54 (dd, 1H), 7.56 (dd, 1H), 7.60 (s, 1H), 7.91 (d, 1H),
8.09 (d, 1H), 8.44 (d, 1H), 8.55 (s, 1H) and 8.93 (dd, 1H)
[1167] MS (ESI): 469 (MH).sup.+ TABLE-US-00065 Elemental analysis
Found C 58.6 H 5.1 N 11.9 C.sub.23H.sub.24N.sub.4O.sub.5S Requires
C 59.0 H 5.2 N 12.0%
EXAMPLE 155
[1168] A mixture of
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (150 mg, 0.42 mmol), (prepared as described for the starting
material in Example 152), potassium carbonate (90 mg, 0.63 mmol)
and 7-hydroxy-4-methylquinoline (71 mg, 0.46 mmol), (Chem. Berich.
1967, 100, 2077), in DMF (5.0 ml) was stirred at 100.degree. C. for
2 hours and allowed to cool to ambient temperature. The DMF solvent
was removed by evaporation and the residue was taken up in 2N
aqueous sodium hydroxide solution. The precipitate was filtered
off, dried, taken up in dichloromethane and then filtered through
phase separating paper. The solution was then evaporated to
dryness. The resulting solid was recrystallised from acetonitrile,
filtered and washed with diethyl ether to give
6methoxy-7-3-(N-methyl-N-methylsulphonylamino)propoxy)-4-(4-methy-
lquinolin-7-yloxy)quinazoline (84 mg, 42%).
[1169] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.09 (m, 2H), 2.71 (s,
3H), 2.79 (s, 3H), 2.89 (s, 3H), 3.25 (t, 2H), 3.98 (s, 3H), 4.25
(t, 2H), 7.37 (s, 1H), 7.38 (d, 1H), 7.61 (dd, 1H), 7.63 (s,1H),
7.89 (d, 1H), 8.20 (d, 1H), 8.54 (s, 1H) and 8.76 (d, 1H)
[1170] MS (ESI): 483 (MH).sup.+ TABLE-US-00066 Elemental analysis
Found C 59.1 H 5.3 N 11.5 C.sub.24H.sub.26N.sub.4O.sub.5S Requires
C 59.1 H 5.0 N 12.0%
EXAMPLE 156
[1171] A mixture of
(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline
(90 mg, 0.28 mmol), (prepared as described for the starting
material in Example 7), potassium carbonate (60 mg, 0.44 mmol) and
7-hydroxy-4-trifluoromethylquinoline (65 mg, 0.31 mmol), (prepared
as in Ukr. Khim. Zh. (Russ. Ed) Vol. 59, No. 4, pp. 408-411, 1993),
in DMF (2 ml) was stirred at 100.degree. C. for 6 hours and then
allowed to cool to ambient temperature. The DMF solvent was removed
by evaporation, the residue was taken up in
methanol/dichloromethane (1/1) and pre-absorbed onto silica. The
crude mixture was purified by silica column chromatography eluting
with dichloromethane/methanol/0.880 aqueous ammonia (95/5/1) and
the product recrystallised from acetonitrile to give
(R,S-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)-4-(4-trifluoromethylqu-
inolin-7-yloxy)quinazoline (58 mg, 42%).
[1172] .sup.1H NMR Spectrum: (DMSOd.sub.6 100.degree. C.) 1.24 (m,
1H), 1.59 (m, 1H), 1.70 (m, 1H), 1.83 (m, 1H), 2.05 (m, 2H), 2.17
(m, 1H), 2.24 (s, 3H), 2.64 (dt, 1H), 2.84 (dd, 1H), 4.05 (s, 3H),
4.18 (d, 2H), 7.43 (s, 1H), 7.69 (s, 1H), 7.87 (dd, 1H), 7.96 (d,
1H), 8.18 (s, 1H), 8.25 (dd, 1H), 8.59 (s, 1H) and 9.16 (d, 1H)
[1173] MS (ESI): 499 (MH).sup.+ TABLE-US-00067 Elemental analysis
Found C 62.2 H 5.1 N 11.0 C.sub.26H.sub.25N.sub.4F.sub.3O.sub.3
Requires C 62.6 H 5.1 N 11.2%
EXAMPLE 157
[1174] A mixture of
(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline
(150 mg, 0.46 mmol), (prepared as described for the starting
material in Example 7), potassium carbonate (106 mg, 0.77 mmol) and
3-fluoro-7-hydroxyquinoline (119 mg, 0.73 mmol) in DMF (5 ml) was
stirred at 100.degree. C. for 2 hours and then allowed to cool to
ambient temperature. The solvent was removed by evaporation and the
residue treated with 1.0 N aqueous sodium hydroxide solution (30
ml) then allowed it to stir for 30 minutes. The crude solid was
collected by filtration and washed with water. The resultant solid
was dissolved in dichloromethane and filtered through phase
separating paper. The solvent was removed by evaporation and the
solid residue was recrystallised from acetonitrile to give
(R,S)-4-3-fluoroquinolin-7-yloxy)-6methoxy-7-((1-methylpiperidin-3-yl)met-
hoxy)quinazoline (83 mg, 40%).
[1175] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.11 (m, 1H), 1.50 (m,
1H), 1.64 (m, 1H), 1.84 (m, 3H), 2.10 (m, 1H), 2.15 (s, 3H), 2.62
(d, 1H), 2.83 (d, 1H), 4.00 (s, 3H), 4.08 (d, 2H), 7.38 (s, 1H),
7.62 (s, 1H), 7.68 (dd, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.34 (dd,
1H), 8.54 (s, 1H) and 8.97 (d, 1H),
[1176] MS (ESI): 449 (MH).sup.+ TABLE-US-00068 Elemental analysis
Found C 66.2 H 5.6 N 12.3
C.sub.25H.sub.25N.sub.4FO.sub.30.2H.sub.2O Requires C 66.4 H 5.7 N
12.4%
[1177] The starting material, 3-fluoro-7-hydroxyquinoline was
prepared as follows:
[1178] 3-Fluoro-7-methoxyquinol-2(1H)-one (300 mg, 1.55 mmol),
(prepared as in Tetrahedron, Vol. 52, No. 9, pp. 3223-3228, 1996),
was dissolved in thionyl chloride (3 ml), treated with DMF (1 drop)
and heated at reflux for 1 hour. The excess thionyl chloride was
removed by evaporation and the residue azeotroped with toluene
(3.times.). The residue was basified to pH8 with saturated aqueous
sodium hydrogen carbonate solution and extracted with ethyl acetate
(3.times.20 ml). The organic solution was washed with water and
brine then dried (MgSO.sub.4) and evaporated to dryness to give
2-chloro-3-fluoro-7-methoxyquinoline (320 mg, 97%).
[1179] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.95 (s, 3H), 7.25 (dd,
1H), 7.37 (d, 1H), 7.67 (d, 1H) and 7.78 (d, 1H)
[1180] MS (ESI): 212 (MH).sup.+
[1181] A mixture of 2-chloro-3-fluoro-7-methoxyquinoline (310 mg,
1.47 mmol), triethylamine (310 mg, 0.4 ml, 3.07 mmol) and 10%
palladium on activated charcoal (50 mg) in dry ethanol (5 ml) was
stirred under hydrogen gas at ambient temperature for 24 hours. The
mixture was then filtered through celite. The celite was washed
with methanol and the solvent was removed by evaporation from the
combined filtrates. The crude material was purified by
chromatography on silica, eluting with 10% ethyl acetate in
isohexane to give 3-fluoro-7-methoxyquinoline (130 mg, 54%).
[1182] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.96 (s, 3H), 7.24 (dd,
1H), 7.44 (d, 1H), 7.66 (d, 1H) and 7.73 (dd, 1H) and 8.76 (d,
1H)
[1183] MS (ESI): 178 (MH).sup.+
[1184] 3-Fluoro-7-methoxyquinoline (130 mg, 0.74 mmol) was taken up
in dichloromethane (2 ml) under nitrogen and treated with boron
tribromide (4 ml of a 1.0M solution of in dichloromethane). The
reaction mixture was stirred for 24 hours at ambient temperature
followed by quenching the reaction by the slow addition of excess
methanol. The solution was stirred for a further 2 hours and
evaporated to dryness to give 3-fluoro-7-hydroxyquinoline which was
used without further purification.
[1185] MS (ESI): 164 (MH).sup.+
EXAMPLE 158
[1186] A mixture of
(R,S)-4-chloro-6-methoxy-7-((1-methylpiperidin-3-yl)methoxy)quinazoline
(240 mg, 0.75 mmol), (prepared as described for the starting
material in Example 7), potassium carbonate (160 mg, 1.16 mmol) and
3-fluoro-7-hydroxy-2-methylquinoline (150 mg, 0.85 mmol) in DMF (6
ml) was stirred at 100.degree. C. for 5 hours and then allowed to
cool to ambient temperature. The solvent was removed by
evaporation, then the residue was treated with water and 1.0 N
aqueous sodium hydroxide solution (30 ml) then allowed to stir for
30 minutes. The crude solid was collected by filtration and washed
with water. The resulting solid was dissolved in dichloromethane
and filtered through phase separating paper. The solvent was
removed by evaporation to give a solid residue which was
recrystallised from acetonitrile to give
4-(3-fluoro-2-methylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-3-y-
l)methoxy)quinazoline (71 mg, 21%).
[1187] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.11 (m, 1H), 1.68 (m,
5H), 2.10 (m, 1H), 2.20 (s, 3H), 2.64 (m, 4H), 2.87 (d, 1H), 3.98
(s, 3H), 4.09 (d, 2H), 7.37 (s, 1H), 7.57 (dd, 1H), 7.60 (s, 1H),
7.86 (d, 1H), 8.02 (d, 1H), 8.20 (d, 1H) and 8.53 (s, 1H)
[1188] MS (ESI): 463 (MH).sup.+ TABLE-US-00069 Elemental analysis
Found C 66.4 H 6.1 N 11.8
C.sub.26H.sub.27N.sub.4FO.sub.30.4H.sub.2O Requires C 66.5 H 6.0 N
11.9%
[1189] The starting material was prepared as follows:
[1190] 2-Chloro-3-fluoro-7-methoxyquinoline (210 g, 1 mmol),
(prepared as described for the starting material in Example 157),
in anhydrous THF (1 ml) was added to a mixture of copper(I)bromide
(570 mg, 4.0 mmol) and methylmagnesium bromide (3.0M solution in
diethyl ether, 2.7 ml, 8 mmol) in anhydrous THF (20 ml) at
-78.degree. C. The mixture was stirred for 1 hour at -78.degree.
C., allowed to warm to ambient temperature and then stirred for a
further 18 hours. Saturated aqueous ammonium chloride solution and
5N aqueous sodium hydroxide solution (pH 12) were added and the
product extracted with ethyl acetate (3.times.). The organic
solution was washed with water, brine, dried (MgSO.sub.4) and
evaporated to dryness to yield 3-fluoro-7-methoxy-2-methylquinoline
(0.17 g, 91%).
[1191] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.70 (d, 3H), 3.94 (s,
3H), 7.17 (dd, 1H), 7.37 (d, 1H) and 7.61 (m, 2H)
[1192] MS (ESI): 192 (MH).sup.+
[1193] 3-Fluoro-7-methoxy-2-methylquinoline (0.16 g, 0.85 mmol) was
taken up in dichloromethane (4 ml) under nitrogen and treated with
boron tribromide solution (4 ml of a 1.0M solution in
dichloromethane, 4.0 mmol). The reaction was stirred for 24 hours
at ambient temperature followed by the slow addition of excess
methanol. The solution was stirred for a further 2 hours and then
evaporated to dryness to give 3-fluoro-7-hydroxy-2-methylquinoline
which was used without further purification.
[1194] MS (ESI): 178 (MH).sup.+
EXAMPLE 159
[1195] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (400 mg, 1.19
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (255 mg, 1.84 mmol) and 7-hydroxyquinoline
(180 mg, 1.32 mmol) in DMF (10 ml) was stirred at 100.degree. C.
for 4 hours and then allowed to cool to ambient temperature. The
resulting mixture was treated with 1.0 N aqueous sodium hydroxide
solution (30 ml) and allowed to stir for 1 hour. The crude solid
was collected by filtration and washed with water. The resulting
solid was dissolved in dichloromethane and filtered through phase
separating paper. The solvent was removed by evaporation to give a
solid residue which was recrystallised from acetonitrile to give
6-methoxy-7-(3-piperidinopropoxy)-4-(quinolin-7-yloxy)quinazoline
(0.27 g, 52%).
[1196] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.37 (m, 2H), 1.51 (m,
4H), 1.95 (m, 2H), 2.32 (m, 4H), 2.42 (t, 2H), 3.98 (s, 3H), 4.23
(t, 2H), 7.38 (s, 1H), 7.56 (m, 2H), 7.62 (s, 1H), 7.91 (d, 1H),
8.09 (d, 1H), 8.44 (d, 1H), 8.54 (s, 1H) and 8.91 (dd, 1H)
[1197] MS (ESI): 445 (MH).sup.+ TABLE-US-00070 Elemental analysis
Found C 70.9 H 6.3 N 12.7 C.sub.26H.sub.28N.sub.4O.sub.3 Requires C
70.3 H 6.3 N 12.6%
EXAMPLE 160
[1198] A mixture of
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine (360 mg, 1.00 mmol), (prepared as described for the starting
material in Example 152), potassium carbonate (215 mg, 1.56 mmol)
and 2,3-dimethyl-5-hydroxyindole (177 mg, 1.10 mmol), (Arch. Pharm.
1972, 305, 159), in DMF (8.0 ml) was stirred at 100.degree. C. for
5 hours and allowed to cool to ambient temperature. The solvent was
removed by evaporation and the residue purified by silica column
chromatography eluting with methanol (2.5%) in dichloromethane. The
resulting solid was recrystallised from tertbutyl methyl
ether/acetonitrile, filtered and washed with diethyl ether to give
4-(2,3-dimethylindol-5yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylam-
ino)propoxy)quinazoline (201 mg, 42%).
[1199] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.07 (m, 2H), 2.12 (s,
3H), 2.31 (s, 3H), 2.79 (s, 3H), 2.89 (s, 3H), 3.25 (t, 2H), 3.97
(s, 3H), 4.23 (t, 2H), 6.86 (dd, 1H), 7.20 (d, 1H), 7.25 (d, 1H),
7.35 (s, 1H), 7.58 (s, 1H), 8.46 (s, 1H) and 11.17 (s, 1H)
[1200] MS (ESI): 485 (MH).sup.+ TABLE-US-00071 Elemental analysis
Found C 59.5 H 5.8 N 11.4 C.sub.24H.sub.28N.sub.4O.sub.5S Requires
C 59.5 H 5.8 N 11.6%
EXAMPLE 161
[1201] A mixture of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (322 mg,
1.00 mmol), (prepared as described in Example 49), potassium
carbonate (414 mg, 3.00 mmol) and epibromohydrin (274 mg, 2.00
mmol) in DMF (7.0 ml) was stirred at 60.degree. C. for 2 hours and
allowed to cool to ambient temperature. The solvent was removed by
evaporation and the residue taken up in dichloromethane (10 ml). An
aliquot (5 ml) of this solution was treated with morpholine (48 ul,
0.6 mmol) and stirred for 24 hours at ambient temperature. The
solvent was removed by evaporation, treated with water and stirred
vigorously for 30 minutes. The precipitate was filtered, washed
with water and dried. The resultant solid was stirred as a
suspension in acetone, filtered, washed with diethyl ether and
dried to give
7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline (127 mg, 27%).
[1202] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.38 (s, 3H), 2.45 (m,
6H), 3.57 (t, 4H), 3.95 (s, 3H), 4.03-4.14 (m, 2H), 4.23 (m, 1H),
4.95 (s, 1H), 6.12 (s, 1H), 6.86 (dd, 1H), 7.23 (d, 1H) 7.29 (d,
1H), 7.37 (s, 1H), 7.57 (s, 1H), 8.47 (s, 1H) and 10.98 (s, 1H)
[1203] MS (ESI): 465 (MH).sup.+ TABLE-US-00072 Elemental analysis
Found C 62.7 H 5.9 N 11.5 C.sub.25H.sub.28N.sub.4O.sub.50.7H.sub.2O
Requires C 62.9 H 6.2 N 11.7%
EXAMPLE 162
[1204] A mixture of
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.27 mmol) and piperidine (79 ul, 0.8 mmol) in DMF (4ml)
was heated at 70.degree. C. for 24 hours. The solvent was removed
by evaporation and the residue was recrystallised from
acetonitrile. The solid was filtered, washed with diethyl ether and
dried to give
7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quin-
azoline (80 mg, 65%).
[1205] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35 (m, 2H), 1.51 (m,
4H), 2.39 (m, 9H), 3.96 (s, 3H), 4.08 (m, 2H), 4.21 (dd, 1H), 4.86
(br s, 1H), 6.11 (s, 1H), 6.87 (dd, 1H), 7.23 (d, 1H), 7.29 (d,
1H), 7.37 (s, 1H), 7.56 (s, 1H), 8.45 (s, 1H) and 10.98 (s, 1H)
[1206] MS (ESI): 464 (MH).sup.+ TABLE-US-00073 Elemental analysis
Found C 66.2 H 6.4 N 11.9 C.sub.26H.sub.30N.sub.4O.sub.40.4H.sub.2O
Requires C 66.5 H 6.6 N 11.9%
[1207] The starting material was prepared as follows:
[1208] A mixture of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (1.89 g,
5.90 mmol), (prepared as described in Example 49), potassium
carbonate (2.43 g, 17.6 mmol) and epibromohydrin (1.61 g, 11.7
mmol) in DMF (40 ml) was stirred at 60.degree. C. for 2 hours and
allowed to cool to ambient temperature. The insoluble inorganic
material was removed by filtration and the solvent was removed by
evaporation. The residue was triturated with diethyl ether,
filtered, washed with further diethyl ether and dried to give
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoli-
ne (1.97 g, 89%).
[1209] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.38 (s, 3H), 2.76 (m,
1H), 2.90 (t, 1H), 3.43 (m, 1H), 3.97 (s, 3H), 4.04 (m, 1H), 4.57
(dd, 1H), 6.11 (s, 1H), 6.86 (dd, 1H), 7.27 (m, 2H), 7.38 (s, 1H),
7.59 (s, 1H), 8.46 (s, 1H) and 10.92 (s, 1H)
[1210] MS (ESI): 378 (M).sup.+
EXAMPLE 163
[1211] A mixture of
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.27 mmol), (prepared as described for the starting
material in Example 162), and pyrrolidine (67 ul, 0.8 mmol) in DMF
(4 ml) was heated at 70.degree. C. for 24 hours. The solvent was
removed by evaporation and the residue purified by silica column
chromatography eluting with dichloromethane/methanol/0.880 aqueous
ammonia (100/8/1). The relevant fractions were evaporated to
dryness then the residue treated with a little dichloromethane and
dried under high vacuum to give
7-(2-hydroxy-3-pyrrolidin-1-ylpropoxy)-6-methoxy-4-(2-methylindol-5-yloxy-
)quinazoline (44 mg, 37%) as a white foam.
[1212] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.69 (br s, 4H), 2.38
(s, 3H), 2.50 (m, 6H), 3.97 (s, 3H), 4.07 (m, 2H), 4.21 (dd, 1H),
4.96 (br s, 1H), 6.11 (s, 1H), 6.86 (dd, 1H), 7.23 (d, 1H), 7.29
(d, 1H), 7.35 (s, 1H), 7.56 (s, 1H), 8.46 (s, 1H) and 10.98 (s,
1H)
[1213] MS (ESI): 450 (MH).sup.+ TABLE-US-00074 Elemental analysis
Found C 65.5 H 6.3 N 11.8 C.sub.25H.sub.28N.sub.4O.sub.40.4H.sub.2O
Requires C 65.9 H 6.4 N 12.3%
EXAMPLE 164
[1214] A mixture of
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.27 mmol), (prepared as described for the starting
material in Example 162), and diethylamine (100 ul, 0.8 mmol) in
DMF (4 ml) was heated at 70.degree. C. for 24 hours. The solvent
was removed by evaporation and the residue was purified by silica
column chromatography eluting with dichloromethane/methanol/0.880
aqueous ammonia (100/8/1). The relevant fractions were evaporated
to dryness then the residue treated with a little dichloromethane
and dried under high vacuum to give
7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-2-methylindol-5-ylo-
xy)quinazoline (55 mg, 46%) as a white foam.
[1215] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.96 (t, 6H), 2.38 (s,
3H), 2.52 (m, 6H), 3.96 (s, 3H), 3.97 (m, 1H), 4.09 (m, 1H), 4.23
(dd, 1H), 4.84 (br s, 1H), 6.12 (s, 1H), 6.88 (dd, 1H), 7.24 (d,
1H), 7.29 (d, 1H), 7.36 (s, 1H), 7.56 (s, 1H), 8.45 (s, 1H) and
10.98 (s, 1H)
[1216] MS (ESI): 452 (MH).sup.+ TABLE-US-00075 Elemental analysis
Found C 66.2 H 6.7 N 12.4 C.sub.25H.sub.30N.sub.4O.sub.4 Requires C
66.6 H 6.7 N 12.4%
EXAMPLE 165
[1217] A mixture of
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.27 mmol), (prepared as described for the starting
material in Example 162), and N-methylpiperazine (200 ul, 1.8 mmol)
in DMF (4 ml) was heated at 70.degree. C. for 24 hours. The solvent
was removed by evaporation and the residue was recrystallised from
acetonitrile. The solid was filtered, washed with diethyl ether and
dried to give
7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindo-
l-5-yloxy)quinazoline (41 mg, 32%).
[1218] .sup.1H NMR Spectrum: (DMSOd.sub.6): 2.11 (s, 3H), 2.29 (m,
4H), 2.40 (s, 3H), 2.47 (m, 6H), 3.96 (s, 3H), 4.07 (m, 2H), 4.20
(dd, 1H), 4.89 (d, 1H), 6.11 (s, 1H), 6.87 (dd, 1H), 7.23 (d, 1H),
7.29 (d, 1H), 7.35 (s, 1H), 7.58 (s, 1H), 8.46 (s, 1H) and 10.98
(s, 1H)
[1219] MS (ESI): 479 (MH).sup.+ TABLE-US-00076 Elemental analysis
Found C 64.4 H 6.5 N 14.4 C.sub.26H.sub.31N.sub.5O.sub.40.3H.sub.2O
Requires C 64.7 H 6.6 N 14.5%
EXAMPLE 166
[1220] A mixture of
7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline
(100 mg, 0.27 mmol), (prepared as described for the starting
material in Example 162), and isopropylamine (100 ul, 0.8 mmol) in
DMF (4 ml) was heated at 70.degree. C. for 24 hours. The solvent
was removed by evaporation and the residue was purified by silica
column chromatography eluting with dichloromethane/methanol/0.880
aqueous ammonia (100/8/1) to give
7-(2-hydroxy-3-isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5--
yloxy)quinazoline (18 mg, 16%).
[1221] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.00 (d, 6H), 2.40 (s,
3H), 2.56-2.78 (m, 3H), 3.97 (m, 4H), 4.07-4.28 (m, 2H), 5.04 (m,
1H), 6.12 (s, 1H), 6.88 (dd, 1H), 7.22-7.33 (m, 2H), 7.38 (s, 1H),
7.58 (s, 1H), 8.48 (s, 1H) and 10.98 (s, 1H)
[1222] MS (ESI): 437 (MH).sup.+
EXAMPLE 167
[1223] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (276 mg, 2.0 mmol) and
5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0
ml) were stirred at 95.degree. C. for 1.5 hours and allowed to cool
to ambient temperature. The reaction mixture was filtered and the
filtrate evaporated under vacuum. The residue was purified by
silica column chromatography eluting with
dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) to give a
partially purified oil. This oil was further purified by high
performance column chromatography on octadecylsilane reverse phase
silica eluting with acetonitrile/water/trifluoroacetic acid
(60/39.8/0.2) to give an oil which was dissolved in dichloromethane
and washed with saturated aqueous sodium hydrogen carbonate
solution. The dichloromethane layer was evaporated to give
6methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinaz-
oline (62 mg, 25%).
[1224] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.45 (m, 2H), 1.60 (m,
4H), 2.13 (m, 2H), 2.44 (m, 4H), 2.56 (m, 2H), 4.04 (s, 3H), 4.27
(t, 2H), 6.63 (br s, 1H), 7.33 (s, 1H), 7.40 (t, 1H), 7.61 (s, 1H),
7.67 (s, 1H), 7.75 (s, 1H) and 8.60 (m, 2H)
[1225] MS (ESI): 501 (MH).sup.+ TABLE-US-00077 Elemental analysis
Found C 62.0 H 5.6 N 10.6
C.sub.26H.sub.27F.sub.3N.sub.4O.sub.30.35H.sub.2O, Requires C 61.6
H 5.5 N 11.0%
[1226] The starting material was prepared as follows:
[1227] Sodium hydride (1.8 g, of a 60% dispersion in oil, 45 mmol)
was added in portions to a stirred solution of benzyl alcohol (10.8
g, 100 mmol) in DMA (100 ml) with vigorous stirring under an
atmosphere of nitrogen at ambient temperature. After warming to
45.degree. C. for 30 minutes the mixture was cooled to ambient
temperature and added dropwise to a stirred solution of
2-chloro-5-nitro-trifluoromethylbenzene (11.3 g, 50 mmol) in DMA
(30 ml), keeping the temperature below 10.degree. C. The mixture
was stirred at 25.degree. C. for 1 hour, then acidified with acetic
acid and evaporated to give a yellow solid. The residue was
dissolved in dichloromethane, washed with water then dried
(MgSO.sub.4), and evaporated. The residue was suspended in a
mixture of hexane (70 ml) and diethyl ether (10 ml) and the
resulting solid filtered off to give
2-benzyloxy-5-nitro-trifluoromethylbenzene (6.6 g, 49%).
[1228] .sup.1H NMR Spectrum: (CDCl.sub.3) 5.33 (s, 2H), 7.13 (d,
1H), 7.31-7.43 (m, 5H), 8.35 (dd, 1H), 8.52 (d, 1H)
[1229] Potassium tert-butoxide (3.94 g, 35.4 mmol) was dissolved in
anhydrous DMF (15 ml) and a mixture of
2-benzyloxy-5-nitro-trifluoromethylbenzene (3.5 g, 16.1 mmol) and
4-chlorophenylacetonitrile (2.96 g, 17.7 mmol) in DMF (20 ml) was
added over 30 minutes keeping the temperature at -15.degree. C. The
mixture was stirred at -10.degree. C. for 1 hour, then poured into
1M hydrochloric acid (150 ml) and the product extracted with
dichloromethane (2.times.100 ml). The organic extracts were dried
(MgSO.sub.4) and purified by silica column chromatography eluting
with dichloromethane/hexane (1/1) to give
5-benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (5.2 g,
77%).
[1230] .sup.1H NMR Spectrum: (CDCl.sub.3) 4.30 (s, 2H), 5.38 (s,
2H), 7.25 (s, 1H), 7.33-7.50 (m, 5H) and 8.51 (s, 1H)
[1231] MS (ESI): 335 (M-H).sup.-
[1232] 5-Benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile
(2.22 g, 6.6 mmol) was dissolved in ethanol (45 ml), water (5 ml)
and acetic acid (0.32 ml) then hydrogenated with 10% palladium on
carbon at 1 atmosphere pressure for 2 hours. The catalyst was
filtered off and filtrate evaporated to give
5-hydroxy-6-trifluoromethylindole (1.12 g, 84%).
[1233] .sup.1H NMR Spectrum: (CDCl.sub.3) 4.48 (s, 1H), 6.48 (m,
1H), 7.14 (s, 1H), 7.32 (t, 1H), 7.57 (s, 1H) and 8.20 (br s,
1H)
[1234] MS (ESI): 200 (M-H).sup.-
EXAMPLE 168
[1235] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.6
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (248 mg, 1.8 mmol) and
5-hydroxy-6-methoxyindole (127 mg, 0.78 mmol) in DMA (4.0 ml) was
stirred at 95.degree. C. for 2.5 hours. The reaction mixture was
allowed to cool to ambient temperature, filtered and the filtrate
evaporated under vacuum. The residue was purified by silica column
chromatography eluting with dichloromethane/methanol/0.880 aqueous
ammonia (89/10/1) and the resulting oil triturated with diethyl
ether to give 4-(6-
methoxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(106 mg, 38%).
[1236] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.38 (m, 2H), 1.47 (m,
4H), 1.95 (m, 2H), 2.32 (m, 4H), 2.40 (m, 2H), 3.66 (3H, s), 3.97
(s, 3H), 4.28 (t, 2H), 6.35 (br s, 1H), 7.06 (s, 1H), 7.24 (t, 1H),
7.34 (s, 1H), 7.36 (s, 1H), 7.55 (s, 1H) and 8.41 (s, 1H)
[1237] MS (ESI): 463 (MH).sup.+ TABLE-US-00078 Elemental analysis
Found C 65.2 H 6.8 N 11.2
C.sub.26H.sub.30N.sub.4O.sub.41.0H.sub.2O, Requires C 64.9 H 7.0 N
11.1% 0.3 diethyl ether
[1238] The 5-hydroxy-6-methoxyindole starting material was made as
follows:
[1239] 5-Benzyloxy-6-methoxyindole (253 mg, 1.0 mmol) was
hydrogenated at 1 atmosphere pressure in methanol (10 ml) with 10%
palladium on carbon (50 mg) for 2 hours at 25.degree. C. The
catalyst was filtered off and the filtrate evaporated to give
5-hydroxy-6-methoxyindole (141 mg, 87%).
[1240] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.92 (s, 3H), 5.40 (s,
1H), 6.42 (br s, 1H), 6.87 (s, 1H), 7.07 (m, 1H), 7.13 (s, 1H),
7.93 (br s, 1H)
[1241] MS (ESI): 162 (M-H).sup.-
EXAMPLE 169
[1242] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg,
0.595 mmol), (prepared as described for the starting material in
Example 67), potassium carbonate (411 mg, 2.98 mmol) and
4-hydroxyindole (103 mg, 0.774 mmol) in DMA (2.0 ml) was stirred at
85.degree. C. for 3 hours and allowed to cool to ambient
temperature. The reaction mixture was filtered and the filtrate
evaporated to give a solid residue. The residue was purified by
silica column chromatography, with gradient elution using
dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give
4-(indol-4-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (131
mg, 51%).
[1243] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.39 (m, 2H), 1.50 (m,
4H), 1.98 (t, 2H), 2.35 (m, 4H), 2.40 (t, 2H), 3.98 (s, 3H), 4.25
(t, 2H), 6.10 (t, 1H), 6.90 (d, 1H), 7.15 (t, 1H), 7.30 (t, 1H),
7.35 (d, 1H), 7.38 (s, 1H), 7.62 (s, 1H), 8.45 (s, 1H) and 11.29
(s, 1H)
[1244] MS (ESI): 433 (MH).sup.+
[1245] m.p. 80-82.degree. C.
EXAMPLE 170
[1246] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg,
0.595 mmol), (prepared as described for the starting material in
Example 67), potassium carbonate (411 mg, 2.98 mmol) and
3-hydroxycarbazole (142 mg, 0.774 mmol) in DMA (2.0 ml) was stirred
at 85.degree. C. for 3 hours then allowed to cool to ambient
temperature. The reaction mixture was filtered and the filtrate
evaporated to give a solid residue. The residue was purified by
silica column chromatography with gradient elution using
dichloromethane with 0%, 2%, 4%, 10% methanolic ammonia to give
4-(9H-carbazol-3-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(212 mg, 74%).
[1247] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.39 (m, 2H), 1.50 (m,
4H), 2.35 (m, 4H), 2.40 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 7.05
(dd, 1H), 7.15 (t, 1H), 7.35 (t, 1H), 7.38 (s, 1H), 7.40 (s, 1H),
7.50 (d, 1H), 7.60 (s, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.55 (s,
1H) and 11.33 (s, 1H)
[1248] MS (ESI): 483 (MH).sup.+
EXAMPLE 171
[1249] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (84 mg, 0.24
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (162 mg, 1.18 mmol) and ethyl
7-chloro-5-hydroxyindole-2-carboxylate (62 mg, 0.26 mmol) in DMA
(2.0 ml) was stirred at 100.degree. C. for 2 hours and allowed to
cool to ambient temperature. The reaction mixture was filtered and
the filtrate evaporated. The residue was purified by silica column
chromatography using gradient elution dichloromethane with 2.5%,
5%, 10% methanol, then dichloromethane with 2% ammonia) to give
4-(7-chloro-2-(ethoxycarbonyl)indol-5-yloxy)-6-(methoxy-7-3-piperidinopro-
poxy)quinazoline (78 mg, 63%).
[1250] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.30 (t, 3H), 1.40 (m,
2H), 1.50 (m, 4H), 1.98 (t, 2H), 2.35 (m, 4H), 2.40 (t, 2H), 3.98
(s, 3H), 4.25 (t, 2H), 4.30 (q, 2H), 7.15 (m, 1H), 7.18 (s, 1H),
7.60 (s, 1H), 8.40 (s, 1H) and 12.60 (s, 1H)
[1251] MS (ESI): 539 (MH).sup.+ TABLE-US-00079 Elemental analysis
Found C 61.2 H 5.9 N 10.3
C.sub.28H.sub.31ClN.sub.4O.sub.50.5H.sub.2O Requires C 61.4 H 5.9 N
10.2%
[1252] The starting material was prepared as follows:
[1253] 2-Chloro-4-methoxyaniline (2.719 g, 14 mmol) was added to
8.0M aqueous hydrochloric acid (15 ml) and the suspension cooled to
-5.degree. C. Sodium nitrite (1.063 g, 15.4 mmol) was added as a
solution in water (3 ml). After addition the pH was brought to pH
4-5 by addition of sodium acetate. In a separate flask,
ethyl-.alpha.-ethyl acetoacetate (2.18 ml, 15.4 mmol) in ethanol
(15 ml) at -5.degree. C. was treated with potassium hydroxide (864
mg, 15.4 mmol) in water (3 ml) followed by ice (4 g). The diazonium
salt prepared initially was then added rapidly to the second
solution and stirred at -5.degree. C. for 4 hours then allowed to
warm to ambient temperature overnight. The mixture was extracted
with ethyl acetate (3.times.100 ml) and the organic solutions dried
(MgSO.sub.4), filtered and solvent removed in vacuo to give an
orange oil. This oil was dissolved in ethanol (35 ml) and the flask
fitted with a reflux condenser. Concentrated sulphuric acid (35 ml)
was then added dropwise, this caused the reaction to reflux with no
external heating. The solution was stirred for I hour then the
solvent removed by evaporation. The residue was taken up in water
then extracted with ethyl acetate (3.times.100 ml). The organic
solution was washed with brine, dried (MgSO.sub.4), filtered and
evaporated to give a brown oil. The crude oil was purified by
silica column chromatography, eluting with dichloromethane to give
ethyl 7-chloro-5-methoxyindole-2-carboxylate (125 mg, 4%).
[1254] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.40 (t, 3H), 3.98 (s,
3H), 4.40 (q, 2H), 6.60 (d, 1H), 7.05 (d, 1H), 7.15 (s, 1H) and
9.10 (s, 1H)
[1255] MS (ESI): 254 (MH).sup.+
[1256] To a solution of ethyl
7-chloro-5-methoxyindole-2-carboxylate (82 mg, 0.323 mmol) in
dichloromethane (5 ml) at -78.degree. C. was added boron tribromide
(1.07 ml of a 1.0 M solution in DCM, 1.07 mmol) and the reaction
stirred at -78.degree. C. for 30 minutes then allowed to warm to
ambient temperature overnight. Water was carefully added and the pH
adjusted to pH 6-7 by addition of 2M sodium hydroxide. The mixture
was extracted with ethyl acetate (2.times.50 ml), and the organic
solution washed with brine, dried (MgSO.sub.4), filtered and
evaporated to give ethyl 7-chloro-5-hydroxyindole-2-carboxylate (55
mg, 71%) as an orange solid.
[1257] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.38 (t, 3H), 4.35 (q,
2H), 6.60 (d, 1H), 6.95 (d, 1H), 7.10 (d, 1H), 9.80 (s, 1H) and
11.80 (s, 1H)
[1258] MS (ESI): 238 (MH).sup.-
EXAMPLE 172
[1259] A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (1.5
g, 4.99 mmol), (prepared as described for the starting material in
Example 1), potassium carbonate (2.07 g, 15 mmol) and
2,3-dimethyl-5-hydroxyindole (1.21 g, 7.5 mmol), (Arch. Pharm.
1972, 305, 159), in DMF (75 ml) was stirred at 100.degree. C. for 2
hours and allowed to cool to ambient temperature. The reaction
mixture was filtered and the filtrate evaporated. The solid residue
was purified by silica column chromatography, eluting with 2.5%
methanol in dichoromethane to give
7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (976
mg, 46%).
[1260] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.10 (s, 3H), 2.30 (s,
3H), 3.98 (s, 3H), 5.30 (s, 2H), 6.85 (dd, 1H), 7.20 (d, 1H), 7.25
(d, 1H), 7.40 (m, 6H), 7.60 (s, 1H), 8.40 (s, 1H) and 10.74 (s,
1H), MS (ESI): 426 (MH).sup.+
EXAMPLE 173
[1261] A mixture of
7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (912
mg, 2.14 mmol), (prepared as described in Example 172),
di-tert-butyl dicarbonate (1.871 g, 8.56 mmol) and
4-dimethylaminopyridine (70 mg, 5 mol %) in acetonitrile (40 ml )
was stirred at ambient temperature overnight. The solvent was then
evaporated and the residue dissolved in ethyl acetate. The organic
solution was washed with 2N hydrochloric acid twice and then with
brine. The organic layer was then dried (MgSO.sub.4), filtered and
evaporated to give 7-
benzyloxy-4-(1-tert-butoxycarbonyl-2,3-dimethylindol-5yloxy)-6-methoxyqui-
nazoline (1.108 g, 99%) as a yellow solid.
[1262] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.70 (s, 9H), 2.08 (s,
3H), 2.50 (s, 3H), 4.10 (s, 3H), 5.35 (s, 2H), 7.15 (dd, 1H), 7.38
(m, 6H), 7.60 (s, 1H), 8.20 (d, 1H) and 8.60 (s, 1H)
[1263] MS (ESI): 526 (MH).sup.+
EXAMPLE 174
[1264] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (106 mg, 0.77 mmol) and 2-hydroxyquinoline
(111 mg, 0.76 mmol) in DMF (7.5 ml) was stirred at 100.degree. C.
for 5 hours and allowed to cool to ambient temperature. The
reaction mixture was treated with 1.0 N aqueous sodium hydroxide
solution (40 ml) and allowed to stir at ambient temperature for a
few minutes. The reaction mixture was extracted 3 times with ethyl
acetate and the extracts washed with water and brine. The organic
extracts were dried over magnesium sulphate, filtered and the
solvent removed by evaporation. The residue was purified by silica
column chromatography eluting with dichloromethane/methanol (95/5)
to give a solid which was triturated with ether, filtered and dried
to give
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-2-yloxy)quinazoline
(33 mg, 11%).
[1265] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (m, 2H), 2.38 (m,
4H), 2.48 (t, 2H), 3.58 (m, 4H), 3.98 (s, 3H), 4.26 (t, 2H), 7.41
(s, 1H), 7.52 (d, 1H), 7.58 (s, 1H), 7.64 (t, 1H), 7.78 (m, 1H),
7.88 (d, 1H), 8.06 (d, 1H), 8.56 (d, 1H) and 8.57 (s, 1H)
[1266] MS (ESI): 447 (MH).sup.+ TABLE-US-00080 Elemental analysis
Found C 66.8 H 5.9 N 12.4 C.sub.25H.sub.26N.sub.4O.sub.40.2H.sub.2O
Requires C 66.7 H 5.9 N 12.4%
EXAMPLE 175
[1267] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (106 mg, 0.77 mmol) and 5-hydroxyquinoline
(111 mg, 0.77 mmol) in DMF (7.5 ml) was stirred at 100.degree. C.
for 5 hours and allowed to cool to ambient temperature. The
reaction mixture was treated with 1.0 N aqueous sodium hydroxide
solution (40 ml) and allowed to stir at ambient temperature for a
few minutes. The resulting precipitate was filtered off, washed
with water and air dried for a short while. The damp solid was
dissolved in dichloromethane, filtered through phase separating
paper and the filtrate evaporated under vacuum. The residue was
triturated with ether, filtered and dried to give
6-methoxy-7-(3-morpholinopropoxy)-4-(quinolin-5-yloxy)-quinazoline
(178 mg, 59%).
[1268] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (m, 2H), 2.39 (m,
4H), 2.48 (t, 2H), 3.59 (t, 4H), 4.01 (s, 3H), 4.28 (t, 2H), 7.42,
(s, 1H), 7.50 (m, 1H), 7.59 (d, 1H), 7.74 (s, 1H), 7.87 (t, 1H),
8.02 (d, 1H), 8.20 (m, 1H), 8.44 (s, 1H) and 8.96 (m, 1H) MS (ESI):
447 (MH).sup.+ TABLE-US-00081 Elemental analysis Found C 66.2 H 5.7
N 12.4 C.sub.25H.sub.26N.sub.4O.sub.40.4H.sub.2O Requires C 66.2 H
6.0 N 12.4%
EXAMPLE 176
[1269] A mixture of
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(200 mg, 0.57 mmol), potassium carbonate (106 mg, 0.77 mmol) and
7-hydroxyquinoline (111 mg, 0.76 mmol) in DMF (7 ml) was stirred at
100.degree. C. for 5 hours and allowed to cool to ambient
temperature. The reaction mixture was treated with 1.0 N aqueous
sodium hydroxide solution (40 ml) and allowed to stir at ambient
temperature for a few minutes. The reaction mixture was extracted 4
times with ethyl acetate and the organic extracts washed with water
and brine. The organic extracts were dried over magnesium sulphate,
filtered and the solvent removed by evaporation. The residue was
triturated with ether/isohexane, filtered and dried to give
6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(quinolin-7-yloxy)quina-
zoline (102 mg, 39%).
[1270] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.96 (m, 2H), 2.15 (s,
3H), 2.35 (m, 8H), 2.46 (t, 2H), 3.99 (s, 3H), 4.24 (t, 2H), 7.39
(s, 1H), 7.56 (m, 1H), 7.61 (m, 1H), 7.62 (s, 1H), 7.92 (d, 1H),
8.10 (d, 1H), 8.44 (d, 1H), 8.54 (s, 1H) and 8.92 (m, 1H)
[1271] MS (ESI): 460 (MH).sup.+ TABLE-US-00082 Elemental analysis
Found C 67.2 H 6.2 N 15.0 C.sub.26H.sub.29N.sub.5O.sub.30.3H.sub.2O
Requires C 67.2 H 6.4 N 15.1%
[1272] The starting material was prepared as follows:
[1273] A solution of 1-(3-hydroxypropyl)-4-methylpiperazine (2.4 g,
15 mmol), (prepared as described for the starting material in
Example 133), in dichloromethane (60 ml) was treated with
triethylamine (4.6 ml, 33 mmol) and p-toluenesulphonyl chloride
(3.2 g, 17 mmol) and stirred at ambient temperature for 2 hours.
The solution was washed with saturated aqueous sodium hydrogen
carbonate solution followed by water and filtered through phase
separating paper. The filtrate was evaporated under vacuum to give
3-(4-methyl-piperazin-1-yl)propyl-4-toluene sulphonate as an oil
which crystallised on standing (3.7 g, 78%).
[1274] MS (ESI): 313 (MH).sup.+
[1275] A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (J. Med.
Chem. 1977, vol 20, 146-149, 10 g, 0.04 mol) and Gold's reagent
(7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at
reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic
acid (1.65 ml, 0.029 mol) 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. Recrystallisation from acetic acid gave
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
[1276] A mixture of
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g, 0.01
mol), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred and
heated at reflux for 1 hour. The mixture was evaporated and
azeotroped with toluene to give
7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45
g).
[1277] 4-Chloro-2-fluoro-phenol (264 mg, 1.8 mmol) was added to a
solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride
(506 mg, 1.5 mmol) in pyridine (8 ml) and the mixture heated at
reflux for 45 minutes. The solvent was removed by evaporation and
the residue partitioned between ethyl acetate and water. The
organic layer was washed with 0.1M HCl, water and brine, dried
(MgSO.sub.4) and the solvent removed by evaporation. The solid
residue was triturated with petroleum ether and the crude product
collected by filtration and purified by flash chromatography
eluting with methylene chloride/ether (9/1) to give
7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (474
mg, 77%) as a cream solid.
[1278] m.p. 179-180.degree. C.
[1279] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.99(s, 3H); 5.36(s,
2H); 7.35-7.5(m, 4H); 7.55-7.65(m, 5H), 7.72(d, 1H); 8.6(s, 1H)
[1280] MS-ESI: 411 [MH].sup.+ TABLE-US-00083 Elemental analysis:
Found C 63.38 H 4.07 N 6.78
C.sub.22H.sub.16ClFN.sub.2O.sub.30.06H.sub.2O0.05CH.sub.2Cl.sub.2
Requires C 63.64 H 3.93 N 6.73%
[1281] A solution of
7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451
mg, 1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The
mixture was diluted with toluene and the volatiles removed by
evaporation. The residue was triturated with methylene chloride,
collected by filtration, washed with ether and dried under vacuum
to give 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline
(320 mg, 90%).
[1282] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.0(s, 3H); 7.27(s, 1H);
7.43(dd, 1H); 7.56(t, 1H); 7.57(s, 1H); 7.72(dd, 1H); 8.5(s,
1H)
[1283] MS-ESI: 321 [MH].sup.+
[1284] A mixture of the trifluoroacetic acid salt of
4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g,
7.4 mmol), potassium carbonate (6.1 g, 44.2 mmol) and
3-(4-methyl-1-piperazinyl)propyl-4-toluene sulphonate (3.0 g 9.6
mmol) in DMF (60 ml) was stirred at 90.degree. C. for 5 hours and
allowed to cool to ambient temperature. The reaction mixture was
poured into water (700 ml) and extracted 5 times with ethyl
acetate. The combined extracts were washed with water, saturated
aqueous sodium hydrogen carbonate, water and saturated brine. The
ethyl acetate solution was dried over magnesium sulphate, filtered
and the solvent removed under vacuum to give a residue which was
purified by silica column chromatography, eluting with
dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The
relevant fractions were combined and evaporated under vacuum to
give a residue which was triturated with ether, filtered and dried
to give
4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propo-
xy)quinazoline (1.64 g, 48%).
[1285] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95 (m, 2H), 2.14 (s,
3H), 2.35 (m, 8H), 2.44 (t, 2H), 3.96 (s, 3H), 4.22 (t, 2H), 7.38
(s, 1H), 7.40 (m, 1H), 7.54 (m, 2H), 7.68 (m, 1H) and 8.55 (s,
1H)
[1286] MS (ESI): 461 (MH).sup.+ TABLE-US-00084 Elemental analysis
Found C 59.6 H 5.7 N 12.2 C.sub.23H.sub.26ClFN.sub.4O.sub.3
Requires C 59.9 H 5.7 N 12.2%
[1287]
4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-y-
l)propoxy)quinazoline (2.6 g, 5.6 mmol) was treated with 2.0 N
aqueous hydrochloric acid (45 ml) and the mixture stirred at
95.degree. C. for 2 hours. The mixture was cooled, basified by the
addition of solid sodium hydrogen carbonate and the water removed
by azeotroping with toluene. The residue was purified by silica
column chromatography eluting with dichloromethane/methanol/0.880
aqueous ammonia (50/8/1) to give
6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazolin-4-o-
ne (1.8 g, 96%).
[1288] MS (ESI): 333 (MH).sup.+
[1289]
6-Methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazo-
lin-4-one (2.15 g, 6.48 mmol) was suspended in thionyl chloride (25
ml) and DMF (0.18 ml) and stirred under reflux for 2 hours. The
thionyl chloride was evaporated under vacuum and the residue
azeotroped twice with toluene. The residue was taken up in water,
basified with saturated with aqueous sodium hydrogen carbonate
solution and the aqueous solution extracted 4 times with
dichloromethane. The combined extracts were washed with water and
brine then filtered through phase separating paper. The filtrate
was evaporated under vacuum and the residue purified by silica
column chromatography eluting with dichloromethane/methanol/0.880
aqueous ammonia (100/8/1) to give a solid which was triturated with
a little acetone, filtered and dried to give
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(1.2 g, 53%). This was used without further purification.
[1290] MS (ESI): 351 (MH).sup.+
EXAMPLE 177
[1291] A mixture of
4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (200
mg, 0.64 mmol), potassium carbonate (102 mg, 0.74 mmol) and
7-hydroxyquinoline (107 mg, 0.74 mmol) in DMSO (5 ml) was stirred
at 100.degree. C. for 5 hours and allowed to cool to ambient
temperature. The mixture was poured into water, washed with
dichloromethane and extracted twice with a 10/1 mixture of
dichloromethane/methanol. The extracts were washed with water and
brine, dried over magnesium sulphate, filtered and the filtrate
evaporated under vacuum. The residue was purified by silica column
chromatography, eluting with dichloromethane/methanol/0.880 aqueous
ammonia (100/8/1) to give an oil which crystallised on trituration
with ether to give
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline
(148 mg, 55%).
[1292] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.25 (s, 3H), 3.50 (t,
2H), 3.60 (t, 2H), 3.80 (t, 2H), 4.00 (s, 3H), 4.30 (t, 2H), 7.40
(s, 1H), 7.55 (m, 1H), 7.60 (m, 1H), 7.65 (s, 1H), 7.90 (d, 1H),
8.10 (d, 1H), 8.40 (m, 1H), 8.50 (s, 1H) and 8.90 (m, 1H)
[1293] MS (ESI): 422 (MH).sup.+ TABLE-US-00085 Elemental analysis
Found C 65.8 H 5.2 N 10.0 C.sub.23H.sub.23N.sub.3O.sub.5 Requires C
65.6 H 5.5 N 10.0%
[1294] The starting material was prepared as follows:
[1295] Diethyl azodicarboxylate (864 .mu.l, 5.5 mmol) was added
dropwise to a mixture of 7-
hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(1.2 g, 3.9 mmol) (prepared as described for the starting material
in Example 12), triphenylphosphine (1.44 g, 5.5 mmol) and
2-(2-methoxyethoxy)ethanol (653 .mu.l, 5.5 mmol) in methylene
chloride (70 ml) cooled at 0.degree. C. The mixture was stirred for
1.5 hours at ambient temperature and the solvent was removed by
evaporation. The residue was purified by column chromatography
eluting with a mixture of ethyl acetate/methylene chloride (50/50
followed by 80/20). The purified solid was suspended in ether,
collected by filtration and dried under vacuum to give
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihyd-
roquinazolin-4-one (1.70 g, 100%).
[1296] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.13(s, 9 H); 3.26(s,
3H); 3.5(m, 2H); 3.65(m, 2H); 3.85(m, 2H); 3.91(s, 3H); 4.3(m, 2H);
5.9(s, 2H); 7.2(s, 1H); 7.5(s, 1H); 8.4(s, 1H)
[1297] Saturated methanolic ammonia (20 ml) was added to a solution
of 6-methoxy-7-(2-
(2-methoxyethoxy)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4--
one (2.26 g, 5.5 mmol) in a mixture of ethanol (40 ml) and
methylene chloride (15 ml). The mixture was stirred for 24 hours at
ambient temperature, and further methanolic ammonia (20 ml) was
added. The mixture was stirred for a further 24 hours at ambient
temperature and the volatiles were removed by evaporation. The
residue was triturated with ether, collected by filtration, dried
under vacuum to give
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one
(975 mg, 78%).
[1298] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.25(s, 3H); 3.45(t,
2H); 3.6(t, 2H); 3.8(t, 2H); 3.9(s,3H); 4.2(t, 2H); 7.15(s, 1H);
7.45(s, 1H); 8.0(s, 1H)
[1299] MS-EI: 294 [M].sup.+
[1300] A solution of
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one
(930 mg, 3.16 mmol) in thionyl chloride (15 ml) and DMF (150 .mu.l)
was heated at 60.degree. C. for 1.5 hours. The mixture was allowed
to cool and the volatiles were removed by evaporation and by
azeotroping with toluene. The residue was dissolved in methylene
chloride and 5% aqueous sodium hydrogen carbonate solution was
added until the aqueous layer was at pH8. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and the solvent
removed by evaporation. The residue was purified by flash
chromatography eluting with ethyl acetate to give
4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (863
mg, 87%).
[1301] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.24(s, 3H); 3.47(m,
2H); 3.62(m, 2H); 3.84(t, 2H); 4.01(s, 3H); 4.25(t, 2H); 7.41(s,
1H); 7.49(s, 1H); 8.88(s, 1H)
EXAMPLE 178
[1302] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (207 mg, 1.5 mmol),
3-methyl-5-hydroxyindole (88 mg, 0.6 mmol), (Can. J. Chem. 1964,
42, 514), and DMA (2.0 ml) was purged with nitrogen for 5 minutes
at 25.degree. C. This mixture was then stirred at 100.degree. C.
for 3 hours then allowed to cool to ambient temperature, was
filtered and the filtrate evaporated under vacuum. The residue was
purified by silica column chromatography eluting with
dichloromethane/methanolic ammonia (7M) (90/10) to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-3-piperidinopropoxy)quinazoline
(155 mg, 69%).
[1303] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.37 (m, 2H), 1.50 (m,
4H), 1.95 (m, 2H), 2.21 (s, 3H), 2.34 (m, 4H), 2.42 (t, 2H), 3.96
(s, 3H), 4.22 (t, 2H), 6.95 (dd, 1H), 7.16 (s, 1H), 7.35 (m, 3H),
7.58 (s, 1H), 8.48 (s, 1H) and 10.82 (s, 1H) MS (ESI): 447
(MH).sup.+ TABLE-US-00086 Elemental analysis Found C 68.2 H 6.8 N
12.6 C.sub.26H.sub.30N.sub.4O.sub.30.5H.sub.2O, Requires C 68.5 H
6.8 N 12.3%
EXAMPLE 179
[1304] Using an analogous procedure to that described in Example
178, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline,
(prepared as described for the starting material in Example 9), was
used to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (154 mg, 79%).
[1305] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.68 (m, 4H), 1.97 (m,
2H), 2.22 (s, 3H), 2.43 (m, 4H), 2.55 (t, 2H), 3.96 (s, 3H), 4.22
(t, 2H), 6.93 (dd, 1H), 7.16 (s, 1H), 7.35 (m, 3H), 7.58 (s, 1H),
8.48 (s, 1H) and 10.82 (br s, 1H)
[1306] MS (ESI): 433 (MH).sup.+
[1307] m.p. 75-77.degree. C.
EXAMPLE 180
[1308] Using an analogous procedure to that described in Example
178, 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline was used
to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-piperidinoethoxy)quinazoline
(156 mg, 80%).
[1309] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.38 (m, 2H), 1.50 (m,
4H), 2.24 (s, 3H), 2.73 (t, 2H), 3.96 (s, 3H), 4.28 (t, 2H), 6.93
(dd, 1H), 7.16 (s, 1H), 7.32 (d, 1H), 7.37 (m, 2H), 7.58 (s, 1H),
8.47 (s, 1H) and 10.82 (br s, 1H)
[1310] MS (ESI): 433 (MH).sup.+ TABLE-US-00087 Elemental analysis
Found C 67.0 H 6.5 N 13.0
C.sub.25H.sub.28N.sub.4O.sub.30.75H.sub.2O Requires C 67.3 H 6.6 N
12.6%
[1311] The starting material was prepared as follows:
[1312] 1-(2-Chloroethyl)piperidine hydrochloride (0.83 g, 4.5 mmol)
was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.73
mmol), (prepared as described for the starting material in Example
1), and potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml), and
the mixture heated at 110.degree. C. for 2.5 hours and allowed to
cool. The insolubles were removed by filtration, and the volatiles
were removed from the filtrate by evaporation. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (9/1) to give
6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.2 g,
85%).
[1313] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.38(m, 2H); 1.50(m,
4H); 2.4-2.5(m, 4H); 2.75(t, 2H); 3.95(s, 3H); 4.27(t, 2H); 7.30(m,
3H); 7.40(s, 1H); 7.46(m, 2H); 7.54(s, 1H); 8.52(s, 1H)
[1314] MS-ESI: 380 [MH].sup.+
[1315] A mixture of
6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.15 g, 3.0
mmol) and 2M hydrochloric acid (20 ml) was heated at 90.degree. C.
for 2 hours and allowed to cool. The mixture was neutralised with
solid sodium hydrogen carbonate and extracted with methylene
chloride. The organic phase was separated, passed through phase
separating paper and the volatiles removed by evaporation to give a
solid product (230 mg). The aqueous phase was adjusted to pH10, the
resulting precipitate was collected by filtration, washed with
water and dried to give a second crop of product (220 mg). The
products were combined to give
6-methoxy-7-(2-piperidinoethoxy)-3,4-dihydroquinazolin-4-one (450
mg, 50%).
[1316] MS-ESI: 304 [MH].sup.+
[1317] A mixture of
6-methoxy-7-(2-piperidinoethoxy)-3,4-dihydroquinazolin-4-one (440
mg, 1.45 mmol), thionyl chloride (15 ml) and DMF (3 drops) was
heated at reflux for 3 hours then allowed to cool. The excess
thionyl chloride was removed by evaporation and the residue was
azeotroped with toluene to give a crude
4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline hydrochloride
(640 mg).
[1318] 4-Chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline
hydrochloride was suspended in methylene chloride (10 ml) and
saturated aqueous sodium hydrogen carbonate solution (5 ml) then
stirred vigorously for 10 minutes at ambient temperature. The
layers were separated and the organic layer dried (MgSO.sub.4) then
evaporated to give a white solid. This solid was triturated with
methanol (2.5 ml), the resulting solid filtered off, washed with
cold methanol and dried to give
4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (0.36 g).
EXAMPLE 181
[1319] Using an analogous procedure to that described in Example
178,
4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazol-
ine, (prepared as described for the starting material in Example
152), was used to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-N-methyl-N-methylsulphonylamino)-
propoxy)quinazoline (104 mg, 49%).
[1320] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.08 (m, 2H), 2.22 (s,
3H), 2.80 (s, 3H), 2.88 (s, 3H), 3.27 (t, 2H), 3.97 (s, 3H), 4.22
(t, 2H), 6.95 (dd, 1H), 7.17 (s, 1H,), 7.35 (m, 3H), 7.59 (s, 1H),
8.48 (s, 1H) and 10.82 (br s, 1H)
[1321] MS (ESI): 471 (MH).sup.+ TABLE-US-00088 Elemental analysis
Found C 57.0 H 5.6 N 11.4
C.sub.23H.sub.26F.sub.4N.sub.4O.sub.5S0.5H.sub.2O, Requires C 57.5
H 5.7 N 11.7%
EXAMPLE 182
[1322] A mixture of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218
mg, 0.68 mmol), (prepared as described for the starting material in
Example 9), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol)
and potassium carbonate (280 mg, 2.0 mmol) in DMF (4 ml) was
stirred at 95.degree. C. for 6 hours and allowed to cool to ambient
temperature. The reaction mixture was treated with 1.0 N aqueous
sodium hydroxide solution and allowed to stir at ambient
temperature for a few minutes. The resulting precipitate was
filtered off, washed with water and air dried to give a crude
product which was purified by column chromatography, eluting with
dichloromethane/methanol/880 ammonia (100/8/1). The relevant
fractions were combined and evaporated `in vacuo` to give a white
solid. This was recolumned using dichloromethane/methanol (4/1)
solvent to give a white solid which was triturated with acetone,
filtered and dried to give
6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yl-
oxy)quinazoline (50 mg, 18%).
[1323] m.p. 184.0-185.5.degree. C.
[1324] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.70 (m, 4H), 1.99 (m,
2H), 2.46 (m, 4H), 2.58 (t, 2H), 4.00 (s, 3H), 4.26 (t, 2H), 6.48
(t, 1H), 7.36 (s, 1H), 7.55 (t, 1H), 7.60 (s, 1H), 7.92 (d,1H),
8.19 (d, 1H), 8.50 (s,1H) and 11.78 (br s, 1H)
[1325] MS (ESI): 420 (MH).sup.+ TABLE-US-00089 Elemental analysis
Found C 63.9 H 5.9 N 16.1 C.sub.23H.sub.25N.sub.5O.sub.30.7H.sub.2O
Requires C 63.9 H 6.2 N 16.2%
[1326] The starting material was prepared as follows:
[1327] A suspension of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (210 mg,
1.42 mmol), (Heterocycles 50, (2), 1065-1080, (1999)), in
dichloromethane (10 ml) was stirred in an inert atmosphere, a 1.0M
solution of boron tribromide in dichloromethane (4.3 ml, 4.3 mmol)
added dropwise and the mixture stirred at ambient temperature
overnight. The reaction mixture was taken to pH6 by the dropwise
addition of 5N aqueous sodium hydroxide and further diluted with
water. The aqueous solution was extracted several times with ethyl
acetate, the extracts combined, washed with water followed by brine
and dried over magnesium sulphate. The ethyl acetate solvent was
removed `in vacuo` and the residue purified by column
chromatography, eluting with dichloromethane/methanol (95/5), to
give a white solid. The solid was triturated with ether, filtered
and dried to give 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (108 mg,
57%).
[1328] m.p. 206-209.degree. C.
[1329] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.25 (s,1H), 7.27
(s,1H), 7.33 (s, 1H), 7.82 (s, 1H), 9.00 (s,1H) and 11.20 (s,
1H)
[1330] MS (ESI): 135 (MH).sup.+
EXAMPLE 183
[1331] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (345 mg, 5.0 mmol),
5-hydroxy-2-indolecarboxylic acid (106 mg, 0.6 mmol) and DMA (2.0
ml) was purged with nitrogen for 5 minutes at 25.degree. C. This
mixture was then stirred at 100.degree. C. for 3 hours, allowed to
cool to ambient temperature, filtered and the filtrate evaporated
under vacuum. The residue was purified on octadecylsilane reverse
phase silica eluting with acetonitrile/water/trifluoroacetic acid
(as a gradient from 30/69.8/0.2 to 50/49.8/0.2) and the product
further purified by silica column chromatography eluting with
dichloromethane/methanolic ammonia (7M) (90/10) to give
4-(2-carboxyindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(85 mg 36%).
[1332] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.43 (m, 2H), 1.56 (m,
4H), 2.04 (m, 2H), 2.59 (m, 6H), 3.97 (s, 3H), 4.24 (t, 2H), 7.01
(s, 1H), 7.11 (dd, 1H), 7.36 (s, 1H), 7.48 (m, 2H), 7.58 (s, 1H),
8.48 (s, 1H) and 11.53 (br s, 1H)
[1333] MS (ESI): 477 (MH).sup.+
EXAMPLE 184
[1334] 4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline
(0.15 g, 0.45 mmol), (prepared as described for the starting
material in Example 50), potassium carbonate (94 mg, 0.68 mmol) and
7-hydroxyquinoline (79 mg, 0.54 mmol) were suspended in anhydrous
DMF (1.5 ml) and heated to 90.degree. C. overnight. The compound
was precipitated upon addition of water. The precipitate was
collected by filtration, washed with water and dried under vacuum
over phosphorus pentoxide to give
6-methoxy-7-(3-methylsulphonylpropoxy)-4-(quinolin-7-yloxy)quinazoline
(161 mg, 81%).
[1335] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.26 (m, 2H); 3.08 (s,
3H); 3.35 (m, 2H); 4.03 (s, 3H); 4.38 (m, 2H); 7.45 (s, 1H); 7.60
(m, 1H); 7.65 (m, 1H); 7.70 (s, 1H); 7.95 (d, 1H); 8.15 (d, 1H);
8.46 (d, 1H); 8.60 (s, 1H); 8.95 (d, 1H)
[1336] MS (ESI): 440 [MH].sup.+
EXAMPLES 185-188
[1337] Using an analogous procedure to that described in Example
184, 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline
(0.15 g, 0.45 mmol), (prepared as described for the starting
material in Example 50), was reacted with the appropriate phenols
to give the compounds in Table X. TABLE-US-00090 TABLE X ##STR84##
Ex- am- ple MS- num- weight yield ESI ber (mg) % [MH]+ R Note 185
199 93 474 ##STR85## a 186 171 85 422 ##STR86## b 187 183 88 460
##STR87## c 188 83 40 455 ##STR88## d a) Using
4-chloro-7-hydroxyquinoline (96 mg) gave
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinaz-
oline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.24(m, 2H); 3.04(s,
3H); 3.35(m, 2H); 3.99(s, 3H); 4.32(m, 2H); 7.42(s, 1H); 7.64(s,
1H); 7.80(d, 2H); 8.04(d, 1H); 8.29(d, 1H); 8.55(s, 1H); 8.87(d,
1H) b) Using 5-hydroxy-2-methylindole (80 mg) gave
6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-methylsuiphonylpropoxy)quinazoli-
ne. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.24(m, 2H); 2.40(s, 3H);
3.05(s, 3H); 3.35(m, 2H); 4.0(s, 3H); 4.32(m, 2H); 6.13(s, 1H);
6.88(d, 1H); 7.25(d, 1H); 7.32(d, 1H); 7.39(s, 1H); 7.60(s, 1H);
8.50(s, 1H) c) Using 5-hydroxy-2-methylbenzothiazole (90 mg) gave
6-methoxy-4-(2-methyl-1,3-benzothiazol-5-yloxy)-7-(3-methylsulphonylpropo-
xy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.24(m, 2H);
2.28(s, 3H); 3.05(s, 3H); 3.35(m, 2H); 4.0(s, 3H); 4.32(m, 2H);
7.36(d, 1H); 7.41(s, 1H); 7.65(s, 1H); 7.87(d, 1H); 8.11(d, 1H);
8.53(s, 1H) d) Using 2,7-dihydroxynaphtalene (87 mg) gave
4-(7-hydroxy-2-naphthyloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazo-
line. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.24(m, 2H); 3.05(s, 3H);
3.35(m, 2H); 3.98(s, 3H); 4.32(m, 2H); 7.06(d, 18); 7.12(s, 1H);
7.18(d, 1H); 7.40(d, 1H); 7.59(m, 28); 7.85(m, 2H); 8.55(d, 18);
9.8 (brs, 1H)
EXAMPLE 189
[1338] To a portion of 2-chloro-5-hydroxybenzimidazole (191 mg,
0.75 mmol) in DMF (3 ml) was added sodium hydride (60 mg, 1.5 mmol)
under argon at ambient temperature. Ten minutes later
4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline
(200 mg, 0.62 mmol), (prepared as described for the starting
material in Example 10), was added and the mixture heated at
100.degree. C. for 2 hours. More 2-chloro-5-hydroxybenzimidazole
(30 mg, 0.12 mmol) and sodium hydride (11 mg, 0.28 mmol) were then
added as the reaction was found to be incomplete. The heating was
continued for an additional 1 hour. Work-up using ethyl acetate and
a saturated aqueous solution of ammonium chloride followed by
drying of the organic phase (MgSO.sub.4) and evaporation of the
solvent gave a crude product which was adsorbed on alumina using
dichloromethane/methanol and purified by flash chromatography using
neutral alumina and dichloromethane/methanol (98:2) as the eluent.
Evaporation of the solvent and trituration in ether gave
4-(2-chloro-1H-benzimidazol-6-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl-
)methoxy)quinazoline (46 mg, 16%).
[1339] .sup.1H NMR Spectrum: (DMSOd.sub.6+TFA) 1.60 (m, 2H); 2.05
(d, 2H); 2.15 (m, 1H); 2.80 (s, 3H); 3.05 (m, 2H); 3.55 (m, 2H);
4.05 (s, 3H); 4.15 (d, 2H); 7.20 (dd, 1H); 7.50 (dd, 2H); 7.65 (d,
1H); 7.70 (s, 1H); 8.80 (s, 1H)
[1340] MS (ESI): 454 [MH].sup.+
[1341] The starting material was synthesised as follows:
[1342] 2-Chloro-5-methoxybenzimidazole (0.3 g, 1.64 mmol) was
suspended in dichloromethane (20 ml) under argon followed by the
addition of boron tribromide (233 ul, 2.46 mmol). The reaction
mixture was stirred for 2 hours at ambient temperature. The solvent
was evaporated and the resulting powder was added in portions to
methanol (30 ml). Silica was added and the solvent was evaporated.
The resulting powder was placed on the top of a silica column and
the product was eluted off using dichloromethane/methanol (95/5).
Evaporation of the solvent and trituration in ether gave
2-chloro-5-hydroxybenzimidazole (440 mg, 99%).
EXAMPLE 190
[1343] Using an analogous procedure to that described in Example
189,
4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline,
(prepared as described for the starting material in Example 10),
was reacted with 5-hydroxy-2-methylbenzimidazole (200 mg, 0.62
mmol) and after work-up and purification on a 10 g silica ISOLUTE
column using successively dichloromethane, dichloromethane/methanol
(95/5) and dichloromethane/methanol saturated with ammonia (95/5),
gave
6-methoxy-4-2-methyl-1H-benzimidazol-6-yloxy)-7-((1-methylpiperidin-4-yl)-
methoxy)quinazoline (68 mg, 25%).
[1344] .sup.1H NMR Spectrum: (DMSOd.sub.6+TFA) 1.60 (m, 2H); 2.10
(m, 2H); 2.20 (m, 1H); 2.80 (s, 3H); 2.85 (s, 3H); 3.05 (m, 2H);
3.50 (m, 2H); 4.05 (s, 3H); 4.15 (d, 2H); 7.50 (s, 1H); 7.55 (d,
1H); 7.70 (s, 1H); 7.85 (d, 1H); 7.90 (d, 1H); 8.65 (s, 1H)
[1345] MS (ESI): 434 [MH].sup.+
[1346] The starting material was prepared as follows:
[1347] The free base of 4-methoxy-1,2-phenylenediamine
dihydrochloride (10 g) was obtained by shaking it with a mixture of
ethyl acetate and a saturated aqueous solution of sodium hydrogen
carbonate. The organic phase was then washed with brine, dried
(MgSO.sub.4) and the solvent evaporated. The obtained dark oil
(6.08 g, 50 mmol) was solubilised in toluene (60 ml) and p-toluene
sulfonic acid (60 mg) and triethyl orthoacetate (9.15 ml, 50 mmol)
were added in turn. The mixture was heated to 110.degree. C. until
no more ethanol distilled off. The remaining toluene was removed by
rotary evaporation and the residue purified by flash chromatography
using dichloromethane/methanol (95/5) as the eluent. The obtained
dark oil was triturated in ether and the solid collected by
filtration to give 5-methoxy-2-methyl benzimidazole (4.15 g,5
1%).
[1348] .sup.1H NMR Spectrum (DMSOd.sub.6+TFA) 2.75 (s, 3H); 3.85
(s, 3H); 7.15 (dd, 1H); 7.25 (s, 1H); 7.70 (d, 1H)
[1349] Using an analogous procedure to that described for the
synthesis of 2-chloro-5-hydroxybenzimidazole in Example 189,
5-methoxy-2-methylbenzimidazole (4.0 g, 25 mmol) was reacted with
boron tribromide (7 ml, 74 mmol) in dichloromethane (150 ml) to
give, after work-up and purification by flash chromatography using
dichloromethane/methanol (90/10), 5-hydroxy-2-methylbenzimidazole
(4.4 g, 76%).
[1350] .sup.1H NMR Spectrum (DMSOd.sub.4) 2.70 (s, 3H); 6.95 (dd,
1H); 7.00 (d, 1H); 7.55 (d, 1H)
EXAMPLE 191
[1351]
4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(200 mg, 0.62 mmol), (prepared as described for the starting
material in Example 10), was suspended in DMF (3 ml) under argon.
3-Cyano-7-hydroxyquinoline (116 mg, 0.68 mmol) and potassium
carbonate (129 mg, 0.93 mmol) were added and the reaction mixture
was heated at 95.degree. C. for 90 minutes. Upon cooling to ambient
temperature the mixture was diluted with dichloromethane and poured
on the top of an ISOLUTE silica column. Elution was done using
successively dichloromethane, dichloromethane/methanol (95/5) and
dichloromethane/methanol saturated with ammonia (95/5). Evaporation
of the solvent and trituration of the solid in ether gave
4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-
quinazoline (244 mg, 86%).
[1352] .sup.1H NMR Spectrum: (DMSOd.sub.6+TFA) 1.60 (m, 2H); 2.10
(m, 3H); 2.85 (s, 3H); 3.05 (m, 2H); 3.55 (m, 2H); 4.05 (s, 3H);
4.20 (d, 2H); 7.55 (s, 1H); 7.80 (s, 1H); 7.85 (dd, 1H); 8.15 (s,
1H); 8.3 (d, 1H); 8.85 (s, 1H); 9.20 (s, 1H); 9.25 (s, 1H)
[1353] MS (ESI): 456 [MH].sup.+ 456
[1354] The starting material was prepared as follows:
[1355] m-Anisidine (50 g, 407 mmol) and diethyl
ethoxymethylenemalonate (102 g, 407 mmol) were heated at 60.degree.
C. for 20 minutes. Diphenyl ether (270 ml) was then added and the
temperature was raised to 240.degree. C. over 30 minutes. The
ethanol formed distilled off. Heating was maintained at this
temperature for I hour then the reaction mixture was allowed to
cool to 120.degree. C. at which point the reaction mixture was
diluted with heptane and allowed to stand overnight at ambient
temperature. The brown solid was collected by filtration and washed
with methanol and ether to give ethyl
7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (45 g, 45%).
This reaction was repeated twice.
[1356] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.25 (t, 3H); 3.85 (s,
3H); 4.20 (q, 2H); 6.95 (d, 1H); 7.00 (s, 1H); 8.05 (d, 1H); 8.50
(s, 1H)
[1357] Phosphorus oxychloride (88 ml) was added to ethyl
7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (58 g, 235 mmol)
and the mixture was heated at reflux for 45 minutes under anhydrous
conditions. Upon cooling to ambient temperature, phosphorus
oxychloride was evaporated and the solid residue was added in
portions to a mixture of ammonia (150 ml) and ice (200 g). External
cooling as well as further addition of ammonia to maintain the pH
around 8 was needed during this hydrolysis step. The aqueous phase
was extracted with dichloromethane and the organic phase was washed
with water and brine, dried (MgSO.sub.4) and concentrated to about
300 ml. Pentane (400 ml) was added and the precipitate formed
collected by filtration. Drying under vacuum gave
4-chloro-3-ethoxycarbonyl-7-methoxyquinoline (45.5 g, 73%).
[1358] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (t, 3H); 4.00 (s,
3H); 4.45 (q, 2H); 7.45 (dd, 1H); 7.55 (d, 1H); 8.30 (d, 1H); 9.10
(s, 1H)
[1359] 4-Chloro-3-ethoxycarbonyl-7-methoxyquinoline (43 g, 162
mmol) was dissolved in acetic acid (250 ml), with 10% palladium on
charcoal (1.5 g) and hydrogenated at atmospheric pressure during 8
hours. The catalyst was removed by filtration over a pad of celite
and the solvent evaporated. The residue was diluted with water and
the pH adjusted to 7-8 with a saturated solution of sodium hydrogen
carbonate. The solid was collected by filtration, washed with water
and dried under vacuum over phosphorus pentoxide to give
3-ethoxycarbonyl-7-methoxyquinoline (33 g, 88%) as a beige
powder.
[1360] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (t, 3H); 3.95 (s,
3H); 4.40 (q, 2H); 7.35 (dd, 1H); 7.50 (d, 1H); 8.15 (d, 1H); 8.90
(d, 1H); 9.25 (d, 1H)
[1361] 3-Ethoxycarbonyl-7-methoxyquinoline (28 g, 120 mmol) was
added to a methanol solution saturated with ammonia. The suspension
was stirred at ambient temperature in a glass pressure vessel for 2
weeks. The white solid was collected by filtration, washed with
methanol and dried under vacuum to give
3-carbamoyl-7-methoxyquinoline (21 g, 86%).
[1362] .sup.1H NMR Spectrum (DMSOd.sub.6) 3.95 (s, 3H); 7.35 (dd,
1H); 7.45 (d, 1H); 7.60 (br s, 1H); 8.00 (d, 1H); 8.20 (br s, 1H);
8.75 (s, 1H); 9.25 (s, 1H)
[1363] 3-Carbamoyl-7-methoxyquinoline (4 g, 20 mmol) was suspended
in anhydrous dichloromethane (60 ml) under argon. Anhydrous
dimethyl sulphoxide (2.25 ml, 32 mmol) was added, the mixture was
cooled to -78.degree. C. and a solution of oxalyl chloride (2.08
ml, 24 mmol) in dichloromethane (20 ml) was added dropwise over the
course of I hour. 15 Minutes after the end of the addition,
triethylamine (8.3 ml, 60 mmol) was added dropwise and the
heterogeneous reaction mixture stirred for an additional 1 hour at
-78.degree. C. then left to rise to ambient temperature. The
unreacted starting material was removed by filtration and the
filtrate was diluted with water and extracted with ethyl acetate.
The organic phases were combined, washed with brine, dried
(MgSO.sub.4) and the solvent evaporated. The residue was purified
by flash chromatography using dichloromethane/methanol (97/3). The
obtained solid was triturated with ether and gave, after drying
under vacuum, 3-cyano-7-methoxyquinoline (1.47 g, 40%).
[1364] .sup.1H NMR Spectrum (DMSOd.sub.6) 4.00 (t, 3H); 7.40 (dd,
1H); 7.50 (d, 1H); 8.00 (d, 1H); 8.95 (s, 1H); 9.10 (d, 1H)
[1365] 3-Cyano-7-methoxyquinoline (380 mg, 2.1 mmol) was suspended
in benzene (10 ml), aluminium trichloride (826 mg, 6.2 mmol) was
added and the mixture heated at reflux for 30 minutes. More
aluminium trichloride (275 mg, 2.1 mmol) was added and the mixture
refluxed for a further 2 hours. The solvent was evaporated, the
dark green solid was added to ice and extracted with ethyl acetate.
The organic phase was washed with brine, dried (MgSO.sub.4) and
evaporated. The solid was found to contain some aluminium salts
which were removed as follows. The solid was dissolved in
dichloromethane (200 ml) was stirred vigorously with a saturated
sodium hydrogen carbonate solution for 1 hour. The product was
collected by filtration of the aqueous phase and dried over
phosphorus pentoxide under vacuum to give
3-cyano-7-hydroxyquinoline (238 mg, 68%).
[1366] .sup.1H NMR Spectrum (DMSOd.sub.6) 7.25 (d, 1H); 7.30(d,
1H); 7.95 (d, 1H); 8.85 (d, 1H); 9.00 (d, 1H)
EXAMPLE 192
[1367] To
6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,-
3,4-tetrahydroquinolin-6-yl)oxy)quinazoline (110 mg, 0.2 mmol) in
solution in dichloromethane (3 ml) was added TFA (0.3 ml) and the
mixture stirred for 1 hour at ambient temperature. The solvents
were evaporated and the remaining oil was diluted with
dichloromethane and the pH adjusted to 9 with a saturated solution
of sodium hydrogen carbonate. The organic phase was washed with,
brine, dried (MgSO.sub.4), filtered and the solvent evaporated to
give
6-methoxy-7-(3-morpholinopropoxy)-4-(1,2,3,4-tetrahydroquinolin-6-yloxy)q-
uinazoline (84 mg, 93%).
[1368] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.95 (m, 2H); 2.15 (m,
2H); 2.45 (m, 4H); 2.60 (t, 2H); 2.80 (t, 2H); 3.35 (t, 2H); 3.75
(m, 4H); 3.90 (br s, 1H); 4.05 (s, 3H); 4.30 (t, 2H); 6.55 (d, 1H);
6.85 (m, 2H); 7.30 (s, 1H); 7.55 (s, 1H); 8.65 (s, 1H)
[1369] MS (ESI): 451 [MH].sup.+ TABLE-US-00091 Elemental analysis:
Found C 66.4 H 6.9 N 12.4 C.sub.2H.sub.1N.sub.1O.sub.1; 1HCl,
2H.sub.2O Requires C 66.7 H 6.7 N 12.4%
[1370] The starting material was prepared as follows:
[1371] 6-Hydroxyquinoline (1 g, 6.9 mmol) was dissolved in methanol
and hydrogenated at 3 atmospheres pressure with platinum(IV) oxide
(276 mg) over 24 hours. The catalyst was removed by filtration over
a pad of celite and the solvent was evaporated. The solid was
washed with ether to give 6-hydroxy-(1,2,3,4)-tetrahydroquinoline
(698 mg, 68%).
[1372] .sup.1H NMR Spectrum (DMSOd.sub.6) 1.75 (m, 2H); 2.60 (m,
2H); 3.05 (m, 2H); 4.90 (br s, 1H); 6.30 (m, 3H); 8.25 (br s,
1H)
[1373] 6-Hydroxy-(1,2,3,4)-tetrahydroquinoline (250 mg, 1.7 mmol)
was suspended in acetone (1 ml) and trichloromethane (1 ml) under
argon. Tert-Butoxycarbonylanhydride (365 mg, 1.7 mmol) in solution
in acetone was added dropwise followed by THF (2 ml) to help the
solubilisation. The reaction mixture was stirred overnight at
ambient temperature, the solvent was evaporated, the residue was
partitioned between ethyl acetate and water, the organic phase was
washed with water, brine, dried (MgSO.sub.4), filtered and the
solvent evaporated. The resulting gum was purified by flash
chromatography using dichloromethane/methanol (97/3) as solvent.
Evaporation of the solvent gave
6-hydroxy-4-(1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinoline (344
mg, 82%) as a brown foam.
[1374] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.50 (m, 9H); 1.90 (m,
2H); 2.70 (t, 2H); 3.65 (t, 2H); 4.75 (br s, 1H); 6.55 (d, 1H);
6.65 (dd, 1H); 7.45 (d, 1H)
[1375]
6-Hydroxy-4-(1-tertbutoxycarbonyl-1,2,3,4-tetrahydroquinoline (82
mg, 0.32 mmol) was dissolved in anhydrous dimethylformamide under
argon, with potassium carbonate (61 mg, 0.44 mmol) and
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (100 mg, 0.3
mmol), (prepared as described for the starting material in Example
1). No reaction occurred after 2 hours at 60.degree. C. Sodium
hydride (12 mg, 0.3 mmol) was added and the reaction mixture was
heated at 120.degree. C. for 90 minutes. The cooled mixture was
poured into water and ethyl acetate. The organic phase was washed
with water, brine, dried (MgSO.sub.4), filtered and the solvent
evaporated. The residue was purified by flash chromatography using
first dichloromethane/methanol (97/3) as solvent. Evaporation of
the solvent gave
6-methoxy-7-(3-morpholinopropoxy)-4-((1-tertbutoxycarbonyl-1,2,3,4-tetrah-
ydroquinolin-6-yl)oxy)quinazoline (115 mg, 71%) as a white
solid.
[1376] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.55 (s, 9H); 1.95 (m,
2H); 2.15 (m, 2H); 2.50 (m, 4H); 2.60 (t, 2H); 2.85 (t, 2H); 3.75
(m, 6H); 4.05 (s, 3H); 4.30 (t, 2H); 7.00 (m, 2H); 7.35 (s, 1H);
7.55 (s, 1H); 7.80 (d, 1H); 8.65 (s, 1H)
EXAMPLE 193
[1377] Using an analogous procedure to that described in Example
192,
4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(3-(pyrrol-
idin-1-yl)propoxy)quinazoline (169 mg, 0.32 mmol) was reacted with
TFA (1 ml) to give, after work-up and purification,
4-(2,3-dihydro-1H-indol-5yl)oxy-6-methoxy-7-(3-(pyrrolidin-1-
yl)propoxy)quinazoline (124 mg, 91%).
[1378] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.90 (br, 4H); 2.30 (br,
2H); 2.70 (br d, 6H); 3.10 (t, 2H); 3.65 (t, 2H); 4.05 (s, 3H);
4.30 (t, 2H); 6.70 (d, 1H); 6.80 (dd, 1H); 7.00 (s, 1H); 7.30 (s,
1H);7.55 (s, 1H); 8.65 (s, 1H)
[1379] MS (ESI): 421 [MH].sup.+
[1380] The starting material was prepared as follows:
[1381] 5-Hydroxyindole (2 g, 15 mmol) was dissolved in methanol (60
ml) under argon. Sodium cyanoborohydride (1.89 g, 30 mmol) and
trifluoroboron etherate (4.2 ml, 33 mmol) were added and the
mixture was heated at reflux for 3 hours then left to cool to
ambient temperature. The solvent was evaporated and the residue was
partitioned between ethyl acetate and water. Ammonia was added to
adjust the pH to 10 and the aqueous phase was extracted with more
ethyl acetate. The combined organic phases were washed with water,
brine, dried (MgSO.sub.4), filtered and the solvent evaporated. The
residue was purified by flash chromatography using
dichloromethane/methanol (95/5) as solvent. Evaporation of the
solvent gave 5-hydroxy-2,3-dihydro-1H-indole (1.45 g, 73%) as an
off white solid.
[1382] .sup.1H NMR Spectrum: (DMSOd.sub.6+ TFA) 3.15 (t, 2H); 3.70
(t, 2H); 6.75 (dd, 1H); 6.85 (d, 1H); 7.30 (d, 1H)
[1383] 5-Hydroxy-2,3-dihydro-1H-indole (1.5 g, 11.1 mmol) was
suspended in a mixture of acetone (7 ml) trichloromethane (7 ml)
and THF (6 ml). tert-Butoxycarbonylanhydride (2.42 g, 11 mmol) in
solution in THF (7 ml) was added dropwise. The reaction mixture was
stirred overnight at ambient temperature, the solvent was
evaporated, the residue was partitioned between ethyl acetate and
water, the organic phase was washed with water, brine, dried
(MgSO.sub.4), filtered and the solvent evaporated. The solid was
purified by flash chromatography using dichloromethane/methanol
(95/5) as solvent. Evaporation of the solvent gave
5-hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole (2.28 g, 87%) as
an off white solid.
[1384] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.05 (t, 2H); 3.95 (br s,
2H); 4.70 (br s, 1H); 6.60 (d, 1H); 6.65 (s, 1H); 7.70 (br s,
1H)
[1385] Sodium hydride (22 mg, 0.56 mmol) was suspended in anhydrous
dimethylformamide under argon.
5-Hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole (131 mg, 0.56
mmol) was added followed 10 minutes later by
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (150
mg, 0.47 mmol), (prepared as described for the starting material in
Example 9). The reaction mixture was heated at 110.degree. C. for 3
hours, cooled to ambient temperature and partitioned between ethyl
acetate and water. The organic phase was washed with water, brine,
dried (MgSO.sub.4), filtered and the solvent evaporated. The
residue was purified by flash chromatography using increasingly
polar solvent mixtures starting with dichloromethane/methanol
(90/10) and ending with dichloromethane/methanol/methanol saturated
with ammonia (80/15/5). Evaporation of the solvent gave
4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(3-(pyrrol-
idin-1-yl)propoxy)quinazoline (178 mg, 73%) as a white solid.
[1386] .sup.1H NMR Spectrum: (DMSOd.sub.1) 1.60 (s, 9H); 1.80 (m,
4H); 2.20 (m, 2H); 2.55 (m, 4H); 2.70 (t, 2H); 3.15 (t, 2H); 4.05
(br s, 5H); 4.30 (t, 2H); 7.00 (d, 1H); 7.05 (s, 1H); 7.30 (s, 1H);
7.55 (s, 1H); 7.90 (br s, 1H); 8.60 (s, 1H)
EXAMPLE 194
[1387] Using an analogous procedure to that described in Example
192,
4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylp-
iperidin-4-ylmethoxy)quinazoline (191 mg, 0.37 mmol) was reacted
with TFA (1 ml) to give, after work-up and purification,
4-(2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-
quinazoline (103 mg, 67%).
[1388] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.65 (m, 2H); 2.00 (m,
3H); 2.25 (m, 2H); 2.45 (s, 3H); 3.10 (m, 4H); 3.65 (t, 2H); 4.05
(s, 3H); 4.10 (d, 2H); 6.70 (d, 1H); 6.85 (dd, 1H); 7.0 (s, 1H);
7.25 (s, 1H); 7.55 (s, 1H); 8.60 (s, 1H)
[1389] MS (ESI): 421 [MH].sup.+
[1390] The starting material was prepared as follows:
[1391] Using an analogous procedure to that described in Example
193,
4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
(150 mg, 0.47 mmol), (prepared as described for the starting
material in Example 10), was reacted with
5-hydroxy-(1-tertbutoxycarbonyl)-2,3-dihydroindole (132 mg, 0.56
mmol), (prepared as described for the starting material in Example
193), to give, after work-up and purification,
4-(1-tertbutoxycarbonyl-2,3-dihydro-indol-5-yloxy)-6-methoxy-7-(1-methylp-
iperidin-4-ylmethoxy)quinazoline (197 mg, 81%) as a white
solid.
[1392] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.50 (br s, 11H); 2.00
(m, 5H); 2.30 (s, 3H); 2.90 (d, 2H); 3.15 (t, 2H); 4.05 (br s, 7H);
7.05 (br s, 2H); 7.30 (s, 1H); 7.55 (s, 1H); 7.95 (br s, 1H); 8.60
(s, 1H)
EXAMPLE 195
[1393] To a suspension of
4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (250 mg, 0.78
mmol), (prepared as described for the starting material in Example
180), in DMF (10 ml) was added anhydrous potassium carbonate (320
mg, 2.30 mmol) and 7-hydroxyquinoline (135 mg, 0.94 mmol), and the
reaction heated under reflux at 90 C for 1 hour. The reaction was
cooled to ambient temperature and 1N aqueous sodium hydroxide
added. The resulting precipitate was filtered, washed with water
and acetone, and dried under suction to give
6-methoxy-7-(2-piperidinoethoxy)-4-(quinolin-7-yloxy)quinazoline
(248 mg, 0.58 mmol, 75%) as a white solid.
[1394] .sup.1H NMR Spectrum: d.sub.H (300 MHz, CDCl.sub.3): 1.5
(2H, m; NCH.sub.2CH.sub.2CH.sub.2), 1.6 (4H, m;
2.times.NCH.sub.2CH.sub.2), 2.6 (4H, t; 2.times.NCH.sub.2); 2.9
(2H, t; NCH.sub.2), 4.1 (3H, s; OCH.sub.3), 4.3 (2H, t; OCH.sub.2),
7.3 (1H, s; ArH), 7.4 (1H, dd; ArH), 7.5 (1H, dd; ArH), 7.6 (1H, s;
ArH), 7.9 (1H, d; ArH), 8.0 (1H, d; ArH), 8.2 (1H, d; ArH), 8.6
(1H, s; ArH) and 8.9 (1H, dd; ArH)
[1395] m/z (ESP+) 431 (MH.sup.+, 100%)
EXAMPLE 196
[1396] To a suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline
(1.82 g, 6.1 mmol), (prepared as described for the starting
material in Example 1), in DMF (50 ml) was added potassium
carbonate (2.50 g, 18.1 mmol) and 7-hydroxyquinoline (1.06 g, 7.3
mmol), and the reaction heated under reflux at 90 C for 4 hours.
The reaction was poured into 1N aqueous sodium hydroxide and the
resulting precipitate filtered, washed with water, and dried under
suction. Further drying in a vacuum oven gave
7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (1.50 g, 3.7
mmol, 60%) as a cream solid.
[1397] .sup.1H NMR Spectrum: d.sub.H (300 MHz, DMSO-d.sub.6): 4.0
(3H, s; OCH.sub.3), 5.4 (2H, s; OCH.sub.2), 7.3-7.7 (9H, m;
9.times.ArH), 7.9 (1H, br s; ArH), 8.1 (1H, d; ArH), 8.4 (1H, d;
ArH), 8.5 (1H, s; ArH) and 8.9 (1H, d; ArH)
EXAMPLE 197
[1398] A solution of
7-benzyloxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (1.50 g, 3.70
mmol), (prepared as described in Example 196), in trifluoroacetic
acid (50 ml) was heated at reflux for 150 minutes. The reaction was
concentrated in vacuo and the reaction neutralised with saturated
aqueous ammonium hydroxide. The resulting precipitate was filtered,
washed with acetone and dried under suction to give
7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (0.90 g, 2.82
mmol, 76%) as a white solid.
[1399] .sup.1H NMR Spectrum: d.sub.H (300 MHz, DMSO-d.sub.6): 4.0
(3H, s; OCH.sub.3), 7.1 (1H, s; s; ArH), 7.3-7.4 (3H, m;
3.times.ArH), 7.9 (1H, br s; ArH), 8.1 (1H, d; ArH), 8.4-8.5 (2H,
d; 2.times.ArH) and 8.9 (1H, d; ArH)
[1400] m/z (ESP+) 320 (MH.sup.+, 100%)
EXAMPLE 198
[1401] To a suspension of
7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (450 mg, 1.40
mmol), (prepared as described in Example 197), in DMF (50 ml) was
added anhydrous potassium carbonate (773 mg, 5.60 mmol) and
4-(2-hydroxyethyl)morpholine (335 mg, 1.80 mmol), and the reaction
heated under reflux for 2 hours. The DMF was evaporated in vacuo,
and the residue partitioned between dichloromethane and 1N aqueous
sodium hydroxide. The mixture was extracted with dichloromethane
(3.times.200 ml), dried (MgSO.sub.4) and concentrated in vacuo. The
crude product was triturated with hexane/ether to afford a solid
which was filtered and dried under suction to give
6-methoxy-7-(2-morpholinoethoxy)-4-(quinolin-7-yloxy)quinazoline
(430 mg, 1.00 mmol, 71%) as a light brown solid.
[1402] .sup.1H NMR Spectrum: d.sub.H (300 MHz, CDCl.sub.3): 2.7
(4H, t; 2.times.NCH.sub.2); 3.0 (2H, t; NCH.sub.2), 3.7 (4H, t;
2.times.OCH.sub.2), 4.1 (3H, s; OCH.sub.3), 4.4 (2H, t; OCH.sub.2),
7.2 (1H, s; ArH), 7.4 (1H, dd; ArH), 7.5 (1H, dd; ArH), 7.6 (1H, s;
ArH), 7.9 (1H, d; ArH), 8.0 (1H, br s; ArH), 8.2 (1H, d; ArH), 8.6
(1H, s; ArH) and 8.9 (1H, dd; ArH)
[1403] m/z (ESP+) 433 (MH.sup.+, 100%) TABLE-US-00092 Elemental
analysis Found C 65.0 H 5.6 N 12.6
C.sub.24H.sub.24N.sub.4O.sub.40.5H.sub.2O Requires C 65.3 H 5.7 N
12.7%
EXAMPLE 199
[1404] To a solution of
7-hydroxy-6-methoxy-4-(quinolin-7-yloxy)quinazoline (100 mg, 0.31
mmol), (prepared as described in Example 197), and
(S)-(+)-5-(hydroxymethyl)-2-pyrrolidinone (101 mg, 0.47 mmol) in
dichloromethane (10 ml) was added triphenylphosphine (244 mg, 0.93
mmol) and DEAD (0.15 ml, 162 mg, 0.93 mmol), and the reaction
stirred at ambient temperature overnight. The reaction mixture was
placed directly onto a 2 g SCX ion-exchange column, and eluted with
dichloromethane, then dichloromethane/methanol (4/1), then
dichloromethane/methanol/ammonium hydroxide (20/5/1). The
appropriate fractions were concentrated in vacuo, and the residue
triturated with ether to give a solid which was filtered and dried
under suction to give
(5S)-6-methoxy-7-(5-oxo-pyrrolidin-2-ylmethoxy)-4-(quinolin-7-yloxy)quina-
zoline (55 mg, 0.13 mmol, 43%) as a yellow solid.
[1405] .sup.1H NMR Spectrum: d.sub.H (300 MHz, CDCl.sub.3): 2.3-2.5
(4H, m; 2.times.pyrrolidinone-CH.sub.2), 4.0-4.1 (4H, m;
pyrrolidinone-CH; OCH.sub.3), 4.2-4.3 (2H, m; OCH.sub.2), 6.1 (1H,
br s; NH), 7.3 (1H, s; ArH), 7.4 (1H, dd; ArH), 7.5 (1H, dd; ArH),
7.9 (1H, d; ArH), 8.0 (1H, br s; ArH), 8.2 (1H, d; ArH), 8.6 (1H,
s; ArH) and 8.9 (1H, dd; ArH)
[1406] m/z (ESP+) 417 (MH.sup.+, 100%)
EXAMPLE 200
[1407] To a solution of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (100
mg, 0.31 mmol), (prepared as described for the starting material in
Example 9), in DMF (10 ml) was added potassium carbonate (124 mg,
0.9 mmol, 3 eq.) followed by 2-hydroxycarbazole (66 mg, 0.36 mmol,
1.2 eq.) and the reaction heated at 100.degree. C. for 4 hours. The
DMF was removed in vacuo, the residue dissolved in dichloromethane
and placed onto a 2 g SCX ion-exchange column. Elution with
dichloromethane, followed by 20% methanol/dichloromethane then 20%
methanol/dichloromethane +3% ammonium hydroxide, gave the crude
product as a brown solid. Further purification by silica bond elut
chromatography eluting with dichloromethane to 15%
methanol/dichloromethane+1% ammonium hydroxide, followed by
trituration with ether gave
4-(9H-carbazol-2-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoli-
ne (31 mg, 22%) as a white solid.
[1408] .sup.1H NMR Spectrum: d.sub.H (300 MHz, DMSO-d.sub.6) 1.7
(4H, m; 2.times.pyrrolidine-CH.sub.2), 2.0 (2H, t;
OCH.sub.2CH.sub.2), 2.5 (4H, m; 2.times.pyrrolidine-NCH.sub.2), 2.6
(2H, t; NCH.sub.2), 4.0 (3H, s; OCH.sub.3), 4.2 (2H, t; OCH.sub.2),
7.1 (1H, br d; ArH), 7.2 (1H, t; ArH), 7.3-7.4 (3H, m;
3.times.ArH), 7.5 (1H, br d; ArH), 7.6 (1H, s; ArH), 8.1-8.2 (2H,
m; 2.times.ArH), 8.5 (1H, s; ArH), 11.3 (1H, s; carbazole NH)
[1409] m/z (ESP+) 469 (MH.sup.+, 100%)
EXAMPLE 201
[1410] To a solution of
7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg, 0.32
mmol), 2-((N-(3,6-dichloropyridazin-4-yl)-N-methyl)amino)ethanol
(107 mg, 0.48 mmol), (prepared as described for the starting
material in Example 142), triphenylphosphine (168 mg, 0.64 mmol) in
methylene chloride (1 ml) and DMF (0.5 ml) cooled at 4.degree. C.
was added a solution of diethyl azodicarboxylate (101 .mu.l, 0.64
mmol) in methylene chloride (0.4 ml). The mixture was stirred for
12 hours at 4.degree. C. and overnight at ambient temperature. The
precipitate was filtered, washed with ether and dried under vacuum
to
give7-(2-((N-(3,6-dichloropyridazin-4yl)-N-methyl)amino)ethoxy)-4-(indol--
5-ylamino)-6-methoxyquinazoline (72 mg, 44%).
[1411] MS-ESI: 510-512 [MH].sup.+
[1412] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.12 (s, 3H); 3.85 (s,
3H); 4.1 (t, 2H; 4.45 (t, 2H); 6.45 (s, 1H); 7.2 (s, 1H); 7.3 (s,
1H); 7.35 (m, 2H); 7.42 (d, 1H); 7.8 (s, 1H); 7.85 (s, 1H); 8.35
(s, 1H); 9.45 (s, 1H)
[1413] The starting material was prepared as follows:
[1414] A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline (5
g, 16.6 mmol), (prepared as described for the starting material in
Example 1), 5-aminoindole (2.4 g, 18.2 mmol) in isopropanol (60 ml)
containing 5N hydrogen chloride in isopropanol (260 .mu.l, 1.6
mmol) was refluxed for 90 minutes. After cooling the volatiles were
removed under vacuum. The solid was triturated with isopropanol,
filtered, washed with isopropanol followed by ether and dried under
vacuum to give 7-benzyloxy-4-(indol-5-ylamino)-6-methoxyquinazoline
hydrochloride (6.9 g, 96%).
[1415] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.05 (s, 3H); 5.35 (s,
2H); 6.5 (s, 1H); 7.3 (d, 1H); 7.4-7.65 (m,9H); 7.8(s, 1H); 8.3(s,
1H); 8.7(s, 1H)
[1416] A solution of give
7-benzyloxy-4-(indol-5-ylamino)-6-methoxyquinazoline hydrochloride
(10 g, 23.1 mmol) in methanol (300 ml) and DMF (100 ml) containing
ammonium formate (22 gr, 347 mmol) and 10% palladium on charcoal (1
g) was stirred overnight at ambient temperature. The solution was
filtered over celite and washed with DMF followed by methanol. The
filtrate was evaporated. The residue was dissolved in aqueous
ammonia 2 mM (300 ml) and stirred for 15 minutes. The solid was
filtered, washed with water followed by ethyl acetate and ether and
dried under vacuum at 50.degree. C. for 2 days. The solid was
purified by column chromatography eluting with methanol/methylene
chloride (1/9). The volatiles were removed under vacuum and the
solid was left under vacuum at 70.degree. C. for 2 days to give
7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (6.8 g, 97%)
[1417] MS-ESI: 307 [MH]+
[1418] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.98 (s, 3H); 6.42 (s,
1H); 7.0 (s, 1H); 7.3-7.45 (m, 3H); 7.85 (s, 2H); 8.28 (s, 1H);
9.35 (s, 1H); 10.25 (br s, 1H); 11.05 (s, 1H)
EXAMPLES 202-204
[1419] Using an analogous procedure to that described in Example
201, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline, (prepared
as described for the starting material in Example 201), was used in
the synthesis of the compounds described in Table XI.
TABLE-US-00093 TABLE XI ##STR89## Ex- am- ple MS- num- Weight Yield
ESI ber (mg) % [MH].sup.+ Note R 202 83 59 441 a ##STR90## 203 91
72 398 b ##STR91## 204 76 55 432 c ##STR92## a)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline was reacted with
2-(N-methyl-N-(4-pyridyl)amino)ethanol (73 mg), (EP 0359389), to
give
4-(indol-5-ylamino)-6-methoxy-7-(2-(N-methyl-N-(4-pyridyl)amino)ethoxy)qu-
inazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.08(s, 3H); 3.9(t,
2H); 3.95(s, 3H); 4.35(t, 2H); 6.45(s, 1H); 6.75(d, 2H); 7.15(s,
1H); 7.35(m, 2H); 7.4(d, 1H); 7.85(s, 1H); 7.9(s, 1H); 8.15(d, 2H);
8.38(s, 1H); 9.45(s, 1H) b)
7-Hydroxy-4-(indoI-5-ylanino)-6-methoxyquinazoline was reacted with
3-hydroxymethyl pyridine (53 mg) to give
4-(indol-5-ylamino)-6-methoxy-7-((3-pyridyl)methoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 4.0(s, 3H); 5.35(s, 2H);
6.42(s, 1H); 7.3-7.55(m, 5H); 7.8-8.0(m, 3H); 8.4(s, 1H); 8.6(d,
1H); 8.75(s, 1H); 9.5(s, 1H) c)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline was reacted with
5-(2-hydroxyethyl)-4-methylthiazole (69 mg) to give
4-(indol-5-ylamino)-6-methoxy-7-(2-(4-methyl-1,3-thiazol-5-yl)ethoxy)quin-
azoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.45(s, 3H); 3.32(t,
2H); 3.95(s, 3H); 4.32(t, 2H); 6.45(s, 1H); 7.15(s, 1H);
7.3-7.45(m, 3H); 7.85(s, 1H); 7.9(s, 1H); 8.35(s, 1H); 8.85(s, 1H);
9.45 (s, 1H)
EXAMPLE 205
[1420] To a solution of
7-hydroxy-6-methoxy-4-2-methylindol-5-ylamino)quinazoline (102 mg,
0.32 mmol), 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol),
(prepared as described for the starting material in Example 60),
triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (1 ml)
and DMF (0.5 ml) cooled at 4.degree. C. was added a solution of
diethyl azodicarboxylate (101 .mu.l, 0.64 mmol) in methylene
chloride (0.4 ml). The mixture was stirred for 12 hours at
4.degree. C. and overnight at ambient temperature. The mixture was
poured onto a column of silica (IST isolute.RTM. 10 g of silica)
and was eluted with methylene chloride (15 ml) followed by 5%
methanol in methylene chloride (45 ml) followed by 5% methanol
(saturated with ammonia) in methylene chloride (30 ml) followed by
10% methanol (saturated with ammonia) in methylene chloride (45 ml)
followed by 15% methanol (saturated with ammonia) in methylene
chloride (30 ml). The fractions containing the expected product
were evaporated to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline
(63 mg, 44%).
[1421] MS-ESI: 448 [MH].sup.+
[1422] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0 (m, 2H); 2.4 (s,
3H); 2.3-2.6 (m, 6H); 3.6 (t, 4H); 3.95 (s, 3H); 4.2 (t, 2H); 6.12
(s, 1H); 7.12 (s, 1H); 7.3 (br s, 2H); 7.7 (s, 1H); 7.85 (s, 1H);
8.35 (s, 1H); 9.4 (s, 1H)
[1423] The starting material was prepared as follows:
[1424] A solution of 2-methyl-5-nitroindole (1 g, 5.7 mmol) in
ethanol (25 ml) and THF (25 ml) containg 10% palladium on charcoal
(128 mg) was hydrogenated until uptake of hydrogen ceased. The
mixture was filtered and the filtrate was evaporated to give
5-amino-2-methylindole (830 mg, quant.).
[1425] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3 (s, 3H): 4.3 (br s,
2H); 5.8 (s, 1H); 6.35 (d, 1H); 6.55 (s, 1H); 6.95 (d, 1H); 10.35
(br s, 1H)
[1426] Using an analogous procedure to that described for the
synthesis of the starting material in Example 201,
7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.6 mmol),
(prepared as described for the starting material in Example 1), was
reacted with 5-amino-2-methylindole (1.07 g, 7.3 mmol) to give
7-benzyloxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline
hydrochloride (2.9 g, quanti.).
[1427] MS-ESI: 411 [MH]+
[1428] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.41 (s, 3H); 4.01 (s,
3H); 5.33 (s, 2H); 6.18 (s, 1H); 7.25 (d, 1H); 7.3-7.7 (m, 8H); 8.3
(s, 1H); 8.7 (s, 1H); 11.1 (s, 1H); 11.4 (s, 1H)
[1429] Using an analogous procedure to that described for the
synthesis of the starting material in Example 201,
7-benzyloxy-6methoxy-4-(2-methylindol-5-ylamino)quinazoline
hydrochloride (2.87 g, 6.4 mmol) was reacted with ammonium formate
(6 g, 9.6 mmol) to give
7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (1.91 g,
93%).
[1430] MS-ESI: 321 [MH]+
[1431] .sup.1H NMR Spectrum: (DMSO.sub.6) 2.4 (s, 3H); 3.95 (s,
3H); 6.12 (s, 1H); 7.0 (s, 1H); 7.25 (s, 1H); 7.7 (s, 1H); 7.85 (s,
1H); 8.3 (s, 1H); 9.35 (s, 1H); 10.2 (br s, 1H); 10.9 (s, 1H)
EXAMPLES 206-207
[1432] Using an analogous procedure to that described for Example
205, 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline,
(prepared as described for the starting material in Example 205),
was used in the synthesis of the compounds described in Table XII.
TABLE-US-00094 TABLE XII ##STR93## Ex- am- ple MS- num- Weight
Yield ESI ber (mg) % [MH].sup.+ Note R 206 65 41 496 a ##STR94##
207 62 45 b ##STR95## a)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (98 mg)
was reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg),
(prepared as described for the starting material in Example 5), to
give
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(2-methylindol-5-ylami-
no)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0(m, 2H);
2.4(s, 3H); 2.7(t, 2H); 2.95(m, 4H); 3.15(m, 4H); 3.95(s, 3H);
4.2(t, 2H); 6.15(s, 18); 7.18(s, 1H); 7.28(m, 2H); 7.7(s, 1H);
7.85(s, 1H); 8.35(s, 1H); 9.4(s, 1H) b)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (98 mg)
was reacted with 1-(2-hydroxyethyl)piperidine (62 mg) to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(2-piperidinoethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4(m, 2H); 1.45-1.6(m, 4H);
2.42(s, 3H); 2.45(br s, 4H); 2.75(t, 2H); 3.95(s, 3H); 4.25(t, 2H);
6.15(s, 1H); 7.15(s, 1H); 7.25(br s, 2H); 7.7(s, 1H); 7.88(s, 1H);
8.35(s, 1H); 9.4(s, 1H)
EXAMPLE 208
[1433] Using an analogous procedure to that described in Example
205, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquirnazoline (98 mg,
0.32 mmol), (prepared as described for the starting material in
Example 201), was reacted with 3-(1,2,3-triazol-1-yl)propan-1-ol
(61 mg, 0.48 mmol) to give
4-(indol-5-ylamino)-6-methoxy-7-(3-(1,2,3-triazol-1-yl)propoxy)quinazolin-
e (56 mg, 42%).
[1434] MS-ESI: 416 [MH].sup.+
[1435] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (m, 2H); 4.0 (s,
3H); 4.2 (t, 2H); 4.65 (t, 2H); 6.45 (s, 1H); 7.15 (s, 1H); 7.35
(m, 2H); 7.42 (d, 1H); 7.75 (s, 1H); 7.88 (s, 1H); 7.9 (s, 1H); 8.2
(s, 1H); 8.38 (s, 1H); 9.42 (s, 1H)
[1436] The starting material was prepared as follows:
[1437] A mixture of 1,2,3-triazole (5 g, 72.4 mmol) and ethyl
acrylate (7.8 ml, 72.4 mmol) containing pyridine (50 drops) was
heated at 90.degree. C. for 4 hours. After cooling, the volatiles
were removed under vacuum and the residue was purified by column
chromatography eluting with methylene chloride/ether to give ethyl
(1H-1,2,3-triazol-1-yl)propanoate (8.96 g, 73%).
[1438] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.25 (t, 3H); 2.95 (t,
2H); 4.15 (q, 2H); 4.7 (t, 2H); 7.65 (s, 1H); 7.7 (s, 1H)
[1439] A solution of ethyl (1H-1,2,3-triazol-1-yl)propanoate (8.96
g, 53 mmol) in THF (50 ml) was added dropwise to a suspension of
lithium aluminium hydride (3 g, 79 mmol) in THF (250 ml) cooled at
0.degree. C. After stirring for 1 hour at 5 .degree. C., the
mixture was stirred for 1 hour at ambient temperature. The mixture
was cooled at 0.degree. C. and 4N sodium hydroxide (30 ml) was
added dropwise. The mixture was filtered and the solid was washed
with THF followed by ethyl acetate. The filtrate was dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography, eluting with methylene chloride/methanol (94/6) to
give 3-(1,2,3-triazol-1-yl)propan-1-ol (6.2 g, 92%).
[1440] .sup.1H NMR Spectrum: (CDCl.sub.3): 2.1-2.2 (m, 3H); 3.65
(m, 2H); 4.6 (t, 2H); 7.6 (s, 1H); 7.72 (s, 1H)
EXAMPLES 209-216
[1441] Using an analogous procedure to that described in Example
208, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline, (prepared
as described for the starting material in Example 201), was used in
the synthesis of the compounds described in Table XIII.
TABLE-US-00095 TABLE XIII ##STR96## Ex- am- ple MS- num- Weight
Yield ESI ber (mg) % [MH].sup.+ Note R 209 77 57 422 a ##STR97##
210 64 45 446 b ##STR98## 211 76 49 482 c ##STR99## 212 70 48 462 d
##STR100## 213 85 59 447 e ##STR101## 214 62 54 365 f ##STR102##
215 71 54 409 g ##STR103## 216 73 55 418 h ##STR104## a)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 2-(N-(2-methoxyethyl)-N-methylamino)ethanol (64 mg),
(prepared as described for the starting material in Example 59), to
give
4-(indol-5-ylamino)-6-methoxy-7-(2-(N-(2-methoxyethyl)-N-methylamino)etho-
xy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35(s, 3H);
2.68(t, 2H); 2.82(t, 2H); 3.25(s, 3H); 3.5(t, 2H); 3.97(s, 3H);
4.22(t, 2H), 6.45(s, 1H); 7.18(s, 1H); 7.3-7.45(m, 3H); 7.88(m,
2H); 8.35(s, 1H); 9.42(s, 1H) b)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 1-(3-hydroxypropyl)pyrrolidin-2,5-dione (76 mg) to
give
7-(3-(2,5-dioxopyrrolidin-1-yl)propoxy)-4-(indol-5-ylamino)-6-methoxyquin-
azoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.05(m, 2H); 2.65(s,
3H); 3.6(t, 2H); 3.98(s, 2H); 4.15(t, 2H); 6.45(s, 1H); 7.1(s, 1H);
7.3-7.45(m, 3H); 8.7(s, 1H); 8.8(s, 1H); 8.35(s, 1H); 9.45(s, 1H)
The starting material was prepared as follows: A solution of
pyrrolidine-2,5-dione (5 g, 50.5 mmol) and 3-bromopropan-1-ol (6.85
ml, 76 mmol) in acetonitrile (80 ml) contaning potassium carbonate
(14 g, 100 mmol) was refluxed overnight. After cooling, the mixture
was filtered and the filtrate was evaporated. The residue was
dissolved in methylene chloride and purified by column
chromatography, eluting with ethylacetate/petroleum ether (4/1).
After evaporation of the volatiles, the residue was distilled at
100-125.degree. C. under about 0.1 mm Hg to give
1-(3-hydroxypropyl)pyrrolidin-2,5-dione (2.6 g, 34%). .sup.1H NMR
Spectrum: (CDCl.sub.3) 1.8(m, 2H); 2.52(t, 1H); 2.78(s, 4H);
3.58(q, 2H); 3.7 (t, 2H) c)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg),
(prepared as described for the starting material in Example 5), to
give
7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-ylamino)-6-methoxyquina-
zoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0(m, 2H); 2.7(t, 2H);
2.95(br s, 4H); 3.15(br s, 4H); 3.97(s, 3H); 4.2(t, 2H); 6.45(s,
1H); 7.2(s, 1H); 7.3-7.5(m, 3H); 7.9(2s, 2H); 8.35(s, 1H); 9.42(s,
1H) d) 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg)
was reacted with
3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (83 mg) to
give
4-(indol-5-ylamino)-6-methoxy-7-(3-((4-methyl-4H-1,2,4-triazol-3-yl)-
sulphanyl)propoxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
2.22(m, 2H); 3.3(m, 2H); 3.65(s, 3H); 3.95(s, 3H); 4.25(t, 2H);
6.45(s, 1H); 7.15(s, 1H); 7.3-7.45(m, 3H); 7.88(s, 1H); 8.0(s, 1H);
8.35(s, 1H); 8.58(s, 1H); 9.45(s, 1H) The starting material was
prepared as follows: A solution of
4-methyl-4-H-1,2,4-triazole-3-thiol (1.72 g, 15 mmol) and
3-bromopropan-1-ol (1.39g, 10 mmol) in DMF (10 ml) containing
potassium carbonate (1.57 g, 14 mmol) was heated at 40.degree. C.
for 30 minutes. The mixture was then partitioned between saturated
ammonium chloride and ethyl acetate. The aqueous layer was
evaporated to dryness and the residue was triturated with ethyl
acetate and methylene chloride. The suspension was filtered and the
filtrate was dried (MgSO.sub.4) and evaporated. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (9/1) to give
3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (510 mg,
30%). .sup.1H NMR Spectrum: (CDCl.sub.3) 2.02(m, 2H); 3.45(t, 2H);
3.55(s, 3H); 3.75(t, 2H); 8.15(s, 1H) e)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (76 mg),
(prepared as described for the starting material in Example 133),
to give
4-(indol-5-ylamino)-6-metoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazo-
line. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0(m, 2H); 2.2(s, 3H);
2.25-2.55(m, 10H); 4.0(s, 3H); 4.2(t, 2H); 6.45(s, 1H); 7.15(s,
1H); 7.35(m, 2H); 7.42(d, 1H); 7.88(br s, 2H); 8.38(s, 1H); 9.42(s,
1H) f) 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg)
was reacted with 2-methoxyethanol (37 mg) to give
4-(indol-5-ylamino)-6-methoxy-7-(2-methoxyethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 3.4(s, 3H); 3.75(t, 2H);
3.98(s, 3H); 4.38(t, 2H); 6.45(s, 1H); 7.18(s, 1H); 7.35(m, 2H);
7.42(d, 1H); 7.85(s, 1H); 7.9(s, 1H); 8.38(s, 1H); 9.5(s, 1H) g)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 2-(2-methoxyethoxy)ethanol (58 mg) to give
4-(indol-5-ylamino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 3.3(s, 3H); 3.5(t, 2H); 3.65(t,
2H); 3.85(t, 2H); 4.0(s, 3H); 4.28(t, 2H); 6.45(s, 1H); 7.18(s,
1H); 7.35(m, 2H); 7.45(d, 1H); 7.88(s, 1H); 7.9(s, 1H); 8.35(s,
1H); 9.45(s, 1H) h)
7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 1-(2-hydroxyethyl)piperidine (62 mg) to give
4-(indol-5-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.6(m, 6H); 2.5(br s, 4H);
2.7(t, 2H); 3.98(s, 3H); 4.25(t, 2H); 6.45(s, 1H); 7.18(s, 1H);
7.35(m, 2H); 7.42(d, 1H); 7.9(br s, 2H); 8.38(s, 1H); 9.42(s,
1H)
EXAMPLE 217-223
[1442] Using an analogous procedure to that described in Example
205, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline was used in
the synthesis of the compounds described in Table XIV.
[1443] The starting material was prepared as follows:
[1444] Using an analogous procedure to that described for the
preparation of the starting material in Example 201, 6-nitroindole
(500 mg, 3 mmol) was hydrogenated to give 6-aminoindole (395 mg,
quant.).
[1445] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.41 (s, 1H); 6.6 (dd,
1H); 6.63 (s, 1H); 7.0 (t, 1H); 7.4 (d, 1H); 7.87 (br s, 1H)
[1446] Using an analogous procedure to that described for the
preparation of the starting material in Example 201,
7-benzyloxy-4-chloro-6-methoxyquinazoline (2.5 g, 8.3 mmol),
(prepared as described for the starting material in Example 1), was
reacted with 6-aminoindole (1.5 g, 11.4 mmol) to give
7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride
(3.18 g, 89%).
[1447] MS-ESI: 397 [MH]+
[1448] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.02 (s, 3H); 5.35 (s,
2H); 6.5 (s, 1H); 7.25 (dd, 1H); 7.35-7.6 (m, 5H); 7.63 (d, 1H);
7.72 (s, 1H); 8.3 (s, 1H); 8.75 (s, 1H); 11.3 (br s, 1H)
[1449] Using an analogous procedure to that described for the
preparation of the starting material in Example 201,
7-benzyloxy-4-(indol-6-ylamino)-6-methoxyquinazoline hydrochloride
was treated with ammonium formate (655 mg, 10.4 mmol) to give
7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (162 mg,
76%).
[1450] MS-ESI: 307 [MH]+
[1451] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.0 (s, 3H); 6.4 (s,
1H); 7.0 (s, 1H); 7.3 (m, 2H); 7.5 (d, 1H); 7.85 (s, 1H); 8.0 (s,
1H); 8.35 (s, 1H); 9.35 (s, 1H); 11.05 (s, 1H) TABLE-US-00096 TABLE
XIV ##STR105## Ex- am- ple MS- num- Weight Yield ESI ber (mg) %
[MH].sup.+ Note R 217 46 35 416 a ##STR106## 218 57 37 482 b
##STR107## 219 37 25 462 c ##STR108## 220 38 29 418 d ##STR109##
221 10 7 418 e ##STR110## 222 94 61 483 f ##STR111## 223 56 44 398
g ##STR112## a) 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline
(98 mg) was reacted with 3-(1,2,3-triazol-1-yl)propan-I-ol (61 mg),
(prepared as described for the starting material in Example 208),
to give
4-(indol-6-ylamino)-6-methoxy-7-(3-(1,2,3-triazole-1-yl)propoxy)quinazoli-
ne. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.42(t, 2H); 4.02(s, 3H);
4.2(t, 2H); 4.62(t, 2H); 6.42(s, 1H); 7.15(s, 1H); 7.3(m, 2H);
7.55(d, 1H); 7.75(s, 1H); 7.92(s, 1H); 8.02(s, 1H); 8.2(s, 1H);
8.42(s, 1H); 9.45(s, 1H) b)
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 3-(1,1-dioxothiomorpholino)-1-propanol (93 mg),
(prepared as described for the starting material in Example 5), to
give
7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-6-ylamino)-6-methoxyquina-
zoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0(m, 2H); 2.7(t, 2H);
2.95(br s, 4H); 3.12(br s, 4H); 4.0(s, 3H); 4.2(t, 2H); 6.42(s,
1H); 7.2(s, 1H); 7.3(m, 2H); 7.55(d, 1H); 7.9(s, 1H); 8.02(s, 1H);
8.42(s, 1H); 9.48(s, 1H) c)
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)prop-1-ol
(83 mg), (prepared as described for the starting material in
Example 212), to give
4-(indol-6-ylamino)-6-methoxy-7-(3-((4-methyl-4H-1,2,4-triazol-3-yl)sulph-
anyl)propoxy)quinazoline .sup.1H NMR Spectrum: (DMSOd.sub.6)
2.22(t, 2H); 3.3(t, 2H); 3.6(s, 3H); 4.0(s, 3H); 4.28(t, 2H);
6.4(s, 1H); 7.18(s, 1H); 7.3(m, 2H); 7.53(d, 1H); 7.9(s, 1H)
8.02(s, 1H); 8.42(s, 1H); 8.58(s, 1H); 9.45(s, 1H) d)
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 1-(2-hydroxyethyl)piperidine (62 mg) to give
4-(indol-6-ylamino)-6-methoxy-7-(2-piperidinoethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.6(m, 6H); 2.5(br s, 4H);
2.75(t, 2H); 4.0(s, 3H); 4.25(t, 2H); 6.42(s, 1H); 7.2(s, 1H);
7.3(m, 2H); 7.55(d, 1H); 7.9(s, 1H); 8.02(s, 1H) 8.42(s, 1H);
9.45(s, 1H) e) 7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline
(98 mg) was reacted with 1-(3-hydroxypropyl)pyrrolidine (62 mg) to
give
4-(indol-6-ylamino)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline.
The starting material was prepared as follows: A solution of
pyrrolidine (50 g, 0.7 mol) and 3-chloropropan-1-ol (66.15 g, 0.7
mol) in acetonitrile (1 l) containing potassium carbonate (145 g,
1.05 mol) was refluxed for 20 hours. After cooling, the mixture was
filtered, the solid was washed with acetonitrile and the filtrate
was evaporated. The residue was distilled at about 130.degree. C.
under about 70 mm Hg to give 1-(3-hydroxypropyl)pyrrolidine (62.1
g, 69%). MS-ESI: 130 [MH]+ .sup.1HNMR Spectrum: (CDCl.sub.3)
1.6-1.8(m, 6H); 2.55(brs, 4H); 2.75(t, 2H); 3.85(t, 2H);
5.2-5.8(brs, 1H) f)
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with
3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93 mg)
to give
7-(3-((N-2,6-dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-4-(indol-6--
ylamino)-6-methoxyquinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6)
2.08(m, 2H); 2.22(s, 6H); 2.95(s, 3H); 3.6(t, 2H); 4.05(s, 3H);
4.15(t, 2H); 6.35(s, 2H); 6.42(s, 1H); 7.15(s, 1H); 7.3(m, 2H);
7.55(d, 1H); 7.92(s, 1H); 8.02(s, 1H); 8.4(s, 1H); 9.45(s, 1H) The
starting material was prepared as follows: A solution of
4-chloro-2,6-dimethylpyridine (2.12 g, 15 mmol) and
3-(N-methylamino)-propan-1-ol (4g, 45 mmol) containing 2N hydrogen
chloride in ether (10 drops) was heated at 140.degree. C. for 1
hour. The mixture was diluted with water (10 ml) and poured onto a
suspension of MgSO.sub.4(125 g) in ethyl acetate (200 ml). The
mixture ws filtered. The filtrate was evaporated and the residue
was triturated with ether. The solid was filtered and dried under
vacuum to give 3-((N-(2,6-dimethyl
-4-pyridyl)-N-methyl)amino)propan-1-ol (1.76 g, 61%). MS-EI: 194
[M.]+ .sup.1H NMR Spectrum: (CDCl.sub.3) 1.75-1.95(m, 2H); 2.4(s,
6H); 3.0(s, 3H); 3.48(t, 2H); 3.7(t, 2H); 6.25(s, 2H) g)
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 3-hydroxymethyl pyridine (53 mg) to give
4-(indol-6-ylamino)-methoxy-7-((3-pyridyl)methoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 4.02(s, 3H); 5.35(s, 2H);
6.42(s, 1H); 7.22-7.4(m, 3H); 7.5(m, 1H); 7.55(d, 1H); 7.95(s, 1H);
7.97(d, 1H); 8.0(s, 1H); 8.42(s, 1H); 8.6(d, 1H) 8.78(s, 1H);
9.5(s, 1H)
EXAMPLE 224
[1452] Using an analogous procedure to that described in Example
208, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg,
0.32 mmol), (prepared as described for the starting material in
Example 201), was reacted with (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol
(68 mg, 0.48 mmol), (prepared as described for the starting
material in Example 129). After evaporation of the fractions
containing the expected product, the residue was triturated with
isopropanol (1 ml) containing 6.2 N hydrogen chloride in
isopropanol (100 .mu.l). After stirring at ambient temperature for
10 minutes, ether (500 .mu.l) was added. The precipitate was
filtered and washed several times with ether to give
4-(indol-5-ylamino)-6-methoxy-7-((E)4-(pyrrolidin-1-yl)but-2-en-1-yloxy)q-
uinazoline hydrochloride (14 mg, 10%).
[1453] MS-ESI: 430 [MH].sup.+
[1454] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.85-2.7 (br s, 4H);
2.95-3.1 (br s, 2H); 3.0 (m, 2H); 3.0 (m, 2H); 3.4-3.5 (m, 2H); 3.8
(d, 2H); 4.0 (s, 3H); 4.8 (d, 2H); 6.0-6.3 (m, 2H); 6.5 (s, 1H);
7.2-7.53 (m, 4H); 7.75 (s, 1H); 8.25 (s, 1H); 8.8 (br s, 1H)
EXAMPLE 225
[1455] 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline,
(prepared as described for the starting material in Example 201),
was treated as follows. After purification by chromatography and
evaporation of the solvent, the residue was triturated in a
solution of isopropanol (1 ml) containing 6.2 N hydrogen chloride
in isopropanol (100 .mu.l). After stirring for 10 minutes at
ambient temperature, ether (500 .mu.l) was added. The solid was
filtered and dried under vacuum to give
7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline
hydrochloride.
[1456] Using an analogous procedure to that described in Example
224, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline
hydrochloride was used in the synthesis of the compounds described
in Table XV. TABLE-US-00097 TABLE XV ##STR113## Example MS-ESI
Number Weight (mg) Yield % [MH].sup.+ Note R 225 77 50 483 a
##STR114## a 7-Hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline
hydrochloride (98 mg) was reacted with
3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93mg),
(prepared as described for the starting material in Example 222),
to give
7-(3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-4-(indol-5-ylam-
ino)-6-methoxyquinoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.2
(m, 2H); 2.5 (2brs, 6H); 3.2 (s, 3H); 3.8 (t, 2H); 4.1 (s, 3H);
4.25 (t, 2H); 6.52 (s, 1H); 6.75 (br s, 1H); 6.9 (br s, 1H); 7.35
(dd, 1H) ; 7.45 (br s, 2H); 7.5 (d, 1H); 7.8 (s, 1H); 8.4 (s, 1H);
8.75 (s, 1H)
EXAMPLE 226
[1457] Using an analogous procedure to that described in Example
224, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline, (prepared
as described for the starting material in Example 217), (98 mg,
0.32 mmol) was reacted with 4-(3-hydroxypropyl)morpholine (70 mg,
0.48 mmol), (prepared as described for the starting material in
Example 60), to give
4-(indol-6-ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
hydrochloride (26 mg, 19%). MS-ESI: 434 [MH].sup.+
[1458] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.35 (m,
2H); 3.15 (m, 2H); 3.3 (t, 2H); 3.52 (d, 2H); 3.8 (t, 2H); 4.0 (d,
2H); 4.1 (s, 3H); 4.3 (t, 2H); 6.5 (s, 0.5 H, partly exchanged);
7.3 (d, 1H); 7.4 (s, 1H); 7.45 (s, 1H); 7.65 (d, 1H); 7.75 (s, 1H);
8.3 (s, 1H); 8.75 (s, 1H)
EXAMPLES 227-229
[1459] Using an analogous procedure to that described in Example
226, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline, (prepared
as described for the starting material in Example 217), was used in
the synthesis of the compounds described in Table XVI.
TABLE-US-00098 TABLE XVI ##STR115## Ex- am- ple num- Weight Yield
MS-ESI ber (mg) % [MH].sup.+ Note R 227 24 17 441 a ##STR116## 228
14 10 430 b ##STR117## 229 15 10 447 c ##STR118## a
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg) was
reacted with 2-((N-methyl-N-(4-pyridyl))amino)ethanol (73 mg), (EP
0359389A1), to give
4-(indol-6-ylamino)-6-methoxy-7-(2-((N-methyl-N-(4-pyridyl))amino)et-
hoxy)quinazoline hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6)
3.3 (s, 3H); 4.0 (s, 3H); 4.18 (t, 2H); 4.45 (t, 2H); 6.5 (s, 1H);
7.35 (d, 1H); 7.35-7.5 (m, 4H); 7.62 (d, 1H); 7.75 (s, 1H); 8.3 (d,
2H); 8.4 (s, 1H); 8.75 (s, 1H) b
7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinoline (98 mg) was
reacted with (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (68 mg, 0.48
mmol), (prepared as described for the starting material in Example
129) to give
4-(indol-6-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)-
quinazoline hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6)
1.8-2.1 (m, 4H); 2.9-3.1 (m, 2H); 3.4-3.5 (br s, 2H); 3.87 (d, 2H);
4.05 (s, 3H); 4.9 (d, 2H); 6.1 (m, 1H); 6.3 (m, 1H); 6.5 (s, 1H);
7.25 (d, 1H); 7.45 (m, 2H); 7.65 (d, 1H); 7.75 (s, 1H); 8.3 (s,
1H); 8.8 (s, 1H) c 7-Hydroxy-4-(indol-6-ylamino)-6-methoxyquinoline
(98 mg) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (76
mg), (prepared as described for the starting material in Example
133), to give
4-(indol-6-ylamino)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinaz-
oline hydrochloride.
EXAMPLE 230
[1460] Using an analogous procedure to that described in Example
224, 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline
(102 mg, 0.32 mmol), (prepared as described for the starting
material in Example 205), was reacted with
1-(3-hydroxypropyl)-2-methylimidazole (67 mg, 0.48 mmol), (EP
0060696 A1), to give
6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)-4-(2-methylindol-5-ylamino-
)quinazoline (53 mg, 37%).
[1461] MS-ESI: 443 [MH].sup.+
[1462] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.42 (s, 3H); 2.62 (s,
3H); 4.03 (s, 3H); 4.3 (t, 2H); 4.35 (t, 2H); 6.2 (s, 1H); 7.22 (d,
1H); 7.35 (d, 1H); 7.45 (s, 1H); 7.6 (dd, 1H); 7.65 (dd, 1H); 7.7
(s, 1H); 8.35 (s, 1H); 8.75 (s, 1H)
EXAMPLES 231-235
[1463] Using an analogous procedure to that described in Example
224 7-hydroxy-6- methoxy-4-(2-methylindol-5-ylamino)quinazoline
(102 mg, 0.32 mmol), (prepared as described for the starting
material in Example 205), was used in the synthesis of the
compounds described in Table XVII. TABLE-US-00099 TABLE XVII
##STR119## Example MS-ESI number Weight (mg) Yield % [MH].sup.+
Note R 231 49 31 497 a ##STR120## 232 25 18 444 b ##STR121## 233 23
15 476 c ##STR122## 234 33 22 461 d ##STR123## 235 26 19 423 e
##STR124## a
7-Hydroxy-6-methoxy-4-(2-methylmdol-5-ylamino)quinazoline (102 mg)
was reacted with
3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propan-1-ol (93 mg),
(prepared as described for the startmg material m Example 222), to
give
7-(3-((N-(2,6-dimethyl-4-pyridyl)-N-methyl)amino)propoxy)-6-metho-
xy-4-(2-methylmdol-5-ylamino)qumazolme. .sup.1H NMR Spectrum:
(DMSOd.sub.6) 2.2 (m, 2H); 2.4 (s, 6H); 2.45 (s, 3H); 3.15 (s, 3H);
3.75 (t, 2H); 4.02 (s, 3H); 4.25 (t, 2H); 6.2 (s, 1H); 6.72 (br s,
1H); 6.85 (br s, 1H); 7.2 (dd, 1H); 7.3-7.4 (m, 2H); 7.62 (s, 1H);
8.3 (s, 1H); 8.7 (s, 1H) b
7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg)
was reacted with (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (68 mg, 0.48
mmol), (prepared as described for the starting material in Example
129) to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-((E-4-(pyrrolidin-1-yl)but-2-en-1-
-yloxy)quinazoline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.8-2.1 (m,
4H); 2.4 (s, 3H); 2.9-3.1 (m, 2H); 3.4-3.6 (m, 2H); 3.9 (d, 2H);
4.05 (s, 3H); 4.9 (d, 2H); 6.1 (m, 1H); 6.2 (s, 1H); 6.3 (d, t,
1H); 7.2 (m, 1H); 7.37 (d, 1H); 7.4 (s, 1H); 7.32 (s, 1H); 8.3 (s,
1H); 8.75 (s, 1H) c)
7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg)
was reacted with
3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (83 mg),
(prepared as described for the starting material m Example 212), to
give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-((4-methyl-4h-1,2,4-tr-
iazol-3-yl)sulphanyl)propoxy)quinazoline. .sup.1H NMR Spectrum:
(DMSOd6) 2.25 (m, 2H); 2.45 (s, 3H); 3.35 (t, 2H); 3.65 (s, 3H);
4.05 (s, 3H); 4.35 (t, 2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.35 (s, 1H);
7.37 (d, 1H); 7.62 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H); 8.9 (s, 1H)
d 7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102
mg) was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (76
mg), (prepared as described for the starting material in Example
133), to give
6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-(4-methylpiperazin-1-yl)propox-
y)quinazoline. e
7-Hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg)
was reacted with 2-(2-methoxyethoxy)ethanol to give
6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(2-methylindol-5-ylamino)quinaz-
oline. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.45 (s, 3H); 3.28 (s,
3H); 3.5 (t, 2H), 3.65 (t, 2H); 3.9 (t, 2H); 4.02 (s, 3H); 4.33 (t,
2H); 6.2 (s, 1H); 7.2 (d, 1H); 7.4 (m, 2H); 7.63 (s, 1H); 8.28 (s,
1H); 8.73 (s, 1H)
EXAMPLE 236
[1464] A solution of
4-chloro-6-methoxy-7-((1-cyanomethylpiperidin-4-yl)methoxy)quinazoline
(200 mg, 0.58 mmol) and 5-hydroxyindole (85 mg, 0.63 mmol) in DMF
(3 ml) containing cesium carbonate (282 mg, 0.86 mmol) was stirred
at 90.degree. C. for 90 minutes. After cooling, the mixture was
poured onto water (25 ml). The precipitate was filtered, dried
under vacuum and purified by reverse phase column chromatography on
silica (kromasil.RTM. C18) eluting with methanol/water (1% acetic
acid) (1/1). The fractions containing the expected product were
combined and evaporated to give
7-((1-cyanomethyl)piperidin-4-ylmethoxy)-4-(indol-5-yloxy)-6-methoxyquina-
zoline (44 mg, 17%).
[1465] MS-ESI: 444 [MH].sup.+
[1466] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.7 (m,
2H); 2.15 (d, 2H); 2.2-2.35 (m, 1H); 3.20 (t, 2H); 3.65 (d, 2H);
4.1 (s, 3H); 4.25 (d, 2H); 4.62 (s, 2H); 6.5 (s, 0.5 H, partly
exchanged); 7.1 (dd, 1H); 7.5 (s, 1H); 7.5-7.6 (m, 3H); 7.85 (s,
1H); 9.1 (s, 1H)
[1467] The starting material was prepared as follows:
[1468] To a suspension of
6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroqu-
inazolin-4-one hydrochloride (34 g, 84 mmol), (prepared as
described for the starting material in Example 12), in water cooled
at 0.degree. C. was added 1N sodium hydroxide until the mixture was
at pH8. The solution was extracted with trichloromethane and the
organic layer was dried (MgSO.sub.4), filtered and evaporated to
give
6-methoxy-7-piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroqui-
nazolin-4-one (29 g).
[1469] To a solution of
6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroqu-
inazolin-4-one (28.9 g, 72 mmol) and aqueous formaldehyde 12 M
(11.95 ml, 141 mmol) in methanol/THF (1/1) (580 ml) was added
sodium cyanoborohydride (5.7 g, 86 mmol) in portions. After
stirring for 90 minutes at ambient temperature, the volatiles were
removed under vacuum and the residue was partitioned between
methylene chloride and water. The organic layer was separated,
dried (MgSO.sub.4) and evaporated. The residue was dissolved in
methanol saturated with ammonia (500 ml). The mixture was stirred
for 36 hours at ambient temperature. The volatiles were removed
under vacuum. The residue was triturated with a mixture
ether/methylene chloride, filtered, washed with ether and dried
under vacuum. The solid was dissolved in thionyl chloride (180 ml)
and DMF (1.8 ml) was added. After stirring at 80.degree. C. for 75
minutes the volatiles were removed under vacuum. The residue was
azeotroped with toluene twice and the solid was partitioned between
methylene chloride and water and the pH of the aqueous layer was
adjusted to 9 with 2N sodium hydroxide. The organic layer was dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography on aluminium oxide eluting with methylene chloride,
followed by methylene chloride/ethyl acetate (70/30 followed by
50/50) followed by ethyl acetate and ethyl acetate/methanol (80/20)
to give
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(11.2 g) (identical to the starting material prepared in Example
10) and
4-chloro-6-methoxy-7-((1-(cyanomethyl)piperidin-4-yl)methoxy)quinazoline
(2.55 g).
[1470] MS-ESI: 347 [MH].sup.+
[1471] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.42 (m, 2H); 1.85 (d,
2H); 1.8-1.9 (m, 1H); 2.2 (t, 2H); 2.85 (d, 2H); 3.75 (s, 2H); 4.05
(s, 3H); 4.15 (d, 2H); 7.42 (s, 1H); 7.5 (s, 1H); 8.9 (s, 1H)
EXAMPLE 237
[1472] ##STR125##
[1473] A solution of
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(2 gr, 6.22 mmol), (prepared as described for the starting material
in Example 10), and 4-fluoro-5-hydroxy-2-methylindole (1.23 g, 7.46
mmol) in DMF (30 ml) containing potassium carbonate ( 1.28 g, 9.33
mmol) was stirred at 95.degree. C. for 2 hours. After cooling, the
volatiles were removed under vacuum and the residue was triturated
with ether, filtered and dried under vacuum. The residue was
purified by column chromatography eluting with methanol/methylene
chloride (1/9) followed by methanol/methanol saturated with
ammonia/methylene chloride (20/1/79 followed by 20/5/75). The
fractions containing the expected product were combined and
evaporated. The solid was triturated with methanol, filtered and
dried under vacuum to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)m-
ethoxy)quinazoline (1.95 g, 69%).
[1474] MS-ESI: 451 [MH].sup.+
[1475] .sup.1H NMR Spectrum (DMSOd.sub.6) 1.4 (m, 2H); 1.8 (d, 2H);
1.7-1.9 (m, 1H); 1.9 (t, 2H); 2.2 (s, 3H); 2.45 (s, 3H); 2.8 (d,
2H); 4.02 (s, 3H); 4.1 (d, 2H); 6.25 (s, 1H); 7.2 (d, 1H); 7.4 (s,
1H); 7.62 (s, 1H); 8.5 (s, 1H) TABLE-US-00100 Elemental analysis:
Found C 64.2 H 6.5 N 11.7
C.sub.25H.sub.27FN.sub.4O.sub.30.91methanol Requires C 63.9 H 6.4 N
11.5% 0.08CH.sub.2Cl.sub.20.1H.sub.2O
[1476] The starting material was prepared as follows:
[1477] To a solution of 2-fluoro-4-nitroanisole (9.9 g, 58 mmol)
and 4-chlorophenoxyacetonitrile (10.7 g, 64 mmol) in DMF (50 ml)
cooled at -15.degree. C. was added potassium tert-butoxide (14.3 g,
127 mmol) in DMF (124 ml). After stirring for 30 minutes at
-15.degree. C., the mixture was poured onto cooled 1N hydrochloric
acid. The mixture was extracted with ethyl acetate. The organic
layer was washed with 1N sodium hydroxide, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with methylene chloride. The fractions
containing the expected product were combined and evaporated. The
residue was dissolved in ethanol (180 ml) and acetic acid (24 ml)
containing 10% palladium on charcoal (600 mg) and the mixture was
hydrogenated under 3 atmospheres pressure for 2 hours. The mixture
was filtered, and the volatiles were removed under vacuum. The
residue was partitioned between ethyl acetate and water. The
organic layer was separated, and washed with saturated sodium
hydrogen carbonate followed by brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by column chromatography
eluting with methylene chloride to give a mixture of
4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole (5.64 g, 59%)
in a ratio 1/2.
[1478] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.85 (s, 3H); 6.38 (s,
1H, 6-Fluoro); 6.45 (s, 1H; 4-Fluoro); 6.9-7.4 (m, 3H)
[1479] A solution of 4-fluoro-5-methoxyindole and
6-fluoro-5-methoxyindole in a ratio 1/2 (496 mg, 3 mmol),
di-tertbutyl dicarbonate (720 mg, 3.3 mmol) in acetonitrile (12 ml)
containing DMAP (18 mg, 0.15 mmol) was stirred at ambient
temperature for 24 hours. The volatiles were removed under vacuum.
The residue was dissolved in ethyl acetate, washed with 1N
hydrochloric acid, followed by water, brine, dried (MgSO.sub.4) and
evaporated to give a mixture of
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2 (702
mg, 88%).
[1480] .sup.1H NMR Spectrum: (DMSO.sub.6) 1.65 (s, 9H); 3.9 (s,
3H); 6.6 (d, 1H, 6-fluoro); 6.72 (d, 1H, 4-fluoro); 7.2 (t, 1H,
6-fluoro); 7.4 (d, 1H, 4-fluoro); 7.62 (d, 1H, 6-fluoro); 7.68 (d,
1H, 4-fluoro); 7.78 (s, 1H, 4-fluoro); 7.85 (s, 1H, 6-fluoro)
[1481] To a solution of
4-fluoro-5-methoxy-1-tert-butoxycarbonylindole and
6-fluoro-5-methoxy-1-tert-butoxycarbonylindole in a ratio 1/2 (8.1
g, 30.5 mmol) in THF (100 ml) cooled at -65.degree. C. was added
tert-butyllithium (1.7 M) (23 ml, 35.7 mmol). After stirring for 4
hours at -70.degree. C., methyl iodide (8.66 g, 61 mmol) was added
and the mixture was left to warm-up to ambient temperature. Water
was added and the mixture was extracted with ether. The organic
layer was washed with water, brine, dried (MgSO.sub.4) and
evaporated and was used directly in the next step.
[1482] The crude product was dissolved in methylene chloride (100
ml) and TFA (25 ml) was added. After stirring for 1 hour at ambient
temperature, the volatiles were removed under vacuum. The residue
was dissolved in ethyl acetate and the organic layer was washed
with 1N sodium hydroxide, followed by water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography, eluting with ethyl acetate/petroleum ether (3/7) to
give 6-fluoro-5-methoxy-2-methylindole (1.6 g) and
4-fluoro-5-methoxy-2-methylindole (0.8 g, 48%).
[1483] 6-fluoro-5-methoxy-2-methylindole:
[1484] MS-ESI: 180 [MH].sup.+
[1485] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H); 3.8 (s,
3H); 6.05 (s, 1H); 7.1 (s, 1H); 7.12 (s, 1H); 10.8 (s, 1H)
[1486] 4-fluoro-5-methoxy-2-methylindole:
[1487] MS-ESI: 180 [MH].sup.+
[1488] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H); 3.8 (s,
3H); 6.15 (s, 1H); 6.9 (t, 1H); 7.05 (d, 1H); 11.0 (s, 1H)
[1489] To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg,
3.95 mmol) in methylene chloride (9 ml) cooled at -30.degree. C.
was added a solution of boron tribromide (2.18 g, 8.7 mmol) in
methylene chloride (1 ml). After stirring for 1 hour at ambient
temperature, the mixture was poured onto water and was diluted with
methylene chloride. The pH of the aqueous layer was adjusted to 6.
The organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography, eluting with ethyl acetate/petroleum ether (3/7) to
give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70%).
[1490] MS-ESI: 166 [MH].sup.+
[1491] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H); 6.05 (s,
1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s, 1H); 10.9 (s, 1H)
[1492] .sup.13C NMR Spectrum: (DMSOd.sub.6) 13.5; 94,0; 106,0; 112;
118.5 (d); 132 (d); 136 (d); 136.5; 142.5 (d)
[1493] Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be
prepared as follows:
[1494] To a suspension of sodium hydride (5.42 g, 226 mmol)
(prewashed with pentane) in THF (100 ml) cooled at 10.degree. C.
was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the
temperature below 15.degree. C. After completion of addition, the
mixture was further stirred for 15 minutes and cooled to 5.degree.
C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g, 113 mmol) in
THF (150 ml) was added while keeping the temperature below
5.degree. C. The mixture was then left to warm up to ambient
temperature and stirred for 24 hours. The volatiles were removed
under vacuum and the residue was partitioned between ethyl acetate
and 2N aqueous hydrochloric acid. The organic layer was washed with
water, brine, dried (MgSO.sub.4) and evaporated. The residue was
dissolved in concentrated hydrochloric acid (650 ml) and acetic
acid (600 ml) and the mixture was refluxed for 15 hours. After
cooling, the volatiles were removed under vacuum and the residue
was partitioned between aqueous sodium hydrogen carbonate (5%) and
ethyl acetate. The organic layer was washed with sodium hydrogen
carbonate, water, brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by column chromatography eluting with
ethylacetate/petroleum ether (75/25) to give
3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).
[1495] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.4 (s, 3H); 4.25 (s,
2H); 7.25 (dd, 1H); 8.0 (dd, 1H)
[1496] A solution of 3-acetylmethyl-1,2-difluoro-4-nitrobenzene
(500 mg, 2.3 mmol) in methylene chloride (5 ml) containing
montmorillonite K10 (1 g) and trimethyl orthoformate (5 ml) was
stirred for 24 hours at ambient temperature. The solid was
filtered, washed with methylene chloride and the filtrate was
evaporated to give
1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg,
88%).
[1497] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2 (s, 3H); 3.2 (s, 6H);
3.52 (s, 2H); 7.18 (dd, 1H); 7.6 (m, 1H)
[1498] To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA
(1.5 ml) was added 60% sodium hydride (82 mg, 2.05 mmol). The
mixture was stirred for 1 hour at ambient temperature. A solution
of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (534 mg,
2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred
for 3 hours at ambient temperature. The mixture was diluted with 1N
hydrochloric acid (10 ml) and extracted with ethyl acetate. The
organic layer was evaporated and the residue was dissolved in THF
(2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was
stirred for 1 hour at ambient temperature and the solvents were
removed under vacuum. The residue was partitioned between ethyl
acetate and water. The organic layer was separated, washed with
brine, dried (MgSO.sub.4) and evaporated. The solid was triturated
with ether, filtered, washed with ether and dried under vacuum to
give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56
%.
[1499] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.35 (s, 3H); 4.25 (s,
2H); 5.25 (s, 2H); 7.0 (dd, 1H); 7.32-7.5 (m, 5H); 8.0 (dd, 1H)
[1500] A solution of
3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99
mmol) in ethanol (10 ml) and acetic acid (1 ml) containing I0%
palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres
pressure for 2 hours. The mixture was filtered and the filtrate was
evaporated. The residue was dissolved in ethyl acetate and the
organic layer was washed with aqueous sodium hydrogen carbonate,
brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole. The
residue was purified by column chromatography eluting with ethyl
acetate/petroleum ether (3/7) to give
4-fluoro-5-hydroxy-2-methylindole (63 mg, 30%). Analytical data as
above.
[1501] Alternatively the 4-fluoro-5-methoxy-2-methylindole can be
prepared as follows:
[1502] A solution of sodium methoxide (freshly prepared from sodium
(1.71 g) and methanol (35 ml)) was added to a solution of
1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62
mmol), (prepared as described above), in methanol (200 ml) cooled
at 5.degree. C. The mixture was left to warm to ambient temperature
and was stirred for 3 days. The volatiles were removed under vacuum
and the residue was partitioned between ethyl acetate and 2N
hydrochloric acid (1 ml). The organic layer was concentrated to a
total volume of 100 ml and THF (100 ml) and 6N hydrochloric acid
(25 ml) were added. The mixture was stirred for 1 hour at ambient
temperature. The volatiles were removed under vacuum and the
residue was partitioned between ethyl acetate and water. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with ethyl acetate/petroleum ether (3/7) to
give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g,
90%).
[1503] MS-ESI: 250 [MNa]+
[1504] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.38 (s, 3H); 4.0 (s,
3H); 4.25 (s, 2H); 7.0 (dd, 1H); 8.05 (d, 1H)
[1505] To a solution of
3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (11.36 g, 50 mmol)
in acetone (200 ml) was added 4M aqueous ammonium acetate (700 ml)
followed by a solution of titanium trichloride (15% in water, 340
ml) dropwise. The mixture was stirred for 10 minutes at ambient
temperature and the mixture was extracted with ether. The organic
layer was washed with 0.5N aqueous sodium hydroxide followed by
water, brine, dried (MgSO.sub.4) and the volatiles were removed
under vacuum. The residue was purified by column chromatography
eluting with methylene chloride to give
4-fluoro-5-methoxy-2-methylindole (8.15 g,90%).
[1506] .sup.1H NMR Spectrnm: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1
(s, 1H); 6.85 (dd, 1H); 7.02 (d, 1H)
[1507] Cleavage of 4-fluoro-5-methoxy-2-methylindole with boron
tribromide to give 4-fluoro-5-hydroxy-2-methylindole is described
above.
EXAMPLE 238
[1508] ##STR126##
[1509] Using an analogous procedure to that described in Example
237, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.65 g,
4.89 mmol), (prepared as described for the starting material in
Example 67), was reacted with 4-fluoro-5-hydroxy-2-methylindole
(970 mg, 5.88 mmol), (prepared as described for the starting
material in Example 237), to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperdinopropoxy)quinaz-
oline ( 1.9 g, 83%).
[1510] MS-ESI: 465 [MH].sup.+
[1511] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.4 (br s, 2H); 1.5 (m,
4H); 1.95 (m, 2H); 2.25-2.5 (m, 6H); 2.45 (s, 3H); 4.0 (s, 3H);
4.25 (t, 2H); 6.25 (s, 1H); 7.0 (dd, 1H); 7.15 (d, 1H); 7.4 (s,
1H); 7.6 (s, 1H); 8.5 (s, 1H)
EXAMPLE 239
[1512] ##STR127##
[1513] Using an analogous procedure to that described in Example
237,
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(106 mg, 0.30 mmol), (prepared as described for the starting
material in Example 176), was reacted with
4-fluoro-5-hydroxy-2-methylindole (60 mg, 0.36 mmol), (prepared as
described for the starting material in Example 237), to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1yl)-
propoxy)quinazoline (100 mg, 70%).
[1514] MS-ESI: 480 [MH].sup.+
[1515] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0 (t, 2H); 2.15 (s,
3H); 2.45 (s, 3H); 2.2-2.6 (m, 10H); 4.02 (s, 3H); 4.25 (t, 2H);
6.25 (s, 1H); 7.0 (dd, 1H); 7.18 (d, 1H); 7.4 (s, 1H); 7.62 (s,
1H); 8.5 (s, 1H)
EXAMPLE 240
[1516] ##STR128##
[1517] Using a procedure identical to that described in Example
237, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (
2 g, 6.22 mmol), (prepared as described for the starting material
in Example 9), was reacted with 4-fluoro-5-hydroxy-2-methylindole
(1.23 g, 7.46 mmol), (prepared as described for the starting
material in Example 237), to give
4-(4-fluoro-2-methylindol-5-yloxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy-
)quinazoline (1.41 g, 50%).
[1518] MS-ESI: 451 [MH]+
[1519] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7 (br s, 4H); 2.0 (m,
2H); 2.41 (s, 3H); 2.5 (br s, 4H); 2.6 (t, 2H); 4.0 (s, 3H); 4.25
(t, 2H); 6.25 (s, 1H); 7.0 (dd, 1H); 7.2 (d, 1H); 7.4 (s, 1H); 7.6
(s, 1H); 8.5 (s, 1H) TABLE-US-00101 Elemental analysis: Found C
63.3 H 6.4 N 11.9 C.sub.25H.sub.27FN.sub.4O.sub.31.08H.sub.2O;
Requires C 63.6 H 6.3 N 11.8% 0.16 methanol
EXAMPLE 241
[1520] A solution of
4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline
(300 mg, 0.9 mmol) and 4-fluoro-5-hydroxyindole (162 mg, 1 mmol),
(prepared as described for the starting material in Example 242),
in DMF (4.5 ml) containing potassium carbonate (185 mg, 1.3 mmol)
was stirred at 90.degree. C. for 1 hour. After cooling, the mixture
was filtered and the solid was washed with DMF. The filtrate was
evaporated and the residue was purified by column chromatography,
eluting with methylene chloride followed by methanol/methylene
chloride (1/99) followed by methanol saturated with
ammonia/methylene chloride (2/98). The fractions containing the
expected product were combined and evaporated. The solid was
triturated with ether, filtered, washed with ether and dried under
vacuum to give
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)q-
uinazoline (282 mg, 69%).
[1521] MS-ESI: 451 [MH]+
[1522] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.2-1.3 (m, 2H);
1.4-1.55 (m, 1H); 1.7-1.9 (m, 6H); 2.15 (s, 3H); 2.75 (d, 2H); 4.0
(s, 3H); 4.3 (t, 2H); 6.55 (s, 1H); 7.1 (dd, 1H); 7.3 (d, 1H); 7.4
(s, 1H); 7.5 (s, 1H); 7.6(s, 1H); 8.5 (s, 1H); 11.5 (s, 1H)
[1523] The starting material was prepared as follows:
[1524] To a solution of
4-(2-hydroxyethyl)-(1-tert-butoxycarbonyl)piperidine (12.9 g, 56
mmol), (prepared as described for the starting material in Example
126), in tert-butyl methyl ether (120 ml) containing
1,4-diazabicyclo[2.2.2]octane (9.8 g, 87 mmol) cooled at -5.degree.
C. was added a solution of tosyl chloride (14.5 gr, 76 mmol) in
tert-butyl methyl ether (120 ml) dropwise whilst keeping the
temperature below 0.degree. C. After completion of addition, the
mixture was left to warm up to ambient temperature and stirred for
1 hour. The mixture was poured onto petroleum ether (240 ml). The
precipitae was filtered and washed with petroleum ether. The
filtrate was evaporated and the residue was dissolved in ether. The
ether layer was washed with 0.5 N hydrochloric acid, followed by
saturated sodium hydrogen carbonate, dried (MgSO.sub.4) and
evaporated to give
4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine
(20.9 g, 97%).
[1525] .sup.1H NMR Spectrum: (CDCl.sub.3) 0.95-1.05 (m, 4H); 1.45
(s, 9H); 1.4-1.6 (m, 3H)2.45 (s, 3H); 2.62 (t, 2H); 3.9-4.1 (m,
2H); 4.1 (t, 2H); 7.35 (d, 2H); 7.8 (d, 2H)
[1526] A suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(7 g, 23 mmol), (prepared as described for the starting material in
Example 12),
4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine
(11.4 g, 30 mmol) in DMF (70 ml) containing potassium carbonate
(6.32 g, 46 mmol) was stirred at 100.degree. C. for 3 hours. After
cooling, the volatiles were removed under vacuum and the residue
was partitioned between ether and water. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated. The solid was triturated with pentane, filtered and
dried under vacuum to give
7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloylox-
y)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 88%).
[1527] MS-ESI: 540 [MNa].sup.+
[1528] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2 (s, 9H); 1.15-1.25
(m, 2H); 1.48 (s, 9H); 1.65-1.75 (m, 1H); 1.7 (d, 2H); 1.9 (dd,
2H); 2.72 (t, 2H); 4.0 (s, 3H); 4.0-4.2 (m, 2H); 4.2 (t, 2H); 5.95
(s, 2H); 7.1 (s, 1H); 7.65 (s, 1H); 8.2 (s, 1H)
[1529] A solution of
7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloylox-
y)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 20 mmol) in
methylene chloride (100 ml) containing TFA (25 ml) was stirred for
1 hour at ambient temperature. Water (50 ml) and methylene chloride
(100 ml) were added and the pH of the aqueous layer was adjusted to
8 with solid sodium hydrogen carbonate. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was triturated with ether and the solid was
filtered and dried under vacuum to give
7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydr-
oquinazolin-4-one (8.3 g, 100%).
[1530] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.2 (s, 9H); 1.65 (m,
2H); 1.9 (br s, 2H); 1.8-1.9 (m, 1H); 2.0 (d, 2H); 2.9 (t, 2H);
3.45 (d, 2H); 4.0 (s, 3H); 4.2 (t, 2H); 5.95 (s, 2H); 7.1 (s, 1H);
7.65 (s, 1H); 8.2 (s, 1H)
[1531] To a solution of
7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydr-
oquinazolin-4-one (6 g, 14.4 mmol) in methanol (30 ml) and
methylene chloride (60 ml) was added 37% aqueous formaldehyde (2.2
ml; 28.9 mmol) followed by acetic acid (990 .mu.l; 17.3 mmol).
Sodium borohydride triacetate (4.6 g, 21.6 mmol) was added in
portions. After stirring for 1 hour at ambient temperature, the
volatiles were removed under vacuum and the residue was partitioned
between water (50 ml) and methylene chloride (50 ml). The pH of the
aqueous layer was adjusted to 7, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The solid was triturated with ether,
filtered, washed with ether and dried under vacuum to give
7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,-
4-dihydroquinazolin-4-one (4.2 g, 68%).
[1532] MS-ESI: 432 [MH].sup.+
[1533] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.22 (s, 9H); 1.68 (br s,
3H); 1.9 (m, 4H); 2.32 (br s, 2H); 2.52 (s, 3H); 3.18 (d, 2H); 4.0
(s, 3H); 4.2 (t, 2H); 5.95 (s, 2H); 7.1 (s, 1H); 7.65 (s, 1H); 8.2
(s, 2H)
[1534] A solution of
7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,-
4-dihydroquinazolin-4-one (4.2 g, 9.7 mmol) in methanol saturated
with ammonia (150 ml) was stirred overnight at ambient temperature.
The volatiles were removed under vacuum and the residue was
triturated with ether. The solid was filtered, washed with ether
and dried under vacuum to give
7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazo-
lin-4-one (3.12 g, 100%).
[1535] MS-ESI: 318 [MH].sup.+
[1536] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3 (m, 2H); 1.58 (br s,
1H); 1.72 (dd, 2H); 1.8 (d, 2H); 2.4 (s, 3H); 2.2-2.45 (m, 2H); 3.0
(br s, 2H); 3.85 (s, 3H); 4.15 (t, 2H); 7.15 (s, 1H); 7.45 (s, 1H);
8.0 (s, 1H)
[1537] A solution of
7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-on-
e (3.1 g, 9.8 mmol) in thionyl chloride (40 ml) containing DMF (400
.mu.l) was refluxed for 4 hours. After cooling, the volatiles were
removed under vacuum. The residue was partitioned between methylene
chloride and water and the pH of the aqueous layer was adjusted to
11 with solid sodium hydrogen carbonate and aqueous ammonia. The
organic layer was separated, dried (MgSO.sub.4) and evaporated. The
residue was triturated with ether, filtered, washed with ether and
dried under vacuum to give
4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline
(1.83 g, 54%).
[1538] MS-ESI: 336 [MH].sup.+
[1539] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.4-1.7 (m, 3H); 1.8 (d,
2H); 1.9 (dd, 2H); 2.05 (t, 2H); 2.35 (s, 3H); 2.95 (d, 2H); 4.05
(s, 3H); 4.25 (t, 2H); 7.3 (s, 1H); 7.4 (s, 1H); 8.88 (s, 1H)
EXAMPLE 242
[1540] A solution of
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(213 mg, 0.662 mmol), (prepared as described for the starting
material in Example 10), and 6-fluoro-5-hydroxyindole (120 mg,
0.794 mmol) in DMF (3 ml) containing potassium carbonate (137 mg,
0.994 mmol) was stirred at 95.degree. C. for 3.5 hours. After
cooling, the mixture was poured onto water. The mixture was
filtered and the solid was washed with water. The solid was
dissolved in methylene chloride. The organic layer was dried
(MgSO.sub.4), and evaporated. The residue was triturated with
ether/ethyl acetate and the solid was filtered and dried under
vacuum to give
4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quin-
azoline (135 mg, 46%).
[1541] MS-ESI: 437 [MH].sup.+
[1542] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45 (m, 2H); 1.8
(d, 2H); 1.9 (t, 2H); 1.7-1.9 (m, 1H); 2.17 (s, 3H); 2.8 (d, 2H);
4.0 (s, 3H); 4.1 (d, 2H); 6.48 (br s, 1H); 7.38 (d, 1H); 7.4 (s,
1H); 7.42 (t, 1H); 7.58 (d, 1H); 7.6 (s, 1H); 8.5 (s, 1H)
TABLE-US-00102 Elemental analysis Found C 65.0 H 5.8 N 12.7
C.sub.24H.sub.25FN.sub.4O.sub.30.4H.sub.2O Requires C 65.0 H 5.9 N
12.6%
[1543] The starting material was prepared as follows:
[1544] A mixture of 2-fluoro-4-nitrophenol (15 gr, 95.5 mmol) and
benzyl bromide (18 g, 105 mmol) in acetone (125 ml) containing
potassium carbonate (26.5 gr, 190 mmol) was refluxed for 2 hours.
The volatiles were removed and the residue was partitioned between
2N hydrochloric acid and ethyl acetate. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and the
volatiles were removed under vacuum. The solid was triturated with
petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23 g,
97%).
[1545] .sup.1H NMR Spectrum: (CDCl.sub.3) 5.3 (s. 2H); 7.1 (t, 1H);
7.35-7.55 (m, 5H); 8.0(m, 2H)
[1546] To a solution of potassium tert-butoxide (1.72 g, 15.4 mmol)
in DMF (15 ml) cooled at -30.degree. C., was added dropwise a
solution of 2-fluoro-4-nitro-benzyloxybenzene (1.73 g, 7 mmol) and
4-chlorophenoxyacetonitrile (1.29 g, 7.7 mmol) while maintaining
the temperature below -25.degree. C. After completion of addition,
the mixture was stirred for 30 minutes at -20.degree. C. and then
poured onto a mixture of cold 1N hydrochloric acid and ether. The
organic layer was separated, washed with 1N sodium hydroxide,
followed by water, brine, dried (MgSO.sub.4). The volatiles were
removed under vacuum and the residue was purified by column
chromatography eluting with methylene chloride/petroleum ether
(3/1) to give a mixture of
3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and
5cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (1.2 g, 60%).
[1547] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.22 (s, 2H,
3-cyanomethyl isomer); 4.3 (s, 2H, 5-cyanomethyl isomer); 5.32 (s,
2H, 5-cyanomethyl isomer); 5.36 (s, 2H, 3-cyanomethyl isomer);
7.3-7.7 (m, 6H); 8.1 (d, 1H, 3-cyanomethyl isomer); 8.2 (d, 1H,
5-cyanomethyl isomer)
[1548] A solution of a mixture of
3-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene and
5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (23 g, 80.4 mmol) in
ethanol (220 ml) and acetic acid (30 ml) containing 10% palladium
on charcoal (600 mg) was hydrogenated under 3 atmospheres pressure
until hydrogen uptake ceased. The mixture was filtered and the
filtrate was evaporated under vacuum. The residue was purified on
column chromatography using a Prochrom.RTM. equipment eluting with
methylene chloride/petroleum ether (20/80) to give
4-fluoro-5-hydroxyindole (2.48 g) and 6-fluoro-5-hydroxyindole (3.5
g).
[1549] 4-fluoro-5-hydroxyindole:
[1550] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.32 (s, 1H); 6.75 (dd,
1H); 7.0 (d, 1H); 7.28 (dd, 1H); 8.8 (br s, 1H); 11.05 (brs,
1H)
[1551] 6-fluoro-5-hydroxyindole:
[1552] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.25 (s, 1H); 7.0 (d,
1H); 7.12 (d, 1H); 7.2 (dd, 1H); 9.0 (br s, 1H)
EXAMPLE 243
[1553] ##STR129##
[1554] A solution of
4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(213 mg, 0.662 mmol), (prepared as described for the starting
material in Example 10), and 4-fluoro-5-hydroxyindole (120 mg,
0.794 mmol), (prepared as described for the starting material in
Example 242), in DMF (3 ml) containing potassium carbonate (137 mg,
0.994 mmol) was stirred at 95.degree. C. for 3 hours. After
cooling, the mixture was partitioned between ethyl acetate and
water. The organic layer was washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was triturated in cold
ether. The solid was filtered and dried under vacuum to give
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin4-ylmethoxy)quina-
zoline (77 mg, 26%).
[1555] MS-ESI: 437 [MH].sup.+
[1556] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5 (m, 2H); 1.8 (d,
2H); 1.9 (t, 2H); 1.7-1.95 (m, 1H); 2.2 (s, 3H); 2.8 (d, 2H); 4.02
(s, 3H); 4.1 (d, 2H); 6.55 (s, 1H); 7.1 (t, 1H); 7.3 (d, 1H); 7.4
(s, 1H); 7.48 (t, 1H); 7.62 (s, 1H); 8.5 (s, 1H) TABLE-US-00103
Elemental analysis Found C 64.8 H 5.8 N 12.6
C.sub.24H.sub.25FN.sub.4O.sub.30.4H.sub.2O Requires C 65.0 H 5.9 N
12.6%
EXAMPLE 244
[1557] A mixture of
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(282 mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794
mmol), (prepared as described for the starting material in Example
242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994
mmol) was heated at 95.degree. C. for 3 hours. After cooling, the
residue was poured in water (12 ml) and the pH was adjusted to 8.
The mixture was extracted with ethyl acetate. The organic layer was
separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated. The residue was purified by preparative column
chromatography on C.sup.18 silica eluting with 60% methanol in
aqueous ammonium carbonate (2 g ammonium carbonate/litre saturated
with CO.sub.2). The fractions containing the expected product were
combined and evaporated. The residue was triturated with ether and
the solid was filtered, dried under vacuum to give
4-(6fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)q-
uinazoline (147 mg, 48%).
[1558] MS-ESI: 466 [MH].sup.+
[1559] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.3-2.4
(m, 2H); 3.0 (s, 3H); 3.2-3.9 (m, 8H); 3.5 (t, 2H); 4.1 (s, 3H);
4.4 (t, 2H); 6.52 (d, 1H); 7.45 (d, 1H); 7.48 (s, 1H); 7.6 (s, 1H);
7.65 (d, 1H); 7.82 (s, 1H); 9.0 (s, 1H) TABLE-US-00104 Elemental
analysis Found C 62.1 H 6.4 N 14.2
C.sub.25H.sub.28FN.sub.5O.sub.30.9H.sub.2O Requires C 62.3 H 6.2 N
14.5%
[1560] The starting material was prepared as follows:
[1561] To a suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(29 g, 94.7 mmol), (prepared as described for the starting material
in Example 12), in methylene chloride (280 ml) coiled at 5.degree.
C. was added triphenylphosphine (37.1 g, 141.6 mmol) followed by
3-bromo-1-propanol (12.8 ml, 141.6 mmol) and diethyl
azodicarboxylate (2.4 ml, 141.6 mmol) dropwise. After stirring for
2 hours at ambient temperature, the volatiles were removed under
vacuum and the residue was purified by column chromatography
eluting with methylene chloride/methanol (98/2). The fractions
containing the expected product were combined and evaporated and
the solid was triturated with ether, filtered, washed with ether
and dried under vacuum to give
7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazoli-
n-4-one (37.22 g, 92%).
[1562] MS-ESI: 427-429 [MH]+
[1563] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.18 (s, 9H); 2.32 (m,
2H); 3.7 (t, 2H); 3.92 (s, 3H); 4.28 (t, 2H); 5.95 (s, 2H); 7.2 (s,
1H); 7.5 (s, 1H); 8.4 (s, 1H)
[1564] A suspension of
7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazoli-
n-4-one (36.7 g, 86 mmol) in 1-methylpiperazine (370 ml) was
stirred at 100.degree. C. for 90 minutes. After removal of the
volatiles under vacuum, the residue was partitioned between
methylene chloride and aqueous ammonium chloride. The organic layer
was separated, washed with water, brine, dried (MgSO.sub.4) and
evaporated. The solid was triturated with ether, filtered, washed
with ether and dried under vacuum to give
7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3-
,4-dihydroquinazolin-4-one (31.9 gr, 83%).
[1565] MS-ESI: 447 [MH]+
[1566] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.15 (s,
9H); 2.25 (t, 2H); 2.5 (s, 3H); 3.45 (t, 2H); 3.2-4.0 (m, 8H); 3.9
(s, 3H); 4.25 (t, 2H); 5.95 (s, 2H); 7.22 (s, 1H), 7.55 (s, 1H);
8.6 (s, 1H)
[1567] A suspension of
7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3-
,4-dihydroquinazolin-4-one (31.8 g, 71.3 mmol) in methanol
saturated with ammonia was stirred at ambient temperature
overnight. The volatiles were removed under vacuum. The solid was
triturated with ether containing about 10% of methylene chloride,
filtered, washed with ether containing about 10% methylene chloride
and dried under vacuum to give
7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-o-
ne (22.63 g, 95%).
[1568] MS-ESI: 333 [MH].sup.+
[1569] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.92 (m, 2H); 2.15 (s,
3H); 2.2-2.5 (m, 10 H); 3.88 (s, 3H); 4.15 (t, 2H); 7.1 (s, 1H);
7.45 (s, 1H); 7.98 (s, 1H)
[1570] A solution of
7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-o-
ne (22.6 g, 68 mmol) in thionyl chloride (300 ml) containing DMF (5
ml) was refluxed for 2 hours. After cooling, the volatiles were
removed under vacuum and the residue was azeotroped with toluene
twice. The solid was dissolved in methulene chloride and water was
added. The mixture was cooled to 0.degree. C. and the pH of the
aqueous layer was adjusted to 7 with solid hydrogen carbonate and
then raised to 10 with 6N Sodium hydroxide. The organic layer was
separated and the aqueous layer was extracted with methylene
chloride. The organic layer was washed with brine, dried
(MgSO.sub.4), filtered and the volatiles were removed under vacuum.
The residue was triturated with ether, filtered, washed with ether
and dried under vacuum to give
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(16.3 gr, 68%).
[1571] MS-ESI: 351-353 [MH]+
[1572] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (t, 2H); 2.18 (s,
3H); 2.45 (t, 2H); 2.22-2.5 (m, 8H); 4.05 (s, 3H); 4.28 (t, 2H);
7.4 (s, 3H); 7.45 (s, 1H); 8.9 (s, 1H)
EXAMPLE 245
[1573] ##STR130##
[1574] Using an analogous procedure to that described in Example
243, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
(213 mg, 0.662 mmol), (prepared as described for the starting
material in Example 9), was reacted with 6-fluoro-5-hydroxyindole
(120 mg, 0.794 mmol), (prepared as described for the starting
material in Example 242), in DMF (3 ml) containing potassium
carbonate (137 mg, 0.993 mmol) to give
4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (154 mg, 53%).
[1575] MS-ESI: 437 [MH].sup.+
[1576] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7-1.8 (m, 4H); 2.0-2.1
(m, 2H); 2.48 (br s, 4H); 2.6 (t, 2H); 4.02 (s, 3H); 4.3 (t, 2H);
6.5 (s, 1H); 7.4 (d, 1H); 7.4 (s, 1H); 7.45 (t, 1H); 7.6 (d, 1H);
7.62 (s, 1H); 8.52 (s, 1H) TABLE-US-00105 Elemental analysis Found
C 65.4 H 6.0 N 12.9 C.sub.24H.sub.25HN.sub.4O.sub.30.2H.sub.2O
Requires C 65.5 H 5.8 N 12.7%
EXAMPLE 246
[1577] To a solution of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(500 mg, 1.2 mmol), (prepared as described in Example 70), in
methanol (11.5 ml) containing potassium iodide (99 mg, 0.6 mmol)
was added 4-(2-chloroethyl)morpholine hydrochloride (134 mg, 0.72
mmol) followed by sodium hydrogen carbonate (151 mg, 1.8 mmol).
After stirring for 1 hour at reflux, 4-(2-chloroethyl)morpholine
hydrochloride (134 mg, 0.72 mmol) and sodium hydrogen carbonate
(151 mg, 1.8 mmol) were added. After stirring 1 hour at reflux, the
mixture was cooled and the precipitate was filtered, washed with
methanol followed by water and dried over phosphorus pentoxide to
give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-morpholinoethyl)piperidin-4-y-
lmethoxy)quinazoline (470 mg, 73%).
[1578] MS-ESI: 532 [MH].sup.+
[1579] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.45 (m, 2H); 1.8
(d, 2H); 1.7-1.9 (m, 1H); 2.0 (t, 2H); 2.3-2.45 (m, 8H); 2.4 (s,
3H); 2.95 (d, 2H); 3.6 (t, 4H); 4.0 (s, 3H); 4.08 (d, 2H); 6.18 (s,
1H); 6.9 (dd, 1H); 7.3 (s, 1H); 7.35 (d, 1H); 7.4 (s, 1H); 7.6 (s,
1H); 8.5 (s, 1H); 11.05 (s, 1H) TABLE-US-00106 Elemental analysis
Found C 65.3 H 7.1 N 12.6 C.sub.30H.sub.37N.sub.5O.sub.40.6H.sub.2O
Requires C 65.4 H 7.3 N 12.5% 0.6 Methanol
EXAMPLE 247
[1580] ##STR131##
[1581] A solution of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.76
g, 5.47 mmol), (prepared as described for the starting material in
Example 9), 4-fluoro-5-hydroxyindole (0.992 g, 6.57 mmol),
(prepared as described for the starting material in Example 242),
in DMF (25 ml) containing potassium carbonate (1.14 g; 8.21 mmol)
was heated at 95.degree. C. for 1 hour. After cooling, the mixture
was filtered and washed with DMF. The filtrate was evaporated and
the residue was purified by column chromatography eluting with
methanol/methylene chloride (1/9) followed by methanol/methanol
chloride/methanol (containing ammonia) (16/80/4). The fractions
containing the expected product were combined and evaporated. The
residue was repurified by column chromatography eluting with a
gradient of methylene chloride/methanol (80/20 to 40/60). The
fractions containing the expected product were combined and
evaporated. The residue was triturated in cold methanol and the
solid was filtered, washed with ether and dried under vacuum to
give
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (1.24 g, 52%).
[1582] MS-ESI: 437 [MH].sup.+
[1583] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7 (br s, 4H); 2.0 (m,
2H); 2.45 (br s, 4H); 2.6 (t, 2H); 4.05 (s, 3H); 4.28 (t, 2H); 6.58
(s, 1H); 7.1 (t, 2H); 7.35 (d, 1H); 7.4 (s, 1H); 7.5 (t, 1H); 7.65
(s, 1H); 8.52 (s, 1H) TABLE-US-00107 Elemental analysis Found C
65.3 H 5.9 N 12.6 C.sub.24H.sub.25FN.sub.4O.sub.30.19 Requires C
65.2 H 5.9 N 12.6% Methanol, 0.17H.sub.2O
EXAMPLE 248
[1584] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (222 mg,
0.662 mmol), (prepared as described for the starting material in
Example 67), and 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol),
(prepared as described for the starting material in Example 242),
in DMF (3 ml) containing potassium carbonate (137 mg, 0.993 mmol)
was heated at 95.degree. C. for 3.5 hours. After cooling the
mixture was poured onto water and extracted with ethyl acetate. The
organic layers were washed,with water, brine, dried (MgSO.sub.4)
and evaporated. The residue was triturated with ether, filtered and
dried under vacuum to give
4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(139 mg, 46%).
[1585] MS-ESI: 451 [MH].sup.+
[1586] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.45 (m, 2H);
1.45-1.6 (m, 4H); 2.0 (m, 2H); 2.35 (br s, 4H); 2.42 (t, 2H); 4.05
(s, 3H); 4.25 (t, 2H); 6.5 (s, 1H); 7.4 (d, 1H); 7.42 (s, 1H); 7.44
(t, 1H); 7.6 (d, 1H); 7.65 (s, 1H); 8.5 (s, 1H) TABLE-US-00108
Elemental analysis Found C 65.9 H 6.2 N 12.3
C.sub.25H.sub.27FN.sub.4O.sub.30.3H.sub.2O Requires C 65.9 H 6.1 N
12.3%
EXAMPLE 249
[1587] ##STR132##
[1588] Using an analogous procedure to that described in Example
244, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (407 mg,
1.21 mmol), (prepared as described for the starting material in
Example 67), 4-fluoro-5-hydroxyindole (220 mg, 1.45 mmol) (prepared
as described for the starting material in Example 242), and
potassium carbonate (251 mg, 1.82 mmol) in DMF (6 ml) were heated
at 95.degree. C. for 90 minutes and purified to give
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(367 mg, 67%).
[1589] MS-ESI: 451 [MH].sup.+
[1590] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.35-1.45 (m, 2H); 1.55
(m, 4H); 2.0 (m, 2H); 2.38 (br s, H); 2.45 (t, 2H); 4.02 (s, 3H);
4.25 (t, 2H); 6.55 (s, 1H); 7.12 (dd, 1H); 7.32 (d, 1H); 7.4 (s,
1H); 7.5 (s, 1H); 7.65 (s, 1H); 8.52 (s, 1H) TABLE-US-00109
Elemental analysis Found C 66.0 H 6.2 N 12.4
C.sub.25H.sub.27FN.sub.4O.sub.30.2H.sub.2O Requires C 66.1 H 6.1 N
12.3%
EXAMPLE 250
[1591] Using an analogous procedure to that described in Example
248, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
(268 mg, 0.833 mmol), (prepared as described for the starting
material in Example 9), was reacted with
6-fluoro-5-hydroxy-2-methylindole (165 mg, 1 mmol) in DMF (3.5 ml)
containing potassium carbonate (173 mg, 1.25 mmol) to give
4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)p-
ropoxy)quinazoline (215 mg, 57%).
[1592] MS-ESI: 451 [MH].sup.+
[1593] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65-1.8 (br s, 4H);
2.02 (m, 2H); 2.4 (s, 3H); 2.48 (br s, 4H); 2.6 (t, 2H); 4.02 (s,
3H); 4.3 (t, 2H); 6.18 (s, 1H); 7.25 (d, 1H); 7.4 (s, 1H); 7.45 (d,
1H); 7.6 (s, 1H); 8.5 (s, 1H) TABLE-US-00110 Elemental analysis
Found C 65.6 H 6.1 N 12.2
C.sub.25H.sub.27FN.sub.4O.sub.30.4H.sub.2O Requires C 65.6 H 6.1 N
12.2%
[1594] The starting material was prepared as follows:
[1595] To a solution of 6-fluoro-5-methoxy-2-methylindole (1.23 g,
6.86 mmol), (prepared as described for the starting material in
Example 237), in methylene chloride (15 ml) cooled at -30.degree.
C. was added a solution of boron tribromide (3.78 g, 15.1 mmol) in
methylene chloride (2 ml). After stirring for 90 minutes at ambient
temperature, the mixture was poured onto ice and diluted with
methylene chloride. The pH of the aqueous layer was adjusted to 6.
The organic layer was separated, washed with water, brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by column
chromatography eluting with ethylacetate/petroleum ether (8/2) to
give 6-fluoro-5-hydroxy-2-methylindole (905 mg, 80%).
[1596] MS-ESI: 166 [MH].sup.+
[1597] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.3 (s, 3H); 5.95 (s,
1H); 6.9 (d, 1H); 7.0 (d, 1H); 8.85 (s, 1H); 10.6 (s, 1H)
[1598] .sup.13C NMR Spectrum: (DMSOd.sub.6) 13.3; 97.4 (d); 98.3;
105.5; 124.5; 128.8 (d); 135.6; 138.5 (d); 148.3 (d).
EXAMPLE 251
[1599] ##STR133##
[1600] A mixture of
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline
(232 mg, 0.662 mmol), (prepared as described for the starting
material in Examples 176 or 244), and 4-fluoro-5-hydroxyindole (120
mg, 0.794 mmol), (prepared as described for the starting material
in Example 242), in DMF (3 ml) containing potassium carbonate (137
mg, 1 mmol) was stirred at 95.degree. C. for 3 hours. After
cooling, the residue was poured onto water (12 ml) and extracted
with ethyl acetate. The organic layer was washed with water, brine,
dried (MgSO.sub.4) and evaporated. The residue was purified by
reversed phase C.sub.18 column chromatography eluting with
methanol/ammonium carbonate (2 g of ammonium carbonate/litre
saturated with CO.sub.2) (60/40 followed by 70/30). The fractions
containing the expected product were combined and evaporated. The
residue was dissolved in ethyl acetate, dried (MgSO.sub.4) and the
volatiles were removed under vacuum. The residue was triturated
with ether, filtered and dried under vacuum to give
4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-
quinazoline (130 mg, 42%).
[1601] MS-ESI: 466 [MH].sup.+
[1602] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.3-2.4
(m, 2H); 2.97 (s, 3H); 3.2-4.1 (m, 8H); 3.5 (t, 2H); 4.07 (s, 3H);
4.4 (t, 2H); 6.6 (d, 1H); 7.15 (t, 1H); 7.38 (d, 1H); 7.5 (d, 1H);
7.6 (s, 1H); 7.82 (s, 1H); 8.95 (s, 1H) TABLE-US-00111 Elemental
analysis Found C 64.4 H 6.1 N 15.0 C.sub.25H.sub.28FN.sub.5O.sub.3
Requires C 64.5 H 6.1 N 15.0%
EXAMPLE 252
[1603] A mixture of
6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline
(600 mg, 1.43 mmol), (prepared as described in Example 70),
1-(2-chloroethyl)-pyrrolidine (292 mg, 1.72 mmol) in methanol (14
ml) containing sodium carbonate (262 mg, 4.3 mmol) and potassium
iodide (48 mg, 0.29 mmol) was heated at 50.degree. C. for 20 hours.
After cooling, the volatiles were removed under vacuum. The residue
was purified by preparation HPLC on reverse C.sub.18 silica eluting
with methanol/aqueous ammonium carbonate (2 g ammonium carbonate
per litre saturated with CO.sub.2) (60/40 followed by 70/30). The
fractions containing the expected product were combined and the
volatiles were removed under vacuum. The residue was triturated
with ether and the solid was filtered, washed with ether and dried
under vacuum to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-piper-
idin4-ylmethoxy)quinazoline (102 mg, 20%).
[1604] MS-ESI: 516 [MH].sup.+
[1605] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.3-1.5 (m, 2H);
1.6-1.75 (m, 4H); 1.8 (d, 2H); 1.7-1.9 (m, 1H); 1.95 (t, 2H); 2.45
(s, 3H); 2.4-2.5 (m, 5H); 2.95 (d, 2H); 3.35 (d, 2H); 4.0 (s, 3H);
4.1 (d, 2H); 6.18 (s, 1H); 6.9 (d, 1H); 7.25 (s, 1H); 7.35 (d, 1H);
7.38 (s, 1H); 7.6 (s, 1H); 8.5 (s, 1H); 11.05 (s, 1H)
TABLE-US-00112 Elemental analysis Found C 68.6 H 7.2 N 13.3
C.sub.30H.sub.37N.sub.5O.sub.30.5H.sub.2O Requires C 68.7 H 7.3 N
13.4%
EXAMPLE 253
[1606] A mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (110 mg,
0.325 mmol), (prepared as described for the starting material in
Example 1), and 6-fluoro-5-hydroxyindole (59 mg, 0.39 mmol),
(prepared as described for the starting material in Example 242),
in DMF (1.8 ml) containing potassium carbonate (67 mg, 0.487 mmol)
was heated at 90.degree. C. for 2 hours. After cooling, water was
added. The solid was separated and triturated with methanol. Water
was added and the solid was filtered, washed with water and dried
under vacuum to give
4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(55 mg, 41%).
[1607] MS-ESI: 453 [MH].sup.+
[1608] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95-2.05 (m, 2H); 2.45
(br s, 4H); 2.5 (t, 2H); 3.62 (t, 4H); 4.02 (s, 3H); 4.3 (t, 2H);
6.5 (s, 1H); 7.4 (d, 1H); 7.45 (s, 1H); 7.47 (t, 1H); 7.58 (d, 1H);
7.62 (s, 1 H); 8.5 (s, 1H) TABLE-US-00113 Elemental analysis Found
C 61.6 H 5.5 N 11.9 C.sub.24H.sub.25FN.sub.4O.sub.40.8H.sub.2O
Requires C 61.7 H 5.7 N 12.0%
EXAMPLE 254
[1609] To a solution of
7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6
mmol), (prepared as described for the starting material in Example
107), triphenylphosphine (235 mg, 0.89 mmol) and
4-(2-hydroxyethyl)morpholine (93 mg, 0.72 mmol) in methylene
chloride (4 ml) cooled at 10.degree. C. was added diethyl
azodicarboxylate (140.mu.l, 0.89 mmol). After stirring at ambient
temperature for 3 hours, the mixture was left overnight at
5.degree. C. The mixture was poured onto a column of silica and
eluted with methylene chloride followed by methanol/methylene
chloride (2/98) followed by 3N ammonia methanol/methylene chloride
(2/98). The fractions containing the expected products were
combined and evaporated to give
4-(indol-5-yloxy)-6-methoxy-7-2-morpholinoethoxy)quinazoline (137
mg, 55%).
[1610] MS-ESI: 421 [MH].sup.+
[1611] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 3.30 (t,
2H); 3.65 (d, 2H); 3.7-3.8 (m, 4H); 4.05 (d, 2H); 4.1 (s, 3H); 4.7
(t, 2H); 6.5 (s, 1H); 7.05 (dd, 1H); 7.4-7.6 (m, 3H); 7.65 (s, 1H);
7.82 (s, 1H); 9.0 (s, 1H)
EXAMPLES 255-257
[1612] Using an analogous procedure to that described in Example
254, 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6
mmol), (prepared as described for the starting material in Example
107), was used to prepare the compounds in Table XVIII.
TABLE-US-00114 TABLE XVIII ##STR134## Ex- am- ple num- Weight Yield
MS-ESI ber (mg) % [MH].sup.+ R Note 255 123 51 405 ##STR135## a 256
124 48 434 ##STR136## b 257 165 62 448 ##STR137## c a
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol)
was reacted with 1-(2-hydroxyethyl)pyrrolidine (82 mg) to give
4-(indol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline.
.sup.1H NMR Spectrum: (DMSOd.sub.6) 1.72 (br s, 4H); 2.6 (br s,
4H); 2.9 (t, 2H); 4.0 (s, 3H); 4.3 (t, 2H); 6.48 (s, 1H); 7.0(dd,
1H); 7.4-7.5 (m, 3H); 7.6 (s, 1H); 8.5 (s, 1H); 11.3 (br s, 0H) b
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol)
was reacted with 4-(2-hydroxyethyl)-1-methylpiperazine (103 mg) to
give
4-(indol-5-yloxy)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoli-
ne. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.5 (s, 3H);
3.35 (t, 2H); 3.65 (d, 2H); 3.7-3.8 (m, 4H); 4.05 (d, 2H); 4.1 (s,
3H); 4.7 (t, 2H); 7.05 (dd, 1H); 7.45 (s, 1H); 7.5-7.6 (m, 2H) 7.65
(s, 1H); 7.82 (s, 1H); 9.0 (s, 1H) The starting material was
prepared as follows:- 2-Bromoethanol (2.3 6g, 19 mmol) was added
dropwise to a mixture of 1-methylpiperazine (1.26g, 13 mmol) and
potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml)
and the mixture heated at reflux for 18 hours. The mixture was
allowed to cool and the precipitates were removed by filtration and
the solvent volatiles were removed by evaporation. The residue was
treated with acetone/methylene chloride, the insolubles were
removed by filtration and the solvent was removed from # the
filtrate by evaporation to give
4-(2-hydroxyethyl)-1-methylpiperazine (870 mg, 48%) as a light
brown oil. .sup.1H NMR Spectrum: (CDCl.sub.3) 2.18 (s, 3H); 2.3-2.7
(br m, 8H); 2.56 (t, 2H); 3.61 (t, 2H) MS-ESI: 145 [MH].sup.30 c
7-Hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (183 mg, 0.6 mmol)
was reacted with 1-(3-hydroxypropyl)-4-methylpiperazine (113 mg),
(prepared as described for the starting material in Example 133),
to give
4-(indol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazol-
ine. .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.15 (s, 3H); 2.3-2.4 (br
s, 4H); 2.5-2.6 (m, 4H); 2.8 (t, 2H); 4.0 (s, 3H); 4.35 (t, 2H);
6.45 (s, 1H); 7.0 (dd, 1H); 7.4-7.5 (m, 4H); 7.62 (s, 1H); 8.5 (s,
1H)
EXAMPLE 258
[1613] A solution of
(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-
-yloxy)-6-methoxyquinazoline (570 mg, 1.12 mmol) in methanol
saturated with ammonia (7 ml) was stirred overnight at ambient
temperature. The volatiles were removed under vacuum and the
residue was purified by column chromatography eluting with
methylene chloride/methanol containing ammonia (approximately 3N)
to give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-
-yloxy)-6-methoxyquinazoline (390 mg; 75%).
[1614] MS-ESI: 467 [MH]+
[1615] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.85-2.0
(m, 2H); 2.0-2.15 (m, 2H); 2.42 (s, 3H); 3.15 (m, 2H); 3.4 (d, 2H);
3.65 (m, 2H); 4.1(s, 3H); 4.32 (d, 2H); 4.4 (m, 1H); 7.05 (dd, 1H);
7.22 (d, 1H); 7.6 (s, 1H); 7.85 (s, 1H); 9.02 (s, 1H)
[1616] The starting material was prepared as follows:
[1617] A suspension of
7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(1.2 g, 3.91 mmol), (prepared as described for the starting
material in Example 12), and 2-(R)-(-)-Glycidyl tosylate (1.25 g,
5.47 mmol) in DMF (10 ml) containing potassium carbonate (1.61 g,
11.7 mmol) was stirred at 60.degree. C. for 4 hours. After cooling,
the mixture was filtered and the solid was washed with DMA. The
filtrate was evaporated and the residue was partitioned between
ethyl acetate and aqueous ammonia. The organic layer was separated,
washed with water, brine, dried (MgSO.sub.4) and evaporated. The
residue was purified by column chromatography eluting with ethyl
acetate. The fractions containing the expected product were
combined and evaporated to give
(2R)-7-(oxiran-2-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydro-
quinazolin-4-one (1.21 g, 85%).
[1618] MS-ESI: 363 [MH].sup.+
[1619] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.12 (s, 9H); 2.75 (m,
1H); 2.9 (t, 1H); 3.4 (m, 1H); 3.93 (s, 3H); 4.0 (dd, 1H); 4.52
(dd, 1H); 5.9 (s, 2H); 7.2 (s, 1H); 7.52 (s, 1H); 8.35 (s, 1H)
[1620] A solution of
(2R-7-(oxiran-2-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroq-
uinazolin-4-one (1.1 g, 3 mmol) and pyrrolidine (216 mg, 3 mmol) in
trichloromethane (15 ml) was refluxed for 11 hours. The volatiles
were removed under vacuum and the residue was purified by column
chromatography eluting with methylene chloride/methanol (85/15
followed by 70/30) to give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxyme-
thyl)-3,4-dihydroquinazolin-4-one (1.18 g, 90%).
[1621] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.15 (s, 9H); 1.7 (br s,
4H); 2.48 (m, 1H); 2.5 (br s, 4H); 2.65 (dd, 1H); 3.9 (s, 3H); 4.0
(br s, 1H); 4.05 (dd, 1H); 4.18 (dd, 1H); 4.95 (br s, 1H); 5.9 (s,
2H); 7.2 (s, 1H); 7.5 (s, 1H); 8.35 (s, 1H)
[1622] A solution of
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxyme-
thyl)-3,4-dihydroquinazolin-4-one (778 mg, 1.8 mmol) in methanol
saturated with ammonia (20 ml) was stirred for 24 hours at ambient
temperature. The volatiles were removed under vacuum. The residue
was triturated with ether and the residue was filtered, washed with
ether and dried under vacuum to give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinaz-
olin-4-one (800 mg, quant.).
[1623] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.92 (m,
2H); 2.05 (m, 2H); 3.15 (m, 2H); 3.35 (d, 2H); 3.62 (m, 2H); 3.98
(s, 3H); 4.18 (d, 2H); 4.32 (m, 1H); 7.35 (s, 1H); 7.6 (s, 1H); 9.2
(s, 1H)
[1624] A mixture of
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinaz-
olin-4-one (803 mg, 2.51 mmol) in acetic anhydride (1.2 ml, 12.5
mmol) was stirred at ambient temperature for 1 hour. Water (360
.mu.l, 20 mmol) was added and stirring was continued for 90
minutes. The mixture was partitioned between aqueous sodium
hydrogen carbonate and methylene chloride. The organic layer was
separated, washed with brine, dried (MgSO.sub.4) and evaporated.
The residue was triturated with ether, filtered and dried under
vacuum to give
(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinaz-
olin-4-one (595 mg, 65%).
[1625] MS-ESI: 362 [MH]+
[1626] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7 (br s, 4H); 2.05 (s,
3H); 2.5 (br s, 4H); 2.72 (m, 2H); 3.9 (s, 3H); 4.3 (m, 2H); 5.25
(m, 1H); 7.2 (s, 1H); 7.45 (s, 1H); 8.0 (s, 1H)
[1627] A solution of
(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinaz-
olin-4-one (556 mg, 1.54 mmol) in thionyl chloride (6 ml)
containing DMF (3 drops) was heated at 80.degree. C. for 4 hours.
The volatiles were removed under vacuum. The residue was dissolved
in methylene chloride and the organic layer was washed with aqueous
sodium hydrogen carbonate, brine, dried (MgSO.sub.4) and evaporated
to give
(2R)-7-2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazolin-
e (530 mg, 90%).
[1628] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7 (br s, 4H); 2.05 (s,
3H); 2.55 (br s, 4H); 2.75 (br s, 2H); 4.02 (s, 3H); 4.35-4.5 (m,
2H); 5.3 (m, 1H); 7.4 (s, 1H); 7.5 (s, 1H); 7.9 (s, 1H)
[1629] A suspension of
(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-chloro-6-methoxyquinazoli-
ne (530 mg, 1.4 mmol) and 4-fluoro-5-hydroxy-2-methylindole (277
mg, 1.68 mmol), (prepared as described for the starting material in
Example 237), in DMF (8 ml) containing potassium carbonate (290 mg,
2.1 mmol) was stirred at 90.degree. C. for 2 hours. After cooling,
the volatiles were removed under vacuum and the residue was
purified by column chromatography eluting with methylene
chloride/methanol (95/5) to give
(2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-
-yloxy)-6-methoxyquinazoline (580 mg, 81%).
[1630] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.7 (br s, 4H); 2.05 (s,
3H); 2.4 (s, 3H); 2.52 (br s, 4H); 2.65-2.82 (m, 2H); 4.0 (s, 3H);
4.4 (m, 2H); 5.3 (m, 1H); 6.25 (s, 1H); 7.0 (dd, 1H); 7.18 (d, 1H);
7.48 (s, 1H); 7.62 (s, 1H); 8.5 (s, 1H)
EXAMPLE 259
[1631] A solution of
4-chloro-6-methoxy-7(3-(pyrrolidin-1-yl)propoxy)quinazoline (61 mg,
0.19 mmol), (prepared as described for the starting material in
Example 9), and 5-aminoindole (30 mg, 0.23 mmol) in isopropanol (2
ml) containing 6.2 N hydrogen chloride in isopropanol (33 .mu.l)
was heated at 80.degree. C. for 6 hours. After cooling, the
precipitate was filtered, washed with ether and dried under vacuum
to give
4-(indol-5-ylamino)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline
hydrochloride (80 mg, 72%).
[1632] MS-ESI:418 [MH].sup.+
[1633] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 1.9 (m,
2H); 2.05 (m, 2H); 2.3 (m, 2H); 3.1 (m, 2H); 3.4 (t, 2H); 3.65 (m,
2H); 4.05 (s, 3H); 4.35 (t, 2H); 6.5 (s, 0.5H, partly exchanged);
7.3 (d, 1H); 7.4 (s, 1H); 7.45 (s, 1H); 7.55 (d, 1H); 7.8 (s, 1H);
8.25 (s, 1H) 8.8 (s, 1H)
EXAMPLE 260-265
[1634] Using an analogous procedure to that described in Example
259, 5-aminoindole (30 mg, 0.23 mmol) was used in the synthesis of
the compounds described in Table XIX. TABLE-US-00115 TABLE XIX
##STR138## Example MS-ESI number Weight (mg) Yield (%) [MH].sup.30
Note R 260 101 76 510 a ##STR139## 261 92 83 418 b ##STR140## 262
92 80 434 c ##STR141## 263 84 80 427 d ##STR142## 264 78 79 401 e
##STR143## 265 72 70 416 f ##STR144## a
4-Chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-
quinazoline (78 mg), (prepared as described for the starting
material in Example 12), was reacted with 5-aminoindole to give
4-(indol-5-ylamino)-6-methoxy-7-((1-(2-
methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline
hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65-1.8 (m,
2H); 2.05 (d, 2H); 2.2 (br s, 1H); 3.1 (br s, 2H); 3.2 (s, 3H); 3.5
(br s, 2H); 3.6 (d, 2H); 3.8 (m, 2H) 4.05 (s, 3H) 4.1 (d, 2H); 6.5
(s, 1H); 7.3 (d, 1H); 7.42 (m, 2H); 7.5 (d, 1H); 7.8 (s, 1H); 8.4
(s, 1H); 8.7 (s, 1H); 11.15 (br s, 1H); 11.32 (s, 1H). 11.5 (s, 1H)
b 4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline
(61 mg), (prepared as described for the starting material in
Example 10), was reacted with 5-aminoindole to give
4-(indol-5-ylamino)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoli-
ne hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.6-1.8 (m,
2H); 2.02 (d, 2H); 2.15 (br s, 1H); 2.75 (s, 3H); 3.0 (br s, 2H);
3.45 (d, 2H); 4.02 (s, 3H); 4.1 (d, 2H); 6.5 (s, 1H); 7.3 (d, 1H);
7.4 (m, 2H); 7.5 (d, 1H); 7.8 (s, 1H); 8.3 (s, 1H); 8.7 (s, 1H);
10.4 (br s, 1H); 11.3 (s, 1H) The presence of a second form of the
piperidine ring (due to protonation effects) is detectable in the
NMR Spectrum as a doublet at 4.3 ppm (approximately 20% of parent
compound). c 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline
(64 mg), (prepared as described for the starting material in
Example 1), was reacted with 5-aminoindole to give 4-(indol-5-
ylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
hydrochloride. .sup.1H NMR Spectrum (DMSOd.sub.6; CF.sub.3COOD):
2.35 (m, 2H); 3.15 (t, 2H); 3.3 (t, 2H); 3.57 (d, 2H); 3.8 (m, 2H);
4.02 (d, 2H); 4.03 (s, 3H); 4.3 (t, 2H); 6.5 (d, 1H); 7.3 (dd, 1H);
7.4 (s, 1H); 7.45 (s, 1H); 7.52 (d, 1H); 7.8 (s, 1H); 8.25 (s, 1H);
8.78 (s, 1H) d
4-Chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (62 mg),
(prepared as described for the starting material in Example 50),
was reacted with 5-aminoindole in the presence of 6.2 N hydrogen
chloride in isopropanol (4 .mu.l) to give 4-(indol-5-ylamino)-6-
methoxy-7-(3-methylsulphonylpropoxy)quinazoline hydrochloride.
.sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.2-2.4 (m, 2H);
3.07 (s, 3H); 3.35 (t, 2H); 4.05 (s, 3H); 4.35 (t, 2H); 6.5 (d,
0.5H, partly exchanged); 7.2-7.35 (m, 2H); 7.45 (s, 1H); 7.5 (d,
1H); 7.8 (s, 1H); 8.2 (s, 1H); 8.75 (s, 1H) e
4-Chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (58 mg)
was reacted with 5- aminoindole in the presence of 6.2 N hydrogen
chloride in isopropanol (4 .mu.l) to give 4-(indol-
5-ylamino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline
hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD)
4.03 (s, 3H); 4.65 (t, 2H); 4.8 (t, 2H); 6.5 (d, 1H, partly
exchanged); 7.30 (d, 1H); 7.4 (s, 1H); 7.45 (s, 1H); 7.52 (d, 1H);
7.75 (s, 1H); 7.8 (s, 1H); 7.9 (s, 1H); 8.25 (s, 1H); 8.75 (s, 1H);
9.25 (s, 1H) The starting material was prepared as follows: Diethyl
azodicarboxylate (435 mg, 2.5 m.mol) was added dropwise to a
suspension of 7-
hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one
(612 mg, 2 mmol), (prepared as described for the starting material
in Example 12), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J.
Med. Chem. 1993,25 4052-4060), and triphenylphosphine (655 mg, 2.5
mmol) in methylene chloride (10 ml) at 5.degree. C. The mixture was
stirred for 10 minutes at 5.degree. C. and then 1 hour at ambient
temperature. The mixture was poured directly on to a silica column
and eluted with methylene chloride/methanol (95/5) to give
7-(2-(imidazol-1-
yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)3,4-dihydroquinazolin-4-one
(640 mg, 80%). .sup.1H NMR Spectrum: (CDCl.sub.3) 1.19 (s, 9H);
3.98 (s, 3H); 4.34 (m, 2H); 4.45 (m, 2H); 5.94 (s, 2H); 7.02 (s,
1H); 7.07 (s, 1H); 7.11 (s, 1H); 7.64(s, 1H); 7.67 (s, 1H); 8.17
(s, 1H) MS-ESI: 423 [MNa].sup.+ Elemental Analysis: Found C 58.3 H
6.4 N 13.9 C.sub.20H.sub.24N.sub.4O.sub.50.7H.sub.2O Requires C
58.2 H 6.2 N 13.6% A solution of
7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-
dihydroquinazolin-4-one (640 mg, 1.6 mmol) in saturated methanolic
amuionia (10 ml) was stirred for 15 hours at ambient temperature.
The volatiles were removed by evaporation, the solid was triturated
with ether, collected by filtration and dried under vacuum to give
7-(2- (imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin (412
mg, 90%). .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.89 (s, 3H); 4.44.5
(m, 4H); 6.9 (s, 1H); 7.16 (s, 1H); 7.28(s, 1H); 7.47 (s, 1H); 7.7
(s, 1H); 7.99 (s, 1H) MS-ESI: 287 [MH].sup.+ Elemental Analysis:
Found C 57.8 H 5.2 N 19.3 C.sub.14H.sub.14N.sub.4O.sub.3H.sub.2O
Requires C 57.7 H 5.1 N 19.2% A mixture of
7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one
(412 mg, 1.44 mmol), thionyl chloride (5 ml) and DMF (0.2 ml) was
heated at reflux for 1 hour. The mixture was diluted with toluene
and the volatiles were removed by evaporation. The residue was
suspended in methylene chloride, cooled to 0.degree.C and aqueous
sodium hydrogen carbonate solution was added. The resulting
precipitate was collected by filtration and dried under vacuum to
give 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinzazoine (258
mg, 59%). .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.01 (s, 3H); 4.47
(m, 2H); 4.53 (m, 2H); 6.89 (s, 1H); 7.27 (s, 1H); 7.41 (s, 1H);
7.49 (s, 1H); 7.70 (s, 1H); 8.88 (s, 1H) MS-ESI: 327 [MNa].sup.+ f
4-Chloro-6-methoxy-7-(3-(1H-1,2,4-triazol-1-yl)propoxy)quinazoline
(61 mg) was reacted with 5-aminoindole in the presence of 6.2 N
hydrogen chloride in isopropanol (4 .mu.l) to give 4-
(indol-5-ylamino)-6-methoxy-7-(3-(1H-1,2,4-triazol-1-yl)propoxy)quinazolin-
e hydrochloride. .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD)
2.5 (m, 2H); 4.0 (s, 3H); 4.3 (t, 2H); 4.6 (t, 2H); 6.52 (d, O.5H
partly exchanged); 7.3 (s, 1H); 7.35 (d, 1H); 7.45 (s, 1H); 7.55
(d, 1H); 7.8 (s, 1H); 8.16 (s, 1H); 8.66 (s, 1H); 8.77 (s, 1H);
9.43 (s, 1H)
EXAMPLE 266
[1635] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (144 mg, 0.43
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (91 mg, 0.66 mmol) and
3-fluoro-7-hydroxyquinoline (77 mg, 0.47 mmol), (prepared as
described for the starting material in Example 157), in DMF (3 ml)
was stirred at 100.degree. C. for 2 hours and then allowed to cool
to ambient temperature. The reaction mixture was evaporated to
dryness and the residue chromatographed on silica eluting with
methanol/dichloromethane/aqueous ammonia (0.880) (5/100/1). The
relevant fractions were combined and evaporated to dryness to give
4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazolin-
e (87 mg, 44%).
[1636] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.37(m, 2H); 1.49(m,
4H); 1.96(m, 2H); 2.34(m, 4H); 2.43(t, 2H); 4.00(s, 3H); 4.23(t,
2H); 7.38(s, 1H); 7.62(s, 1H); 7.69(dd, 1H); 8.00(d, 1H); 8.12(d,
1H); 8.34(dd, 1H); 8.54(s, 1H); 8.98(d, 1H)
[1637] MS (ESI): 463 (MH).sup.+
EXAMPLE 267
[1638] A mixture of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (218
mg, 0.68 mmol), (prepared as described for the starting material in
Example 9), potassium carbonate (138 mg, 1.13 mmol) and
3-fluoro-7-hydroxyquinoline (117 mg, 0.72 mmol), (prepared as
described for the starting material in Example 157), in DMF (4.5
ml) was stirred at 100.degree. C. for 4 hours and then allowed to
cool to ambient temperature. The reaction mixture was evaporated to
dryness and the residue taken up in dichloromethane, washed with
water, brine and dried (MgSO.sub.4). The organic fractions were
evaporated to dryness and the residue recrystallised from
acetonitrile to give
4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)qui-
nazoline (86 mg, 28%).
[1639] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.90(m, 2H); 2.00(m,
2H); 2.27(m, 2H); 3.02(m, 2H); 3.32(m, 2H); 3.59(m, 2H); 4.00(s,
3H); 4.33(t, 2H); 7.43(s, 1H); 7.62(s, 1H); 7.70(dd, 1H); 7.99(d,
1H); 8.11(d, 1H); 8.35(dd, 1H); 8.54(s, 1H); 8.97(d, 1H)
[1640] MS (ESI): 449 (MH).sup.+
EXAMPLE 268
[1641] A mixture of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg,
0.87 mmol), (prepared as described in Example 49), potassium
carbonate (370 mg, 2.68 mmol) and
4-(1-methyl-2-oxopiperidin-4-yl)methyl-4-toluene sulphonate (260
mg, 0.87 mmol) in DMF (8 ml) was stirred at 95.degree. C. for 4
hours and allowed to cool to ambient temperature. The reaction
mixture was diluted with acetone, filtered and the filtrate
evaporated `in vacuo` to give a residue which was purified by
column chromatography, eluting with dichloromethane/methanol/0.88
ammonia (100/8/1). The relevant fractions were combined and
evaporated `in vacuo` to give an oil which crystallised on
trituration with diethyl ether to give
6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-methyl-2-oxopiperidin-4-ylmethox-
y)quinazoline (66 mg, 17%).
[1642] m. p. 250-251.degree. C.
[1643] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.66 (m, 1H), 2.10 (m,
2H), 2.40 (s, 3H), 2.50 (m, 2H), 2.84 (s, 3H), 3.34 (m, 2H), 3.99
(s, 3H), 4.12 (d, 2H), 6.12 (s, 1H), 6.86 (m, 1H), 7.25 (d, 1H),
7.30 (d, 1H), 7.38 (s, 1H), 7.59 (s, 1H), 8.48 (s, 1H) and 10.98
(brs, 1H).
[1644] MS (ESI): 447 (MH).sup.+ TABLE-US-00116 Elemental analysis
Found C 66.8 H 5.9 N 12.4 C.sub.25H.sub.26N.sub.4O.sub.40.2H.sub.2O
Requires C 66.7 H 5.9 N 12.5%
[1645] The starting material was prepared as follows:
[1646] A solution of 4-hydroxymethyl-1-methyl-2-piperidone (120 mg,
0.84 mmol), 5 (Yakugaku Zasshi 88, (5), 573-582, (1968)), in
dichloromethane was treated with triethylamine (187 mg, 1.85 mmol)
followed by p-toluenesulphonyl chloride (176 mg, 0.92 mmol) and the
mixture stirred at ambient temperature overnight. The reaction
mixture was diluted with dichloromethane and washed successively
with aqueous sodium hydrogen carbonate, water and brine. The
dichloromethane solution was dried over magnesium sulphate,
filtered and the filtrate evaporated `in vacuo` to give a dark oily
residue. This was washed several times with diethyl ether to remove
the product from insoluble impurities, the washings combined and
evaporated `in vacuo` to give
4-(1-methyl-2-oxopiperidin4-yl)methyl-4-toluene sulphonate as a
light brown oil (130 mg, 52%). This was used without further
purification.
[1647] MS (ESI): 298 (MH).sup.+ and impurities
EXAMPLE 269
[1648] A mixture of
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (300 mg, 0.79 mmol), and 1-methylpiperazine (0.26 ml, 2.38 mmol)
in DMF (10 ml) was stirred at 70.degree. C. for 24 hours and
allowed to cool to ambient temperature. The solvents were removed
in vacuo and the residue purified by silica column chromatography,
gradient elution (dichloromethane, 5% methanol/95% dichloromethane,
dichloromethane/methanol/0.88 amnmonia (100/8/1) and evaporated in
vacuo to give
(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4--
(2-methylindol-5-yloxy)quinazoline (344 mg, 91%).
[1649] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.10 (s, 3H), 2.4 (m,
13H), 3.98 (s, 3H), 4.06 (m, 3H), 4.90 (br s, 1H), 6.12 (s, 1H),
6.85 (dd, 1H), 7.3 (m, 2H), 7.58 (s, 1H), 8.42 (s, 1H) and 10.98
(br s, 1H)
[1650] MS (ESI): 478 (MH).sup.+ TABLE-US-00117 Elemental analysis:
Found C 61.3 H 6.3 N 13.8
C.sub.26H.sub.30N.sub.4O.sub.40.2H.sub.2O.0.5dichloromethane
Requires C 61.9 H 6.2 N 13.4%
[1651] The starting material was prepared as follows:
[1652] A mixture of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (300 mg,
0.93 mmol), (prepared as described in Example 49), potassium
carbonate (385 mg, 2.79 mmol) and (2R)-(-)- glycidyl tosylate (426
mg, 2.79 mmol) in DMF (15 ml) was stirred at 60.degree. C. for 2
hours and allowed to cool to ambient temperature. The reaction
mixture was filtered and the filtrate exaporated in vacuo. The
residue was dissolved in dichloromethane and washed with saturated
sodium hydrogen carbonate solution. The organic layer was then
dried (MgSO.sub.4), filtered and the solvent removed in vacuo to
give a yellow solid. This was triturated with ether, filtered off
and dried to give
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e as a yellow solid (185 mg, 53%).
[1653] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.75 (m,
1H), 2.90 (m, 1H), 3.40 (m, 1H), 3.98 (s, 3H), 4.05 (m, 1H), 4.60
(m, 1H), 6.15 (s, 1H), 6.85 (dd, 1H), 7.30 (m, 2H) 7.40 (s, 1H),
7.60 (s, 1H), 8.45 (s, 1H) and 10.98 (s, 1H)
[1654] MS (ESI): 378 (MH).sup.+
EXAMPLE 270
[1655] A mixture of
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (300 mg, 0.79 mmol), (prepared as described for the starting
material in Example 269), and diethylamine (0.25 ml, 2.38 mmol) in
DMF (10 ml) was stirred at 70 .degree. C. for 24 hours and allowed
to cool to ambient temperature. The solvents were removed in vacuo
and the residue purified by silica column chromatography, gradient
elution (dichloromethane, 5% methanol/95% dichloromethane,
dichloromethane/methanol/0.88 ammonia (100/8/1)) to give
(2R)-7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-
-5-yloxy)quinazoline (288 mg, 81%).
[1656] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 0.95 (t, 6H), 2.10 (s,
3H), 2.4 (m, 6H), 3.98 (s, 3H), 4.14 (m, 3H), 4.84 (br s, 1H), 6.12
(s, 1H), 6.85 (dd, 1H), 7.3 (m, 3H), 7.58 (s, 1H), 8.42 (s, 1H) and
10.98 (br s, 1H)
[1657] MS (ESI): 448 (MH).sup.+ TABLE-US-00118 Elemental analysis:
Found C 64.3 H 6.6 N 12.0
C.sub.25H.sub.30N.sub.4O.sub.40.4dichloromethane Requires C 64.0 H
6.4 N 11.6%
EXAMPLE 271
[1658] A mixture of
7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (7.76 g,
18.9 mmol), ammonium formate (17.82 g, 282 mmol) and 10% palladium
on charcoal (800 mg) in DMF (350 ml) was stirred at ambient
temperature for 1 hour. The catalyst was filtered off through
celite and the cake washed with DMF. The solvent was removed in
vacuo and the residue stirred with a saturated solution of sodium
hydrogen carbonate for 2 hours. The suspension was then filtered,
washed with water and dried to give
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (5.49 g,
91%).
[1659] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.20 (s, 3H), 3.98 (s,
3H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.35 (m, 3H), 7.58
(s, 1H), 8.40 (s, 1H) and 10.82 (br s, 1H)
[1660] MS (ESI): 322 (MH).sup.+
[1661] The starting material was prepared as follows:
[1662] A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline
(7.859 g, 26.1 mmol), (prepared as described for the starting
material in Example 1), potassium carbonate (18.03 g, 130 mmol) and
5-hydroxy-3-methylindole (5.00 g, 34.0 mmol), (Journal of Organic
Chemistry 1993, 58, 3757 ), in DMA (600 ml) was stirred at 75
.degree. C. for 2 hours and allowed to cool to ambient temperature.
The reaction mixture was filtered and the filtrate evaporated in
vacuo. The crude solid was purified by silica column
chromatography, eluting with 2.5% methanol/97.5% dichloromethane to
give 7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline
(7.791 g, 73%). p
[1663] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.30 (s, 3H), 4.10 (s,
3H), 5.36 (s, 2H), 7.04 (m, 2H), 7.43 (m, 8H), 7.62 (s, 1H), 8.02
(s, 1H), and 8.60 (s, 1H)
[1664] MS (ESI): 412 (MH).sup.+
EXAMPLE 272
[1665] A mixture of
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (800 mg,
2.49 mmol), (prepared as described in Example 271), potassium
carbonate (687 mg, 4.98 mmol) and 1-chloro-3-morpholinopropane (448
mg, 2.74 mmol), (prepared as described for the starting material in
Example 1), in DMF (20 ml) was stirred at 80 .degree. C. for 2
hours and allowed to cool to ambient temperature. The reaction
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica column chromatography, gradient
elution (dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
and the product was recrystallised from ethanol to give
6-methoxy-4-3-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline
(570 mg, 51%).
[1666] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.98 (m, 2H), 2.20 (s,
3H), 2.40 (t, 4H), 2.50 (m, 2H), 3.60 (t, 4H), 3.98 (s, 3H), 4.20
(t, 2H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H),
8.45 (s, 1H), and 10.82 (br s, 1H)
[1667] MS (ESI): 449 (MH).sup.+ TABLE-US-00119 Elemental analysis:
Found C 64.2 H 6.0 N 11.8
C.sub.25H.sub.28N.sub.4O.sub.40.7H.sub.2O0.7ethanol Requires C 64.2
H 6.9 N 11.4%
EXAMPLE 273
[1668] A mixture of
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (800 mg,
2.49 mmol), (prepared as described for the starting material in
Example 271), potassium carbonate (1.031 g, 7.47 mmol) and
4-(2-chloroethyl)morpholine hydrochloride (510 mg, 2.74 mmol) in
DMF (25 ml) was stirred at 80 .degree. C. for 2 hours and allowed
to cool to ambient temperature. The reaction mixture was filtered
and the filtrate removed in vacuo. The residue was purified by
silica column chromatography, gradient elution (dichloromethane, 5%
methanol/95% dichloromethane, methanol/dichloromethane/0.880
saturated aqueous ammonia (100/8/1)) and the product recrystallised
from ethanol to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline
(510 mg, 47%).
[1669] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.20 (s, 3H), 2.55 (t,
4H), 2.80 (t, 2H), 3.60 (t, 4H), 3.98 (s, 3H), 4.30 (t, 2H), 6.98
(dd, 1H), 7.18 (s, 1H), 7.35 (m, 2H), 7.40 (s, 1H), 7.60 (s, 1H),
8.45 (s, 1H), and 10.82 (br s, 1H)
[1670] MS (ESI): 449 (MH).sup.+ TABLE-US-00120 Elemental analysis:
Found C 64.1 H 6.3 N 12.2
C.sub.24H.sub.26N.sub.4O.sub.40.4H.sub.2O0.8ethanol Requires C 64.3
H 6.1 N 11.7%
EXAMPLE 274
[1671] A mixture of
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.00 g,
3.11 mmol), (prepared as described for the starting material in
Example 271), potassium carbonate (1.288 g, 9.33 mmol) and
4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine
(1.264 g, 3.42 mmol), (prepared as described for the starting
material in Example 10), in DMF (35 ml) was stirred at 80.degree.
C. for 2 hours and allowed to cool to ambient temperature. The
reaction mixture was filtered and the solvent removed in vacuo. The
residue was purified by silica column chromatography, 5%
methanol/95% dichloromethane and the product was recrystallised
from ethanol to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-y-
lmethoxy)quinazoline (1.011 g, 63%).
[1672] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.3 (m, 4H), 1.42 (s,
9H), 1.90 (d, 2H), 2.10 (m, 1H), 2.28 (s, 3H), 2.80 (m, 2H), 3.98
(s, 3H), 4.08 (d, 2H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H),
7.60 (s, 1H), 8.45 (s, 1H), and 10.82 (br s, 1H)
[1673] MS (ESI): 519 (MH).sup.+
EXAMPLE 275
[1674] A mixture of
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (600 mg,
1.87 mmol), (prepared as described for the starting material in
Example 271), potassium carbonate (773 mg, 5.60 mmol) and
3-(1,1-dioxothiomorphlino)propoxy tosylate (1.296 g, 3.74 mmol) in
DMF (30 ml) was stirred at 75.degree. C. overnight and allowed to
cool to ambient temperature. The reaction mixture was filtered and
the solvent removed in vacuo. The residue was purified by silica
column chromatography, gradient elution (dichloromethane, 5%
methanol/95% dichloromethane, methanol/dichloromethane/0.880
saturated aqueous ammonia (100/8/1)) and the product recrystallised
from ethanol to give
7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy-
)quinazoline (525 mg, 56%).
[1675] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.98 (m, 2H), 2.17 (s,
3H), 2.65 (t, 2H), 2.90 (t, 4H), 3.10 (t, 4H), 3.98 (s, 3H), 4.25
(t, 2H), 6.95 (dd, 1H), 7.15 (s, 1H), 7.30 (d, 1H), 7.35 (m, 2H),
7.60 (s, 1H), 8.45 (s, 1H), and 10.82 (br s, 1H)
[1676] MS (ESI): 497 (MH).sup.+ TABLE-US-00121 Elemental analysis:
Found C 58.4 H 5.5 N 11.1
C.sub.25H.sub.28N.sub.4O.sub.5S0.8H.sub.2O Requires C 58.8 H 5.8 N
11.0%
EXAMPLE 276
[1677] A mixture of
6-methoxy-4-3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-yl-
methoxy)quinazoline (1.290 g, 2.49 mmol), (prepared as described in
Example 274), in 25% trifluoroacetic acid/75% dichloromethane
solution (75 ml) was stirred at ambient temperature for 2 hours.
The solvents were then removed in vacuo and the dark yellow gum
triturated with concentrated ammonia. The resulting solid was
filtered off and dried to give
6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazo-
line (648 mg, 62%).
[1678] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.35 (m, 2H), 1.80 (m,
2H), 2.05 (m, 1H), 2.10 (s, 3H), 2.70 (m, 2H), 3.10 (m, 2H), 3.98
(s, 3H), 4.05 (d, 2H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.34 (m, 3H),
7.60 (s, 1H), 8.45 (s, 1H), and 10.82 (br s, 1H)
[1679] MS (ESI): 419 (MH).sup.+
EXAMPLE 277
[1680] A mixture of
6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin4-ylmethoxy)quinazoline
(460 mg, 1.10 mmol), (prepared as described in Example 276),
triethylamine (5 ml) and chloroacetonitrile (0.38 ml, 6.05 mmol) in
methanol (5 ml) was stirred at ambient temperature for 24 hours.
The solvents were removed in vacuo and the residue purified by
silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
and the product recrystallised from acetonitrile to give
7-(1-cyanomethylpiperidin-4-ylmethoxy)-6-methoxy-4-(3-methylindol-5-yloxy-
)quinazoline (178 mg,35%).
[1681] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.40 (m, 2H), 1.80 (m,
4H), 2.20 (m, 4H), 2.81 (m, 2H), 3.65 (s, 2H), 3.98 (s, 3H), 4.05
(d, 2H), 6.98 (dd, 1H), 7.15 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H),
8.45 (s, 1H), and 10.83 (br s, 1H)
[1682] MS (ESI): 458 (MH.sup.+ TABLE-US-00122 Elemental analysis:
Found C 66.3 H 6.1 N 14.8 C.sub.26H.sub.27N.sub.5O.sub.30.7H.sub.2O
Requires C 66.4 H 6.1 N 14.9%
EXAMPLE 278
[1683] A mixture of
7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.35 g,
4.2 mmol), (prepared as described for the starting material in
Example 271), potassium carbonate (1.74 g, 12.6 mmol) and
(2R)-(-)-glycidyl tosylate (1.92 g, 8.4 mmol) in DMF (25 ml) was
stirred at 60.degree. C. for 2 hours and allowed to cool to ambient
temperature. The reaction mixture was filtered and the solvent
removed in vacuo. The residue was dissolved in dichloromethane and
washed with saturated sodium hydrogen carbonate solution. The
organic layer was then dried (MgSO.sub.4), filtered and solvent
removed in vacuo to give a solid. This was triturated with ether
and the solid filtered off and dried to give
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (842 mg, 53%).
[1684] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.20 (s, 3H), 2.80 (m,
1H), 2.90 (m, 1H), 3.42 (m, 1H), 3.42 (m, 1H), 3.98 (s, 3H), 4.02
(m, 1H), 4.60 (m, 1H), 6.98 (dd, 1H), 7.18 (s, 1H) 7.35 (m, 3H),
7.60 (s, 1H), 8.45 (s, 1H) and 10.82 (s, 1H)
[1685] MS (ESI): 378 (MH).sup.+
EXAMPLE 279
[1686] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (300 mg, 0.65 mmol), (prepared as described in Example 278), and
piperidine (0.2 ml, 2.04 mmol) in DMF (5 ml) was stirred at
60.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography, gradient elution
(dichloromethane, 5% methanol/95% dichloromethane, 1% 0.880
saturated aqueous ammonia/10% methanol/89% dichloromethane)
(2R)-7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy-
)quinazoline (237 mg, 78%).
[1687] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.38 (m, 2H), 1.50 (m,
4H), 2.34 (m, 9H), 3.98 (s, 3H), 4.16 (m, 3H), 4.85 (br s, 1H),
6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.4 (s,
1H) and 10.82 (brs, 1H)
[1688] MS (ESI): 464 (MH).sup.+ TABLE-US-00123 Elemental analysis:
Found C 66.3 H 6.6 N 12.1 C.sub.26H.sub.30N.sub.4O.sub.40.5methanol
Requires C 66.5 H 6.7 N 11.7%
EXAMPLE 280
[1689] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (300 mg, 0.65 mmol), (prepared as described in Example 278), and
pyrrolidine (0.17 ml, 2.04 mmol) in DMF (5 ml) was stirred at
60.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol--
5-yloxy)quinazoline (257 mg, 88%).
[1690] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.65 (m, 4H), 1.98 (m,
2H), 2.20 (s, 3H), 2.50 (m, 2H), 2.62 (m, 2H), 3.98 (s, 3H), 4.17
(m, 3H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H),
8.42 (s, 1H) and 10.82 (br s, 1H)
[1691] MS (ESI): 449 (MH).sup.+ TABLE-US-00124 Elemental analysis:
Found C 64.1 H 6.4 N 12.6 C.sub.25H.sub.28N.sub.4O.sub.41.0H.sub.2O
Requires C 64.4 H 6.5 N 12.0%
EXAMPLE 281
[1692] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
1-methylpiperazine (0.31 ml, 2.78 mmol) in DMF (5 ml) was stirred
at 60.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(3-methy-
lindol-5-yloxy)quinazoline (352 mg, 80%).
[1693] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.10 (s, 3H), 2.20 (s,
3H), 2.40 (m, 10H), 3.98 (s, 3H), 4.13 (m, 3H), 6.98 (dd, 1H), 7.18
(s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82 (br s,
1H)
[1694] MS (ESI): 478 (MH).sup.+ TABLE-US-00125 Elemental analysis:
Found C 61.6 H 6.4 N 14.4
C.sub.26H.sub.31N.sub.5O.sub.41.0H.sub.2O.0.25Methanol Requires C
61.6 H 6.8 N 13.9%
EXAMPLE 282
[1695] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
morpholine (0.24 ml. 2.78 mmol) in DMF (5 ml) was stirred at
60.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy-
)quinazoline (398 mg, 93%).
[1696] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.20 (s, 3H), 2.44 (m,
6H), 3.48 (t, 4H), 3.98 (s, 3H), 4.13 (m, 3H), 4.98 (br s, 1H),
6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s,
1H) and 10.82 (br s, 1H)
[1697] MS (ESI): 465 (MH).sup.+ TABLE-US-00126 Elemental analysis:
Found C 58.5 H 6.0 N 11.2
C.sub.25H.sub.28N.sub.4O.sub.52.5H.sub.2O. Requires C 58.9 H 6.5 N
11.0%
EXAMPLE 283
[1698] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
2.0 M dimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml)
was stirred at 60.degree. C. for 24 hours and allowed to cool to
ambient temperature. The solvents were removed in vacuo and the
residue purified by silica column chromatography, gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yl-
oxy)quinazoline (308 mg, 78%). ,
[1699] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 2.10 (m, 9H), 2.20 (m,
2H), 3.98 (s, 3H), 4.13 (m, 3H), 4.98 (br s, 1H), 6.98 (dd, 1H),
7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H) and 10.82
(br s, 1H)
[1700] MS (ESI): 423 (MH).sup.+ TABLE-US-00127 Elemental analysis:
Found C 65.5 H 6.2 N 13.2 C.sub.23H.sub.20N.sub.4O.sub.4 Requires C
65.4 H 6.2 N 13.3%
EXAMPLE 284
[1701] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
diethylamine (0.29 ml. 2.78 mmol) in DMF (5 ml) was stirred at
60.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-((N,N-diethylamino)propoxy))-6-methoxy-4-(3-methylind-
ol-5-yloxy)quinazoline (338 mg, 81%).
[1702] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 0.95 (t, 6H), 2.11 (s,
3H), 2.40 (m, 6H), 3.98 (s, 3H), 4.13 (m, 3H), 4.84 (br s, 1H),
6.98 (dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), and 10.82
(br s, 1H)
[1703] MS (ESI): 451 (MH).sup.+ TABLE-US-00128 Elemental analysis:
Found C 64.4 H 6.6 N 12.0
C.sub.25H.sub.30N.sub.4O.sub.41.0H.sub.2O. Requires C 64.1 H 6.9 N
12.0%
EXAMPLE 285
[1704] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
isopropylamine (0.29 ml, 4.65 mmol) in DMF (5 ml) was stirred at
100.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-
-yloxy)quinazoline (307 mg, 75%).
[1705] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 0.98 (d, 6H), 2.20 (s,
3H), 2.55-2.80 (m, 3H), 3.98 (s, 3H), 4.02-4.20 (m, 3H), 4.98 (br
s, 1H), 6.98 (dd, 1H), 7.18 (s, 1H), 7.30-7.40 (m, 3H), 7.60 (s,
1H), 8.42 (s, 1H) and 10.82 (br s, 1H)
[1706] MS (ESI): 437 (MH).sup.+ TABLE-US-00129 Elemental analysis:
Found C 63.3 H 6.3 N 12.4
C.sub.24H.sub.28N.sub.4O.sub.41.0H.sub.2O. Requires C 63.4 H 6.7 N
12.3%
EXAMPLE 286
[1707] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (350 mg, 0.93 mmol), (prepared as described in Example 278), and
diisopropylamine (0.78 ml, 5.58 mmol) in DMF (10 ml) was stirred at
130.degree. C. for 24 hours and allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified by silica column chromatography using gradient elution
(dichloromethane, 5% methanol/95% dichloromethane,
methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1))
to give
(2R)-7-(2-hydroxy-3-(N,N-diisopropyl)amino)propoxy)-6-methoxy-4-(3-methyl-
indol-5yloxy)quinazoline (398 mg, 93%).
[1708] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 0.98 (d, 12H), 2.20 (s,
3H), 2.72 (m, 2H), 3.00 (m, 2H), 3.98 (s, 3H), 4.11 (m, 3H), 6.98
(dd, 1H), 7.18 (s, 1H), 7.35 (m, 3H), 7.60 (s, 1H), 8.42 (s, 1H)
and 10.82 (br s, 1H)
[1709] MS (ESI): 479 (MH).sup.+ TABLE-US-00130 Elemental analysis:
Found C 65.4 H 6.8 N 11.3
C.sub.27H.sub.34N.sub.4O.sub.40.8H.sub.2O. Requires C 55.8 H 7.2 N
11.4%
EXAMPLE 287
[1710] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (100 mg, 0.28 mmol), (prepared as described in Example 278), and
4-(3-aminopropyl)morpholine (0.12 ml, 0.84 mmol) in DMF (5 ml) was
heated to 70.degree. C. for 3 hours. The solvents were removed in
vacuo and the residue taken up in dichloromethane. This was washed
with water, dried (MgSO.sub.3), filtered and evaporated. The
residue was purified by silica column chromatography using gradient
elution (dichloromethane, 5% methanol/95% dichloromethane, 20%
methanolic ammonia (7M)/80% dichloromethane) to give
(2R)-7-(2-hydroxy-3-(3-morpholinopropylamino)propoxy)-6-methoxy-4-(3-meth-
ylindol-5-yloxy)quinazoline (67 mg, 46%).
[1711] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.28 (m, 2H), 2.30 (t,
4H), 2.56 (t, 2H), 2.650 (m, 4H), 3.55 (t, 4H), 3.98 (s, 3H), 4.15
(m, 3H), 6.42 (s, 1H), 6.98 (dd, 1H), 7.42 (m, 4H), 7.60 (s, 1H),
8.45 (s, 1H), and 11.19 (br s, 1H)
[1712] MS (ESI): 508 (MH).sup.+ TABLE-US-00131 Elemental analysis:
Found C 59.7 H 6.6 N 13.4 C.sub.27H.sub.33N.sub.5O.sub.51.8H.sub.2O
Requires C 60.1 H 6.8 N 13.0%
EXAMPLE 288
[1713] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (100 mg, 0.28 mmol), (prepared as described in Example 278), and
1-(3-aminopropyl)-4-methylpiperazine (132 mg, 0.84 mmol) in DMF (5
ml) was heated to 70.degree. C. for 3 hours. The solvents were
removed in vacuo and the residue taken up in dichloromethane. This
was washed with water, dried (MgSO.sub.4), filtered and evaporated.
The residue was purified by silica column chromatography using
gradient elution (dichloromethane, 5% methanol/95% dichloromethane,
20% methanolic ammonia (7M)/80% dichloromethane) to give
(2R)-7-(2-hydroxy-3-(3(3-(4-methylpiperazin-1-yl)propylamino)propoxy)-6-m-
ethoxy-4-(3-methylindol-5-yloxy)quinazoline (44 mg, 31%).
[1714] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.55 (m, 2H), 2.10 (s,
3H), 2.30 (t, 8H), 2.62 (m, 6H), 3.98 (s, 3H), 4.12 (m, 3H), 6.42
(s, 1H), 6.98 (dd, 1H), 7.42 (m, 4H), 7.60 (s, 1H), 8.45 (s, 1H),
and 11.19 (brs, 1H)
[1715] MS (ESI): 521 (MH).sup.+ TABLE-US-00132 Elemental analysis:
Found C 61.3 H 7.3 N 16.1 C.sub.28H.sub.36N.sub.6O.sub.41.6H.sub.2O
Requires C 61.2 H 7.2 N 16.3%
EXAMPLE 289
[1716] A mixture of
(2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (70 mg, 0.19 mmol), (prepared as described in Example 278), and
1-(3-aminopropyl)pyrrolidine (74 mg, 0.58 mmol) in DMF (5 ml) was
heated to 60.degree. C. overnight. The solvents were removed in
vacuo and the residue purified by column chromatography using
gradient elution (dichloromethane, 5% methanoy/95% dichloromethane,
20% methanolic ammonia (7M)/80% dichloromethane) to give
(2R)-7-(2-hydroxy-3-(3-(pyrrolidin-1-yl)propylamino)propoxy)-6-methoxy-4--
(3-methylindol-5-yloxy)quinazoline (64 mg, 68%).
[1717] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.60 (m, 6H), 2.25 (m,
4H), 2.60 (m, 4H), 3.08 (m, 2H), 3.98 (s, 3H), 4.12 (m, 3H), 6.42
(s, 1H), 6.98 (dd, 1H), 7.34 (m, 4H), 7.58 (s, 1H), 8.42 (s, 1H),
and 11.80 (brs, 1H)
[1718] MS (ESI): 492 (MH).sup.+
EXAMPLE 290
[1719] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (380 mg, 1.13
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (469 mg, 3.4 mmol),
4-bromo-5-hydroxyindole (240 mg, 1.13 mmol) and DMA (4.0 ml) were
stirred at 90.degree. C. for 3 hours and allowed to cool to ambient
temperature. The reaction mixture was filtered and the filtrate
evaporated under vacuum. The residue was purified by column
chromatography eluting with dichloromethane/methanolic ammonia (7M)
(95/5) to give an oil. This oil was further purified by column
chromatography eluting with dichloromethane/methanol (60/40) to
give
4-(4-bromoindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(256 mg, 44%).
[1720] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.47 (m, 2H), 1.60 (m,
4H), 2.14 (m, 2H), 2.44 (m, 4H), 2.54 (t, 2H), 4.08 (s, 3H), 4.27
(t, 2H), 6.67 (m, 1H), 7.15 (d, 1H), 7.32 (t, 1H), 7.36 (s, 1H),
7.42 (d, 1H), 7.69 (s, 1H) 8.55 (br s, 1H) and 8.62 (s, 1H)
[1721] MS (ESI): 511, 513 (MH).sup.+ TABLE-US-00133 Elemental
analysis Found C 58.2 H 5.3 N 10.8
C.sub.25H.sub.27BrN.sub.4O.sub.30.25H.sub.2O, Requires C 58.2 H 5.4
N 10.9%
[1722] The starting material was prepared as follows:
[1723] Ethyl 4-bromo-5-hydroxyindole-2-carboxylate (1.49 g, 5
mmol.), (Jnl. Org. Chem. 1984, 49, 4761), was dissolved in ethanol
(10 ml) and water (3.5 ml). Potassium hydroxide (840 mg) was added
and the mixture stirred at 50.degree. C. under an atmosphere of
nitrogen for 1 hour then cooled to ambient temperature. The solvent
was evaporated and the residue re-dissolved in water (25 ml). 2M
Aqueous hydrochloric acid was added until the reaction mixture was
at pH4, giving a precipitate which was filtered off, washes with
water and dried under vacuum to give
4-bromo-5-methoxyindole-2-carboxylic acid (1.30, 96%).
[1724] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 3.83 (s, 3H), 6.90 (d,
1H), 7.16 (d, 1H), 7.40 (d, 1H), 11.88 (br s, 1H) and 13.19 (br s,
1H)
[1725] MS (ESI): 268, 270 (M-H)
[1726] 4-Bromo-5-methoxyindole-2-carboxylic acid (1.25 g,4.19
mmol), quinoline (15 ml) and copper chromite (313 mg) were mixed
together. Nitrogen was gently bubbled through the mixture for 5
minutes, then the mixture heated quickly to 245.degree. C. under an
atmosphere of nitrogen. After 90 minutes the mixture was cooled to
ambient temperature diluted with ethyl acetate (100 ml) and washed
with 2M aqueous hydrochloric acid (60 ml). The ethyl acetate layer
was filtered, the filtrate dried (MgSO.sub.4) and the solvent
evaporated. The residue was purified by silica column
chromatography eluting with dichloromethane/hexane (1/1) to give
4-bromo-5-methoxyindole (635 mg, 60%).
[1727] .sup.1H NMR Spectrum (CDCl.sub.3) 3.94 (s, 3H), 6.55 (m,
1H), 6.93 (d, 1H), 7.27 (m, 2H). 8.18 (br s, 1H)
[1728] MS (ESI): 224, 226 (M-H).sup.31
[1729] A solution of 4-bromo-5-methoxyindole (540 mg, 2.4 mmol) in
dichloromethane (12 ml) was cooled to -40.degree. C. under an
atmosphere of nitrogen. Boron tribromide (4.8 ml of a 1M solution
in dichloromethane, 4.8 mmol) was added dropwise then the mixture
warmed to ambient temperature and stirred for 1 hour. The mixture
was diluted with dichloromethane (5 ml) and washed with 2M aqueous
hydrochloric acid (3 ml). The organic layer was separated, dried
(MgSO.sub.4) and evaporated to give a dark oil. This was purified
by silica column chromatography eluting with dichloromethane/ethyl
acetate (8/2) to give 4-bromo-5-hydroxyindole (295 mg, 55%).
[1730] .sup.1H NMR Spectrum: (CDCl.sub.3) 6.46 (m, 1H), 7.92 (d,
1H), 7.22 (m, 2H), 8.80 (br s, 1H)
[1731] MS (ESI): 210, 212 (M-H).sup.-
EXAMPLE 291
[1732] Nitrogen was bubbled through a mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (335 mg, 0.68
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (281.5 mg, 2.04 mmol),
5-hydroxy-1-methylindole (100 mg, 0.68 mmol) and DMA (4.0 ml) for 5
minutes. The mixture was then stirred at 90.degree. C. for 4 hours
under an atmosphere of nitrogen and allowed to cool to ambient
temperature. The reaction mixture was filtered and the filtrate
evaporated under vacuum. The residue was purified by trituration
with methanol then water to give
6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline
(148 mg, 49%).
[1733] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.38 (m, 2H), 1.51 (m,
4H), 1.93 (m, 2H), 2.35 (m, 4H), 2.41 (t, 2H), 3.83 (s, 3H), 3.97
(s, 3H), 4.24 (t, 2H), 6.42 (d, 1H), 7.06 (dd, 1H), 7.33 (s, 1H),
7.42 (m, 2H), 7.50 (d, 1H), 7.59 (s, 1H) and 8.47 (s, 1H)
[1734] MS (ESI): 447 (MH).sup.+ TABLE-US-00134 Elemental analysis
Found C 69.5 H 6.8 N 12.5 C.sub.26H.sub.30N.sub.4O.sub.3 Requires C
69.9 H 6.8 N 12.6%
[1735] The starting material was prepared as follows:
[1736] A solution of 5-benzyloxy-1-methylindole (3.5 g, 15.7 mmol),
in ethanol (100 ml) was hydrogenated at ambient temperature and I
atmosphere pressure hydrogen for 4 hours using 10% palladium on
carbon (0.5 g) as catalyst. The catalyst was filtered off and the
filtrate evaporated in vacuo. The residue was purified by silica
column chromatography eluting with ethyl acetate/dichloromethane
(10/90) to give 5-hydroxy-1-methylindole (2.1 g, 97%).
[1737] MS (ESI): 146 (M-H).sup.-
[1738] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.74 (s, 3H), 4.50 (S,
1H), 6.33 (d, 1H), 6.79 (dd, 1H), 7.00 (m, 2H), 7.17 (d, 1H)
EXAMPLE 292
[1739] A mixture of
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(300 mg, 0.83 mmol), and pyrrolidine (176 mg, 2.48 mmol) in DMF (5
ml) was stirred at 75.degree. C. for 3 hours under an atmosphere of
nitrogen and allowed to cool to ambient temperature. The solvents
were removed in vacuo and the residue purified on silica gel,
gradient elution with dichloromethane, dichloromethane/methanol
(95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to
give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxy-
quinazoline (326 mg, 87%).
[1740] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.80 (m, 4H), 2.56 (m,
3H), 2.71 (m, 2H), 2.87 (m, 1H), 4.04 (s, 3H), 4.23 (m, 3H), 6.59
(m, 1H), 7.07 (dd, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H),
7.50 (d, 1H), 7.61 (s, 1H), 8.30 (br s, 1H) and 8.60 (s, 1H)
[1741] MS (ESI): 435(MH).sup.+ TABLE-US-00135 Elemental analysis
Found C 63.4 H 5.9 N 12.3 C.sub.24H.sub.26N.sub.4O.sub.4.1H.sub.2O
Requires C 63.7 H 6.2 N 12.4%
[1742] The starting material was prepared as follows:
[1743] Nitrogen was bubbled through a mixture of
7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol),
(prepared as described for the starting material in Example 107),
potassium carbonate (4.14 g, 30 mmol) and (2R)-(-)-glycidyl
tosylate (4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. The
mixture was then stirred at 60.degree. C. for 2 hours under an
atmosphere of nitrogen and allowed to cool to ambient temperature.
The reaction mixture was filtered and the filtrate evaporated in
vacuo. The residue was purified by column chromatography on silica
by gradient elution with dichloromethane/methanol (100/0 to 95/5),
to give
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
as a yellow solid (1.92 g, 53%).
[1744] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.75 (m, 1H), 2.89 (m,
1H), 3.44 (m, 1H), 3.97 (s, 3H), 4.06 (m, 1H), 4.58 (dd, 1H), 6.44
(m, 1H), 6.95 (dd, 1H), 7.40 (m, 4H) 7.62 (s, 1H), 8.47 (s, 1H),
11.19 (br s 1H)
[1745] MS (ESI): 364 (MH).sup.+
EXAMPLE 293
[1746] Using an analogous procedure to that described in Example
292,
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(300 mg, 0.83 mmol), (prepared as described for the starting
material in Example 292), was reacted with morpholine (211 mg, 2.49
mmol) to give
(2R)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line (338 mg, 85%).
[1747] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.48 (m, 2H), 2.624 (m,
2H), 2.68 (m, 2H), 3.78 (m, 4H), 4.04 (s, 3H), 4.24 (m, 3H), 6.58
(m, 1H), 7.08 (dd, 1H), 7.29 (m, 1H), 7.34 (s, 1H), 7.46 (d, 1H),
7.50 (d, 1H), 7.62 (s, 1H), 8.31 (br s, 1H) and 8.62 (s, 1H)
[1748] MS (ESI): 451(MH).sup.+ TABLE-US-00136 Elemental analysis
Found C 60.3 H 5.9 N 12.3
C.sub.24H.sub.26N.sub.4O.sub.5.1.5H.sub.2O Requires C 60.4 H 6.1 N
11.7%
EXAMPLE 294
[1749] Using an analogous procedure to that described in Example
292,
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(300 mg, 0.83 mmol), (prepared as described for the starting
material in Example 292), was reacted with piperidine (211 mg, 2.49
mmol) to give
(2R)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line (325 mg, 86%).
[1750] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.47 (m, 2H), 1.61 (m,
4H), 2.39 (m, 2H), 2.54 (d, 2H), 2.64 (m, 2H), 4.04 (s, 3H), 4.24
(m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H), 7.29 (m, 1H), 7.32 (s, 1H),
7.45 (d, 1H), 7.48 (d, 1H), 7.62 (s, 1H), 8.28 (br s, 1H) and 8.60
(s, 1H)
[1751] MS (ESI): 449 (MH).sup.+ TABLE-US-00137 Elemental analysis
Found C 65.9 H 6.3 N 12.3
C.sub.25H.sub.28N.sub.4O.sub.4.0.5H.sub.2O Requires C 65.6 H 6.4 N
12.3%
EXAMPLE 295
[1752] A mixture of
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(300 mg, 0.83 mmol), (prepared as described for the starting
material in Example 292), and dimethylamine (1.24 ml of a 2M
solution in THF, 2.48 mmol) in DMF (5 ml) was stirred at 75.degree.
C. for 3 hours under an atmosphere of nitrogen then allowed to cool
to ambient temperature. The solvents were removed in vacuo and the
residue purified by trituration with methanol to give
(2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquin-
azoline (265 mg, 63%).
[1753] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.21 (s, 6H), 2.38 (m,
2H), 3.97 (s, 3H), 4.073 (m, 2H), 4.21 (m, 1H), 4.96 (d, 1H), 6.43
(m, 1H), 6.97 (dd, 1H), 7.37 (s, 1H), 7.43 (m, 3H), 7.62 (s, 1H),
8.48 (s, 1H) and 11.20 (br s, 1H)
[1754] MS (ESI): 409(MH).sup.+ TABLE-US-00138 Elemental analysis
Found C 62.8 H 5.8 N 13.2
C.sub.22H.sub.24N.sub.4O.sub.4.0.7H.sub.2O Requires C 62.8 H 6.1 N
13.3%
EXAMPLE 296
[1755] A mixture of
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(300 mg, 0.83 mmol), (prepared as described for the starting
material in Example 292), and diisopropylamine (1.35 ml, 9.7 mmol)
in DMF (5 ml) was stirred at 70.degree. C. for 19 hours under an
atmosphere of nitrogen then allowed to cool to ambient temperature.
The solvents were removed in vacuo and the residue purified on
silica gel using gradient elution with dichloromethane,
dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia
(7M) (98/2 to 90/10) to give
(2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6--
methoxyquinazoline (343 mg, 86%).
[1756] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.08 (m, 12H), 1.57 (m,
1H), 1.75 (m, 1H), 3.10 (m, 2H), 4.04 (s, 3H), 4.16 (m, 3H), 6.58
(m, 1H), 7.08 (dd, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H),
7.50 (d, 1H), 7.61 (s, 1H), 8.32 (br s, 1H) and 8.61 (s, 1H)
[1757] MS (ESI): 465(MH).sup.+ TABLE-US-00139 Elemental analysis
Found C 64.8 H 6.8 N 11.9
C.sub.26H.sub.32N.sub.4O.sub.4.1.0H.sub.2O Requires C 64.6 H 7.0 N
11.6%
EXAMPLE 297
[1758] A mixture of
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), and pyrrolidine (60 mg, 0.84 mmol) in DMF (5
ml) was stirred at 75.degree. C. for 3 hours under an atmosphere of
nitrogen and then allowed to cool to ambient temperature. The
solvents were removed in vacuo and the residue purified on silica
gel, gradient elution with dichloromethane,
dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia
(7M) (98/2 to 90/10), to give
(2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxy-
quinazoline (114 mg, 92%).
[1759] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.80 (m, 4H), 2.56 (m,
3H), 2.71 (m, 2H), 2.86 (m, 1H), 4.04 (s, 3H), 4.23 (m, 3H), 6.59
(m, 1H), 7.07 (dd, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H),
7.50 (d, 1H), 7.61 (s, 1H), 8.30 (br s, 1H) and 8.60 (s, 1H)
[1760] MS (ESI): 435(MH).sup.+ TABLE-US-00140 Elemental analysis
Found C 64.7 H 6.0 N 12.6
C.sub.24H.sub.26N.sub.4O.sub.4.0.5H.sub.2O Requires C 64.9 H 6.1 N
12.7%
[1761] The starting material was prepared as follows:
[1762] Nitrogen was bubbled through a mixture of
7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (3.07 g, 10 mmol),
(prepared as described for the starting material in Example 107),
potassium carbonate (4.14 g, 30 mmol) and (2S)-(+)-glycidyl
tosylate (4.57 g, 20 mmol) in DMA (35 ml) for 5 minutes. This
mixture was then stirred at 60.degree. C. for 2 hours under an
atmosphere of nitrogen and allowed to cool to ambient temperature.
The reaction mixture was filtered and the filtrate evaporated in
vacuo. The residue was purified by column chromatography on silica
by gradient elution with dichloromethane/methanol (100/0 to 95/5),
to give after removal of the solvents in vacuo and trituration of
the residue with ether,
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(1.88 g, 52%) as a yellow solid.
[1763] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.75 (m, 1H), 2.89 (m,
1H), 3.44 (m, 1H), 3.97 (s, 3H), 4.06 (m, 1H), 4.58 (dd, 1H), 6.44
(m, 1H), 6.95 (dd, 1H), 7.46 (m, 4H) 7.62 (s, 1H), 8.47 (s, 1H) and
11.19 (br s 1H)
[1764] MS (ESI): 364 (MH).sup.+
EXAMPLE 298
[1765] Using an analogous procedure to that described in Example
297,
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 297), was reacted with morpholine (73.2 mg,
0.84 mmol) to give
(2S)-7-(2-hydroxy-3-morpholinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line (82 mg, 63%).
[1766] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.48 (m, 2H), 2.62 (m,
2H), 2.68 (m, 2H), 3.78 (m, 4H), 4.04 (s, 3H),4.29 (m, 3H), 6.58
(m, 1H), 7.08 (dd, 1H), 7.29 (m, 1H), 7.34 (s, 1H), 7.46 (d, 1H),
7.50 (d, 1H), 7.62 (s, 1H), 8.31 (br s, 1H) and 8.62 (s, 1H)
[1767] MS (ESI): 451(MH).sup.+ TABLE-US-00141 Elemental analysis
Found C 61.7 H 5.7 N 11.8
C.sub.24H.sub.26N.sub.4O.sub.5.1.0H.sub.2O Requires C 61.5 H 6.0 N
12.0%
EXAMPLE 299
[1768] Using an analogous procedure to that described in Example
297,
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 297), was reacted with piperidine (70 mg, 0.83
mmol), to give
(2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazo-
line (93 mg, 73%).
[1769] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.47 (m, 2H), 1.61 (m,
4H), 2.39 (m, 2H), 2.54 (d, 2H), 2.64 (m, 2H), 4.04 (s, 3H), 4.29
(m, 3H), 6.58 (m, 1H), 7.08 (dd, 1H), 7.29 (m, 1H), 7.32 (s, 1H),
7.45 (d, 1H), 7.48 (d, 1H), 7.62 (s, 1H), 8.28 (br s, 1H) and 8.60
(s, 1H)
[1770] MS (ESI): 449 (MH).sup.+ TABLE-US-00142 Elemental analysis
Found C 65.8 H 6.2 N 12.2
C.sub.25H.sub.28N.sub.4O.sub.4.0.5H.sub.2O Requires C 65.6 H 6.4 N
12.3%
EXAMPLE 300
[1771] A mixture of
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 297), and dimethylamine (0.42 ml of a 2M
solution in THF, 0.84 mmol) in DMF (5 ml) was stirred at 75.degree.
C. for 3 hours under an atmosphere of nitrogen and then allowed to
cool to ambient temperature. The solvents were removed in vacuo and
the residue purified by trituration with methanol to give
(2S)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquin-
azoline (100 mg, 85%).
[1772] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.21 (s, 6H), 2.38 (m,
2H), 3.97 (s, 3H), 4.083 (m, 2H), 4.21 (m, 1H), 4.96 (d, 1H), 6.43
(m, 1H), 6.97 (dd, 1H), 7.37 (s, 1H), 7.43 (m, 3H), 7.62 (s, 1H),
8.48 (s, 1H) and 11.20 (br s, 1H)
[1773] MS (ESI): 409(MH).sup.+ TABLE-US-00143 Elemental analysis
Found C 63.6 H 6.0 N 13.3
C.sub.22H.sub.24N.sub.4O.sub.4.0.5H.sub.2O Requires C 63.3 H 6.0 N
13.4%
EXAMPLE 301
[1774] A mixture of
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 297), and diisopropylamine (0.45 ml, 3.2 mmol)
in DMF (5 ml) was stirred at 70.degree. C. for 19 hours under an
atmosphere of nitrogen and then allowed to cool to ambient
temperature. The solvents were removed in vacuo and the residue
purified on silica gel, using gradient elution with
dichloromethane/methanol (100/0 to 95/5),
dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give
(2S)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6--
methoxyquinazoline (43 mg, 33%).
[1775] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.08 (m, 12H), 1.57 (m,
1H), 1.759 (m, 1H), 3.10 (m, 2H), 4.04 (s, 3H), 4.16 (m, 3H), 6.58
(m, 1H), 7.08 (dd, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.45 (d, 1H),
7.50 (d, 1H), 7.61 (s, 1H), 8.32 (br s, 1H) and 8.61 (s, 1H)
[1776] MS (ESI): 465(MH).sup.+ TABLE-US-00144 Elemental analysis
Found C 67.2 H 7.0 N 11.9 C.sub.26H.sub.32N.sub.4O.sub.4 Requires C
67.2 H 6.9 N 12.1%
EXAMPLE 302
[1777] A mixture of
(2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 292), and isopropylamine (1.0 ml) in THF (10
ml) was stirred at 75.degree. C. for 18 hours under an atmosphere
of nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography, gradient elution
with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to
give
(2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-4-(indol-5-yloxy)-6-methoxyq-
uinazoline (82 mg, 68%).
[1778] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.98 (m, 6H), 2.68 (m,
3H), 3.96 (m, 4H), 4.13 (m, 2H), 5.06 (br s, 1H), 6.44 (s, 1H),
6.98 (dd, 1H), 7.439 (m, 4H), 7.60 (s, 1H), 8.46 (s, 1H) and 11.22
(s, 1H)
[1779] MS (ESI): 423(MH).sup.+ TABLE-US-00145 Elemental analysis
Found C 63.6 H 6.4 N 12.9
C.sub.23H.sub.26N.sub.4O.sub.4.0.6H.sub.2O Requires C 63.8 H 6.3 N
12.9%
EXAMPLE 303
[1780] A mixture of
(2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline
(100 mg, 0.28 mmol), (prepared as described for the starting
material in Example 297), and isopropylamine (1.0 ml) in THF (10
ml) was stirred at 75.degree. C. for 18 hours under an atmosphere
of nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography using gradient
elution with dichloromethane/methanolic ammonia (7M) (100/0 to
90/10) to give
(2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-4-indol-5-yloxy)-6-methoxyqu-
inazoline (66 mg, 56%).
[1781] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.985 (m, 6H), 2.68 (m,
3H), 3.96 (m, 4H), 4.13 (m, 2H), 5.06 (br s, 1H), 6.44 (s, 1H),
6.98 (dd, 1H), 7.43 (m, 4H), 7.60 (s, 1H), 8.46 (s, 1H) and 11.22
(s, 1H)
[1782] MS (ESI): 423(MH).sup.+ TABLE-US-00146 Elemental analysis
Found C 63.1 H 6.3 N 12.7
C.sub.23H.sub.26N.sub.4O.sub.4.0.9H.sub.2O Requires C 63.0 H 6.4 N
12.8%
EXAMPLE 304
[1783] A mixture of
(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (250 mg, 0.66 mmol), and pyrrolidine (1.5 ml) in THF (10 ml) was
stirred at 75.degree. C. for 3 hours under an atmosphere of
nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography using gradient
elution with dichloromethane/methanolic ammonia (7M) (100/0 to
90/10) to give
(2S)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(2-methylindol--
5-yloxy)quinazoline (106 mg, 36%).
[1784] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.60 (s, 4H), 2.38 (s,
3H), 2.57 (m, 6H), 4.11 (m, 6H), 4.95 (d, 1H), 6.14 (s, 1H), 6.88
(dd, 1H), 7.29 (m, 2H), 7.37 (s, 1H), 7.59 (s, 1H), 8.48 (s, 1H)
and 11.00 (s, 1H)
[1785] MS (ESI): 450 (MH).sup.+ TABLE-US-00147 Elemental analysis
Found C 67.0 H 6.5 N 12.0
C.sub.25H.sub.28N.sub.4O.sub.4.0.1H.sub.2O Requires C 66.7 H 6.3 N
12.4%
[1786] The starting material was prepared as follows:
[1787] A mixture of
7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (300 mg,
0.93 mmol), (prepared as described in Example 49), potassium
carbonate (385 mg, 2.79 mmol) and (2S)-(-)- glycidyl tosylate (426
mg, 2.79 mmol) in DMF (15 ml) was stirred at 60.degree. C. for 2
hours and allowed to cool to ambient temperature. The reaction
mixture was filtered and the filtrate evaporated in vacuo. The
residue was dissolved in dichloromethane and washed with saturated
sodium hydrogen carbonate solution. The organic layer was then
dried (MgSO.sub.4), filtered and the solvent removed in vacuo to
give a yellow solid. This was triturated with ether, filtered off
and dried to give
(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e as a yellow solid (277 mg, 78%).
[1788] .sup.1H NMR Spectrum: (DMSO) 2.40 (s, 3H), 2.75 (m, 1H),
2.90 (m, 1H), 3.40 (m, 1H), 3.98 (s, 3H), 4.05 (m, 1H), 4.60 (m,
1H), 6.15 (s, 1H), 6.85 (dd, 1H), 7.30 (m, 2H) 7.40 (s, 1H), 7.60
(s, 1H), 8.45 (s, 1H) and 10.98 (s, 1H)
[1789] MS (ESI): 378 (MH).sup.+
EXAMPLE 305
[1790] A mixture of the
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (250 mg, 0.66 mmol), (prepared as described for the starting
material in Example 269), and pyrrolidine (1.5 ml) in THF (10 ml)
was stirred at 75.degree. C. for 3 hours under an atmosphere of
nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography using gradient
elution with dichloromethane/methanolic ammonia (7M) (100/0 to
90/10) to give
(2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-2-methylindol-5-
-yloxy)quinazoline (165 mg, 55%).
[1791] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.60 (s, 4H), 2.38 (s,
3H), 2.57 (m, 6H), 4.11 (m, 6H), 4.95 (d, 1H), 6.14 (s, 1H), 6.88
(dd, 1H), 7.29 (m, 2H), 7.37 (s, 1H), 7.59 (s, 1H), 8.48 (s, 1H)
and 11.00 (s, 1H)
[1792] MS (ESI): 450 (MH).sup.+ TABLE-US-00148 Elemental analysis
Found C 66.8 H 6.3 N 12.4
C.sub.25H.sub.28N.sub.4O.sub.4.0.1H.sub.2O Requires C 66.7 H 6.3 N
12.4%
EXAMPLE 306
[1793] A mixture of
(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (250 mg, 0.66 mmol), (prepared as described for the starting
material in Example 304), and isopropylamine (1.5 ml) in THF (10
ml) was stirred at 75.degree. C. for 18 hours under an atmosphere
of nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography using gradient
elution with dichloromethane/methanolic ammonia (7M) (100/0 to
90/10) to give
(2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-
-yloxy)quinazoline (210 mg, 73%).
[1794] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.99 (d, 6H), 2.39 (s,
3H), 2.66 (m, 3H), 4.07 ( m, 6H), 5.08 (d, 1H), 6.14 (s, 1H), 6.88
(dd, 1H), 7.29 (m, 2H), 7.37 (s, 1H), 7.58 (s, 1H), 8.49 (s, 1H)
and 11.03 (s, 1H)
[1795] MS (ESI): 437 (MH).sup.+ TABLE-US-00149 Elemental analysis
Found C 64.3 H 6.4 N 12.3
C.sub.24H.sub.28N.sub.4O.sub.4.0.5H.sub.2O Requires C 64.7 H 6.6 N
12.6%
EXAMPLE 307
[1796] A mixture of
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (250 mg, 0.66 mmol), (prepared as described for the starting
material in Example 269), and isopropylamine (1.5 ml) in THF (10
ml) was stirred at 75.degree. C. for 18 hours under an atmosphere
of nitrogen and then allowed to cool to ambient temperature. The
mixture was filtered and the filtrate evaporated in vacuo. The
residue was purified by silica gel chromatography using gradient
elution with dichloromethane/methanolic ammonia (7M) (100/0 to
90/10) to give
(2R)-7-(2-hydroxy-3-isopropylamino)propoxy)-6-methoxy-4-2-methylindol-5-y-
loxy)quinazoline (243 mg, 84%).
[1797] .sup.1H NMR Spectrum: (DMSOd.sub.6): 0.99 (d, 6H), 2.39 (s,
3H), 2.66 (m, 3H), 4.07 (m, 6H), 5.08 (d, 1H), 6.14 (s, 1H), 6.88
(dd, 1H), 7.29 (m, 2H), 7.37 (s, 1H), 7.58 (s, 1H), 8.49 (s, 1H)
and 11.03 (s, 1H)
[1798] MS (ESI): 437 (MH).sup.+ TABLE-US-00150 Elemental analysis
Found C 64.3 H 6.5 N 12.3
C.sub.24H.sub.28N.sub.4O.sub.4.0.5H.sub.2O Requires C 64.7 H 6.6 N
12.6%
EXAMPLE 308
[1799] Nitrogen was bubbled through a mixture of
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (400 mg, 1.19
mmol), (prepared as described for the starting material in Example
1), potassium carbonate (476 mg, 3.45 mmol),
5-hdyroxy-1-methylindole (220 mg, 1.5 mmol), (prepared as described
for the starting material in Example 291), and DMA (5.0 ml) for 5
minutes. The mixture was then stirred at 90.degree. C. for 3 hours
under an atmosphere of nitrogen and allowed to cool to ambient
temperature. The reaction mixture was filtered and the filtrate
evaporated in vacuo. The residue was purified by trituration with
methanol to give
6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline
(312 mg, 59%).
[1800] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.13 (m, 2H), 1.48 (t,
4H), 1.57 (t, 2H), 3.72 (t, 4H), 3.84 (s, 3H), 4.05 (s, 3H), 4.3
(t, 2H), 6.50 (d, 1H), 7.08-7.13 (m, 2H), 7.32 (s, 1H), 7.37 (s,
1H), 7.47 (d, 1H), 7.62 (s, 1H) 8.59 (s, 1H)
[1801] MS (ESI): 449 (MH).sup.+ TABLE-US-00151 Elemental analysis
Found C 66.5 H 6.4 N 12.3
C.sub.25H.sub.28N.sub.4O.sub.4.0.1H.sub.2O Requires C 66.7 H 6.3 N
12.4%
EXAMPLE 309
[1802] Nitrogen was bubbled through a mixture of
4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (400 mg, 1.24
mmol), (prepared as described for the starting material in Example
180), potassium carbonate (500 mg, 3.62 mmol),
5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as
described for the starting material in Example 291), and DMA (5.0
ml) for 5 minutes. The mixture was then stirred at 90.degree. C.
for 3 hours under an atmosphere of nitrogen and then allowed to
cool to ambient temperature. The reaction mixture was filtered and
the filtrate evaporated in vacuo. The residue was purified by
trituration with methanol to give
6-methoxy-4-(1-methylindol-5-yloxy)-7-(2-piperidinopropoxy)quinazoline
(447 mg, 83%).
[1803] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.47 (m, 2H), 1.64 (m,
4H), 2.57 (t, 4H) 2.94 (t, 2H), 3.83 (s, 3H), 4.05 (s, 3H), 4.34
(t, 2H), 6.49 (d, 1H), 7.10 (m, 2H), 7.32 (s, 1H), 7.38 (d, 1H),
7.45 (d, 1H), 7.62 (s, 1H) 8.60 (s, 1H)
[1804] MS (ESI): 433 (MH).sup.+ TABLE-US-00152 Elemental analysis
Found C 69.2 H 6.7 N 12.7 C.sub.25H.sub.28N.sub.4O.sub.3 Requires C
69.4 H 6.5 N 13.0%
EXAMPLE 310
[1805] Nitrogen was bubbled through a mixture of
4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400
mg, 1.24 mmol), (prepared as described for the starting material in
Example 9), potassium carbonate (500 mg, 3.62 mmol),
5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as
described for the starting material in Example 291), and DMA (5.0
ml) for 5 minutes. The mixture was then stirred at 90.degree. C.
for 3 hours under an atmosphere of nitrogen and allowed to cool to
ambient temperature. The reaction mixture was filtered and the
filtrate evaporated in vacuo. The residue was purified by column
chromatography, gradient elution, with dichloromethane/methanolic
ammonia (7M), (100/0 to 90/10) to give
6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazo-
line (247 mg, 44%).
[1806] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.81 (m, 4H), 2.18 (m,
2H), 2.56 (m, 4H), 2.69 (t, 2H), 3.82 (s, 3H), 4.05 (s, 3H), 4.30
(t, 2H), 6.45 (d, 1H), 7.09 (dd, 2H), 7.31 (s, 1H), 7.38 (d, 1H),
7.47 (d, 1H), 7.62 (s, 1H) and 8.59 (s, 1H)
[1807] MS (ESI): 433 (MH).sup.+ TABLE-US-00153 Elemental analysis
Found C 66.5 H 6.3 N 12.4 C.sub.25H.sub.28N.sub.4O.sub.3 Requires C
66.7 H 6.6 N 12.4% 0.1 dichloromethane + 0.7H.sub.2O
EXAMPLE 311
[1808] Nitrogen was bubbled through a mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (114 mg, 0.34
mmol), (prepared as described for the starting material in Example
67), potassium carbonate (141 mg, 1.02 mmol),
5-hydroxy-4-nitroindole (60.5 mg, 0.34 mmol) and DMA (8.5 ml) for 5
minutes at ambient temperature. This mixture was then stirred at
90.degree. C. for 4 hours under an atmosphere of nitrogen and
allowed to cool to ambient temperature. The reaction mixture was
filtered and the filtrate evaporated in vacuo. The residue was
purified by silica column chromatography using gradient elution
with dichloromethane/methanol (100/0 to 95/5) followed by
dichloromethane/methanolic ammonia (7M) (95/5) to give a partially
purified oil. This oil was further purified by silica column
chromatography, gradient elution with ethyl acetate/methanolic
ammonia (95/5 to 80/20) to give
6-methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline
(63 mg, 39%).
[1809] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.46 (m, 2H), 1.60 (m,
4H), 2.16 (m, 2H), 2.43 (m, 4H), 2.54 (t, 2H), 3.85 (s, 3H), 4.33
(t, 2H), 7.04 (d, 1H), 7.10 (s, 1H), 7.47 (s, 1H), 7.57 (d, 1H),
7.83 (d, 1H), 7.95 (d, 1H) and 9.09 (s, 1H)
[1810] MS (ESI): 478 (MH).sup.+ TABLE-US-00154 Elemental analysis
Found C 62.5 H 5.8 N 14.7 C.sub.25H.sub.27N.sub.5O.sub.5 Requires C
62.9 H 5.7 N 14.7%
[1811] The starting material was prepared as follows:
[1812] A mixture of ethyl 5-methoxyindole-2-carboxylate (8.15 g,
37.2 mmol), (prepared by the method described in Heterocycles Vol.
43, No. 2, p. 263-266), nitric acid adsorbed on silica gel (24 g)
and dichloromethane (150 ml) was stirred at ambient temperature for
18 hours. The dichloromethane was removed in vacuo and the product
washed off the silica with acetone. The acetone was evaporated in
vacuo. The residue was treated again with nitric acid on silica
(1g) as above and the work up procedure repeated to give ethyl
5-hydroxy-4-nitroindole-2-carboxylate (5.8 g, 59%).
[1813] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.33 (t, 3H), 3.95 (s,
3H), 4.35 (q, 2H), 7.19 (d, 1H), 7.35 (d, 1H), 7.75 (d, 1H) and
12.45 (br s, 1H)
[1814] Ethyl 5-hydroxy-4-nitroindole-2-carboxylate (1.0 g. 3.8
mmol.) was suspended in a mixture of ethanol (20 ml) and water (5
ml). Potassium hydroxide (840 mg) was added and the mixture stirred
at 50 .degree. C. under an atmosphere of nitrogen for 1 hour then
cooled to ambient temperature. The solvent was evaporated in vacuo
and the residue re-dissolved in water (25 ml). The pH was adjusted
to pH2 using aqueous hydrochloric acid (2M ). The resulting
precipitate was filtered off, washed with water and dried in vacuo
to give 5-methoxy-4-nitroindole-2-carboxylic acid (790 mg). This
was used without further purification.
[1815] The crude 5-methoxy-4-nitroindole-2-carboxylic acid (720 mg,
3.05 mmol), quinoline (9 ml) and copper chromite (180 mg) were
stirred together. Nitrogen was gently bubbled through the mixture
for 5 minutes, then the mixture was heated quickly to 225.degree.
C., and stirred at this temperature for 40 minutes under an
atmosphere of nitrogen. The mixture was cooled to ambient
temperature diluted with ethyl acetate (80 ml) and the insoluble
material filtered off. The filtrate was extracted twice with
aqueous hydrochloric acid (2M) and then with saturated aqueous
sodium hydrogen carbonate solution. The ethyl acetate layer was
dried (MgSO.sub.4), evaporated and the residue purified by silica
column chromatography eluting with dichloromethane to give
5-methoxy-4-nitroindole (129 mg, 22%).
[1816] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.99 (s, 3H), 6.88 (t,
1H), 6.97 (d, 1H), 7.37 (t, 1H). 7.55 (d, 1H) and 8.38 (br s,
1H)
[1817] MS (ESI): 193 (MH).sup.+
[1818] A solution of 5-methoxy-4-nitroindole (110 mg, 0.57 mmol) in
dichloromethane (12 ml) was cooled to -30.degree. C. under an
atmosphere of nitrogen. Boron tribromide (0.74 ml of a 1M solution
in dichloromethane, 0.74 mmol) was added dropwise then the mixture
warmed to ambient temperature and stirred for 1 hour. The mixture
was cooled to 5.degree. C., diluted with dichloromethane (5 ml),
and water (10 ml). After stirring for 5 minutes the insoluble
material was filtered off and the dichloromethane layer separated,
dried (MgSO.sub.4), and evaporated to give a dark oil which was and
purified by silica column chromatography eluting with
dichloromethane to give 5-hydroxy-4-nitroindole (68 mg, 67%).
[1819] .sup.1H NMR Spectrum: (CDCl.sub.3) 6.95 (d, 1H), 7.29 (m,
1H), 7.43 (t, 1H), 7.63 (d, 1H) and 11.60 (br s, 1H)
[1820] MS (ESI): 177 (M-H).sup.-
EXAMPLE 312
[1821]
6-Methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazolin-
e (45 g 0.094 mmol), (prepared as described in Example 311),
ethanol (20 ml) and 10% palladium on charcoal were hydrogenated at
45.degree. C. and 1 atmosphere pressure of hydrogen for 3.5 hours.
The mixture was cooled to ambient temperature, the catalyst
filtered off and the filtrate evaporated in vacuo. The residue was
purified by silica column chromatography using gradient elution
with dichloromethane/methanolic ammonia (7M) (100/0 to 95/5), to
give
4-(4-amino-indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline
(39 mg, 87%).
[1822] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.39(m, 2H), 1.50 (m,
4H), 1.96 (m, 2H), 2.35 (m, 4H), 2.43 (t, 2H), 3.80 (s, 3H), 4.28
(t, 2H), 4.84 (br s, 2H), 6.68 (d, 1H), 6.78 (d, 1H), 7.28 (s, 1H),
7.45 (s, 1H), 7.69 (s, 1H), 8.45 (br s, 1H) and 8.98 (s, 1H)
[1823] MS (ESI): 448 (MH).sup.+ TABLE-US-00155 Elemental analysis
Found C 64.0 H 6.4 N 14.4
C.sub.25H.sub.29N.sub.5O.sub.3.0.3H.sub.2O + Requires C 63.6 H 6.3
N 14.4% 0.4 dichloromethane
EXAMPLE 313
[1824] A mixture of
4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (227 mg, 0.68
mmol), (prepared as described for the starting material in Example
67), 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.75 mmol),
(prepared as described for the starting material in Example 182),
and potassium carbonate (350 mg, 2.5 mmol) in DMF (4 ml) was
stirred at 95.degree. C. for 6 hours and allowed to cool to ambient
temperature. The reaction mixture was treated with 1.0 N aqueous
sodium hydroxide solution and allowed to stir at ambient
temperature for a few minutes. The resulting precipitate was
filtered off, washed with water and air dried to give a crude
product. This was purified by column chromatography, eluting
initially with dichloromethane/methanol (85/15) to isolate a less
polar impurity and then with dichloromethane/methanol/0.88 ammonia
(100/8/1) to isolate the target compound. The relevant fractions
were combined and evaporated in vacuo to give a white solid which
was triturated with acetone, filtered and dried to give
6-methoxy-7-(3-piperidinopropoxy)-4-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)qui-
nazoline (58 mg, 20%).
[1825] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.38 (m, 2H), 1.50 (m,
4H), 1.95 (m, 2H), 2.15 (m, 4H), 2.42 (t, 2H), 3.99 (s, 3H), 4.22
(t, 2H), 6.47 (m, 1H), 7.36 (s, 1H), 7.55 (m, 1H), 7.60 (s, 1H),
7.90 (d, 1H), 8.18 (d, 1H), 8.49 (s, 1H) and 11.76 (br s, 1H)
[1826] MS (ESI): 434 (MH).sup.+ TABLE-US-00156 Elemental analysis
Found C 63.9 H 6.4 N 15.4 C.sub.24H.sub.27N.sub.5O.sub.31.0H.sub.2O
Requires C 63.8 H 6.5 N 15.5%
EXAMPLE 314
[1827] To a solution of
7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200
mg, 0.47 mmol) in methylene chloride was added
4-piperidinopiperidine (237 mg, 1.41 mmol) and the reaction heated
at 40.degree. C. for 1 hour. A further portion of
4-piperidinopiperidine (100 mg, 0.59 mmol) was added and reaction
heated for a further 2 hours. The reaction was purified by flash
chromatography eluting from methylene chloride to 15%
methanol/methylene chloride (+1% ammonium hydroxide). The product
was evaporated, triturated with ether and filtered to give
4-(indol-5-yloxy)-6-methoxy-7-(3-(4-piperidino)piperidinopropoxy)quinazol-
ine (200 mg, 83%) as a yellow solid.
[1828] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.48-2.18 (m, 19H), 2.58
(t, 2H), 3.06 (d, 2H), 4.05 (s, 3H), 4.26 (t, 2H), 6.59 (s, 1H),
7.08 (dd, 1H), 7.28 (d, 1H), 7.36 (s, 1H), 7.50 (d, 1H), 7.63 (s,
1H), 8.30 (s, 1H), 8.59 (s, 1H)
[1829] M S: 516 [MH]+
[1830] The starting material was prepared as follows:
[1831] To a solution of
7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (1 g, 3.2
mmol), (prepared as described for the starting material in Example
107), in DMF (50 ml) was added powdered potassium carbonate (1.32
g, 9.6 mmol) and 1,3-dibromopropane (6.43 g, 32 mmol). The reaction
was heated at 50.degree. C. for 2 hours. The inorganic material was
filtered off and then the DMF removed. The residue was partitioned
between methylene chloride/water. The organics were separated,
dried over MgSO.sub.4, filtered, evaporated in vacuo and purified
by flash chromatography eluting from methylene chloride to 5%
methanol/95% methylene chloride. The product was concentrated in
vacuo, triturated with ether and the resulting solid filtered to
give 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline
(900 mg, 66%) as a white solid.
[1832] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.46-2.57 (m, 2H), 3.68
(t, 2H), 4.08 (s, 3H), 4.38 (t, 2H), 6.58 (s, 1H), 7.09 (d, 1H),
7.27 (s, 1H), 7.35 (s, 1H), 7.46 (d, 1H), 7.50 (s, 1H), 7.63 (s,
1H), 8.30 (s, 1H), 8.62 (s, 1H)
[1833] M S: 428 [MH]+
EXAMPLE 315
[1834] To a solution of
7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline 225
mg, 0.7 mmol), (prepared as described in Example 49), in DMF was
added powdered potassium carbonate (290 mg, 2.1 mmol) and
(5S)-5-(p-toluenesulphonylmethyl)-1-methyl-2-pyrrolidinone (340 mg,
1.2 mmol). The reaction was then heated at 95.degree. C. for 5
hours. The inorganic material was filtered off and the DMF removed
by evaporation. The residue was then purified by chromatography
eluting from methylene chloride to 12% methanol/88% methylene
chloride (+1% ammonium hydroxide). The product was evaporated,
triturated with ether and filtered to give
(5S)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(1-methyl-2-oxopyrrolidin--
5-ylmethoxy)quinazoline (100 mg, 33%) as a white solid.
[1835] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.84-1.96 (m, 1H),
2.10-2.30 (m, 2H), 2.39 (s, 3H), 2.43-2.53 (m, 1H), 2.80 (s, 3H),
3.98 (s, 4H), 4.22 (dd, 1H), 4.40 (dd, 1H), 6.10 (s, 1H), 6.84 (dd,
1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.40 (s, 1H), 7.59 (s, 1H), 8.49
(s, 1H), 10.98 (br s, 1H)
[1836] M S: 429 [MH]+ TABLE-US-00157 Elemental Analysis: Found C
64.4 H 5.4 N 12.6 C.sub.24H.sub.24N.sub.4O.sub.40.8H.sub.2O
Requires C 64.5 H 5.8 N 12.5%
[1837] The starting material was prepared as follows:
[1838] (5S)-5-(p-Toluenesulphonylmethyl)-2-pyrrolidinone (0.8 g, 3
mmol) was dissolved in dry THF and cooled to -70.degree. C. Lithium
diisopropylamide was slowly added and the reaction stirred for 20
minutes before addition of methyl iodide (2 ml, excess). The
reaction was allowed to warm to ambient temperature for over 2
hours. The reaction was partitioned between ethyl acetate and
water, the organic layer separated, dried over MgSO.sub.4,
filtered, and evaporated in vacuo. The residue was purified by
flash chromatography eluting from methylene chloride to 5%
methanol/95% methylene chloride and the product evaporated to give
(5S)-5-(p-toluenesulphonyl-methyl)-1-methyl-2-pyrrolidinone (340
mg, 40%) as a brown oil.
[1839] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.10-2.44 (m, 4H), 2.48
(s, 3H), 2.76 (s, 3H), 3.30-3.54 (m, 1H), 4.04 (dd, 1H), 4.15 (dd,
1H), 7.38 (d, 2H), 7.78 (d, 2H)
[1840] M S: 284 [MH]+
EXAMPLE 316
[1841] To a solution of
7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (600 mg, 1.95
mmol), (prepared as described for the starting material in Example
107), in DMF (20 ml) was added powdered potassuim carbonate (540
mg. 3.9 mmol) and
(5S)-5-(p-toluene-sulphonylmethyl)-2-pyrrolidinone (580 mg, 2.16
mmol). The reaction was then heated at 100.degree. C. for 4 hours.
The inorganic material was filtered off and the DMF removed by
evaporation. The residue was then purified by chromatography
eluting from methylene chloride to 12% methanol/88% methylene
chloride (+1% ammonium hydroxide). The product was evaporated,
triturated with ether, and filtered to give
(5S)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinaz-
oline (240 mg, 31%) as a white solid.
[1842] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.87-2.48 (m, 4H), 3.97
(s, 3H), 4.17 (m, 2H), 6.45 (s, 1H), 6.96 (dd, 1H), 7.38-7.49 (m,
4H), 7.60 (s, 1H), 7.81 (s, 1H), 8.50 (s, 1H)
[1843] M S: 405 [MH]+
EXAMPLE 317
[1844] To a solution of
7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (800 mg, 2.6
mmol), (prepared as described for the starting material in Example
107), in DMF (20 ml) was added powdered potassuim carbonate (1.08
g, 7.8 mmol) and (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone
(1.13 g, 4.2 mmol). The reaction was then heated at 90.degree. C.
for 4 hours. The inorganic material was filtered off and the DMF
removed by evaporation. The residue was then purified by
chromatography eluting from methylene chloride to 12% methanol/88%
methylene chloride (+1% ammonium hydroxide). A small portion was
recolumned using the same gradient. The product was evaporated,
triturated with ether and filtered to give
(5R)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinaz-
oline (70 mg, 6.5%) as a white solid.
[1845] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.64-2.45 (m, 4H), 3.78
(m, 1H), 3.99 (s, 3H), 4.18 (t, 2H), 6.42 (s, 1H), 6.97 (dd, 1H),
7.38-7.48 (m, 3H), 7.60 (s, 1H), 7.73 (s, 2H), 8.48 (s, 1H), 11.18
(br s, 1H)
[1846] M S: 405 [MH]+
[1847] The starting material was prepared as follows:
[1848] To a solution of (5R)-5-hydroxymethyl-2-pyrrolidinone (5.0
g, 43 mmol) in methylene chloride (100 ml) was added
4-dimethylaminopyridine (15.7 g, 129 mmol) and p-toluenesulphonyl
chloride (9.0 g, 47 mmol). The reaction was stirred at ambient
temperature or 16 hours. The reaction was then washed with 1M
hydrochloric acid and the organic layer separated. This was then
dried over MgSO.sub.4, filtered and evaporated to give
(5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (10.3 g, 89%) as
a white solid.
[1849] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.68-1.86 (m, 1H),
2.16-2.38 (m, 3H), 2.48 (s, 3H), 3.86-3.96 (m, 2H), 4.08 (dd, 1H),
6.20 (br s, 1H), 7.38 (d, 2H), 7.80 (d, 2H)
[1850] M S: 270 [MH]+
EXAMPLE 318
[1851] To a suspension of
7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36
g, 4.24 mmol), (prepared as described in Example 49), in DMF (70
ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4 eq.)
followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25
g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting
material in Example 317), and the resulting yellow suspension
heated at reflux. After 4 hours, some starting material remained,
and a further addition of
(5R)-5-(P-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12
mmol, 0.5 eq.) was made. The reaction was heated at reflux for a
further 2 hours resulting in consumption of starting material. The
reaction was cooled to ambient temperature, the inorganic residue
filtered off and the filtrate evaporated in vacuo to leave a brown
oil which was purified by column chromatography (methylene
chloride/methanol, (100/0 to 90/10)) to give a light brown oil.
Trituration with ether afforded a thick oil, which upon
chromatography eluting as above gave a yellow oil. Trituration of
this oil with ether gave an initial crop of
(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmetho-
xy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr).
Chromatography of the residues (eluting as above) followed by ether
trituration gave further crops of
(5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmetho-
xy)quinazoline as a white solid (180 mg, >95% pure by nmr), as
an off-white solid (800 mg, ca. 95% pure by nmr).
[1852] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.8-2.2 (m, 5H), 2.4 (s,
3H), 4.0 (br s, 3H), 4.1-4.2 (m, 2H), 6.1 (brs, 1H), 6.9 (dd, 1H),
7.2 (d, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.8 (s, 1H),
8.5 (s, 1H), 11.0 (br s, 1H)
[1853] MS: 419 [MH].sup.+ TABLE-US-00158 Elemental analysis: Found
C 60.8 H 5.3 N 12.1 C.sub.23H.sub.22N.sub.4O.sub.42H.sub.2O
Requires C 60.8 H 5.7 N 12.3%
EXAMPLE 319
[1854] To a solution of
7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (4.8
g, 15.7 mmol), (prepared as described in Example 49), in DMF (100
ml), was added potassuim carbonate (6.5 g, 47 mmol) and
3-chloropropyl piperidine (3.3 g, 20.4 mmol). The reaction was then
heated to 100.degree. C. for 4 hours. The inorganic material was
filtered off and the DMF removed by evaporation. The residue was
then purified by chromatography eluting from methylene chloride to
10% methanol/90% methylene chloride (+1% ammonium hydroxide). The
relevant fractions were concentrated and the residue dissolved in
ethyl acetate. Hexane was added and the precipitae was filtered
off. The filtrate was evaporated and the residue was triturated
with ether and filtered to give
6-methoxy-4-(1-(3-piperidinopropyl)-1H-indol-5-yloxy)-7-(3-piperidinoprop-
oxy)quinazoline (170 mg, 1.9%) as a white solid.
[1855] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.38 (br s, 4H), 1.50
(br s, 8H), 1.92 (m, 4H), 2.14-2.48 (m, 12H), 3.98 (s, 3H), 4.24
(t, 4H), 6.43 (s, 1H), 7.02 (d, 1H), 7.38 (s, 1H), 7.42 (s, 2H),
7.53 (d, 1H), 7.58 (s, 1H), 8.44 (s, 1H)
[1856] M S: 558 [MH]+
EXAMPLE 320
[1857] A mixture of
(2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (6.201 g, 16.4 mmol), (prepared as described for the starting
material in Example 269), and piperidine (4.8 ml, 49.3 mmol) in DMF
(100 ml) was stirred at 60.degree. C. for 24 hours and allowed to
cool to ambient temperature. The solvents were removed in vacuo and
the residue purified on silica gel, eluting with dichloromethane,
dichloromethane/methanol (95/5) then dichloromethane/methanol/0.880
aqueous ammonia (89:10:1). The product was then recrystallised from
acetonitrile to give
(2R)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropo-
xy)quinazoline (3.33 g, 44%) as an off-white solid.
[1858] .sup.1H NMR Spectrum: (DMSO.sub.6) 1.35 (m, 2H), 1.51 (m,
4H), 2.30-2.40 (m, 9H), 3.98 (s, 3H), 4.08 (m, 2H), 4.21 (m, 1H),
4.86 (m, 1H), 6.10 (s, 1H), 6.87 (dd, 1H), 7.25 (d, 1H) 7.30 (d,
1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H) and 10.98 (br s,
1H)
[1859] MS (ESI): 463 (MH).sup.+ TABLE-US-00159 Elemental analysis:
Found C 66.5 H 6.6 N 12.0 C.sub.26H.sub.30N.sub.4O.sub.40.4H.sub.2O
Requires C 66.5 H 6.6 N 11.9%
EXAMPLE 321
[1860] A mixture of
(2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazolin-
e (175 mg 0.46 mmol), (prepared as described for the starting
material in Example 304), and piperidine (0.14 ml, 1.39 mmol) in
DMF (5 ml) was stirred at 60.degree. C. for 24 hours and allowed to
cool to ambient temperature. The solvents were removed in vacuo and
the residue purified on silica gel, gradient elution eluting with
dichloromethane, dichloromethane/methanol (95/5) then
dichloromethane/methanol/0.880 aqueous ammonia (89:10:1). The
product was then recrystallised from acetonitrile to give
(2S)-6-methoxy-(2-methyl-1H-indol-5-yloxy)-7-(2-hydroxy-3-piperidinopropo-
xy)quinazoline (88 mg, 41%) as an off-white solid.
[1861] .sup.1H NMR Spectrum: (DMSO.sub.6) 1.35 (m, 2H), 1.51 (m,
4H), 2.30-2.40 (m, 9H), 3.98 (s, 3H), 4.08 (m, 2H), 4.21 (m, 1H),
4.86 (m, 1H), 6.10 (s, 1H), 6.87 (dd, 1H), 7.25 (d, 1H) 7.30 (d,
1H), 7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H) and 10.98 (br s,
1H)
[1862] MS (ESI): 463 (MH).sup.+ TABLE-US-00160 Elemental analysis:
Found C 66.2 H 6.8 N 11.9 C.sub.26H.sub.30N.sub.4O.sub.40.5H.sub.2O
Requires C 66.2 H 6.6 N 11.9%
EXAMPLE 322
[1863] ##STR145##
[1864] A solution of
4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline
(1.22 g, 3.65 mmol), (prepared as described for the starting
material in Example 241), 4-fluoro-5-hydroxy-2-methylindole (723
mg, 4.38 mmol), (prepared as described for the starting material in
Example 237), in DMF (20 ml) containing potassium carbonate (756
mg, 5.48 mmol) was stirred at 95.degree. C. for 3 hours. After
cooling, the mixture was filtered and the filtrate was evaporated.
The residue was purified by column chromatography eluting with
methylene chloride/methanol (9/1) followed by methylene
chloride/methanol/methanol saturated with ammonia (90/5/5). The
fractions containing the expected product were combined and
evaporated. The residue was triturated with ether filtered, washed
with ether and dried under vacuum. The solid was dissolved in
methylene chloride/ethyl acetate and the minimum of methanol,
filtered and the volatiles were removed under vacuum. The solid was
triturated with ether, filtered, washed with ether and dried under
vacuum at 50.degree. C. to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl-
)ethoxy)quinazoline (1.06 g, 62%).
[1865] MS-ESI : 465 [MH]+
[1866] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.1-1.3 (m, 2H);
1.35-1.5 (m, 1H); 1.6-1.9 (m, 6H); 2.12 (s, 3H); 2.4 (s, 3H); 2.75
(d, 2H); 3.95 (s, 3H); 4.22 (t, 2H); 6.2 (s, 1H); 6.95 (dd, 1H);
7.15 (d, 1H); 7.4 (s, 1H); 7.6 (s, 1H); 8.5 (s, 1H)
EXAMPLE 323
[1867] Sodium hydride (71 mg, 1.8 mmol) was added to
5-hydroxy-2-methylbenzimidazole (204 mg, 0.89 mmol) in anhydrous
DMF (2.5 ml) under an argon atmosphere. The mixture was stirred at
ambient temperature for 10 minutes.
4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) was added and
the reaction mixture stirred at 95 .degree. C. for 2 hours. Upon
cooling to ambient temperature the mixture was poured in water and
extracted with ethyl acetate. The organic phase was washed with
brine, dried (MgSO.sub.4), silica was added and the solvent
evaporated off. The obtained powder was placed on the top of a
disposable silica column (ISOLUTE) and the product eluted off using
a gradient of methanol/dichloromethane (3/97, 5/95, 8/92).
Evaporation of the solvent gave
6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)quinazoline (145
mg, 48%).
[1868] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.50 (s, 3H); 3.95 (s,
3H); 4.0 (s, 3H); 7.05 (d, 1H); 7.38 (s, 1H); 7.39 (d, 1H); 7.51
(d, 1H); 7.60 (s, 1H); 8.50 (s, 1H)
[1869] MS (ESI): 337 [MH].sup.+
EXAMPLE 324
[1870] ##STR146##
[1871] 7-Hydroxyquinazoline (87 mg, 0.6 mmol) and potassium
carbonate (110 mg, 0.8 mmol) were added to
4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (180 mg, 0.53
mmol), (prepared as described for the starting material in Example
1), in suspension in DMF (3 ml) under an argon atmosphere. The
reaction mixture was heated to 100.degree. C. for 90 minutes. Upon
cooling to ambient temperature the reaction was diluted with ethyl
acetate and a saturated ammonium chloride solution. The aqueous
phase was re-extracted with ethyl acetate, the organic phases
combined, dried (MgSO.sub.4) and the solvent evaporated. The
residue was purified by flash chromatography using a gradient of
methanol/dichloromethane (3/97, 4/96, 5/95). Evaporation of the
solvent and trituration of the solid with ether gave
6-methoxy-7-(3-morpholinopropoxy)-4-(quinazolin-7-yloxy)quinazoline
(197 mg, 83%).
[1872] .sup.1H NMR Spectrum (DMSOd.sub.6) 2.01 (t, 2H); 2.47 (m,
4H); 2.49 (m, 2H); 3.60 (m, 4H); 4.01 (s, 3H); 4.29 (t, 2H); 7.45
(s, 1H); 7.65 (s, 1H); 7.80 (d, 1H); 8.01 (d, 1H); 8.32 (d, 1H);
8.60 (s, 1H); 9.34 (s, 1H); 9.69 (s, 1H)
[1873] MS (ESI): 448 [MH].sup.+ TABLE-US-00161 Elemental analysis:
Found C 63.4 H 5.7 N 15.6 C.sub.24H.sub.25N.sub.5O.sub.4; 0.4
H.sub.2O Requires C 63.4 H 5.7 N 15.4%
[1874] The starting material was prepared as follows:
[1875] Raney Nickel (about 200 mg), (prewashed several times with
ethanol), was added to a solution of
7-hydroxy-4-thiomethylquinazoline (400 mg, 2.08 mmol), (Tet. Lett.
1999, 40, 3881), and the solution was refluxed for 1 hour. Raney
Nickel (100 mg) was added and the mixture was refluxed for a
further 1 hour. The mixture was filtered, washed with ethanol and
the volatiles were removed under vacuum. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(97/3 followed by 96/4) to give 7-hydroxyquinazoline (62 mg,
20%).
EXAMPLE 325
[1876] ##STR147##
[1877] Using an analogous procedure to that described in Example
201, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg,
0.32 mmol), (prepared as described for the starting material in
Example 217), was reacted with 5-(2-hydroxyethyl)-4-methylthiazole
(69 mg, 0.48 mmol) to give
6-methoxy-4-(indol-6-ylamino)-7-(2-(4-methylthiazol-5-yl)ethoxy)quin-
azoline (47 mg, 34%).
[1878] MS-ESI: 432 [MH].sup.+
[1879] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H); 3.3 (t,
2H); 4.0 (s, 3H); 4.35 (t, 2H); 6.45 (s, 1H); 7.2 (s, 1H); 7.25-7.4
(m, 2H); 7.55 (d, 1H); 7.9 (s, 1H); 8.05 (s, 1H); 8.45 (s, 1H) 8.87
(s, 1H); 9.45 (s, 1H)
EXAMPLE 326
[1880] 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-00162 (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
[1881] TABLE-US-00163 (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
[1882] TABLE-US-00164 (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
[1883] TABLE-US-00165 (d) Capsule mg/capsule Compound X 10 Lactose
Ph.Eur 488.5 Magnesium stearate 1.5
[1884] TABLE-US-00166 (e) Injection I (50 mg/ml) Compound X 5.0%
w/v 1N Sodium hydroxide solution 15.0% v/v 0.1N Hydrochloric acid
(to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for
injection to 100%
[1885] TABLE-US-00167 (f) Injection II 10 mg/ml) Compound X 1.0%
w/v Sodium phosphate BP 3.6% w/v 0.1N Sodium hydroxide solution
15.0% v/v Water for injection to 100%
[1886] TABLE-US-00168 (g) Injection III (1 mg/ml, buffered to pH 6)
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
[1887] 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.
* * * * *