U.S. patent application number 11/882604 was filed with the patent office on 2009-06-18 for quinazoline compounds.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Laurent Francois Hennequin.
Application Number | 20090156821 11/882604 |
Document ID | / |
Family ID | 27635895 |
Filed Date | 2009-06-18 |
United States Patent
Application |
20090156821 |
Kind Code |
A1 |
Hennequin; Laurent
Francois |
June 18, 2009 |
Quinazoline compounds
Abstract
The invention relates to compounds of the formula (I): wherein
ring C is as defined herein, for example indolyl, indazolyl or
azaindolyl; Z is --O--, --NH-- or --S--; n is 0-5; m is 0-3;
R.sup.1 and R.sup.2 are defined herein including groups: (i)
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined herein;
(ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are as defined
herein, (iii) Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein
Q.sup.21, W.sup.4 and X.sup.1 are as defined herein, (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined herein and (v) Q.sup.29C.sub.1-5alkylX.sup.1--,
Q.sup.29C.sub.2-5alkenylX.sup.1-- or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1 are
as defined herein; R.sup.2 can also be 6,7-methylenedioxy or
6,7-ethylenedioxy; and salts thereof; their use in the manufacture
of a medicament for use in the production of an antiangiogenic
and/or vascular permeability reducing effect in warm?blooded
animals; processes for the preparation of such compounds;
intermediates used in such processes; processes for making such
intermediates; pharmaceutical compositions containing a compound of
formula I or a pharmaceutically acceptable salt thereof and methods
of treating disease states involving angiogenesis by administering
a compound of formula I or a pharmaceutically acceptable salt
thereof. The compounds of formula I inhibit the effects of VEGF, a
property of value in the treatment of a number of disease states
including cancer and rheumatoid arthritis.
Inventors: |
Hennequin; Laurent Francois;
(Macclesfield, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Assignee: |
AstraZeneca AB
|
Family ID: |
27635895 |
Appl. No.: |
11/882604 |
Filed: |
August 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10502538 |
Jul 28, 2004 |
7268230 |
|
|
PCT/GB03/00343 |
Jan 28, 2003 |
|
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11882604 |
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Current U.S.
Class: |
546/113 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 19/02 20180101; C07D 401/14 20130101; A61P 9/08 20180101; A61P
9/14 20180101; A61P 9/00 20180101; A61P 37/06 20180101; A61P 17/06
20180101; A61P 35/00 20180101; A61P 35/02 20180101; C07D 491/04
20130101; C07D 471/04 20130101; A61P 17/02 20180101; A61P 7/02
20180101; A61P 13/12 20180101; A61P 9/10 20180101; C07D 403/12
20130101; A61P 15/00 20180101; A61P 43/00 20180101; A61P 3/10
20180101; A61P 29/00 20180101 |
Class at
Publication: |
546/113 |
International
Class: |
C07D 471/02 20060101
C07D471/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 2002 |
EP |
EP02290242.3 |
Claims
1-25. (canceled)
26. A process for the production of 5-methoxy-7-azaindole
comprising mixing a solution of the following materials in relative
quantities according to the amounts given herein:
5-bromo-7-azaindole (8.6 g, 44 mmol), copper (I) bromide (12.6 g,
88 mmol) and sodium methoxide (100 g, 1.85 mol) in a mixture of
"degassed" DMF (260 mls) and methanol (175 mls); stirring the
resulting mixture at ambient temperature in a nitrogen atmosphere;
and then heating the mixture at reflux.
Description
[0001] This application is a divisional of U.S. Ser. No.
10/502,538, filed Jul. 28, 2004, which is a 371 of PCT/GB03/00343
filed Jan. 28, 2003, which claims priority from EP02290242.3 filed
on Feb. 1, 2002.
[0002] 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.
[0003] 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.
[0004] Receptor tyrosine kinases (RTKs) are important in the
transmission of biochemical signals across the plasma membrane of
cells. These transmembrane molecules characteristically consist of
an extracellular ligand-binding domain connected through a segment
in the plasma membrane to an intracellular tyrosine kinase domain.
Binding of ligand to the receptor results in stimulation of the
receptor-associated tyrosine kinase activity which leads to
phosphorylation of tyrosine residues on both the receptor and other
intracellular molecules. These changes in tyrosine phosphorylation
initiate a signalling cascade leading to a variety of cellular
responses. To date, at least nineteen distinct RTK subfamilies,
defined by amino acid sequence homology, have been identified. One
of these subfamilies is presently comprised by the fins-like
tyrosine kinase receptor, Flt-1, the kinase insert
domain-containing receptor, KDR (also referred to as Flk-1), and
another fms-like tyro sine kinase receptor, Flt-4. Two of these
related RTKs, Flt-1 and KDR, have been shown to bind VEGF with high
affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al,
1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding
of VEGF to these receptors expressed in heterologous cells has been
associated with changes in the tyrosine phosphorylation status of
cellular proteins and calcium fluxes.
[0005] The present invention is based on the discovery of compounds
that surprisingly inhibit the effects of VEGF, a property of value
in the treatment of disease states associated with angiogenesis
and/or increased vascular permeability such as cancer, diabetes,
psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma,
lymphoedema, acute and chronic nephropathies, atheroma, arterial
restenosis, autoimmune diseases, acute inflammation, excessive scar
formation and adhesions, endometriosis, dysfunctional uterine
bleeding and ocular diseases with retinal vessel proliferation
including macular degeneration.
[0006] VEGF is a key stimulus for vasculogenesis and angiogenesis.
This cytokine induces a vascular sprouting phenotype by inducing
endothelial cell proliferation, protease expression and migration,
and subsequent organisation of cells to form a capillary tube
(Keck, P. J., Hauser, S. D., Krivi, G., Sanzo, K., Warren, T.,
Feder, J., and Connolly, D. T., Science (Washington D.C.), 246:
1309-1312, 1989; Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A.,
Hasty, K. A., and Charles, S. T., Microvasc. Res., 55: 29-42, 1998;
Pepper, M. S., Montesano, R., Mandroita, S. J., Orci, L. and
Vassalli, J. D., Enzyme Protein, 49: 138-162, 1996.). In addition,
VEGF induces significant vascular permeability (Dvorak, H. F.,
Detim, M., Claffey, K. P., Nagy, J. A., van de Water, L., and
Seenger, D. R., (Int. Arch. Allergy Immunol., 107: 233-235, 1995;
Bates, D. O., Heald, R. I., Curry, F. E. and Williams, B. J.
Physiol. (Lond.), 533: 263-272, 2001), promoting formation of a
hyper-permeable, immature vascular network which is characteristic
of pathological angiogenesis.
[0007] It has been shown that activation of KDR alone is sufficient
to promote all of the major phenotypic responses to VEGF, including
endothelial cell proliferation, migration, and survival, and the
induction of vascular permeability (Meyer, M., Clauss, M.,
Lepple-Wienhues, A., Waltenberger, J., Augustin, H. G., Ziche, M.,
Lanz, C., Buttner, M., Rziha, H-J., and Dehio, C., EMBO J., 18:
363-374, 1999; Zeng, H., Sanyal, S, and Mukhopadhyay, D., J. Biol.
Chem., 276: 32714-32719, 2001; Gille, H., Kowalski, J., Li, B.,
LeCouter, J., Moffat, B, Zioncheck, T. F., Pelletier, N. and
Ferrara, N., J. Biol. Chem., 276: 3222-3230, 2001).
[0008] International patent application publication number WO
00/47212 describes VEGF receptor tyrosine kinase inhibitors.
Compounds of WO 00/47212 possess activity against VEGF receptor
tyro sine kinase (RTK) such that they may be used in an amount
sufficient to inhibit VEGF RTK whilst demonstrating no significant
activity against EGF RTK. Their VEGF RTK inhibitory activity is due
both to activity against KDR and against Flt-1, but generally they
are more potent against KDR. Generally they have extended plasma
pharmacokinetics. Some VEGF RTK inhibitors have been found to act
as potassium channel blockers and are positive in a HERG assay;
such activity may give rise to ECG (electrocardiogram) changes in
vivo. Compounds of WO 00/47212 have predominantly basic side
chains.
[0009] Surprisingly we have now found compounds of the present
invention to be very potent KDR inhibitors but to have less
activity against Flt-1 than compounds of WO 00/47212, to have less
extended plasma pharmacokinetics than compounds of WO 00/47212 and
to be inactive or only weakly active in a HERG assay. Compounds of
the present invention have predominantly neutral side chains.
Compounds of the present invention have a beneficial toxicological
profile compared to compounds of WO 00/47212.
[0010] According to one aspect of the present invention there is
provided the use of a compound of the formula I:
##STR00001##
wherein: ring C is an 8, 9, 10, 12 or 13-membered bicyclic or
tricyclic moiety which moiety may be saturated or unsaturated,
which may be aromatic or non-aromatic, and which optionally may
contain 1-3 heteroatoms selected independently from O, N and S;
Z is --O--, --NH-- or --S--;
[0011] n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; R.sup.2
represents hydrogen, hydroxy, halogeno, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or R.sup.5X.sup.1-- (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OC(O)--, --C(O)--,
--S--, --SO--, --SO.sub.2--, --NR.sup.6C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8--, --NR.sup.9SO.sub.2-- or --NR.sup.10--
(wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.5 is selected from one of
the following twenty-two groups: 1) hydrogen,
oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be unsubstituted
or which may be substituted with one or more groups selected from
hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2 represents --O--
or --NR.sup.12-- (in which R.sup.12 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.11
represents C.sub.1-3alkyl, --NR.sup.13R.sup.14 or --OR.sup.15
(wherein R.sup.13, R.sup.14 and R.sup.15 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.16
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.17C(O)--, --C(O)NR.sup.18--,
--SO.sub.2NR.sup.19--, --NR.sup.20SO.sub.2-- or --NR.sup.21--
(wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.5R.sup.22 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.23C(O)--, --C(O)NR.sup.24--,
--SO.sub.2NR.sup.25--, --NR.sup.26SO.sub.2-- or --NR.sup.27--
(wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26 and R.sup.27 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.22 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.23
(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.fC.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.28 (wherein R.sup.28 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.28 (wherein
R.sup.28 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.28
(wherein R.sup.28 is as defined hereinbefore); 9) R.sup.29 (wherein
R.sup.29 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (Linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --C(O)NR.sup.3OR.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.gC.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.29 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.34C(O)--, --C(O)NR.sup.35--,
--SO.sub.2NR.sup.36--, --NR.sup.37SO.sub.2-- or --NR.sup.38--
(wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.29 (wherein X.sup.7
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.39C(O)--,
--C(O)NR.sup.40--, --SO.sub.2NR.sup.41--, --NR.sup.42SO.sub.2-- or
--NR.sup.43-- (wherein R.sup.39, R.sup.40, R.sup.41, R.sup.42 and
R.sup.43 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.29 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.4C(O)--,
--C(O)NR.sup.45--, --SO.sub.2NR.sup.46--, --NR.sup.47SO.sub.2-- or
--NR.sup.48-- (wherein R.sup.4, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.29
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.49C(O)--, --C(O)NR.sup.50--, --SO.sub.2NR.sup.51,
--NR.sup.52SO.sub.2-- or --NR.sup.53-- (wherein R.sup.49, R.sup.50,
R.sup.51, R.sup.52 and R.sup.53 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined hereinbefore); 17)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.2-5alkenyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)ammosulphonyl; 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9 is as defined hereinbefore, q is 0 or 1, r is 0 or
1, and R.sup.54 and R.sup.55 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl), with the proviso that R.sup.54 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); R.sup.1 represents
hydrogen, oxo, halogeno, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4alkoxymethyl, C.sub.1-4alkanoyl, C.sub.1-4haloalkyl,
cyano, amino, C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-3alkanoyloxy, nitro, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl,
N--(C.sub.1-4alkylsulphonyl)amino,
N--(C.sub.1-4alkylsulphonyl)-N--(C.sub.1-4alkyl)amino,
N,N-di(C.sub.1-4alkylsulphonyl)amino, a C.sub.3-7alkylene chain
joined to two ring C carbon atoms,
C.sub.1-4alkanoylaminoC.sub.1-4alkyl, carboxy or a group
R.sup.56X.sup.10 (wherein X.sup.10 represents a direct bond, --O--,
--CH.sub.2--, --OC(O)--, --C(O)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.57C(O)--, --C(O)NR.sup.58--, --SO.sub.2NR.sup.59--,
--NR.sup.60SO.sub.2-- or --NR.sup.61-- (wherein R.sup.57, R.sup.58,
R.sup.59, R.sup.60 and R.sup.61 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), and
R.sup.56 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.11C(O)R.sup.62 (wherein X.sup.11 represents
--O-- or --NR.sup.63-- (in which R.sup.63 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.62
represents C.sub.1-3alkyl, --NR.sup.64R.sup.65 or --OR.sup.66
(wherein R.sup.64, R.sup.65 and R.sup.66 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.12R.sup.67
(wherein X.sup.12 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.68C(O)--, --C(O)NR.sup.69--,
--SO.sub.2NR.sup.70--, --NR.sup.71SO.sub.2-- or --NR.sup.72
(wherein R.sup.68, R.sup.69, R.sup.70, R.sup.71 and R.sup.72 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.67 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.13C.sub.1-5alkylX.sup.14R.sup.73 (wherein
X.sup.13 and X.sup.14 which may be the same or different are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.74C(O)--,
--C(O)NR.sup.75--, --SO.sub.2NR.sup.76, --NR.sup.77SO.sub.2-- or
--NR.sup.78-- (wherein R.sup.74, R.sup.75, R.sup.76, R.sup.77 and
R.sup.78 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.73 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.79
(wherein R.sup.79 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.79 (wherein
R.sup.79 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); 9) R.sup.80 (wherein
R.sup.80 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4
hydroxyalkoxy, carboxy, trifluoromethyl, cyano,
--C(O)NR.sup.81R.sup.82, NR.sup.83C(O)R.sup.84 (wherein R.sup.81,
R.sup.82, R.sup.83 and R.sup.84, which may be the same or
different, each represents hydrogen, C.sub.1-4alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.80 (wherein R.sup.80 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.80
(wherein R.sup.80 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.15R.sup.80 (wherein X.sup.15 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.85C(O)--, --C(O)NR.sup.86--,
--SO.sub.2NR.sup.87, --NR.sup.88SO.sub.2-- or --NR.sup.89--
(wherein R.sup.8, R.sup.86, R.sup.87, R.sup.88 and R.sup.89 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.16R.sup.80 (wherein
X.sup.16 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.90C(O)--, --C(O)NR.sup.91--, --SO.sub.2NR.sup.92--,
--NR.sup.93SO.sub.2-- or --NR.sup.94-- (wherein R.sup.90, R.sup.91,
R.sup.92, R.sup.93 and R.sup.94 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.80 is as defined hereinbefore); 15)
C.sub.2-5alkynylX.sup.17R.sup.80 (wherein X.sup.17 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.90C(O)--,
--C(O)NR.sup.96--, --SO.sub.2NR.sup.97--, --NR.sup.98SO.sub.2-- or
--NR.sup.99-- (wherein R.sup.95, R.sup.96, R.sup.97, R.sup.98 and
R.sup.99 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.80
(wherein X.sup.18 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.100C(O)--, --C(O)NR.sup.101--, --SO.sub.2NR.sup.102--,
--NR.sup.103SO.sub.2-- or --NR.sup.104-- (wherein R.sup.100,
R.sup.101, R.sup.102, R.sup.103 and R.sup.104 each independently
represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 17) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79
(wherein X.sup.18 and R.sup.79 are as defined hereinbefore); 18)
C.sub.2-5alkenyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro,
amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.18C.sub.4alkylR.sup.79 (wherein X.sup.18 and
R.sup.79 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.105(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106
(wherein X.sup.18 is as defined hereinbefore, x is 0 or 1, y is 0
or 1, and R.sup.105 and R.sup.106 are each independently selected
from hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4-aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl) with the proviso that R.sup.105 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
which is linked to X.sup.10 may bear one or more substituents
selected from hydroxy, halogeno and amino); with the proviso that
one or more R.sup.1 and/or one or more R.sup.2 are selected from
one of the following five groups:
(i) Q.sup.1X.sup.1
[0012] wherein X.sup.1 is as defined hereinbefore and Q.sup.1 is
selected from one of the following ten groups: 1) Q.sup.2 (wherein
Q.sup.2 is a 5-6-membered saturated or partially unsaturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which heterocyclic group bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6-fluoroalkyl, C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl
and C.sub.1-6fluoroalkylsulphonyl and which heterocyclic group may
optionally bear a further 1 or 2 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6-fluoroalkyl,
C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 2)
C.sub.1-5alkylW.sup.1Q.sup.2 (wherein W.sup.1 represents --O--,
--S--, --SO--, --SO.sub.2--, --OC(O)--, --NQ.sup.3C(O)--,
--C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-, --NQ.sup.6SO.sub.2-- or
--NQ.sup.7- (wherein Q.sup.3, Q.sup.4, Q.sup.5, Q.sup.6 and Q.sup.7
each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore; 3)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined hereinbefore);
4) C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2 is as defined
hereinbefore); 5) C.sub.2-5alkynylQ.sup.2 (wherein Q.sup.2 is as
defined hereinbefore); 6)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9-, --SO.sub.2NQ.sup.10-, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore); 7)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 8)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 9)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6-fluoroalkyl, C.sub.1-6alkanoyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
Cl.sub.14aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
provisos that Q.sup.13 cannot be hydrogen and one or both of
Q.sup.13 and Q.sup.14 must be a 5-6-membered saturated or partially
unsaturated heterocyclic group as defined hereinbefore which
heterocyclic group bears at least one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-14alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl
and C.sub.1-6fluoroalkylsulphonyl and which heterocyclic group
optionally bears 1 or 2 further substituents selected from those
defined hereinbefore); 10)
C.sub.1-4alkylQ.sup.13C.sub.1-4alkanoylQ.sup.14n wherein Q.sup.13
is as defined hereinbefore and is not hydrogen and Q.sup.14n is a
5-6-membered saturated or partially unsaturated heterocyclic group
containing at least one nitrogen atom and optionally containing a
further nitrogen atom wherein Q.sup.14n is linked to
C.sub.1-6alkanoyl through a nitrogen atom and wherein Q.sup.14n
optionally bears 1, 2 or 3 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl); and
additionally wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino);
(ii) Q.sup.5W.sup.3
[0013] wherein W.sup.3 represents --NQ.sup.16C(O)--,
--C(O)NQ.sup.17-, --SO.sub.2NQ.sup.18-, --NQ.sup.19SO.sub.2-- or
--NQ.sup.20- (wherein Q.sup.16, Q.sup.17, Q.sup.18, Q.sup.19 and
Q.sup.20 each independently represents C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-4haloalkyl), and Q.sup.15 is
C.sub.1-6haloalkyl, C.sub.2-5alkenyl or C.sub.2-5alkynyl; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein W.sup.4 represents
--NQ.sup.22C(O)--, --C(O)NQ.sup.23-, --SO.sub.2NQ.sup.24-,
--NQ.sup.25SO.sub.2-- or --NQ.sup.26- (wherein Q.sup.22, Q.sup.23,
Q.sup.24, Q.sup.25 and Q.sup.26 each independently represents
hydrogen, C.sub.1-3alkyl, C.sub.1-3alkoxyC.sub.2-3alkyl,
C.sub.2-5alkenyl, C.sub.2-5alkynyl or C.sub.1-4haloalkyl), and
Q.sup.21 represents C.sub.1-6haloalkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl, and X.sup.1 is as defined hereinbefore; (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein X.sup.1 is as defined
hereinbefore and Q.sup.28 is an imidazolidinyl group which bears
two oxo substituents and one C.sub.1-6alkyl or C.sub.3-10cycloalkyl
group which C.sub.1-6alkyl or C.sub.3-10cycloalkyl group may bear a
hydroxy substituent on the carbon atom which is linked to the
imidazolidinyl group, and wherein the C.sub.1-5alkyl,
C.sub.1-5alkenyl or C.sub.1-5alkynyl linked to X.sup.1 may bear one
or more substituents selected from hydroxy, halogeno and amino; and
(v) Q.sup.29C.sub.1-5alkylX.sup.1--,
Q.sup.29C.sub.2-5alkenylX.sup.1-- or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein X.sup.1 is as defined
hereinbefore, the C.sub.1-5alkyl, C.sub.1-5alkenyl or
C.sub.1-5alkynyl linked to X.sup.1 may bear one or more
substituents selected from hydroxy, halogeno and amino and Q.sup.29
is a group 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, which may be
represented:
##STR00002##
or R.sup.1 may be selected from any of the groups defined
hereinbefore and R.sup.2 is 6,7-methylenedioxy or
6,7-ethylenedioxy; or a salt thereof, or a prodrug thereof for
example an ester or an amide, in the manufacture of a medicament
for use in the production of an antiangiogenic and/or vascular
permeability reducing effect in warm-blooded animals such as
humans.
[0014] According to one aspect of the present invention there is
provided the use of a compound of the formula I:
##STR00003##
wherein: ring C is an 8, 9, 10, 12 or 13-membered bicyclic or
tricyclic moiety which moiety may be saturated or unsaturated,
which may be aromatic or non-aromatic, and which optionally may
contain 1-3 heteroatoms selected independently from O, N and S;
Z is --O--, --NH-- or --S--;
[0015] n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2 or 3; R.sup.2
represents hydrogen, hydroxy, halogeno, cyano, nitro,
trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3R.sup.4 (wherein R.sup.3 and
R.sup.4, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), or R.sup.5X.sup.1-- (wherein X.sup.1
represents a direct bond, --O--, --CH.sub.2--, --OC(O)--, --C(O)--,
--S--, --SO--, --SO.sub.2--, --NR.sup.6C(O)--, --C(O)NR.sup.7--,
--SO.sub.2NR.sup.8--, --NR.sup.9SO.sub.2-- or --NR.sup.10--
(wherein R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), and R.sup.5 is selected from one of
the following twenty-two groups: 1) hydrogen,
oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be unsubstituted
or which may be substituted with one or more groups selected from
hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.2C(O)R.sup.11 (wherein X.sup.2 represents --O--
or --NR.sup.12-- (in which R.sup.12 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.11
represents C.sub.1-3alkyl, --NR.sup.13R.sup.14 or --OR.sup.15
(wherein R.sup.13, R.sup.14 and R.sup.15 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.3R.sup.16
(wherein X.sup.3 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.17C(O)--, --C(O)NR.sup.18,
--SO.sub.2NR.sup.19--, --NR.sup.20SO.sub.2-- or --NR.sup.21--
(wherein R.sup.17, R.sup.18, R.sup.19, R.sup.20 and R.sup.21 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.16 represents hydrogen,
C.sub.1-3alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which C.sub.1-3alkyl group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno and
C.sub.1-4alkoxy and which cyclic group may bear 1 or 2 substituents
selected from oxo, hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl,
C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.4C.sub.1-5alkylX.sup.1R.sup.22 (wherein X.sup.4
and X.sup.5 which may be the same or different are each --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.23C(O)--, --C(O)NR.sup.24--,
--SO.sub.2NR.sup.25--, --NR.sup.26SO.sub.2-- or NR.sup.27--
(wherein R.sup.23, R.sup.24, R.sup.25, R.sup.26 and R.sup.27 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.22 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.28
(wherein R.sup.28 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--)C(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g is 0
or 1 and ring D is a 5-6-membered saturated heterocyclic group with
1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.2(wherein R.sup.28 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.28 (wherein
R.sup.28 is as defined hereinbefore); 8) C.sub.2-5alkynylR.sup.28
(wherein R.sup.28 is as defined hereinbefore); 9) R.sup.29 (wherein
R.sup.29 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano, --C(O)NR.sup.30R.sup.31,
--NR.sup.32C(O)R.sup.33 (wherein R.sup.30, R.sup.31, R.sup.32 and
R.sup.33, which may be the same or different, each represents
hydrogen, C.sub.1-4alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and a
group --(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or
1, g is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic
group with 1-2 heteroatoms, selected independently from O, S and N,
which cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.29 (wherein R.sup.29 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.29 (wherein
R.sup.29 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.29
(wherein R.sup.29 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.6R.sup.29 (wherein X.sup.6 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.34C(O)--, --C(O)NR.sup.35--,
SO.sub.2NR.sup.36--, --NR.sup.31SO.sub.2-- or --NR.sup.38--
(wherein R.sup.34, R.sup.35, R.sup.36, R.sup.37 and R.sup.38 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.7R.sup.29 (wherein X.sup.7
represents --O--, --S--, --SO--, SO.sub.2--, --NR.sup.39C(O)--,
--C(O)NR.sup.40--, --SO.sub.2NR.sup.41--, --NR.sup.42SO.sub.2-- or
--NR.sup.43-- (wherein R.sup.39, R.sup.40, R.sup.41, R.sup.42 and
R.sup.43 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 15) C.sub.2-5alkynylX.sup.8R.sup.29 (wherein X.sup.8
represents --O--, --S--, --SO--, --SO.sub.2--, --NR.sup.44C(O)--,
--C(O)NR.sup.45--, --SO.sub.2NR.sup.46--, --NR.sup.47 SO.sub.2-- or
--NR.sup.48-- (wherein R.sup.44, R.sup.45, R.sup.46, R.sup.47 and
R.sup.48 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.29
(wherein X.sup.9 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.49C(O)--, --C(O)NR.sup.50--, --SO.sub.2NR.sup.51--,
--NR.sup.52SO.sub.2-- or --NR.sup.53-- (wherein R.sup.49, R.sup.50,
R.sup.51, R.sup.52 and R.sup.53 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.29 is as defined hereinbefore); 17)
C.sub.1-4alkylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 18) C.sub.2-5alkenyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.9C.sub.1-4alkylR.sup.28 (wherein X.sup.9 and
R.sup.28 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55
(wherein X.sup.9 is as defined hereinbefore, q is 0 or 1, r is 0 or
1, and R.sup.54 and R.sup.55 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl), with the proviso that R.sup.54 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.5X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino); R.sup.1 represents
hydrogen, oxo, halogeno, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkyl,
C.sub.1-4alkoxymethyl, C.sub.1-4alkanoyl, C.sub.1-4haloalkyl,
cyano, amino, C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-3alkanoyloxy, nitro, C.sub.1-4alkanoylamino,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkylsulphanyl,
C.sub.1-4alkylsulphinyl, C.sub.1-4alkylsulphonyl, carbamoyl,
N--C.sub.1-4alkylcarbamoyl, N,N-di(C.sub.1-4alkyl)carbamoyl,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl,
N,N-di(C.sub.1-4alkyl)aminosulphonyl,
N--(C.sub.1-4alkylsulphonyl)amino,
N--(C.sub.1-4alkylsulphonyl)-N--(C.sub.1-4alkyl)amino,
N,N-di(C.sub.1-4alkylsulphonyl)amino, a C.sub.3-7alkylene chain
joined to two ring C carbon atoms,
C.sub.1-4alkanoylaminoC.sub.1-4alkyl, carboxy or a group
R.sup.56X.sup.10 (wherein X.sup.10 represents a direct bond, --O--,
--CH.sub.2--, --OC(O)--, --C(O)--, --S--, --SO--, --SO.sub.2--,
--NR.sup.17C(O)--, --C(O)NR.sup.51--, --SO.sub.2NR.sup.19--,
--NR.sup.60SO.sub.2-- or --NR.sup.61-- (wherein R.sup.57, R.sup.58,
R.sup.59, R.sup.60 and R.sup.61 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl), and
R.sup.56 is selected from one of the following twenty-two groups:
1) hydrogen, oxiranylC.sub.1-4alkyl or C.sub.1-5alkyl which may be
unsubstituted or which may be substituted with one or more groups
selected from hydroxy, fluoro, chloro, bromo and amino; 2)
C.sub.1-5alkylX.sup.11C(O)R.sup.62 (wherein X.sup.11 represents
--O-- or --NR.sup.63-- (in which R.sup.63 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.62
represents C.sub.1-3alkyl, --NR.sup.64R.sup.65 or --OR.sup.66
(wherein R.sup.64, R.sup.65 and R.sup.66 which may be the same or
different each represents hydrogen, C.sub.1-5alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl)); 3) C.sub.1-5alkylX.sup.12R.sup.67
(wherein X.sup.12 represents --O--, --S--, --SO--, --SO.sub.2--,
--OC(O)--, --NR.sup.68C(O)--, --C(O)NR.sup.69--,
SO.sub.2NR.sup.70--, --NR.sup.71SO.sub.2-- or NR.sup.72 (wherein
R.sup.68, R.sup.69R.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.1-4-aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 4)
C.sub.1-5alkylX.sup.13C.sub.1-5alkylX.sup.14R.sup.73 (wherein
X.sup.13 and X.sup.14 which may be the same or different are each
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.74C(O)--,
--C(O)NR.sup.75--, --SO.sub.2NR.sup.76--, --NR.sup.77SO.sub.2-- or
--NR.sup.78-- (wherein R.sup.74, R.sup.75, R.sup.76, R.sup.77 and
R.sup.78 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.73 represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl); 5) R.sup.79
(wherein R.sup.79 is a 5-6-membered saturated heterocyclic group
(linked via carbon or nitrogen) with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear 1
or 2 substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 6) C.sub.1-5alkylR.sup.79 (wherein R.sup.79 is as
defined hereinbefore); 7) C.sub.2-5alkenylR.sup.79 (wherein
R.sup.79 is as defined hereinbefore); 8) C.sub.2-5-alkynylR.sup.79
(wherein R.sup.79 is as defined hereinbefore); 9) R.sup.80 (wherein
R.sup.80 represents a pyridone group, a phenyl group or a
5-6-membered aromatic heterocyclic group (linked via carbon or
nitrogen) with 1-3 heteroatoms selected from O, N and S, which
pyridone, phenyl or aromatic heterocyclic group may carry up to 5
substituents selected from oxo, hydroxy, halogeno, amino,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4hydroxyalkyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, C.sub.1-4hydroxyalkoxy,
carboxy, trifluoromethyl, cyano,
--C(O)NR.sup.81R.sup.82, NR.sup.83C(O)R.sup.84 (wherein R.sup.81,
R.sup.82, R.sup.83 and R.sup.84, which may be the same or
different, each represents hydrogen, C.sub.1-4alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl)); 10) C.sub.1-5alkylR.sup.80 (wherein R.sup.80 is
as defined hereinbefore); 11) C.sub.2-5alkenylR.sup.80 (wherein
R.sup.80 is as defined hereinbefore); 12) C.sub.2-5alkynylR.sup.80
(wherein R.sup.80 is as defined hereinbefore); 13)
C.sub.1-5alkylX.sup.15R.sup.80 (wherein X.sup.15 represents --O--,
--S--, --SO--, --SO.sub.2--, --NR.sup.85C(O)--, --C(O)NR.sup.86--,
--SO.sub.2NR.sup.87--, --NR.sup.88SO.sub.2-- or --NR.sup.89--
(wherein R.sup.85, R.sup.86, R.sup.87, R.sup.88 and R.sup.89 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 14) C.sub.2-5alkenylX.sup.16R.sup.80 (wherein
X.sup.16 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.9OC(O)--, --C(O)NR.sup.91--, --SO.sub.2NR.sup.92--,
--NR.sup.93SO.sub.2-- or --NR.sup.94-- (wherein R.sup.90, R.sup.91,
R.sup.92, R.sup.93 and R.sup.94 each independently represents
hydrogen, C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and
R.sup.80 is as defined hereinbefore); 15)
C.sub.2-5alkynylX.sup.17R.sup.80 (wherein X.sup.17 represents
--O--, --S--, --SO--, --SO.sub.2--, --NR.sup.95C(O)--,
--C(O)NR.sup.96--, --SO.sub.2NR.sup.97--, --NR.sup.98SO.sub.2-- or
--NR.sup.99-- (wherein R.sup.95, R.sup.96, R.sup.97, R.sup.98 and
R.sup.99 each independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 16) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.80
(wherein X.sup.18 represents --O--, --S--, --SO--, --SO.sub.2--,
--NR.sup.100C(O)--, --C(O)NR.sup.101--, --SO.sub.2NR.sup.102--,
--NR.sup.103SO.sub.2-- or --NR.sup.104-- (wherein R.sup.100,
R.sup.101, R.sup.102, R.sup.103 and R.sup.104 each independently
represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.80 is as defined
hereinbefore); 17) C.sub.1-4alkylX.sup.18C.sub.1-4alkylR.sup.79
(wherein X.sup.18 and R.sup.79 are as defined hereinbefore); 18)
C.sub.2-5alkenyl which may be unsubstituted or which may be
substituted with one or more groups selected from hydroxy, fluoro,
amino, C.sub.1-4alkylamino, N,N-di(C.sub.1-4alkyl)amino,
aminosulphonyl, N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 19) C.sub.2-5alkynyl which
may be unsubstituted or which may be substituted with one or more
groups selected from hydroxy, fluoro, amino, C.sub.1-4alkylamino,
N,N-di(C.sub.1-4alkyl)amino, aminosulphonyl,
N--C.sub.1-4alkylaminosulphonyl and
N,N-di(C.sub.1-4alkyl)aminosulphonyl; 20)
C.sub.2-5alkenylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); 21)
C.sub.2-5alkynylX.sup.18C.sub.1-4alkylR.sup.79 (wherein X.sup.18
and R.sup.79 are as defined hereinbefore); and 22)
C.sub.1-4alkylR.sup.105(C.sub.1-4alkyl).sub.x(X.sup.18).sub.yR.sup.106
(wherein X.sup.18 is as defined hereinbefore, x is 0 or 1, y is 0
or 1, and R.sup.105 and R.sup.106 are each independently selected
from hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated heterocyclic group with 1-2 heteroatoms,
selected independently from O, S and N, which C.sub.1-3alkyl group
may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno
and C.sub.1-4alkoxy and which cyclic group may bear 1 or 2
substituents selected from oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
cyclic group may bear one or more substituents selected from
C.sub.1-4alkyl) with the proviso that R.sup.105 cannot be
hydrogen); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in R.sup.56X.sup.10--
which is linked to X.sup.10 may bear one or more substituents
selected from hydroxy, halogeno and amino); with the proviso that
one or more R.sup.1 and/or one or more R.sup.2 are selected from
one of the following three groups:
(i) Q.sup.1X.sup.1
[0016] wherein X.sup.1 is as defined hereinbefore and Q.sup.1 is
selected from one of the following nine groups: 1) Q.sup.2 (wherein
Q.sup.2 is a 5-6-membered saturated or partially unsaturated
heterocyclic group with 1-2 heteroatoms, selected independently
from O, S and N, which heterocyclic group bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
C.sub.1-6alkylsulphonyl and C.sub.1-6fluoroalkylsulphonyl and which
heterocyclic group may optionally bear a further 1 or 2
substituents selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
C.sub.1-6alkylsulphonyl, C.sub.1-6fluoroalkylsulphonyl, oxo,
hydroxy, halogeno, cyano, C.sub.1-4cyanoalkyl, C.sub.1-4alkyl,
C.sub.1-4hydroxyalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which cyclic group may bear one or
more substituents selected from C.sub.1-4alkyl)); 2)
C.sub.1-5alkylW.sup.1Q.sup.2 (wherein W.sup.1 represents --O--,
--S--, --SO--, --SO.sub.2--, --OC(O)--, --NQ.sup.3C(O)--,
--C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-, --NQ.sup.6SO.sub.2-- or
--NQ.sup.7- (wherein Q.sup.3, Q.sup.4, Q.sup.5, Q.sup.6 and Q.sup.7
each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore; 3)
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as defined hereinbefore);
4) C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2 is as defined
hereinbefore); 5) C.sub.2-5alkynylQ.sup.2 (wherein Q.sup.2 is as
defined hereinbefore); 6)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9-, --SO.sub.2NQ.sup.11O--, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore); 7)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 8)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); and 9)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
hydrogen, C.sub.1-3alkyl, cyclopentyl, cyclohexyl and a
5-6-membered saturated or partially unsaturated heterocyclic group
with 1-2 heteroatoms, selected independently from O, S and N, which
C.sub.1-3alkyl group may bear 1 or 2 substituents selected from
oxo, hydroxy, halogeno and C.sub.1-4alkoxy and which cyclic group
may bear 1, 2 or 3 substituents selected from C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl,
C.sub.1-6fluoroalkanoyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6fluoroalkylsulphonyl, oxo, hydroxy, halogeno, cyano,
C.sub.1-4cyanoalkyl, C.sub.1-4alkyl, C.sub.1-4hydroxyalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylsulphonylC.sub.1-4alkyl, C.sub.1-4alkoxycarbonyl,
C.sub.1-4aminoalkyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylaminoC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
C.sub.1-4alkylaminoC.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkoxy and a group
--(--O--).sub.f(C.sub.1-4alkyl).sub.gringD (wherein f is 0 or 1, g
is 0 or 1 and ring D is a 5-6-membered saturated or partially
unsaturated heterocyclic group with 1-2 heteroatoms, selected
independently from O, S and N, which heterocyclic group may bear
one or more substituents selected from C.sub.1-4alkyl), with the
provisos that Q.sup.13 cannot be hydrogen and one or both of
Q.sup.13 and Q.sup.14 must be a 5-6-membered saturated or partially
unsaturated heterocyclic group as defined hereinbefore which
heterocyclic group bears at least one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-6fluoroalkyl,
C.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl, C.sub.1-6alkylsulphonyl
and C.sub.1-6fluoroalkylsulphonyl and which heterocyclic group
optionally bears 1 or 2 further substituents selected from those
defined hereinbefore); and additionally wherein any C.sub.1-5alkyl,
C.sub.2-5alkenyl or C.sub.2-5alkynyl group in Q.sup.1X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy, halogeno and amino);
(ii) Q.sup.15W.sup.3--
[0017] wherein W.sup.3 represents --NQ.sup.16C(O)--,
--C(O)NQ.sup.17-, --SO.sub.2NQ.sup.18-, --NQ.sup.19SO.sub.2-- or
--NQ.sup.20- (wherein Q.sup.16, Q.sup.17, Q.sup.18, Q.sup.19 and
Q.sup.20 each independently represents C.sub.2-5alkenyl,
C.sub.2-5alkynyl, C.sub.1-4haloalkyl), and Q.sup.15 is
C.sub.1-6haloalkyl, C.sub.2-5alkenyl or C.sub.2-5alkynyl; and (iii)
Q.sup.21-W.sup.4C.sub.1-5alkylX.sup.1-- wherein W.sup.4 represents
--NQ.sup.22C(O)--, --C(O)NQ.sup.23-, --SO.sub.2NQ.sup.24-,
--NQ.sup.25SO.sub.2-- or --NQ.sup.26- (wherein Q.sup.22, Q.sup.23,
Q.sup.24, Q.sup.25 and Q.sup.26 each independently represents
hydrogen, C.sub.1-3alkyl, C.sub.1-3alkoxyC.sub.2-3alkyl,
C.sub.2-5alkenyl, C.sub.2-5alkynyl or C.sub.1-4haloalkyl), and
Q.sup.21 represents C.sub.1-6haloalkyl, C.sub.2-5alkenyl or
C.sub.2-5alkynyl, and X.sup.1 is as defined hereinbefore; 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.
[0018] According to one aspect of the present invention ring C is a
9-10-membered aromatic bicyclic moiety which may optionally contain
1-3 heteroatoms selected independently from O, N and S.
[0019] According to one aspect of the present invention ring C is a
9-10-membered heteroaromatic bicyclic moiety which contains 1-3
heteroatoms selected independently from O, N and S.
[0020] According to one aspect of the present invention ring C is a
9-10-membered heteroaromatic bicyclic moiety which contains 1 or 2
nitrogen atoms.
[0021] According to one aspect of the present invention ring C is
indolyl, quinolinyl, indazolyl or azaindolyl.
[0022] According to one aspect of the present invention ring C is
indolyl, indazolyl or azaindolyl.
[0023] According to one aspect of the present invention ring C is
indolyl or azaindolyl.
[0024] According to one aspect of the present invention ring C is
azaindolyl.
[0025] According to one aspect of the present invention ring C is
indolyl.
[0026] According to one aspect of the present invention ring C is
indazolyl.
[0027] According to one aspect of the present invention ring Z is
--O-- or --S--.
[0028] According to one aspect of the present invention ring Z is
--O--.
[0029] In one embodiment of the present invention X.sup.1
represents a direct bond, --O--, --S--, --NR.sup.6C(O)--,
--NR.sup.9SO.sub.2-- or --NR.sup.10-- (wherein R.sup.6, R.sup.9 and
R.sup.10 each independently represents hydrogen, C.sub.1-2alkyl or
C.sub.1-2alkoxyethyl).
[0030] In one embodiment of the present invention X.sup.1
represents a direct bond, --O--, --S--, --NR.sup.6C(O)--,
--NR.sup.9SO.sub.2-- (wherein R.sup.6 and R.sup.9 each
independently represents hydrogen or C.sub.1-2alkyl) or NH.
[0031] In one embodiment of the present invention X.sup.1
represents --O--, --S--, --NR.sup.6C(O)-- (wherein R.sup.6
represents hydrogen or C.sub.1-2alkyl) or NH.
[0032] In one embodiment of the present invention X.sup.1
represents --O-- or --NR.sup.6C(O)-- (wherein R.sup.6 represents
hydrogen or C.sub.1-2alkyl).
[0033] In one embodiment of the present invention X.sup.1
represents --O-- or --NHC(O)--.
[0034] In one embodiment of the present invention X.sup.1
represents --O--.
[0035] According to another aspect of the present invention X.sup.1
represents --O-- or a direct bond.
[0036] In one embodiment of the present invention R.sup.1 is
selected from one of the three groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; and/or R.sup.1 represents
oxo, hydroxy, C.sub.1-2alkoxymethyl, amino, halogeno,
C.sub.1-2alkyl, C.sub.1-2alkoxy, trifluoromethyl, cyano, nitro,
C.sub.2-3alkanoyl.
[0037] According to one aspect of the present invention R.sup.1
represents methyl, ethyl, trifluoromethyl or halogeno.
[0038] According to another aspect of the present invention R.sup.1
represents methyl, fluoro, chloro or bromo.
[0039] According to another aspect of the present invention R.sup.1
represents methyl or fluoro.
[0040] In one embodiment of the present invention n is 3.
[0041] In one embodiment of the present invention n is 2.
[0042] In one embodiment of the present invention n is 1.
[0043] In one embodiment of the present invention n is 0.
[0044] In one embodiment of the present invention n is 0, 1 or
2.
[0045] In one embodiment of the present invention m is 1 or 2.
[0046] In one embodiment of the present invention m is 1.
[0047] In one embodiment of the present invention m is 2.
[0048] In one embodiment of the present invention X.sup.3
represents --O--, --S--, --SO--, --SO.sub.2--,
--SO.sub.2NR.sup.19-- or --NR.sup.21-- (wherein R.sup.19 and
R.sup.21 each independently represents hydrogen, C.sub.1-2alkyl or
C.sub.1-2alkoxyethyl).
[0049] In one embodiment of the present invention X.sup.3
represents --O-- or --NR.sup.21-- (wherein R.sup.21 represents
hydrogen or C.sub.1-2alkyl).
[0050] In one embodiment of the present invention X.sup.3
represents --O--.
[0051] In one embodiment of the present invention X.sup.4 and
X.sup.5 which may be the same or different each represents --O--,
--S-- or --NR.sup.27-- (wherein R.sup.27 represents hydrogen,
C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0052] In one embodiment of the present invention X.sup.4 and
X.sup.5 which may be the same or different each represents --O-- or
--NH--.
[0053] In one embodiment of the present invention X.sup.4 and
X.sup.5 each represents --O--.
[0054] In one embodiment of the present invention X.sup.6
represents --O--, --S-- or --NR.sup.38-- (wherein R.sup.38
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0055] In one embodiment of the present invention X.sup.6
represents --O-- or --NR.sup.38-- (wherein R.sup.38 represents
hydrogen or C.sub.1-2alkyl).
[0056] In one embodiment of the present invention X.sup.6
represents --O--.
[0057] In one embodiment of the present invention X.sup.7
represents --O--, --S-- or --NR.sup.43-- (wherein R.sup.43
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0058] In one embodiment of the present invention X.sup.7
represents --O-- or --NR.sup.43-- (wherein R.sup.43 represents
hydrogen or C.sub.1-2alkyl).
[0059] In one embodiment of the present invention X.sup.7
represents --O--.
[0060] In one embodiment of the present invention X.sup.8
represents --O--, --S-- or --NR.sup.48-- (wherein R.sup.48
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0061] In one embodiment of the present invention X.sup.8
represents --O-- or --NR.sup.4-- (wherein R.sup.48 represents
hydrogen or C.sub.1-2alkyl).
[0062] In one embodiment of the present invention X.sup.8
represents --O--.
[0063] In one embodiment of the present invention X.sup.9
represents --O--, --S-- or --NR.sup.53-- (wherein R.sup.53
represents hydrogen, C.sub.1-2alkyl or C.sub.1-2alkoxyethyl).
[0064] In one embodiment of the present invention X.sup.9
represents --O-- or --NR.sup.53-- (wherein R.sup.53 represents
hydrogen or C.sub.1-2alkyl).
[0065] In one embodiment of the present invention X.sup.9
represents --O--.
[0066] In one embodiment of the present invention R.sup.28 is
pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl,
1,3-dioxolan-2-yl, morpholino or thiomorpholino which group may
bear 1 or 2 substituents selected from oxo, hydroxy, 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, morpholino
and thiomorpholino, which cyclic group may bear one or more
substituents selected from C.sub.1-3alkyl).
[0067] In one embodiment of the present invention R.sup.28 is
pyrrodinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 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,
[0068] In one embodiment of the present invention R.sup.29 is
phenyl, pyridyl, imindazolyl, thiazolyl or triazolyl group which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, C.sub.1-4alkyl, C.sub.1-4alkoxy, cyano and
--NR.sup.32C(O)R.sup.33 (wherein R.sup.32 and R.sup.33 are each
independently selected from hydrogen and C.sub.1-4alkyl).
[0069] In one embodiment of the present invention R.sup.54 and
R.sup.55 are each selected from pyrrolidinyl, piperazinyl,
piperidinyl, imidazolidinyl, morpholino and thiomorpholino which
group may bear 1 or 2 substituents selected from oxo, hydroxy,
halogeno, cyano, C.sub.1-3cyanoalkyl, C.sub.1-3alkyl,
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, morpholino
and thiomorpholino, which cyclic group may bear one or more
substituents selected from C.sub.1-3alkyl).
[0070] In one embodiment of the present invention R.sup.2 is
selected from one of the five groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore; and (v)
Q.sup.29C.sub.1-5alkylX.sup.1--, Q.sup.29C.sub.2-5alkenylX.sup.1--
or Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1
are as defined hereinbefore; and/or R.sup.2 represents
6,7-methylenedioxy, 6,7-ethylenedioxy, hydroxy, C.sub.1-3alkyl,
amino or R.sup.5X.sup.1-[wherein X.sup.1 is as hereinbefore defined
and R.sup.5 represents methyl, ethyl, benzyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,
2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl,
2-(ethylsulphonyl)ethyl, 2-(N,N-diimethylsulphamoyl)ethyl,
2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,
2-(methylamino)ethyl, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyaniomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-(N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0071] In one embodiment of the present invention R.sup.2 is
selected from one of the three groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; and/or 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, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidiino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-(N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0072] In one embodiment of the present invention R.sup.2 is
selected from one of the five groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore; and (v) Q.sup.29C.sub.1-5alkylX.sup.1,
Q.sup.29C.sub.2-5alkenylX.sup.1-- or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1 are
as defined hereinbefore; and/or R.sup.2 represents
6,7-methylenedioxy, 6,7-ethylenedioxy, hydroxy, C.sub.1-3alkyl,
amino or R.sup.5X.sup.1-- [wherein X.sup.1 is --O-- and R.sup.5
represents methyl, ethyl, benzyl, trifluoromethyl,
2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,
2-(methylsulphonyl)ethyl, 2-(ethylsulphinyl)ethyl,
2-(ethylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,
2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,
2-(methylamino)ethyl, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-((N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-methylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0073] In one embodiment of the present invention R.sup.2 is
selected from one of the three groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; and/or R.sup.2 represents
hydroxy, C.sub.1-3alkyl, amino or R.sup.5X'-[wherein X.sup.1 is
--O-- and R.sup.5 represents methyl, ethyl, benzyl,
trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,
3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,
2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,
2-(ethylsulphinyl)ethyl, 2-(ethylsulphonyl)ethyl,
2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,
2-sulphamoylethyl, 2-(methylamino)ethyl, 2-(ethylamino)ethyl,
2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl,
2-(N-methyl-N-methylsulphonylamino)ethyl,
3-(N-methyl-N-methylsulphonylamino)propyl, 2-morpholinoethyl,
3-morpholinopropyl, 2-piperidinoethyl, 2-(methylpiperidino)ethyl,
2-(ethylpiperidino)ethyl, 2-((2-methoxyethyl)piperidino)ethyl,
2-((2-methylsulphonyl)ethylpiperidino)ethyl,
3-((2-methylsulphonyl)ethylpiperidino)propyl,
(1-cyanomethylpiperidin-3-yl)methyl,
(1-cyanomethylpiperidin-4-yl)methyl,
2-(1-cyanomethylpiperidin-3-yl)ethyl,
2-(1-cyanomethylpiperidin-4-yl)ethyl,
3-(1-cyanomethylpiperidin-3-yl)propyl,
3-(1-cyanomethylpiperidin-4-yl)propyl,
((2-methoxyethyl)piperidin-3-yl)methyl,
((2-methoxyethyl)piperidin-4-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-3-yl)methyl,
(1-(2-methylsulphonylethyl)piperidin-4-yl)methyl,
2-((2-methylsulphonylethyl)piperidin-3-yl)ethyl,
2-((2-methylsulphonylethyl)piperidin-4-yl)ethyl,
3-((2-methylsulphonylethyl)piperidin-3-yl)propyl,
3-((2-methylsulphonylethyl)piperidin-4-yl)propyl,
2-(piperidin-4-yloxy)ethyl, 3-(piperidin-4-yloxy)propyl,
2-(1-(cyanomethyl)piperidin-4-yloxy)ethyl,
3-(1-(cyanomethyl)piperidin-4-yloxy)propyl,
2-(1-(2-cyanoethyl)piperidin-4-yloxy)ethyl,
3-(1-(2-cyanoethyl)piperidin-4-yloxy)propyl,
2-(piperazin-1-yl)ethyl, (pyrrolidin-2-yl)methyl,
(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
5(R)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(5S)-(2-oxo-tetrahydro-2H-pyrrolidin-5-yl)methyl,
(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,
2-(2-methoxyethylamino)ethyl,
2-(N-(2-methoxyethyl)-N-methylamino)ethyl,
2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,
3-(N-(2-methoxyethyl)-N-methylamino)propyl,
3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,
2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,
2-(imidazol-1-yl)ethyl, 2-(2-methylimidazol-1-yl)ethyl,
2-(2-ethylimidazol-1-yl)ethyl, 3-(2-ethylimidazol-1-yl)propyl,
3-(2-ethylimidazol-1-yl)propyl, 2-(1,2,3-triazol-1-yl)ethyl,
2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,
2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,
3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl,
2-(4-pyridylamino)ethyl, 2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl,
2-(2-oxo-imidazolidin-1-yl)ethyl,
3-(2-oxo-imidazolidin-1-yl)propyl, 2-thiomorpholinoethyl,
3-thiomorpholinopropyl, 2-(1,1-dioxothiomorpholino)ethyl,
3-(1,1-dioxothiomorpholino)propyl, 2-(2-methoxyethoxy)ethyl,
2-(4-methylpiperazin-1-yl)ethyl, 3-(methylsulphinyl)propyl,
3-(methylsulphonyl)propyl, 3-(ethylsulphinyl)propyl,
3-(ethylsulphonyl)propyl, 2-(5-methyl-1,2,4-triazol-1-yl)ethyl,
morpholino,
2-((N-(1-methylimidazol-4-ylsulphonyl)-N-methyl)amino)ethyl,
2-((N-(3-morpholinopropylsulphonyl)-N-methyl)amino)ethyl,
3-(4-oxidomnorpholino)propyl,
2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl,
3-(2-(4-methylpiperazin-1-yl)ethoxy)propyl,
2-(2-morpholinoethoxy)ethyl, 3-(2-morpholinoethoxy)propyl,
2-(tetrahydropyran-4-yloxy)ethyl,
3-(tetrahydropyran-4-yloxy)propyl,
2-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)vinyl,
3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)prop-2-en-1-yl,
1-(2-morpholinoethyl)piperidin-4-ylmethyl,
1-(2-thiomorpholinoethyl)piperidin-4-ylmethyl,
3-morpholino-2-hydroxypropyl, (2R)-3-morpholino-2-hydroxypropyl,
(2S)-3-morpholino-2-hydroxypropyl, 3-piperidino-2-hydroxypropyl,
(2R)-3-piperidino-2-hydroxypropyl,
(2S)-3-piperidino-2-hydroxypropyl,
3-(1n-methylpiperazin-4-yl)-2-hydroxypropyl,
(2R)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl or
(2S)-3-(1-methylpiperazin-4-yl)-2-hydroxypropyl].
[0074] In one embodiment of the present invention R.sup.2
substituents are at the 6- and/or 7-positions of the quinazoline
ring.
[0075] In one embodiment of the present invention R.sup.2 is
selected from one of the five groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; (iv)
Q.sup.28C.sub.5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1-- or
Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1 are
as defined hereinbefore; and (v) Q.sup.29C.sub.1-5alkylX.sup.1--,
Q.sup.29C.sub.2-5alkenylX.sup.1 or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1 are
as defined hereinbefore; and/or R.sup.2 represents methoxy, or
R.sup.2 represents 6,7-methylenedioxy or 6,7-ethylenedioxy.
[0076] In one embodiment of the present invention R.sup.2 is
selected from one of the five groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore; and (v)
Q.sup.29Cl.sub.1-5alkylX.sup.1--, Q.sup.29C.sub.2-5alkenylX.sup.1--
or Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1
are as defined hereinbefore; and/or R.sup.2 represents methoxy.
[0077] In one embodiment of the present invention R.sup.2 is
selected from one of the three groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; and/or R.sup.2 represents
methoxy.
[0078] In one embodiment of the present invention R.sup.2 is
Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore and/or R.sup.2 represents methoxy.
[0079] In one embodiment of the present invention R.sup.2 is
Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are as defined
hereinbefore and/or R.sup.2 represents methoxy.
[0080] In one embodiment of the present invention R.sup.2 is
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore and/or R.sup.2 represents
methoxy.
[0081] In one embodiment of the present invention R.sup.2 is
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore and/or R.sup.2 represents methoxy.
[0082] In one embodiment of the present invention R.sup.2 is
Q.sup.29C.sub.1-5alkylX.sup.1--, Q.sup.29C.sub.2-5alkenylX.sup.1--
or Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1
are as defined hereinbefore and/or R.sup.2 represents methoxy.
[0083] In one embodiment of the present invention R.sup.2 is
6,7-methylenedioxy or 6,7-ethylenedioxy.
[0084] According to another aspect of the present invention there
are provided compounds of the formula I.
[0085] According to another aspect of the present invention there
are provided compounds of the formula Ia:
##STR00004##
[wherein: ring C.sup.a is indolyl, indazolyl or azaindolyl;
R.sup.1a is selected from oxo, hydroxy, C.sub.1-2alkoxymethyl,
amino, halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, trifluoromethyl,
cyano, nitro, C.sub.1-3alkanoyl, (i) Q.sup.1X.sup.1 wherein Q.sup.1
and X.sup.1 are as defined hereinbefore, (ii) Q.sup.15W.sup.3
wherein Q.sup.15 and W.sup.3 are as defined hereinbefore, (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; R.sup.2 is as defined
hereinbefore; ma is 0, 1, 2 or 3;
Z.sup.a is --O-- or --S--;
[0086] and na is 0, 1 or 2; with the proviso that at least one
R.sup.2 is selected from (i), (ii), (iii), (iv) or (v) as defined
hereinbefore in the definitions of R.sup.2, and/or R.sup.1a is
selected from (i), (ii) and (iii) as defined hereinbefore, or
R.sup.2 is 6,7-methylenedioxy or 6,7-ethylenedioxy; and salts
thereof, and prodrugs thereof for example esters, amides and
sulphides, preferably esters and amides.
[0087] According to another aspect of the present invention there
are provided compounds of the formula II:
##STR00005##
[wherein: ring C.sup.a is indolyl, indazolyl or azaindolyl;
R.sup.1a is selected from oxo, hydroxy, C.sub.1-2alkoxymethyl,
amino, halogeno, C.sub.1-3alkyl, C.sub.1-3alkoxy, trifluoromethyl,
cyano, nitro, C.sub.1-3alkanoyl, (i) Q.sup.1X.sup.1 wherein Q.sup.1
and X.sup.1 are as defined hereinbefore; (ii) Q.sup.15W.sup.3
wherein Q.sup.15 and W.sup.3 are as defined hereinbefore; and (iii)
Q.sup.21W.sup.4Cl.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; R.sup.2a and R.sup.2b, are
each independently selected from hydrogen, hydroxy, halogeno,
cyano, nitro, trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3aR.sup.4a (wherein R.sup.3a and
R.sup.4a, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), (i) Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined hereinbefore, (ii) Q.sup.15W.sup.3 wherein
Q.sup.15 and W.sup.3 are as defined hereinbefore, (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore, (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28 C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore or (v) Q.sup.29C.sub.5alkylX.sup.1--,
Q.sup.29C.sub.2-5alkenylX.sup.1-- or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1 are
as defined hereinbefore, or R.sup.2a and R.sup.2b together form
6,7-methylenedioxy or 6,7-ethylenedioxy;
Z.sup.a is --O-- or --S--;
[0088] and na is 0, 1 or 2; with the proviso that at least one of
R.sup.2a and R.sup.2b is selected from (i), (ii), (iii), (iv) or
(v) as defined hereinbefore and/or R.sup.1a is selected from (i),
(ii) and (iii) as defined hereinbefore, or R.sup.2a, and R.sup.2b
together form 6,7-methylenedioxy or 6,7-ethylenedioxy; and salts
thereof, and prodrugs thereof for example esters, amides and
sulphides, preferably esters and amides.
[0089] According to another aspect of the present invention there
are provided compounds of the formula IIa:
##STR00006##
[wherein: ring Ca is indolyl, indazolyl or azaindolyl; R.sup.1a is
selected from oxo, hydroxy, C.sub.1-2alkoxymethyl, amino, halogeno,
C.sub.1-3alkyl, C.sub.1-3alkoxy, trifluoromethyl, cyano, nitro,
C.sub.1-3alkanoyl, (i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1
are as defined hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15
and W.sup.3 are as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; R.sup.2a and R.sup.2b, are
each independently selected from hydrogen, hydroxy, halogeno,
cyano, nitro, trifluoromethyl, C.sub.1-3alkyl, C.sub.1-3alkoxy,
C.sub.1-3alkylsulphanyl, --NR.sup.3aR.sup.4a (wherein R.sup.3a and
R.sup.4a, which may be the same or different, each represents
hydrogen or C.sub.1-3alkyl), (i) Q.sup.1X.sup.1 wherein Q.sup.1 and
X.sup.1 are as defined hereinbefore; (ii) Q.sup.15W.sup.3 wherein
Q.sup.15 and W.sup.3 are as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore;
Z.sup.a is --O-- or --S--;
[0090] and na is 0, 1 or 2; with the proviso that at least one of
R.sup.2a and R.sup.2b is selected from (i), (ii) and (iii) as
defined hereinbefore and/or R.sup.1a is selected from (i), (ii) and
(iii) as defined hereinbefore; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0091] According to another aspect of the present invention there
are provided compounds of the formula IIa as defined hereinbefore
wherein at least one of R.sup.2a and R.sup.2b is selected from (i),
(ii) and (iii) as defined hereinbefore.
[0092] In one embodiment of the present invention Z.sup.a is
--O--.
[0093] In one embodiment of the present invention C.sup.a is
indol-5-yl, indol-6-yl, 7-azaindol-5-yl, indazol-5-yl,
indazol-6-yl.
[0094] In one embodiment of the present invention C.sup.a is
indol-5-yl, 7-azaindol-5-yl or indazol-5-yl.
[0095] In one embodiment of the present invention C.sup.a is
indol-5-yl.
[0096] In one embodiment of the present invention C.sup.a is
7-azaindol-5-yl.
[0097] In one embodiment of the present invention R.sup.1a is
halogeno or C.sub.1-3alkyl.
[0098] In one embodiment of the present invention R.sup.1a is
fluoro or methyl.
[0099] In one embodiment of the present invention R.sup.2a is
methoxy and R.sup.2b is selected from one of the five following
groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore; (iv)
Q.sup.28C.sub.1-5alkylX.sup.1--, Q.sup.28C.sub.2-5alkenylX.sup.1--
or Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1
are as defined hereinbefore; and (v)
Q.sup.29C.sub.1-5alkylX.sup.1--, Q.sup.29C.sub.2-5alkenylX.sup.1--
or Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1
are as defined hereinbefore.
[0100] In one embodiment of the present invention R.sup.2a is
methoxy and R.sup.2b is selected from one of the three following
groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore.
[0101] In another embodiment of the present invention R.sup.2b is
methoxy and R.sup.2a is selected from one of the five following
groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; (iii) Q.sup.21W--C.sub.5alkylX.sup.1--
wherein Q.sup.21, W.sup.4 and X.sup.1 are as defined hereinbefore;
(iv) Q.sup.28C.sub.1-5alkylX.sup.1--,
Q.sup.28C.sub.2-5alkenylX.sup.1-- or
Q.sup.28C.sub.2-5alkynylX.sup.1-- wherein Q.sup.28 and X.sup.1 are
as defined hereinbefore; and (v) Q.sup.29C.sub.1-5alkylX.sup.1--,
Q.sup.29C.sub.2-5alkenylX.sup.1-- or
Q.sup.29C.sub.2-5alkynylX.sup.1-- wherein Q.sup.29 and X.sup.1 are
as defined hereinbefore.
[0102] In another embodiment of the present invention R.sup.2b is
methoxy and R.sup.2a is selected from one of the three following
groups:
(i) Q.sup.1X.sup.1 wherein Q.sup.1 and X.sup.1 are as defined
hereinbefore; (ii) Q.sup.15W.sup.3 wherein Q.sup.15 and W.sup.3 are
as defined hereinbefore; and (iii)
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- wherein Q.sup.21, W.sup.4
and X.sup.1 are as defined hereinbefore.
[0103] According to another aspect of the present invention there
are provided compounds of the formula IIb:
##STR00007##
[wherein:
M is --CH-- or --N--;
[0104] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; Z.sup.a, R.sup.2a and R.sup.2b, are as defined
hereinbefore; with the proviso that at least one of R.sup.2a and
R.sup.2b is selected from (i), (ii), (iii), (iv) and (v) as defined
hereinbefore; and salts thereof, and prodrugs thereof for example
esters, amides and sulphides, preferably esters and amides.
[0105] According to another aspect of the present invention there
are provided compounds of the formula IIc:
##STR00008##
[wherein:
M is --CH-- or --N--;
[0106] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; Z.sup.a, R.sup.2a and R.sup.2b, are as defined
hereinbefore; with the proviso that at least one of R.sup.2a and
R.sup.2b is selected from (i), (ii) and (iii) as defined
hereinbefore; and salts thereof, and prodrugs thereof for example
esters, amides and sulphides, preferably esters and amides.
[0107] According to another aspect of the present invention there
are provided compounds of the formula IId:
##STR00009##
[wherein:
M is --CH-- or --N--;
[0108] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; one of R.sup.2a and R.sup.2b is methoxy and the other
is Q.sup.1X.sup.1 wherein X.sup.1 is as defined hereinbefore and
Q.sup.1 is selected from one of the following ten groups: 1)
Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00010##
which heterocyclic group bears at least one substituent selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-4fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl and which heterocyclic group may
optionally bear a further 1 or 2 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-4fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, 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 selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00011##
which heterocyclic group may bear one or more substituents selected
from C.sub.1-4alkyl)); 2) Cl.sub.1-5alkylW.sup.1Q.sup.2 (wherein
W.sup.1 represents --O--, --S--, --SO--, --SO.sub.2--, --OC(O)--,
--NQ.sup.3C(O)--, --C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-,
--NQ.sup.6SO.sub.2-- or --NQ.sup.7- (wherein Q.sup.3, Q.sup.4, QS,
Q.sup.6 and Q.sup.7 each independently represents hydrogen,
C.sub.1-2alkyl, C.sub.1-2alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl,
C.sub.2-5alkynyl or C.sub.1-4haloalkyl) and Q.sup.2 is as defined
hereinbefore; 3) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is as
defined hereinbefore); 4) C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2
is as defined hereinbefore); 5) C.sub.2-5alkynylQ.sup.2 (wherein
Q.sup.2 is as defined hereinbefore); 6)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9, --SO.sub.2NQ.sup.10, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore); 7)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 8)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 9)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00012##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-4fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, 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 selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00013##
which heterocyclic group may bear one or more substituents selected
from C.sub.1-4alkyl), with the proviso that at least one of
Q.sup.13 and Q.sup.14 bears at least one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-4fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoyl,
di(C.sub.1-4alkyl)carbamoyl, C.sub.1-4alkylsulphonyl and
C.sub.1-4fluoroalkylsulphonyl); and 10)
C.sub.1-4alkylQ.sup.13C.sub.1-4alkanoylQ.sup.14n wherein Q.sup.13
is as defined hereinbefore and is not hydrogen and Q.sup.14n is
selected from pyrrolidinyl, piperidinyl, piperazinyl,
##STR00014##
wherein Q.sup.14n is linked to C.sub.1-6alkanoyl through a nitrogen
atom; and additionally wherein any C.sub.1-5alkyl, C.sub.2-5alkenyl
or C.sub.2-5alkynyl group in Q.sup.1X.sup.1-- which is liked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino); and salts thereof, and prodrugs thereof for
example esters, amides and sulphides, preferably esters and
amides.
[0109] According to another aspect of the present invention there
are provided compounds of the formula IIe:
##STR00015##
[wherein:
M is --CH-- or --N--;
[0110] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; one of R.sup.2a and R.sup.2b is methoxy and the other
is Q.sup.1X.sup.1 wherein X.sup.1 is as defined hereinbefore and
Q.sup.1 is selected from one of the following nine groups: 1)
Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00016##
which heterocyclic group bears at least one substituent selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl and which heterocyclic group may
optionally bear a further 1 or 2 substituents selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4fluoroalkylsulphonyl, 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 selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00017##
which heterocyclic group may bear one or more substituents selected
from C.sub.1-4alkyl)); 2) C.sub.1-5alkylW.sup.1Q.sup.2 (wherein
W.sup.1 represents --O--, --S--, --SO--, --SO.sub.2--, --OC(O)--,
--NQ.sup.3C(O)--, --C(O)NQ.sup.4-, --SO.sub.2NQ.sup.5-,
--NQ.sup.6SO.sub.2-- or --NQ.sup.7- (wherein Q.sup.3, Q.sup.4,
Q.sup.5, Q.sup.6 and Q.sup.7 each independently represents
hydrogen, C.sub.1-2alkyl, C.sub.1-2alkoxyC.sub.2-3alkyl,
C.sub.2-5alkenyl, C.sub.2-5alkynyl or C.sub.1-4haloalkyl) and
Q.sup.2 is as defined hereinbefore; 3) C.sub.1-5alkylQ.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 4)
C.sub.2-5alkenylQ.sup.2 (wherein Q.sup.2 is as defined
hereinbefore); 5) C.sub.2-5alkynylQ.sup.2 (wherein Q.sup.2 is as
defiled hereinbefore); 6)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O--, --S--, --SO--, --SO.sub.2--, --NQ.sup.8C(O)--,
--C(O)NQ.sup.9-, --SO.sub.2NQ.sup.10-, --NQ.sup.11SO.sub.2-- or
--NQ.sup.12- (wherein Q.sup.8, Q.sup.9, Q.sup.10, Q.sup.11 and
Q.sup.12 each independently represents hydrogen, C.sub.1-3alkyl,
C.sub.1-3alkoxyC.sub.2-3alkyl, C.sub.2-5alkenyl, C.sub.2-5alkynyl
or C.sub.1-4haloalkyl) and Q.sup.2 is as defined hereinbefore); 7)
C.sub.2-5alkenylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 8)
C.sub.2-5alkynylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); and 9)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00018##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4fluoroalkylsulphonyl, 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 selected from pyrrolidinyl, piperidinyl,
piperazinyl,
##STR00019##
which heterocyclic group may bear one or more substituents selected
from C.sub.1-4alkyl), with the proviso that at least one of
Q.sup.13 and Q.sup.14 bears at least one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-5alkyl, C.sub.2-5alkenyl or C.sub.2-5alkynyl group in
Q.sup.1X.sup.1-- which is liked to X.sup.1 may bear one or more
substituents selected from hydroxy, halogeno and amino); and salts
thereof, and prodrugs thereof for example esters, amides and
sulphides, preferably esters and amides.
[0111] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
four groups:
1) Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00020##
which heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 4)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00021##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, 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; with the proviso
that at least one of Q.sup.13 and Q.sup.14 bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-4fluoroalkyl, C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-5alkyl, group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino).
[0112] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
four groups:
1) Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00022##
which heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 4)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00023##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4fluoroalkylsulphonyl, 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; with the proviso that at least one
of Q.sup.13 and Q.sup.14 bears at least one substituent selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-5alkyl, group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino).
[0113] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
four groups:
1) Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00024##
which heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4alkanoyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoro alkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2
(wherein Q.sup.2 is as defined hereinbefore); 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 4)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00025##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4alkanoyl,
aminoC.sub.1-6alkanoyl, C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, oxo, hydroxy, 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; with the proviso
that at least one of Q.sup.13 and Q.sup.14 bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-4alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, C.sub.1-6fluoroalkanoyl,
carbamoyl, C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-5alkyl, group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino).
[0114] In one embodiment of the present invention one of R.sup.2a
and R.sup.2b is methoxy and the other is Q.sup.1X.sup.1 wherein
X.sup.1 is --O-- and Q.sup.1 is selected from one of the following
four groups:
1) Q.sup.2 (wherein Q.sup.2 is a heterocyclic group selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00026##
which heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4alkanoyl,
C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl and
C.sub.1-4fluoroalkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2 (wherein
Q.sup.2 is as defined hereinbefore); 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2 and
Q.sup.2 are as defined hereinbefore); 4)
C.sub.1-4alkylQ.sup.13(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14
(wherein W.sup.2 is as defined hereinbefore, j is 0 or 1, k is 0 or
1, and Q.sup.13 and Q.sup.14 are each independently selected from
pyrrolidinyl, piperidinyl, piperazinyl,
##STR00027##
which heterocyclic group may bear 1, 2 or 3 substituents selected
from C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4alkanoyl,
C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl,
C.sub.1-4fluoroalkylsulphonyl, 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; with the proviso
that at least one of Q.sup.13 and Q.sup.14 bears at least one
substituent selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-4alkanoyl, C.sub.1-4fluoroalkanoyl, C.sub.1-4alkylsulphonyl
and C.sub.1-4-fluoroalkylsulphonyl); and additionally wherein any
C.sub.1-5alkyl, group in Q.sup.1X.sup.1-- which is linked to
X.sup.1 may bear one or more substituents selected from hydroxy,
halogeno and amino).
[0115] According to another aspect of the present invention there
are provided compounds of the formula IIf:
##STR00028##
[wherein:
M is --CH-- or --N--;
[0116] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; R.sup.2a and R.sup.2b are each independently selected
from methoxy, Q.sup.15W.sup.3 (wherein Q.sup.15 and W.sup.3 are as
defined hereinbefore) and Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1--
(wherein Q.sup.2, W.sup.4 and X.sup.1 are as defined hereinbefore);
with the proviso that R.sup.2a and R.sup.2b cannot both be methoxy;
and salts thereof, and prodrugs thereof for example esters, amides
and sulphides, preferably esters and amides.
[0117] According to another aspect of the present invention there
are provided compounds of the formula IIg:
##STR00029##
[wherein:
M is --CH-- or --N--;
[0118] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; R.sup.2a and R.sup.2b are each independently selected
from methoxy, Q.sup.15W.sup.3 (wherein W.sup.3 represents
--NQ.sup.16C(O)--, --C(O)NQ.sup.17-, --SO.sub.2NQ.sup.18-,
--NQ.sup.19SO.sub.2-- or --NQ.sup.20- (wherein Q.sup.16, Q.sup.17,
Q.sup.18, Q.sup.19 and Q.sup.20 each independently represents
C.sub.2-5alkenyl or C.sub.2-5alkynyl), and Q.sup.15 is
C.sub.2-5alkenyl or C.sub.2-5alkynyl), and
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- (wherein W.sup.4 represents
--NQ.sup.22C(O)--, --C(O)NQ.sup.23-, --SO.sub.2NQ.sup.24-,
--NQ.sup.25SO.sub.2-- or --NQ.sup.26- (wherein Q.sup.22, Q.sup.23,
Q.sup.24, Q.sup.25 and Q.sup.26 each independently represents
hydrogen, C.sub.1-3alkyl, C.sub.1-3alkoxyC.sub.2-3alkyl,
C.sub.2-5alkenyl, C.sub.2-5alkynyl or C.sub.1-4haloalkyl), and
Q.sup.21 represents C.sub.2-5alkenyl or C.sub.2-5alkynyl, and
X.sup.1 is as defined hereinbefore); with the proviso that R.sup.2a
and R.sup.2b cannot both be methoxy; and salts thereof, and
prodrugs thereof for example esters, amides and sulphides,
preferably esters and amides.
[0119] According to another aspect of the present invention there
are provided compounds of the formula IIh:
##STR00030##
[wherein: M and T each independently represents a carbon atom or a
nitrogen atom with the proviso that M and T cannot both be nitrogen
atoms; R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; either R.sup.2a and R.sup.2b form 6,7-methylenedioxy or
one of R.sup.2a and R.sup.2b is methoxy and the other is selected
from one of the following four groups:
(a) Q.sup.1X.sup.1--
[0120] wherein X.sup.1 is --O-- and Q.sup.1 is selected from one of
the following three groups: 1) Q.sup.2 (wherein Q.sup.2 is a
heterocyclic group selected from pyrrolidinyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substituent
selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl and
C.sub.1-6alkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2
is as defined hereinbefore); and 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O-- and Q.sup.2 is as defined hereinbefore); and
additionally wherein any C.sub.1-5alkyl group in Q.sup.1X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy); (b) Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1--
(wherein X.sup.1 is --O--, W.sup.4 is NQ.sup.2f (wherein Q.sup.26
is hydrogen or C.sub.1-3alkyl) and Q.sup.21 is C.sub.2-5alkynyl);
(c) Q.sup.28C.sub.1-5alkylX.sup.1-- wherein X.sup.1 is --O-- and
Q.sup.2 is an imidazolidinyl group which bears two oxo substituents
and one C.sub.1-6alkyl group which C.sub.1-6alkyl group bears a
hydroxy substituent on the carbon atom which is linked to the
imidazolidinyl group; and (d) Q.sup.29C.sub.1-5alkylX.sup.1--
wherein X.sup.1 is --O-- and Q.sup.29 is a group
1,4-dioxa-8-azaspiro[4.5]dec-8-yl; and salts thereof, and prodrugs
thereof for example esters, amides and sulphides, preferably esters
and amides.
[0121] According to another aspect of the present invention there
are provided compounds of the formula IIi:
##STR00031##
[wherein:
M is --CH-- or --N--;
[0122] R.sup.2c is linked to a carbon atom of the 5-membered ring
and is selected from hydrogen and methyl; R.sup.2d is linked to a
carbon atom of the 6-membered ring and is selected from hydrogen
and fluoro; one of R.sup.2a and R.sup.2b is methoxy and the other
is selected from Q.sup.1X.sup.1-- (wherein X.sup.1 is --O-- and Q'
is C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is a heterocyclic group
selected from pyrrolidinyl, piperidinyl and piperazinyl, which
heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5alkynyl, C.sub.1-4fluoroalkyl,
C.sub.1-4alkanoyl and C.sub.1-4alkylsulphonyl)) and
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- (wherein X.sup.1 is --O--,
W.sup.4 is NQ.sup.26 (wherein Q.sup.26 is hydrogen or
C.sub.1-3alkyl) and Q.sup.21 is C.sub.2-5alkynyl); and salts
thereof, and prodrugs thereof for example esters, amides and
sulphides, preferably esters and amides. In one embodiment of the
present invention R.sup.2a is methoxy. In one embodiment of the
present invention R.sup.2b is selected from is selected from one of
the following four groups:
(a) Q.sup.1X.sup.1--
[0123] wherein X.sup.1 is --O-- and Q.sup.1 is selected from one of
the following three groups: 1) Q.sup.2 (wherein Q.sup.2 is a
heterocyclic group selected from pyrrolidinyl, piperidinyl and
piperazinyl, which heterocyclic group bears one substituent
selected from C.sub.2-5alkenyl, C.sub.2-5alkynyl,
C.sub.1-6fluoroalkyl, C.sub.1-6alkanoyl, aminoC.sub.1-6alkanoyl,
C.sub.1-4alkylaminoC.sub.1-6alkanoyl,
di(C.sub.1-4alkyl)aminoC.sub.1-6alkanoyl, carbamoyl,
C.sub.1-4alkylcarbamoyl, di(C.sub.1-4alkyl)carbamoyl,
carbamoylC.sub.1-6alkyl, C.sub.1-4alkylcarbamoylC.sub.1-6alkyl,
di(C.sub.1-4alkyl)carbamoylC.sub.1-6alkyl and
C.sub.1-6alkylsulphonyl; 2) C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2
is as defined hereinbefore); and 3)
C.sub.1-4alkylW.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
represents --O-- and Q.sup.2 is as defined hereinbefore); and
additionally wherein any C.sub.1-5alkyl group in Q.sup.1X.sup.1--
which is linked to X.sup.1 may bear one or more substituents
selected from hydroxy); (b) Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1--
(wherein X.sup.1 is --O--, W.sup.4 is NQ.sup.26 (wherein Q.sup.26
is hydrogen or C.sub.1-3alkyl) and Q.sup.21 is C.sub.2-5alkynyl);
(c) Q.sup.28C.sub.1-5alkylX.sup.1-- wherein X.sup.1 is --O-- and
Q.sup.28 is an imidazolidinyl group which bears two oxo
substituents and one C.sub.1-6alkyl group which C.sub.1-6alkyl
group bears a hydroxy substituent on the carbon atom which is
linked to the imidazolidinyl group; and (d)
Q.sup.29C.sub.1-5alkylX.sup.1-- wherein X.sup.1 is --O-- and
Q.sup.29 is a group 1,4-dioxa-8-azaspiro[4.5]dec-8-yl. In one
embodiment of the present invention R.sup.2b is selected from
Q.sup.1X.sup.1-- (wherein X.sup.1 is --O-- and Q' is
C.sub.1-5alkylQ.sup.2 (wherein Q.sup.2 is a heterocyclic group
selected from pyrrolidinyl, piperidinyl and piperazinyl, which
heterocyclic group bears one substituent selected from
C.sub.2-5alkenyl, C.sub.2-5 alkynyl, C.sub.1-4alkanoyl and
C.sub.1-4alkylsulphonyl)) and
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1-- (wherein X.sup.1 is --O--,
W.sup.4 is NQ.sup.26 (wherein Q.sup.26 is hydrogen or
C.sub.1-3alkyl) and Q.sup.21 is C.sub.2-5alkenyl). Preferred
compounds of the present invention include: [0124]
4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline, [0125]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyqui-
nazoline, [0126]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2S)-1-isobutyrylpyrrolidin--
2-yl]methoxy}-6-methoxyquinazoline, [0127]
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-1-yl)propoxy]-
quinazoline, [0128]
6-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-me-
thoxyquinazoline, [0129]
6-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-met-
hoxyquinazoline, [0130]
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquin-
azoline, [0131]
4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-1-yl)propoxy]-6--
methoxyquinazoline, [0132]
4-(7-azaindol-5-yloxy)-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-me-
thoxyquinazoline, [0133]
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)pro-
poxy]quinazoline, [0134]
7-[1-(N,N-dimethylaminoacetyl)piperidin-4-ylmethoxy]-4-[(4-fluoro-2-methy-
l-1H-indol)-5-yloxy]-6-methoxyquinazoline, and salts thereof.
[0135] More preferred compounds of the present invention include:
[0136]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
7-methoxyquinazoline, [0137]
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyqui-
nazoline, [0138]
4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline, [0139]
4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)eth-
oxy]quinazoline, [0140]
4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline, [0141]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline, [0142]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxy-
quinazoline, [0143]
7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)o-
xy]-6-methoxyquinazoline, [0144]
7-[(2S)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline, [0145]
7-[(2R)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline, [0146]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroe-
thyl)piperidin-4-ylmethoxy]quinazoline, [0147]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluo-
roethyl)piperazin-1-yl]propoxy}quinazoline, [0148]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluo-
roethyl)piperazin-1-yl]ethoxy}quinazoline, [0149]
7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-in-
dol-5-yl)oxy]-6-methoxyquinazoline, [0150]
7-{2-[2-(4-acetylpiperazin-1-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline, [0151]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)m-
ethoxy]-6-methoxyquinazoline, [0152]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2R)-1-isobutyrylpyrrolidin--
2-yl]methoxy}-6-methoxyquinazoline, [0153]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[1-(methylsulfonyl)-
piperidin-4-yl]methoxy}quinazoline, [0154]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2S)-1-(methylsulf-
onyl)pyrrolidin-2-yl]methoxy}quinazoline, [0155]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-1-(methylsulf-
onyl)pyrrolidin-2-yl]methoxy}quinazoline, [0156]
7-[3-(4-allylpiperazin-1-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquin-
azoline, [0157]
4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)pipera-
zin-1-yl]propoxy}quinazoline, [0158]
7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline, [0159]
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indol-5-yloxy)-6-methoxyquina-
zoline, [0160]
7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-
-5-yl)oxy]-6-methoxyquinazoline, [0161]
7-{3-[4-carbamoylpiperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-
-yl)oxy]-6-methoxyquinazoline, [0162]
7-(3-[2,5-dioxo-4-(1-hydroxy-1-methylethyl)imidazolidin-1-yl]propoxy}-4-[-
(4-fluoro-2-methyl-1H-indol-5-yloxy]-6-methoxyquinazoline, [0163]
6-[(1-acetylpiperidin-4-yl)oxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-
quinazoline, [0164]
4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-{[1-(methylsulphonyl)piperidi-
n-4-yl]oxy}quinazoline, [0165]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{2-[N-methyl-N-(2-pr-
opynyl)amino]ethoxy}quinazoline, [0166]
7-[3-(4-acetylpiperazin-1-yl)propoxy]-6-methoxy-4-[(2-methyl-1H-indol-5-y-
l)oxy]quinazoline, [0167]
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-6-m-
ethoxyquinazoline, [0168]
7-[3-(4-carbamoylmethylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline, [0169]
7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[(2-methyl-1H--
indol-5-yl)oxy]quinazoline, [0170]
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{(2R)-2-hydroxy-3-[4-prop-2-yn-
-1-ylpiperazin-1-yl]propoxy}-6-methoxyquinazoline, [0171]
7-{(2R)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-f-
luoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline, [0172]
7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-fluoro-2-methy-
l-1H-indol-5-yl)oxy]-6-methoxyquinazoline, and salts thereof.
[0173] A particular compound of the present invention is
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
6-methoxyquinazoline and salts thereof. A particular compound of
the present invention is
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquiniazonline and salts thereof.
Compounds of the present invention include [0174]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
7-methoxyquinazoline, [0175]
4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline, [0176]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyqui-
nazoline, [0177]
4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline, [0178]
4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)eth-
oxy]quinazoline, [0179]
4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline, [0180]
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline, and [0181]
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxy-
quinazoline and salts thereof.
[0182] Compounds of the present invention include [0183]
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyqui-
nazoline, and [0184]
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
6-methoxyquinazoline and salts thereof.
[0185] Another compound of the present invention is
4-(7-azaindol-5-yloxy)-7-(3-(4-(2-fluoroethyl)piperazin-1-yl)propoxy)-6-m-
ethoxyquinazoline and salts thereof.
[0186] 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.
[0187] 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.1 alkanoyl is formyl
and refers to CHO. Butanoyl refers to
CH.sub.3--CH.sub.2--CH.sub.2--C(O), isobutyryl refers to
(CH.sub.3).sub.2.CH--C(O). In this specification unless stated
otherwise the term "alkenyl" includes both straight and branched
chain alkenyl groups but references to individual alkenyl groups
such as 2-butenyl are specific for the straight chain version only.
Unless otherwise stated the term "alkenyl" advantageously refers to
chains with 2-5 carbon atoms, preferably 3-4 carbon atoms. In this
specification unless stated otherwise the term "alkynyl" includes
both straight and branched chain alkynyl groups but references to
individual alkynyl groups such as 2-butynyl are specific for the
straight chain version only. Unless otherwise stated the term
"alkynyl" advantageously refers to chains with 2-5 carbon atoms,
preferably 3-4 carbon atoms. Unless stated otherwise the term
"haloalkyl" refers to an alkyl group as defined hereinbefore which
bears one or more halogeno groups, such as for example
trifluoromethyl.
[0188] In this specification the term azaindolyl refers to the
moiety (1H-pyrrolo[2,3-b]pyridinyl) and an analogous convention
applies to similar groups. For example 7-azaindol-5-yl is
(1H-pyrrolo[2,3-b]pyridin-5-yl) and is the group:
##STR00032##
[0189] 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.
[0190] 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.
[0191] 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.
[0192] 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.10--. 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.
[0193] 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.
[0194] 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.
[0195] 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.
[0196] For the avoidance of any doubt, it is to be understood that
when R.sup.2a 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.
[0197] For the avoidance of any doubt, it is to be understood that
when Q.sup.1 is a group C.sub.1-5alkylW.sup.1Q.sup.2 it is the
C.sub.1-5alkyl group which is linked to X.sup.1 which is in turn
linked to the quinazoline ring. Similarly when Q.sup.1 is a group
C.sub.2-5alkenylQ.sup.2 it is the C.sub.2-5alkenyl group which is
linked to X.sup.1 which is in turn linked to the quinazoline ring.
An analogous convention applies to similar groups.
[0198] For the avoidance of any doubt, it is to be understood that
when R.sup.2 is a group Q.sup.15W.sup.3 it is the W.sup.3 group
which is linked to the quinazoline ring.
[0199] For the avoidance of any doubt, it is to be understood that
when R.sup.2 is a group Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1 it is
the X.sup.1 group which is linked to the quinazoline ring.
[0200] For the avoidance of any doubt, it is to be understood that
when R.sup.2 is a group Q.sup.28C.sub.1-5alkylX.sup.1 it is the
X.sup.1 group which is linked to the quinazoline ring and an
analogous convention applies to similar groups.
[0201] 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.
[0202] A compound of the formula I, or salt thereof, and other
compounds of the invention (as herein defined) may be prepared by
any process known to be applicable to the preparation of
chemically-related compounds. Such processes include, for example,
those illustrated in International Patent Application Number WO
00/47212 and in European Patent Applications Publication Nos.
0520722, 0566226, 0602851 and 0635498. Such processes also include,
for example, solid phase synthesis. Such processes, are provided as
a further feature of the invention and are as described
hereinafter. Necessary starting materials may be obtained by
standard procedures of organic chemistry. The preparation of such
starting materials is described within the accompanying
non-limiting Examples. Alternatively necessary starting materials
are obtainable by analogous procedures to those illustrated which
are within the ordinary skill of an organic chemist.
[0203] Thus, the following processes (a) to (t) and (i) to (vi)
constitute further features of the present invention.
Synthesis of Compounds of Formula I
[0204] (a) Compounds of the formula I and salts thereof may be
prepared by the reaction of a compound of the formula III:
##STR00033##
(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:
##STR00034##
(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.
[0205] The reaction is advantageously effected in the presence of a
base. Such a base is, for example, an organic amine base such as,
for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, morpholine,
N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene,
tetramethylguanidine or for example, an alkali metal or alkaline
earth metal carbonate or hydroxide, for example sodium carbonate,
potassium carbonate, calcium carbonate, cesium carbonate, sodium
hydroxide or potassium hydroxide. Alternatively such a base is, for
example, an alkali metal hydride, for example sodium hydride, or an
alkali metal or alkaline earth metal amide, for example sodium
amide, sodium bis(trimethylsilyl)amide, potassium amide or
potassium bis(trimethylsilyl)amide. The reaction is preferably
effected in the presence of an inert solvent or diluent, for
example an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic
hydrocarbon solvent such as toluene, or a dipolar aprotic solvent
such as N,N-dimethylfonmamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethyl sulphoxide. The reaction is
conveniently effected at a temperature in the range, for example,
10 to 150.degree. C., preferably in the range 20 to 90.degree.
C.
[0206] Where R.sup.1 or R.sup.2 contains a heterocyclic ring with a
substituent it is possible to add the substituent after process (a)
above using standard procedures of organic chemistry. Thus for
example a compound of formula III as defined hereinbefore but
wherein R.sup.2 contains an unsubstituted heterocyclic ring may be
reacted with a compound of formula IV as defined hereinbefore to
give an intermediate compound in which R.sup.2 contains an
unsubstituted heterocyclic ring. The intermediate compound can then
be substituted on the heterocyclic ring in R.sup.2 using standard
organic chemistry techniques to give a final compound of formula
I.
[0207] When it is desired to obtain the acid salt, the free base
may be treated with an acid such as a hydrogen halide, for example
hydrogen chloride, sulphuric acid, a sulphonic acid, for example
methane sulphonic acid, or a carboxylic acid, for example acetic or
citric acid, using a conventional procedure.
(b) Production of those compounds of formula I and salts thereof
wherein at least one R.sup.2 is R.sup.5X, Q.sup.1X.sup.1,
Q.sup.21W.sup.3 or Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1, wherein
R.sup.5, Q.sup.1, Q.sup.15, W.sup.3, Q.sup.21 and W.sup.4 are as
defined hereinbefore, and X.sup.1 is --O--, --S--, --OC(O)-- or
--NR.sup.10-- (wherein R.sup.10 independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) can be achieved by
the reaction, conveniently in the presence of a base (as defined
hereinbefore in process (a)) of a compound of the formula V:
##STR00035##
(wherein ring C, Z, W.sup.3, R.sup.1, R.sup.2 and n are as
hereinbefore defined and X.sup.1 is as hereinbefore defined in this
section and s is an integer from 0 to 2) with one of the compounds
of the formulae VIa-d:
R.sup.5-L.sup.1 (VIa)
Q.sup.1-L.sup.1 (VIb)
Q.sup.15-L.sup.1 (VIc)
Q.sup.21-W.sup.4--C.sub.1-5alkyl-L.sup.1 (VId)
(wherein R.sup.5, Q.sup.1, Q.sup.15, Q.sup.21 and W.sup.4 and
L.sup.1 are as hereinbefore defined), L.sup.1 is a displaceable
moiety for example a halogeno or sulphonyloxy group such as a
bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group, or
L.sup.1 may be generated in situ from an alcohol under standard
Mitsunobu conditions ("Organic Reactions", John Wiley & Sons
Inc, 1992, vol 42, chapter 2, David L Hughes). The reaction is
preferably effected in the presence of a base (as defined
hereinbefore in process (a)) and advantageously in the presence of
an inert solvent or diluent (as defined hereinbefore in process
(a)), advantageously at a temperature in the range, for example 10
to 150.degree. C., conveniently at about 50.degree. C. (c)
Compounds of the formula I and salts thereof wherein at least one
R.sup.2 is R.sup.5X', Q.sup.1X.sup.1, Q.sup.15W.sup.3 or
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1, wherein R.sup.5, Q.sup.1,
Q.sup.15, W.sup.3, Q.sup.21 and W.sup.4 are as defined
hereinbefore, and X.sup.1 is --O--, --S--, --OC(O)-- or
--NR.sup.10-- (wherein R.sup.10 represents hydrogen, C.sub.1-3alkyl
or C, 3alkoxyC.sub.2-3alkyl) may be prepared by the reaction of a
compound of the formula VII:
##STR00036##
with one of the compounds of the formulae VIIIa-d:
R.sup.5--X.sup.1--H (VIIIa)
Q.sup.1-X.sup.1--H (VIIb)
Q.sup.15-W.sup.3--H (VIIIc)
Q.sup.21-W.sup.4--C.sub.1-5 alkyl-X.sup.1--H (VIIId)
(wherein L.sup.1, R.sup.1, R.sup.2, R.sup.5, Q.sup.1, Q.sup.15,
W.sup.3, Q.sup.21, W.sup.4, ring C, Z, n and s are all as
hereinbefore defined and X.sup.1 is as hereinbefore defined in this
section). The reaction may conveniently be effected in the presence
of a base (as defined hereinbefore in process (a)) and
advantageously in the presence of an inert solvent or diluent (as
defined hereinbefore in process (a)), advantageously at a
temperature in the range, for example 10 to 150.degree. C.,
conveniently at about 100.degree. C. (d) Compounds of the formula I
and salts thereof wherein at least one R.sup.2 is R.sup.5X.sup.1,
Q.sup.1X.sup.1, Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1,
Q.sup.28C.sub.1-5 alkylX.sup.1 or Q.sup.29C.sub.1-5alkylX.sup.1
wherein X.sup.1 is as defined hereinbefore, R.sup.5 is
C.sub.1-5alkylR.sup.13, wherein R.sup.113 is selected from one of
the following nine groups: 1) X.sup.19C.sub.1-3alkyl (wherein
X.sup.19 represents --O--, --S--, --SO.sub.2--, --NR.sup.114C(O)--
or --NR.sup.115SO.sub.2-- (wherein R.sup.114 and R.sup.115 which
may be the same or different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl); 2) NR.sup.116R.sup.117 (wherein
R.sup.116 and R.sup.17 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 hereinbefore); 4) R.sup.28
(wherein R.sup.28 is as defined hereinbefore); 5) X.sup.21R.sup.29
(wherein X.sup.21 represents --O--, --S--, --SO.sub.2--,
--NR.sup.121C(O)--, --NR.sup.122SO.sub.2--, or --NR.sup.123--
(wherein R.sup.121, R.sup.122, and R.sup.123 which may be the same
or different are each hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as defined
hereinbefore); and 6) X.sup.22C.sub.1-3alkylR.sup.29 (wherein
X.sup.22 represents --O--, --S--, --SO.sub.2--, --NR.sup.124C(O)--,
--NR.sup.125SO.sub.2-- or --NR.sup.126-- (wherein R.sup.124,
R.sup.125 and R.sup.126 each independently represents hydrogen,
C.sub.1-3alkyl or C.sub.1-3alkoxyC.sub.2-3alkyl) and R.sup.29 is as
defined hereinbefore); 7) R.sup.29 (wherein R.sup.29 is as defined
hereinbefore); 8) X.sup.22C.sub.1-4alkylR.sup.28 (wherein X.sup.22
and R.sup.28 are as defined hereinbefore); and 9)
R.sup.54(C.sub.1-4alkyl).sub.q(X.sup.9).sub.rR.sup.55 (wherein q,
r, X.sup.9, R.sup.54 and R.sup.55 are as defined hereinbefore);
Q.sup.1 is C.sub.1-5alkylQ.sup.27 wherein Q.sup.27 is selected
from: 10) W.sup.1Q.sup.2 (wherein W.sup.1 and Q.sup.2 are as
defined hereinbefore); 11) Q.sup.2 (wherein Q.sup.2 is as defined
hereinbefore); 12) W.sup.2C.sub.1-4alkylQ.sup.2 (wherein W.sup.2
and Q.sup.2 are as defined hereinbefore); 13) Q.sup.13
(C.sub.1-4alkyl).sub.j(W.sup.2).sub.kQ.sup.14 (wherein W.sup.2, j,
k, Q.sup.13 and Q.sup.14 are as defined hereinbefore); and 14)
Q.sup.13(C.sub.1-4alkanoyl)Q.sup.14n (wherein Q.sup.13 and
Q.sup.14n are as defined hereinbefore), and Q.sup.21, W.sup.4,
Q.sup.28 and Q.sup.29 are as defined hereinbefore, may be prepared
by reacting a compound of the formula IX:
##STR00037##
(wherein L.sup.1, X.sup.1, R.sup.1, R.sup.2, ring C, Z, n and s are
as hereinbefore defined) with one of the compounds of the formulae
Xa-e:
R.sup.113--H (Xa)
Q.sup.27-H (Xb)
Q.sup.21-W.sup.4--H (Xc)
Q.sup.28-H (Xd)
Q.sup.29-H (Xe)
(wherein R.sup.13, Q.sup.27, Q.sup.28, Q.sup.29, Q.sup.21 and
W.sup.4 are as defined hereinbefore) to give a compound of the
formula I or salt thereof. The reaction may conveniently be
effected in the presence of a base (as defined hereinbefore in
process (a)) and advantageously in the presence of an inert solvent
or diluent (as defined hereinbefore in process (a)), and at a
temperature in the range, for example 0 to 150.degree. C.,
conveniently at about 50.degree. C.
[0208] Processes (a), (b) and (d) are preferred over process
(c).
[0209] Processes (a) and (b) are the more preferred.
(e) The production of those compounds of the formula I and salts
thereof wherein one or more of the substituents (R.sup.2).sub.m is
represented by --NR.sup.127R.sup.128, where one (and the other is
hydrogen) or both of R.sup.127 and R.sup.128 are C.sub.1-3alkyl,
may be effected by the reaction of compounds of formula I wherein
the substituent (R.sup.2).sub.m is an amino group and an alkylating
agent, preferably in the presence of a base as defined
hereinbefore. Such alkylating agents are C.sub.1-3alkyl moieties
bearing a displaceable moiety as defined hereinbefore such as
C.sub.1-3alkyl halides for example C.sub.1-3alkyl chloride, bromide
or iodide. The reaction is preferably effected in the presence of
an inert solvent or diluent (as defined hereinbefore in process
(a)) and at a temperature in the range, for example, 10 to
100.degree. C., conveniently at about ambient temperature. The
production of compounds of formula I and salts thereof wherein one
or more of the substituents R.sup.2 is an amino group may be
effected by the reduction of a corresponding compound of formula I
wherein the substituent(s) at the corresponding position(s) of the
quinazoline group is/are a nitro group(s). The reduction may
conveniently be effected as described in process (i) hereinafter.
The production of a compound of formula I and salts thereof wherein
the substituent(s) at the corresponding position(s) of the
quinazoline group is/are a nitro group(s) may be effected by the
processes described hereinbefore and hereinafter in processes (a-d)
and (i-v) using a compound selected from the compounds of the
formulae (I-XXII) in which the substituent(s) at the corresponding
position(s) of the quinazoline group is/are a nitro group(s). (f)
Compounds of the formula I and salts thereof wherein X.sup.1 is
--SO-- or --SO.sub.2-- may be prepared by oxidation from the
corresponding compound in which X.sup.1 is --S-- or --SO-- (when
X.sup.1 is --SO.sub.2-- is required in the final product).
Conventional oxidation conditions and reagents for such reactions
are well known to the skilled chemist.
Synthesis of Intermediates
[0210] (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:
##STR00038##
wherein R.sup.2 and m are as hereinbefore defined).
[0211] 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.
[0212] The compounds of formula XI and salts thereof may, for
example, be prepared by reacting a compound of the formula XII:
##STR00039##
(wherein R.sup.2, s and L.sup.1 are as hereinbefore defined) with
one of the compounds of formulae VIIIa-d as hereinbefore defined.
The reaction may conveniently be effected in the presence of a base
(as defined hereinbefore in process (a)) and advantageously in the
presence of an inert solvent or diluent (as defined hereinbefore in
process (a)), advantageously at a temperature in the range, for
example 10 to 150.degree. C., conveniently at about 100.degree.
C.
[0213] Compounds of formula XI and salts thereof wherein at least
one R.sup.5 is R.sup.5X.sup.1, Q.sup.1X.sup.1, Q.sup.15W.sup.3 or
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1, wherein R.sup.5, Q.sup.1,
Q.sup.15, W.sup.3, Q.sup.21 and W.sup.4 are as defined
hereinbefore, and wherein X.sup.1 is --O--, --S--, --SO--,
--SO.sub.2--, --C(O)--, --C(O)NR.sup.7--, --SO.sub.2NR.sup.8-- or
--NR.sup.10-- (wherein R.sup.7, R.sup.8 and R.sup.10 each
independently represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), may for example also be prepared by
the reaction of a compound of the formula XIII:
##STR00040##
(wherein R.sup.2, W.sup.3 and s are as hereinbefore defined and
X.sup.1 is as hereinbefore defined in this section) with one of the
compounds of formulae VIa-d 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.
[0214] The compounds of formula XI and salts thereof may also be
prepared by cyclising a compound of the formula XIV:
##STR00041##
(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.
[0215] 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:
##STR00042##
(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.
[0216] Compounds of the formula XV and salts thereof may for
example be prepared by the reaction of a compound of the formula
XVI:
##STR00043##
(wherein R.sup.2, s, L.sup.1 and A.sup.1 are as hereinbefore
defined) with one of the compounds of formulae VIIIa-d as
hereinbefore defined to give a compound of the formula XV. The
reaction of the compounds of formulae XVI and VIIIa-d is
conveniently effected under conditions as described for process (c)
hereinbefore.
[0217] Compounds of formula XV and salts thereof wherein at least
one R.sup.2 is R.sup.5X.sup.1, Q.sup.1X.sup.1, Q.sup.15W.sup.3 or
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1, wherein R.sup.5, Q.sup.1,
Q.sup.15, W.sup.3, Q.sup.21 and W.sup.4 are as defined
hereinbefore, and wherein X.sup.1 is --O--, --S--, --SO.sub.2--,
--C(O)--, --C(O)NR.sup.7--, --SO.sub.2NR.sup.8-- or --NR.sup.10--
(wherein R.sup.7, R.sup.8 and R.sup.10 each independently
represents hydrogen, C.sub.1-3alkyl or
C.sub.1-3alkoxyC.sub.2-3alkyl), may for example also be prepared by
the reaction of a compound of the formula XVII:
##STR00044##
(wherein R.sup.2, s and A.sup.1 are as hereinbefore defined and
X.sup.1 is as hereinbefore defined in this section) with one of the
compounds of formulae VIa-d as hereinbefore defined to yield a
compound of formula XV as hereinbefore defined. The reaction of the
compounds of formulae XVII and VIa-d is conveniently effected under
conditions as described for process (b) hereinbefore.
[0218] 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.
[0219] 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.
[0220] 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.
[0221] The compounds of formula III and salts thereof wherein at
least one R.sup.2 is R.sup.5X', Q.sup.1X.sup.1, Q.sup.15W.sup.3 or
Q.sup.21W.sup.4C.sub.1-5alkylX.sup.1, wherein R.sup.5, Q.sup.1,
Q.sup.15, W.sup.3, Q.sup.21 and W.sup.4 are as defined
hereinbefore, 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:
##STR00045##
(wherein R.sup.2, W.sup.3 and s are as hereinbefore defined,
X.sup.1 is as hereinbefore defined in this section and L.sup.2
represents a displaceable protecting moiety) with one of the
compounds of formulae VIa-d as hereinbefore defined, whereby to
obtain a compound of formula III in which L.sup.1 is represented by
L.sup.2.
[0222] 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.
[0223] The compounds of formula XVIII and salts thereof may for
example be prepared by deprotecting a compound of the formula
XIX:
##STR00046##
(wherein R.sup.2, W.sup.3, 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.
[0224] One compound of formula III may if desired be converted into
another compound of formula III in which the moiety L.sup.1 is
different. Thus for example a compound of formula III in which
L.sup.1 is other than halogeno, for example optionally substituted
phenoxy, may be converted to a compound of formula III in which
L.sup.1 is halogeno by hydrolysis of a compound of formula III (in
which L.sup.1 is other than halogeno) to yield a compound of
formula XI as hereinbefore defined, followed by introduction of
halide to the compound of formula XI, thus obtained as hereinbefore
defined, to yield a compound of formula III in which L.sup.1
represents halogen.
(ii) Compounds of formula IV and salts thereof in which ring C is
indolyl may be prepared by any of the methods known in the art,
such as for example those described in "Indoles Part I", "Indoles
Part II", 1972 John Wiley & Sons Ltd and "Indoles Part III"
1979, John Wiley & Sons Ltd, edited by W. J. Houlihan.
[0225] Examples of the preparation of indoles are given in Examples
1 and 10 hereinafter.
[0226] Compounds of formula IV and salts thereof in which ring C is
quinolinyl may be prepared by any of the methods known in the art,
such as for example those described in "The Chemistry of
Heterocyclic Compounds: Quinolines Parts I, II and III", 1982
(Interscience publications) John Wiley & Sons Ltd, edited by G.
Jones, and in "Comprehensive Heterocyclic Chemistry Vol II by A. R.
Katritzky", 1984 Pergamon Press, edited by A. J. Boulton and A
McKillop.
[0227] Compounds of formula IV and salts thereof in which ring C is
indazolyl may be prepared by any of the methods known in the art,
such as for example those described in Petitcoles, Bull. Soc. Chim.
Fr. 1950, 466 and Davies, J. Chem. Soc. 1955, 2412.
[0228] Compounds of formula IV and salts thereof in which ring C is
azaindolyl may be prepared by any of the methods known in the art,
such as for example those described in Heterocycles 50, (2),
1065-1080, 1999. They may also be made according to the process in
Example 2 hereinafter.
[0229] In Heterocycles 50, (2), 1065-1080, 1999 a process is
described, shown in Scheme 1 hereinafter, wherein 7-azaindole is
halogenated to give
3,3,5-tribromo-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine (12). 12 is
then treated with zinc in acetic acid to give
5-bromo-2-oxo-1,3-dihydropyrrolo[2,3-b]pyridine (13) and 13 is then
treated via two steps to give 5-bromo-7-azaindole (14). This
synthesis is shown in Scheme 1:
##STR00047##
[0230] Surprisingly we have found that it is better to synthesise
the 5-bromo-7-azaindole by three steps outlined in Scheme 2:
##STR00048##
[0231] Scheme 2 is surprisingly better than Scheme 1. Scheme 2
requires smaller quantities of reagent and is more adaptable for
large scale manufacture because it is cheaper, more efficient and
more environmentally friendly than Scheme 1.
Step 1:
[0232] The reduction may be carried out by any of the procedures
known for such a transformation. The reduction may be carried out,
for example, by treating a solution of 7-azaindole in an alcohol,
for example ethanol, or another solvent for example
decahydronaphthalene, with wet Raney Nickel and then stirring the
mixture in a hydrogen atmosphere under pressure, for example at 5
atmospheres pressure, at 50 to 150.degree. C., preferably at about
95.degree. C., over a period of time, for example 2 days, to give,
after purification, 7-azaindoline.
Step 2:
[0233] The bromination may be carried out by any of the procedures
known for such a reaction. The bromination may be carried out, for
example, by mixing 7-azaindoline, p-toluene sulphonic acid
monohydrate and 1,3-dibromo-5,5-dimethylhydantoin in methylene
chloride and stirring the mixture at for example ambient
temperature for a period of time, for example 3 hours. Extraction
and purification gives 5-bromo-7-azaindoline.
Step 3:
[0234] The oxidation may be carried out by any of the procedures
known for such a transformation. The oxidation may be carried out,
for example, by mixing 5-bromo-7-azaindoline and precipitated,
active manganese (IV) oxide in toluene, then heating the mixture at
50 to 150.degree. C., preferably at about 90.degree. C. to give
5-bromo-7-azaindole.
[0235] In Heterocycles 50, (2), 1065-1080, 1999 the
5-bromo-7-azaindole (986 mg, 5.0 mmol) is dissolved, under an inert
atmosphere, in a mixture of DMF (321A) and methanol (20 ml). To
this solution is added successively sodium methoxide (14.3 g, 265
mmol) and copper(I)bromide (1.43 g, 10.0 mmol) at ambient
temperature. The mixture is heated at reflux for 2.5 hours to give,
after extraction and purification, 5-methoxy-7-azaindole (530 mg,
72%).
[0236] We have found that the yield for this reaction is
surprisingly and significantly increased from 72% to 97% if the
reagents are used in proportionately smaller quantities including
for example a different solvent mixture. Thus in Example 2
hereinafter:
[0237] "A solution of 5-bromo-7-azaindole (8.6 g, 44 mmol), copper
(I) bromide (12.6 g, 88 mmol) and sodium methoxide (100 g, 1.85
mol) in a mixture of "degassed" DMF (260 mls) and methanol (175
mls) was stirred at ambient temperature in a nitrogen atmosphere,
and then heated at reflux for 3.5 hours."
[0238] After extraction and partial purification this gave crude
solid, 5-methoxy-7-azaindole (6.3 g, 97%), which was taken through
the next step without further purification.
[0239] The 5-hydroxy-7-azaindole may be generated from the
5-methoxy-7-azaindole by the following process.
[0240] Adding boron tribromide in methylene chloride to a solution
of 5-methoxy-7-azaindole in methylene chloride cooled at about
-30.degree. C. Leaving the mixture to warm up to ambient
temperature and stirring it for a period of time, for example
overnight. Pouring the mixture onto ice and water and adjusting the
pH of the aqueous phase to about 6. Separating the organic phase
and further extracting the aqueous phase with ethyl acetate.
Combining the organic phases washing them with brine, drying them,
for example over magnesium sulphate, and then evaporating them. The
residue may then be purified, for example by column chromatography
eluting with increasingly polar mixtures of methylene chloride and
methanol to give 5-hydroxy-7-azaindole.
[0241] Alternatively the 5-methoxy-7-azaindole may be suspended in
methylene chloride, stirred in a nitrogen atmosphere, cooled in a
cold water bath and a 1.0 M solution of boron tribromide in
methylene chloride added dropwise over a period of time, for
example 30 minutes. The mixture is then allowed to stir at ambient
temperature for a period of time, for example 4 hours, before being
quenched by taking the solution to about pH7, for example by the
dropwise addition of 5N sodium hydroxide. The resulting 2 phase
mixture is allowed to separate and the organic phase collected and
evaporated in vacuo. The residue may be treated with the aqueous
phase from above, the mixture adjusted to about pH7 once more and
subjected to a continuous ethyl acetate extraction over a period of
time for example 18 hours. The resulting ethyl acetate suspension
is then evaporated in vacuo to give a product which may be
purified, for example by column chromatography using Kieselgel 60
silica and methylene chloride/methanol/880 ammonium hydroxide
(100/8/1) solvent to give 5-hydroxyazaindole.
(iii) Compounds of formula V as hereinbefore defined and salts
thereof may be made by deprotecting the compound of formula XX:
##STR00049##
(wherein ring C, Z, R.sup.1, R.sup.2, P.sup.1, W.sup.3, 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.
[0242] 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.
(iv) Compounds of the formula VII and salts thereof may be made by
reacting a compound of the formula XXI:
##STR00050##
(wherein R.sup.2, s and each L.sup.1 are as hereinbefore defined
and the L.sup.1 in the 4-position and the other L.sup.1 in a
further position on the quinazoline ring may be the same or
different) with a compound of the formula IV as hereinbefore
defined, the reaction for example being effected by a process as
described in (a) above. (v) Compounds of formula IX as defined
hereinbefore and salts thereof may for example be made by the
reaction of compounds of formula V as defined hereinbefore with
compounds of the formula XXII:
L.sup.1-C.sub.1-5alkyl-L.sup.1 (XXII)
wherein L.sup.1 is as hereinbefore defined) to give compounds of
formula IX or salts thereof. The reaction may be effected for
example by a process as described in (b) above. (vi) Intermediate
compounds wherein X.sup.1 is --SO-- or --SO.sub.2-- may be prepared
by oxidation from the corresponding compound in which X.sup.1 is
--S-- or --SO-- (when X.sup.1 is --SO.sub.2-- is required in the
final product). Conventional oxidation conditions and reagents for
such reactions are well known to the skilled chemist.
[0243] 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.
[0244] Many of the intermediates defined herein are novel and these
are provided as a further feature of the invention. The preparation
of these compounds is as described herein and/or is by methods well
known to persons skilled in the art of organic chemistry.
[0245] For example the intermediates
7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline
and
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline,
which are both described in Example 7, are novel and each may be
used in the manufacture of compounds of the present invention and
of compounds of WO 00/47212.
7-Benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazo-
line and
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
may each be used in the manufacture of compounds which inhibit
angiogenesis and/or increased vascular permeability.
[0246] According to one embodiment of the present invention there
is provided
7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazol-
ine or a salt thereof.
[0247] According to one embodiment of the present invention there
is provided
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazolin- e
or a salt thereof. According to one embodiment of the present
invention there is provided the use of
7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline
or a salt thereof in the manufacture of a compound of the present
invention or a compound of WO 00/47212.
[0248] According to one embodiment of the present invention there
is provided the use of
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
or a salt thereof in the manufacture of a compound of the present
invention or a compound of WO 00/47212.
[0249] The identification of compounds which inhibit angiogenesis
and/or increased vascular permeability, which potently inhibit the
tyro sine kinase activity associated with the VEGF receptor KDR and
are selective for KDR over Flt-1, which have less extended plasma
pharmacokinetics and which are inactive or only weakly active in
the HERG assay, is desirable and is the subject of the present
invention.
These properties may be assessed, for example, using one or more of
the procedures set out below:
(a) In Vitro Receptor Tyrosine Kinase Inhibition Test
[0250] This assay determines the ability of a test compound to
inhibit tyrosine kinase activity. DNA encoding VEGF, FGF or EGF
receptor cytoplasmic domains may be obtained by total gene
synthesis (Edwards M, International Biotechnology Lab 5(3), 19-25,
1987) or by cloning. These may then be expressed in a suitable
expression system to obtain polypeptide with tyrosine kinase
activity. For example VEGF, FGF and EGF receptor cytoplasmic
domains, which were obtained by expression of recombinant protein
in insect cells, were found to display intrinsic tyrosine kinase
activity. In the case of the VEGF receptor Flt-1 (Genbank accession
number X51602), a 1.7 kb DNA fragment encoding most of the
cytoplasmic domain, commencing with methionine 783 and including
the termination codon, described by Shibuya et al (Oncogene, 1990,
5: 519-524), was isolated from cDNA and cloned into a baculovirus
transplacement vector (for example pAcYM1 (see The Baculovirus
Expression System: A Laboratory Guide, L. A. King and R. D. Possee,
Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available from
Invitrogen Corporation)). This recombinant construct was
co-transfected into insect cells (for example Spodoptera frugiperda
21(Sf21)) with viral DNA (eg Pharmingen BaculoGold) to prepare
recombinant baculovirus. (Details of the methods for the assembly
of recombinant DNA molecules and the preparation and use of
recombinant baculovirus can be found in standard texts for example
Sambrook et al, 1989, Molecular cloning--A Laboratory Manual, 2nd
edition, Cold Spring Harbour Laboratory Press and O'Reilly et al,
1992, Baculovirus Expression Vectors--A Laboratory Manual, W. H.
Freeman and Co, New York). For other tyrosine kinases for use in
assays, cytoplasmic fragments starting from methionine 806 (KDR,
Genbank accession number L04947), methionine 668 (EGF receptor,
Genbank accession number X00588) and methionine 399 (FGF R1
receptor, Genbank accession number X51803) may be cloned and
expressed in a similar manner.
[0251] For expression of cFlt-1 tyrosine kinase activity, Sf21
cells were infected with plaque-pure cFlt-1 recombinant virus at a
multiplicity of infection of 3 and harvested 48 hours later.
Harvested cells were washed with ice cold phosphate buffered saline
solution (PBS) (10 mM sodium phosphate pH7.4, 138 mM sodium
chloride, 2.7 mM potassium chloride) then resuspended in ice cold
HNTG/PMSF (20 mM Hepes pH7.5, 150 mM sodium chloride, 10% v/v
glycerol, 1% v/v Triton X.sup.100, 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.
[0252] 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.
[0253] 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.
[0254] 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 50mM Hepes pH7.4.
[0255] Test compounds were diluted with 10% dimethylsulphoxide
(DMSO) and 251 of diluted compound was transferred to wells in the
washed assay plates. "Total" control wells contained 10% DMSO
instead of compound. Twenty five microlitres of 40 mM
manganese(II)chloride containing 8 .mu.M adenosine-5'-triphosphate
(ATP) was added to all test wells except "blank" control wells
which contained manganese(II)chloride without ATP. To start the
reactions 50 .mu.l of freshly diluted enzyme was added to each well
and the plates were incubated at ambient temperature for 20
minutes. The liquid was then discarded and the wells were washed
twice with PBST. One hundred microlitres of mouse IgG
anti-phosphotyrosine antibody (Upstate Biotechnology Inc. product
05-321), diluted 1 in 6000 with PBST containing 0.5% w/v bovine
serum albumin (BSA), was added to each well and the plates were
incubated for 1 hour at ambient temperature before discarding the
liquid and washing the wells twice with PBST. One hundred
microlitres of horse radish peroxidase (HRP)-linked sheep
anti-mouse Ig antibody (Amersham product NXA 931), diluted 1 in 500
with PBST containing 0.5% w/v BSA, was added and the plates were
incubated for 1 hour at ambient temperature before discarding the
liquid and washing the wells twice with PBST. One hundred
microlitres of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic
acid) (ABTS) solution, freshly prepared using one 50 mg ABTS tablet
(Boehringer 1204 521) in 50 ml freshly prepared 50mM
phosphate-citrate buffer pH5.0+0.03% sodium perborate (made with 1
phosphate citrate buffer with sodium perborate (PCSB) capsule
(Sigma P4922) per 100ml distilled water), was added to each well.
Plates were then incubated for 20-60 minutes at ambient temperature
until the optical density value of the "total" control wells,
measured at 405 nm using a plate reading spectrophotometer, was
approximately 1.0. "Blank" (no ATP) and "total" (no compound)
control values were used to determine the dilution range of test
compound which gave 50% inhibition of enzyme activity.
(b) In Vitro HUVEC Proliferation Assay
[0256] This assay determines the ability of a test compound to
inhibit the growth factor-stimulated proliferation of human
umbilical vein endothelial cells (HUVEC).
[0257] 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
[0258] This test measures the capacity of compounds to inhibit
solid tumour growth.
[0259] CaLu-6 tumour xenografts were established in the flank of
female athymic Swiss nu/nu mice, by subcutaneous injection of
1.times.10.sup.6 CaLu-6 cells/mouse in 100 .mu.l of a 50% (v/v)
solution of Matrigel in serum free culture medium Ten days after
cellular implant, mice were allocated to groups of 8-10, so as to
achieve comparable group mean volumes. Tumours were measured using
vernier calipers and volumes were calculated as: (l.times.w).times.
(l.times.w).times.(.pi./6), where l is the longest diameter and w
the diameter perpendicular to the longest. Test compounds were
administered orally once daily for a minimum of 21 days, and
control animals received compound diluent. Tumours were measured
twice weekly. The level of growth inhibition was calculated by
comparison of the mean tumour volume of the control group versus
the treatment group using a Student T test and/or a Mann-Whitney
Rank Sum Test. The inhibitory effect of compound treatment was
considered significant when p<0.05.
(d) hERG-Encoded Potassium Channel Inhibition Test
[0260] This assay determines the ability of a test compound to
inhibit the tail current flowing through the human
ether-a-go-go-related-gene (hERG)-encoded potassium channel.
[0261] Human embryonic kidney (HEK) cells expressing the
hERG-encoded channel were grown in Minimum Essential Medium Eagle
(EMEM; Sigma-Aldrich catalogue number M2279), supplemented with 10%
Foetal Calf Serum (Labtech International; product number
4-101-500), 10% M1 serum-free supplement (Egg Technologies; product
number 70916) and 0.4 mg/ml Geneticin G418 (Sigma-Aldrich;
catalogue number G7034). One or two days before each experiment,
the cells were detached from the tissue culture flasks with
Accutase (TCS Biologicals) using standard tissue culture methods.
They were then put onto glass coverslips resting in wells of a 12
well plate and covered with 2 ml of the growing media.
[0262] For each cell recorded, a glass coverslip containing the
cells was placed at the bottom of a Perspex chamber containing bath
solution (see below) at ambient temperature (.about.20.degree. C.).
This chamber was fixed to the stage of an inverted, phase-contrast
microscope. Immediately after placing the coverslip in the chamber,
bath solution was perfused into the chamber from a gravity-fed
reservoir for 2 minutes at a rate of .about.2 ml/min. After this
time, perfusion was stopped.
[0263] A patch pipette made from borosilicate glass tubing (GC120F,
Harvard Apparatus) using a P-97 micropipette puller (Sutter
Instrument Co.) was filled with pipette solution (see hereinafter).
The pipette was connected to the headstage of the patch clamp
amplifier (Axopatch 200B, Axon Instruments) via a silver/silver
chloride wire. The headstage ground was connected to the earth
electrode. This consisted of a silver/silver chloride wire embedded
in 3% agar made up with 0.85% sodium chloride.
[0264] The cell was recorded in the whole cell configuration of the
patch clamp technique. Following "break-in", which was done at a
holding potential of -80 mV (set by the amplifier), and appropriate
adjustment of series resistance and capacitance controls,
electrophysiology software (Clampex, Axon Instruments) was used to
set a holding potential (-80 mV) and to deliver a voltage protocol.
This protocol was applied every 15 seconds and consisted of a 1 s
step to +40 mV followed by a 1 s step to -50 mV. The current
response to each imposed voltage protocol was low pass filtered by
the amplifier at 1 kHz. The filtered signal was then acquired, on
line, by digitising this analogue signal from the amplifier with an
analogue to digital converter. The digitised signal was then
captured on a computer running Clampex software (Axon Instruments).
During the holding potential and the step to +40 mV the current was
sampled at 1 kHz. The sampling rate was then set to 5 kHz for the
remainder of the voltage protocol.
[0265] The compositions, pH and osmolarity of the bath and pipette
solution are tabulated below.
TABLE-US-00001 Salt Pipette (mM) Bath (mM) NaCl -- 137 KCl 130 4
MgCl.sub.2 1 1 CaCl.sub.2 -- 1.8 HEPES 10 10 glucose -- 10
Na.sub.2ATP 5 -- EGTA 5 -- Parameter Pipette Bath pH 7.18-7.22 7.40
pH adjustment with 1M KOH 1M NaOH Osmolarity (mOsm) 275-285
285-295
[0266] The amplitude of the hERG-encoded potassium channel tail
current following the step from +40 mV to -50 mV was recorded
on-line by Clampex software (Axon Instruments). Following
stabilisation of the tail current amplitude, bath solution
containing the vehicle for the test substance was applied to the
cell. Providing the vehicle application had no significant effect
on tail current amplitude, a cumulative concentration effect curve
to the compound was then constructed.
[0267] The effect of each concentration of test compound was
quantified by expressing the tail current amplitude in the presence
of a given concentration of test compound as a percentage of that
in the presence of vehicle.
[0268] Test compound potency (IC.sub.50) was determined by fitting
the percentage inhibition values making up the concentration-effect
to a four parameter Hill equation using a standard data-fitting
package. If the level of inhibition seen at the highest test
concentration did not exceed 50%, no potency value was produced and
a percentage inhibition value at that concentration was quoted.
[0269] Plasma pharmacokinetics may be assessed by measuring plasma
half-life in vivo. The longer the plasma half-life in vivo the more
extended are the plasma pharmacokinetics.
[0270] Compounds of the present invention have less extended plasma
pharmacokinetics than compounds of WO 00/47212. Compounds of the
present invention have shorter half-lives in vivo than compounds of
WO 00/47212.
[0271] Plasma half-life in vivo may be determined by standard
methods which are well-known in the art of plasma pharmacokinetics.
Any species may be used and the plasma half-life determined by
standard methodology, for example plasma half-life may be measured
in rat, dog, monkey or human.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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.
[0276] 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.
[0277] 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.
[0278] 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.
[0279] 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.
[0280] As stated above the size of the dose required for the
therapeutic or prophylactic treatment of a particular disease state
will necessarily be varied depending on the host treated, the route
of administration and the severity of the illness being treated.
Preferably a daily dose in the range of 0.1-50 mg/kg is employed.
However the daily dose will necessarily be varied depending upon
the host treated, the particular route of administration, and the
severity of the illness being treated. Accordingly the optimum
dosage may be determined by the practitioner who is treating any
particular patient.
[0281] The antiangiogenic and/or vascular permeability reducing
treatment defined hereinbefore may be applied as a sole therapy or
may involve, in addition to a compound of the invention, one or
more other substances and/or treatments. Such conjoint treatment
may be achieved by way of the simultaneous, sequential or separate
administration of the individual components of the treatment. In
the field of medical oncology it is normal practice to use a
combination of different forms of treatment to treat each patient
with cancer. In medical oncology the other component(s) of such
conjoint treatment in addition to the antiangiogenic and/or
vascular permeability reducing treatment defined hereinbefore may
be: surgery, radiotherapy or chemotherapy. Such chemotherapy may
cover three main categories of therapeutic agent:
(i) other antiangiogenic agents such as those which inhibit the
effects of vascular endothelial growth factor, (for example the
anti-vascular endothelial cell growth factor antibody bevacizunuab
[Avastin.TM.], and those that work by different mechanisms from
those defined hereinbefore (for example linomide, inhibitors of
integrin .alpha.v.beta.3 function, angiostatin, razoxin,
thalidomide), and including vascular targeting agents (for example
combretastatin phosphate and compounds disclosed in International
Patent Applications WO00/40529, WO 00/41669, WO01/92224, WO02/04434
and WO02/08213 and the vascular damaging agents described in
International Patent Application Publication No. WO 99/02166 the
entire disclosure of which document is incorporated herein by
reference, (for example N-acetylcolchinol-O-phosphate)); (ii)
cytostatic agents such as antioestrogens (for example tamoxifen,
toremifene, raloxifene, droloxifene, iodoxyfene), oestrogen
receptor down regulators (for example fulvestrant), progestogens
(for example megestrol acetate), aromatase inhibitors (for example
anastrozole, letrazole, vorazole, exemestane), antiprogestogens,
antiandrogens (for example flutamide, ailutalide, bicalutamide,
cyproterone acetate), LHRH agonists and antagonists (for example
goserelin acetate, luprolide, buserelin), inhibitors of
5.alpha.-reductase (for example finasteride), anti-invasion agents
(for example metalloproteinase inhibitors like marimastat and
inhibitors of urokinase plasminogen activator receptor function)
and inhibitors of growth factor function, (such growth factors
include for example platelet derived growth factor and hepatocyte
growth factor), such inhibitors include growth factor antibodies,
growth factor receptor antibodies, (for example the anti-erbb2
antibody trastuzumab [Herceptin.TM.] and the anti-erbb1 antibody
cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase
inhibitors for example inhibitors of the epidermal growth factor
family (for example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)) and serine/threonine kinase inhibitors); and
(iii) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as antimetabolites (for
example antifolates like methotrexate, fluoropyrimidines like
5-fluorouracil, tegafur, purine and adenosine analogues, cytosine
arabinoside); antitumour antibiotics (for example anthracyclines
like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin and
idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum
derivatives (for example cisplatin, carboplatin); alkylating agents
(for example nitrogen mustard, melphalan, chlorambucil, busulphan,
cyclopholsphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic
agents (for example vinca alkaloids like vincristine, vinblastine,
vindesine, vinorelbine, and taxoids like taxol, taxotere);
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan, camptothecin and
also irinotecan); also enzymes (for example asparaginase); and
thymidylate synthase inhibitors (for example raltitrexed); and
additional types of chemotherapeutic agent include: (iv) biological
response modifiers (for example interferon); (v) antibodies (for
example edrecolomab); (vi) antisense therapies, for example those
which are directed to the targets listed above, such as ISIS 2503,
an anti-ras antisense; (vii) gene therapy approaches, including for
example approaches to replace aberrant genes such as aberrant p53
or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase patient tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and (viii)
immunotherapy approaches, including for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells,
such as transfection with cytokines such as interleukin 2,
interleukin 4 or granulocyte-macrophage colony stimulating factor,
approaches to decrease T-cell energy, approaches using transfected
immune cells such as cytokine-transfected dendritic cells,
approaches using cytokine-transfected tumour cell lines and
approaches using anti-idiotypic antibodies.
[0282] 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).
[0283] It is known from WO 01/74360 that antiangiogenic can be
combined with antihypertensives. A compound of the present
invention can also be administered in combination with an
antihypertensive. An antihypertensive is an agent which lowers
blood pressure, see WO 01/74360 which is incorporated herein by
reference.
[0284] Thus according to the present invention there is provided a
method of treatment of a disease state associated with angiogenesis
which comprises the administration of an effective amount of a
combination of a compound of the present invention or a
pharmaceutically acceptable salt thereof and an anti-hypertensive
agent to a warm-blooded animal, such as a human being.
[0285] According to a further feature of the present invention
there is provided the use of a combination of a compound of the
present invention or a pharmaceutically acceptable salt thereof and
an anti-hypertensive agent for use in the manufacture of a
medicament for the treatment of a disease state associated with
angiogenesis in a warm-blooded mammal, such as a human being.
[0286] According to a further feature of the present invention
there is provided a pharmaceutical composition comprising a
compound of the present invention or a pharmaceutically acceptable
salt thereof and an anti-hypertensive agent for the treatment of a
disease state associated with angiogenesis in a warm-blooded
mammal, such as a human being.
[0287] According to a further aspect of the present invention there
is provided a method for producing an anti-angiogenic and/or
vascular permeability reducing effect in a warm-blooded animal,
such as a human being, which comprises administering to said animal
an effective amount of a combination of a compound of the present
invention or a pharmaceutically acceptable salt thereof and an
anti-hypertensive agent.
[0288] According to a further aspect of the present invention there
is provided the use of a combination of a compound of the present
invention or a pharmaceutically acceptable salt thereof and an
anti-hypertensive agent for the manufacture of a medicament for
producing an anti-angiogenic and/or vascular permeability reducing
effect in a warm-blooded mammal, such as a human being.
[0289] Preferred antihypertensive agents are calcium channel
blockers, angiotensin converting enzyme inhibitors (ACE
inhibitors), angiotensin II receptor antagonists (A-II
antagonists), diuretics, beta-adrenergic receptor blockers
(D-blockers), vasodilators and alpha-adrenergic receptor blockers
(.alpha.-blockers). Particular antihypertensive agents are calcium
channel blockers, angiotensin converting enzyme inhibitors (ACE
inhibitors), angiotensin II receptor antagonists (A-II antagonists)
and beta-adrenergic receptor blockers (.beta.-blockers), especially
calcium channel blockers.
[0290] As stated above the compounds defined in the present
invention are of interest for their antiangiogenic and/or vascular
permeability reducing effects. Such compounds of the invention are
expected to be useful in a wide range of disease states including
cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's
sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies,
atheroma, arterial restenosis, autoimmune diseases, acute
inflammation, excessive scar formation and adhesions,
endometriosis, dysfunctional uterine bleeding and ocular diseases
with retinal vessel proliferation including age-related macular
degeneration. Cancer may affect any tissue and includes leukaemia,
multiple myeloma and lymphoma. In particular such compounds of the
invention are expected to slow advantageously the growth of primary
and recurrent solid tumours of, for example, the colon, breast,
prostate, lungs and skin. More particularly such compounds of the
invention are expected to inhibit any form of cancer associated
with VEGF including leukaemia, multiple myeloma and lymphoma and
also, for example, the growth of those primary and recurrent solid
tumours which are associated with VEGF, especially those tumours
which are significantly dependent on VEGF for their growth and
spread, including for example, certain tumours of the colon,
breast, prostate, lung, vulva and skin.
[0291] 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.
[0292] It is to be understood that where the term "ether" is used
anywhere in this specification it refers to diethyl ether.
[0293] The invention will now be illustrated in the following
non-limiting Examples in which, unless otherwise stated:--
[0294] (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;
[0295] (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;
[0296] (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;
[0297] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0298] (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.
[0299] (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; mA, multiplet; br, broad; q, quartet, quin, quintet;
[0300] (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;
[0301] (viii) HPLC were run under 2 different conditions: [0302] 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; [0303] 2) on a TSK Gel
super ODS 2 .mu.M 4.6mm.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 nm/minute. Detection: U.V. at 254 nm and
light scattering detections.
[0304] (ix) petroleum ether refers to that fraction boiling between
40-60.degree. C.
[0305] (x) the following abbreviations have been used:-- [0306] DMF
N,N-dimethylformamide [0307] DMSO dimethylsulphoxide [0308] TFA
trifluoroacetic acid [0309] THF tetrahydrofuran [0310] DEAD diethyl
azodicarboxylate [0311] DMA dimethylacetamide [0312] DMAP
4-dimethylaminopyridine [0313] LC/MS HPLC coupled to mass
spectrometry
EXAMPLE 1
##STR00051##
[0315] Diethyl azodicarboxylate (0.178 g, 1.02 mmol) was added to a
solution of
4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline
(0.267 g, 0.787 mmol), triphenylphosphine (0.31 g, 1.18 mmol) and
3-(4-acetylpiperazin-1yl)propan-1-ol (0.176 g, 0.945 n-mmol) in
methylene chloride (10 ml). After stirring for 15 minutes at
ambient temperature, further triphenylphosphine (0.062 mg, 0.236
mmol) and diethyl azodicarboxylate (0.041 mg, 0.3 mmol) were added.
After stirring for 1 hour at ambient temperature, the mixture was
poured onto a column of silica and eluted with increasingly polar
mixtures of ethyl acetate and methylene chloride followed by
methylene chloride and methanol. The fractions containing the
expected product were combined and evaporated. The residue was
triturated under diethyl ether and the solid was filtered, washed
with ether and dried under vacuum to give
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
7-methoxyquinazoline 0.210 g, 60%).
[0316] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.1 (s,
3H), 2.35 (m, 2H), 2.45 (s, 3H), 3.0 (m, 2H), 3.2 (m, 1H), 3.4 (dd,
2H), 3.5 (m 1H), 3.65 (d, 2H), 4.1 (m 1H), 4.15 (s, 3H), 4.45 (dd,
2H), 4.55 (d, 1H), 6.3 (s, 0.3H, partly exchanged), 7.05 (dd, 1H),
7.28 (d, 1H), 7.6 (s, 1H), 7.9 (s, 1H), 9.2 (s, 1H)
[0317] MS-ESI: 508.5 [M+H]+
[0318] The starting material was prepared as follows:
[0319] A suspension of 1-acetylpiperazine (3.85 g, 30 mmol),
potassium carbonate (8.3 g, 60 mmol) and 3-bromo-1-propanol (4 ml,
45 mmol) in acetonitrile (30 ml) was heated and stirred at
80.degree. C. for 5 hours. After cooling, the mixture was filtered
and the filtrate was evaporated. The residue was purified by column
chromatography, eluting with increasingly polar mixtures of
methylene chloride and ethanol. The fractions containing the
expected product were combined and evaporated to give
3-(4-acetylpiperazin-1-yl)propan-1-ol (3.15 g, 56%).
[0320] .sup.1H NMR Spectrum (CDCl.sub.3): 1.7 (1, 2H), 2.08 (s,
3H), 2.45 (m, 4H), 2.6 (dd, 2H), 3.45 (dd, 2H), 3.6 (dd, 2H), 3.78
(dd, 2H), 4.6 (br s, 1H)
[0321] MS-ESI: 187 [M+H]+
[0322] A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline
(0.39 g, 1.3 mmol), (EP 1153920 production examples 28-30),
4-fluoro-5-hydroxy-2-methylindole (0.24 g, 1.43 mmol) and cesium
carbonate (1.2 g, 4 mmol) in DMF (4 .mu.l) was stirred at
95.degree. C. for 45 minutes. After cooling, the mixture was
filtered and the filtrate was evaporated under vacuum. The residue
was purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride and ethyl acetate to give
6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline
(0.213 g, 37%).
[0323] .sup.1H NMR Spectrum: (DMSO d.sub.6) 2.42 (s, 3H), 4.05 (s,
3H), 5.3 (s, 2H), 6.25 (s, 1H), 7.0 (dd, 1H), 7.18 (d, 1H),
7.35-7.6 (m 6H), 7.8 (s, 1H), 8.55 (s, 1H)
[0324] MS-ESI: 430 [M+H]+
[0325] A solution of
6-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline
(1.32 g, 3 mmol), ammonium formate (1.94 g, 30 mmol) and 10%
palladium on carbon (0.2 g) in DMF (15ml) containing water (2 ml)
was stirred at ambient temperature for 1 hour. The mixture was
filtered and the filtrate was evaporated. The residue was
triturated under diethyl ether, filtered, washed with diethyl ether
followed by water and dried under vacuum over P.sub.2O.sub.5
overnight to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline
(1 g, 100%).
[0326] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H), 4.0 (s,
3H), 6.25 (s, 1H), 7.0 (m 1H), 7.15 (d, 1H), 7.4 (s, 1H), 7.6 (s,
1H), 8.0 (s, 1H), 8.55 (s, 1H)
[0327] MS-ESI: 340 [M+H]+
[0328] 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.
[0329] .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)
[0330] 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%).
[0331] .sup.1H NMR Spectrum: (DMSOd.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)
[0332] 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.
[0333] 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
6-fluoro-5-methoxy-2-methylindole
[0334] MS-ESI: 180 [MH].sup.+
[0335] .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)
4-fluoro-5-methoxy-2-methylindole
[0336] MS-ESI: 180 [MH].sup.+
[0337] .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)
[0338] 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%).
[0339] MS-ESI: 166 [MH].sup.+
[0340] .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)
[0341] .sup.13C NMR Spectrum: (DMSOd.sub.6) 13.5; 94, 0; 106, 0;
112; 118.5; 132; 136; 136.5; 142.5
[0342] Alternatively the 4-fluoro-5-hydroxy-2-methylindole may be
prepared as follows:
[0343] 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 ethyl
acetate/petroleum ether (75/25) to give
3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).
[0344] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.4 (s, 3H); 4.25 (s,
2H); 7.25 (dd, 1H); 8.0 (dd, 1H)
[0345] 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%).
[0346] .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)
[0347] 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
[0348] .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)
[0349] 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 10%
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.
[0350] Alternatively the 4-fluoro-5-methoxy-2-methylindole can be
prepared as follows:
[0351] 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 (1ml). The organic layer was concentrated to a
total volume of 100ml and THF (100ml) 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%).
[0352] MS-ESI: 250 [MNa]+
[0353] .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)
[0354] To a solution of
3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (11.36 g, 50 mmol)
in acetone (200ml) was added 4M aqueous ammonium acetate (700 ml)
followed by a solution of titanium trichloride (15% in water,
340ml) 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%).
[0355] .sup.1H NMR Spectrum: (DMSO) 2.35 (s, 3H); 3.8 (s, 3H); 6.1
(s, 1H); 6.85 (dd, 1H); 7.02 (d, 1H)
[0356] Cleavage of 4-fluoro-5-methoxy-2-methylindole with boron
tribromide to give 4-fluoro-5-hydroxy-2-methylindole is described
above.
EXAMPLE 2
##STR00052##
[0358] Diethyl azodicarboxylate (0.09 g, 0.518mmol) was added
dropwise to a solution of
4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133 g,
0.432 mmol), triphenylphosphine (0.17 g, 0.647 mmol) and
3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (0.115 g, 0.519
mmol) in DMF (4ml) and the mixture was stirred at ambient
temperature for 1 hour. The volatiles were removed under vacuum and
the residue was purified by column chromatography using
increasingly polar mixtures of ethyl acetate and methylene chloride
followed by methylene chloride and methanol. The fractions
containing the expected product were combined and evaporated. The
solid was then repurified by preparative LC/MS eluting with
acetonitrile/water (containing 1% acetic acid). The fractions
containing the expected product were combined and evaporated. The
residue was dissolved in aqueous sodium hydrogen carbonate and
methylene chloride. The organic phase was separated and dried over
magnesium sulphate and evaporated. The residue was triturated under
diethyl ether, filtered, washed with ether and dried under vacuum
over P.sub.2O.sub.5 to give
4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline (0.09, 40%).
[0359] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.3 (m,
2H), 3.05 (s, 3H), 3.1-3.3 (m, 4H), 3.4 (dd, 2H), 3.7 (d, 2H), 3.8
(d, 2H), 4.1 (s, 3H), 4.4 (dd, 2H), 6.6 (d, 1H), 7.55 (s, 1H), 7.65
(d, 1H), 7.8 (s, 1H), 8.1 (s, 1H), 8.3 (s, 1H), 9.0 (s, 1H)
[0360] MS-ESI: 513 [M+H]+
[0361] The starting material was prepared as follows:
[0362] Methanesulphonyl chloride (2.28 ml) was added dropwise to a
solution of 1-(tert-butoxycarbonyl)piperazine (5 g) in methylene
chloride (90 ml) containing triethylamine (4.5 ml). The solution
was stirred at ambient temperature for 24 hours. The solution was
poured onto cooled water and extracted with methylene chloride. The
organic phase was separated, washed with brine and dried over
magnesium sulphate and evaporated to give tert-butyl
4-(methylsulphonyl)piperazine-1-carboxylate (7 g).
[0363] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 2.75 (s,
3H), 3.15 (m, 4H), 3.5 (m, 4H)
[0364] A solution of tert-butyl
4-(methylsulphonyl)piperazine-1-carboxylate (7 g) in methylene
chloride (150 ml) containing TFA (35 ml) was stirred for 2 hours at
ambient temperature. The volatiles were removed under vacuum and
the resultant residue was partitioned between methylene chloride
and 2N aqueous sodium hydroxide. The organic phase was separated
and washed with brine, dried over magnesium sulphate and evaporated
to give 1-(methylsulphonyl)piperazine (2.18 g).
[0365] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.9 (s, 3H), 3.0 (m, 4H),
3.2 (m, 2H)
[0366] A suspension of 1-(methylsulphonyl)piperazine (3 g, 18.3
mmol), 3-bromopropan-1-ol (3.3 g, 23.8 mmol) and potassium
carbonate (3.28 g, 23.8 mmol) in acetonitrile (20 ml) was stirred
at 70.degree. C. for 4 hours. After cooling, the mixture was
filtered and the filtrate was evaporated. The residue was purified
by column chromatography eluting with increasingly polar mixtures
of methanol and methylene chloride to give
3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (2.93 g, 72%).
[0367] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.72 (m, 2H), 2.55-2.7
(m, 6H), 2.75 (s, 3H), 3.25 (m, 4H), 3.75 (dd, 2H)
[0368] MS-ESI: 223 [M+H]+
[0369] A solution of 7-azaindole (20.0 g, 169 mmol) in ethanol (200
ml) was treated with wet Raney Nickel (4 g, 50% water) and stirred
in a hydrogen atmosphere at 5 atmospheres pressure at 95.degree. C.
over 2 days. The reaction mixture was filtered through diatomaceous
earth and the filtrate evaporated under vacuum. The residue was
purified by column chromatography eluting with ethyl acetate
followed by increasingly polar mixtures of methylene chloride and
methanol (saturated with ammonia) to give 7-azaindoline (12.1 g,
79%).
[0370] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.06 (t, 2H), 3.61 (t,
2H), 4.48 (br s, 1H), 6.50 (m 1H), 7.25 (m, 1H), 7.81 (d, 1H)
[0371] A solution of 7-azaindoline (22.7 g, 189 mmol), p-toluene
sulphonic acid monohydrate (2.95 g, 15 mmol) and
1,3-dibromo-5,5-dimethylhydantoin (27.4 g, 96 mmol) in methylene
chloride (1500 ml) was stirred at ambient temperature for 3 hours.
The reaction solution was then decanted from a black polymeric
material; washed with 0.2 M sodium thiosulphate (4.times.250 mls)
followed by brine and dried over magnesium sulphate. The filtrate
was evaporated under vacuum to give a black solid which was
extracted with boiling ethyl acetate (2.times.800 mls and
2.times.500 mls). The combined extracts were heated at reflux for a
few minutes with decolourising charcoal, filtered and evaporated
under vacuum to give 5-bromo-7-azaindoline (16.6 g, 44%).
[0372] .sup.1H NMR Spectrum: (CDCl.sub.3) 3.07 (t, 2H), 3.64 (t,
2H), 4.52 (s, 1H), 7.31 (d, 1H), 7.84 (d, 1H)
[0373] A mixture of 5-bromo-7-azaindoline (15.6 g, 78 mmol) and
precipitated, active manganese (IV) oxide (21.9 g, 252 mmol) in
toluene (300 mls) was heated at 90.degree. C. for 1 hour and the
hot solution filtered through a pad of diatomaceous earth. The
diatomaceous earth and manganese residues were washed with acetone
and these washings added to the toluene filtrate. Evaporation of
the filtrate under vacuum gave 5-bromo-7-azaindole (12.1 g,
78%).
[0374] .sup.1H NMR spectrum: (CDCl.sub.3) 6.47 (m, 1H), 7.36 (m,
1H), 8.08 (d, 1H), 8.35 (d, 1H), 9.89 (s, 1H)
[0375] A solution of 5-bromo-7-azaindole (8.6 g, 44 mmol), copper
(I) bromide (12.6 g, 88 mmol) and sodium methoxide (100 g, 1.85
mol) in a mixture of "degassed" DMF (260 mils) and methanol (175
mls) was stirred at ambient temperature in a nitrogen atmosphere,
and then heated at reflux for 3.5 hours. The mixture was
concentrated to about half its original volume, cooled in a cold
water bath and treated dropwise with water causing an exotherm. The
resulting suspension was evaporated under vacuum to give a brown
solid which was then treated with water followed by ammonium
hydroxide. The aqueous phase was extracted with ethyl acetate and
the combined extracts were washed with dilute ammonium hydroxide
until no blue colour was seen in the aqueous washings. The ethyl
acetate solution was washed with brine, dried over MgSO.sub.4,
filtered and evaporated under vacuum. This crude solid,
5-methoxy-7-azaindole (6.3 g, 97%), was taken through the next step
without further purification.
[0376] Boron tribromide (0.506 .mu.l, 5.35 mmol) in methylene
chloride (1 ml) was added to a solution of 5-methoxy-7-azaindole
(0.36 g, 2.43 mmol) in methylene chloride (25 ml) cooled at
-30.degree. C. The mixture was left to warm up to ambient
temperature and was stirred overnight. The mixture was poured onto
ice and water and the pH of the aqueous phase was adjusted to 6.
The organic phase was separated and the aqueous phase was further
extracted with ethyl acetate. The organic phases were combined,
washed with brine, dried over magnesium sulphate and evaporated.
The residue was purified by column chromatography eluting with
increasingly polar mixtures of methylene chloride and methanol to
give 5-hydroxy-7-azaindole (0.23 g, 71%).
[0377] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 6.25 (s, 1H), 7.25 (s,
1H), 7.35 (s, 1H), 7.85 (s, 1H), 9.05 (br s, 1H)
[0378] MS-ESI: 135 [M+H].sup.+
[0379] A solution of 6-benzyloxy-4-chloro-7-methoxyquinazoline
(0.449 g, 1.49 mmol), (EP1153920 production examples 28-30),
5-hydroxy-7-azaindole (0.22 g, 1.64mmol) and potassium carbonate
(0.28 g, 2.02 mmol) in DMF (51ml) was stirred at 95.degree. C. for
3 hours. The mixture was filtered and the filtrate was evaporated
and dried overnight under vacuum. The residue was triturated under
methylene chloride and ethyl acetate and the solid was filtered and
dried under vacuum to give
4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g,
60%).
[0380] .sup.1H NMR spectrum (DMSOd.sub.6): 4.05 (s, 3H), 5.35 (s,
2H), 6.5 (s, 1H), 7.35-7.5 (m, 4H), 7.5-7.6 (m, 3H), 7.8 (s, 1H),
7.95 (s, 1H), 8.2 (s, 1H), 8.55 (s, 1H)
[0381] MS-ESI: 399 [M+H]+
[0382] A solution of
4-(7-azaindol-5-yloxy)-6-benzyloxy-7-methoxyquinazoline (0.36 g,
0.873 mmol), ammonium formate (0.55 g, 8.73 mmol) and 10% palladium
on carbon (0.05 g) in DMF (7 ml) containing water (0.3 ml) was
stirred at ambient temperature for 1 hour. The mixture was filtered
and the filtrate was evaporated. The residue was triturated under
diethyl ether and the solid was filtered, washed with ether and
dried under vacuum. The solid was triturated under water, filtered,
washed with water and dried under vacuum over P.sub.2O.sub.5 to
give 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.26 g,
85%).
[0383] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.05 (s, 3H), 6.5 (d,
1H), 7.4 (s, 1H), 7.6 (m, 2H), 7.95 (s, 1H), 8.2 (s, 1H), 8.5 (s,
1H)
[0384] MS-ESI: 307 [M-H]-
EXAMPLE 3
##STR00053##
[0386] Using an analogous procedure to that described for the
preparation of Example 2,
4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazohne (0.133 g,
0.432 mmol), (prepared as described for the starting material in
Example 2), was reacted with 3-(4-acetylpiperazin-1-yl)propan-1-ol
(0.097, 0.51 mmol), (prepared as described for the starting
material in Example 1 or Example 7), to give
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-7-methoxyqui-
nazoline (0.11 g, 53%).
[0387] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3 COOD) 2.08 (s,
3H), 2.3 (m, 2H), 2.9-3.1 (m, 2H), 3.1-3.25 (m, 1H), 3.35 (dd, 2H),
3.45 (m, 1H), 3.6 (d, 2H), 4.0-4.05 (m, 1H), 4.1 (s, 3H), 4.4 (dd,
2H), 4.5 (d, 1H), 6.6 (d, 1H), 7.6 (s, 1H), 7.68 (d, 1H), 7.85 (s,
1H), 8.1 (s, 1H), 8.38 (s, 1H), 9.1 (s, 1H)
[0388] MS-ESI: 477 [M+H]+
EXAMPLE 4
[0389] A solution of
7-(3-(4-acetylpiperazin-n-1-yl)propoxy)-4-chloro-6-methoxyquinazoline
(0.285 g, 0.753 mmol), 5-hydroxy-7-azaindole (0.111 g, 0.828 mmol),
(prepared as described for the starting material in Example 2), and
potassium carbonate (0.114 g, 0.8288 mmol) in DMF (1.6 ml) was
stirred and heated at 95.degree. C. under nitrogen for 3 hours. The
mixture was cooled and filtered and the filtrate was evaporated.
The residue was purified by column chromatography eluting with
increasingly polar mixtures of methylene chloride and methanol
(saturated with ammonia). The fractions containing the expected
product were combined and evaporated and the residue was triturated
under diethyl ether, filtered and dried under vacuum to give
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyqui-
nazoline (0.225 g, 62%).
[0390] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (s, 3H), 1.98 (m,
2H), 2.35 (dd, 2H), 2.4 (dd, 2H), 2.5 (m, 2H), 3.41 (m, 4H), 4.0
(s, 3H), 4.25 (dd, 2H), 6.47 (d, 1H), 7.38 (s, 1H), 7.55 (dd, 1H),
7.6 (s, 1H), 7.9 (d, 1H), 8.18 (d, 1H), 8.5 (s, 1H)
[0391] MS-ESI: 477.6 [M+H]+
[0392] The starting material was prepared as follows
[0393] A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g,
0.04 mol), (J. Med. Chem. 1977, vol 20, 146-149), and Gold's
reagent (7.4 g, 0.05 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 (MgSO.sub.4). Recrystallisation
from acetic acid gave
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
[0394] 10% Palladium on carbon (8.3 g) was added to a suspension of
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (50 g, 0.177 mol)
in dimethylformamide (800 ml) under nitrogen. Ammonium formate
(111.8 g, 1.77 mol) was then added in portions over 5 minutes. The
reaction mixture was stirred for one hour at ambient temperature
then heated to 80.degree. C. for a further hour. The reaction
mixture was filtered hot through diatomaceous earth and the
residues washed with dimethylformamide. The filtrate was then
concentrated and the residue suspended in water. The pH was
adjusted to 7.0 using 2M sodium hydroxide and the resulting mixture
was stirred at ambient temperature for one hour. The solid was
filtered, washed with water and dried over phosphorus pentoxide
yielding 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white
solid (20.52 g, 60%).
[0395] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.85 (s, 3H), 6.95 (s,
1H), 7.40 (s, 1H), 7.85 (s, 1H)
[0396] MS-ESI: 193 [M+H]+
[0397] Pyridine (20 ml) was added to a suspension of
7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.5 g, 107 mmol)
in acetic anhydride (150 ml, 1.6 mol). The reaction mixture was
heated to 120.degree. C. for three hours, during which time the
solid dissolved. The reaction mixture was allowed to cool then
poured into ice-water (900 ml). The reaction mixture was stirred
for one hour then the solid was removed by filtration and dried
over phosphorus pentoxide yielding
7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid
(20.98 g, 84%).
[0398] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.25 (s, 3H), 3.85 (s,
3H), 7.40 (s, 1H), 7.60 (s, 1H), 8.00 (s, 1H)
[0399] MS-ESI: 235 [M+H]+
[0400] 7-Acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1 g, 4.3
mmol) was suspended in thionyl chloride (10.5 ml). One drop of
dimethylformamide was added and the reaction was heated to
80.degree. C. for two hours, during which time the solid dissolved.
The reaction mixture was cooled and the thionyl chloride was
removed in vacuo. The residue was azeotroped with toluene before
being suspended in methylene chloride. A solution of 10% ammonia in
methanol (40 ml) was added and the reaction mixture was heated to
80.degree. C. for 15 minutes. After cooling the solvents were
removed in vacuo and the residue redissolved in water (10 ml) and
the pH adjusted to 7.0 with 2M hydrochloric acid. The resulting
solid was filtered, washed with water and dried over phosphorus
pentoxide yielding 4-chloro-7-hydroxy-6-methoxyquinazoline as a
white solid (680 mg, 75%).
[0401] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.00 (s, 3H), 7.25 (s,
1H), 7.35 (s, 1H), 8.75 (s, 1H)
[0402] MS-ESI: 211-213 [M+H]+
[0403] Diethyl azodicarboxylate (0.243 g, 1.396 mmol) was added
dropwise to a solution of 4-chloro-7-hydroxy-6-methoxyquinazoline
(0.245 g, 1.16 mmol), triphenylphosphine (0.396 g, 1.51 mmol) and
3-(4-acetylpiperazin-1-yl)propan-1-ol (0.238 g, 1.28 mmol),
(prepared as described for the starting material in Example 1 or
Example 7). After stirring at ambient temperature for 1 hour, the
mixture was poured onto silica and eluted with increasingly polar
mixtures of methylene chloride and methanol to give
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline
(0.29 g, 66%).
[0404] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0 (s, 3H), 2.0 (m,
2H), 2.35 (dd, 2H), 2.4 (dd, 2H), 2.5 (dd, 2H), 3.45 (m, 4H), 4.02
(s, 3H), 4.3 (dd, 2H), 7.4 (s, 1H), 7.5 (s, 1H), 8.9 (s, 1H)
[0405] MS-ESI: 379-381 [M+H]+
EXAMPLE 5
##STR00054##
[0407] A suspension of
4-chloro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazol-
ine (0.25 g, 0.6 mmol), 5-hydroxy-7-azaindole (0.089 g, 0.663
mmol), (prepared as described for the starting material in Example
2), and potassium carbonate (0.091 g, 0.66 mmol) in DMF (3 ml) was
stirred at 85.degree. C. for 3 hours. The mixture was filtered and
the filtrate was purified by preparative LC/MS eluting with
acetonitrile/water (containing 1% acetic acid). The fractions
containing the expected product were combined and evaporated. The
residue was dissolved in methylene chloride and washed with 0.5N
aqueous ammonia followed by brine, dried (MgSO.sub.4) and
evaporated. The residue was triturated under diethyl ether,
filtered and dried under vacuum to give
4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)pr-
opoxy)quinazoline (0.138 g, 45%).
[0408] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.02 (m, 2H), 2.52 (m,
6H), 2.9 (s, 3H), 3.15 (m, 4H), 4.02 (s, 3H), 4.3 (dd, 2H), 6.5 (d,
1H), 7.4 (s, 1H), 7.6 (d, 1H), 7.65 (s, 1H), 7.95 (d, 1H), 8.2 (s,
1H), 8.52 (s, 1H)
[0409] MS-ESI: 513.5 [M+H]+
[0410] The starting material was prepared as follows:
[0411] Using an analogous procedure to that described for the
preparation of the starting material in Example 4,
4-chloro-7-hydroxy-6-methoxyquinazoline (0.25 g, 1.19 mmol),
(prepared as described for the starting material in Example 4), was
reacted with 3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (0.29
g, 1.3 mmol), (prepared as described in Example 2), to give
4-chloro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazol-
ine (0.339 g, 69%).
[0412] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.0 (m, 2H), 2.5 (m,
6H), 2.85 (s, 3H), 3.1 (m 4H), 4.0 (s, 3H), 4.3 (dd, 2H), 7.4 (s,
1H), 7.42 (s, 1H), 8.85 (s, 1H)
[0413] MS-ESI: 415-417 [M+H]+
EXAMPLE 6
##STR00055##
[0415] Using an analogous procedure to that described for the
preparation of Example 5,
4-chloro-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazolin-
e (0.25 g, 0.817 mmol) was reacted with 5-hydroxy-7-azaindole (0.12
g, 0.899 mmol), (prepared as described for the starting material in
Example 2), to give
4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)eth-
oxy]quinazoline (0.156 g, 47%).
[0416] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H), 2.9 (dd,
2H), 3.2 (dd, 1H), 3.45 (d, 2H), 4.02 (s, 3H), 4.31 (dd, 2H), 6.5
(d, 1H), 7.45 (s, 1H), 7.6 (dd, 1H), 7.65 (s, 1H), 7.95 (d, 1H),
8.2 (d, 1H), 8.52 (s, 1H)
[0417] MS-ESI: 404 [M+H]+
[0418] The starting material was prepared as follows:
[0419] 6N Aqueous sodium hydroxide (4.2 ml) was added to a solution
of 2-(methylamino)ethanol (1.42 g, 18.9 mmol), propargyl bromide in
toluene (1.5 g, 12.6 mmol; 1.6 ml) in dioxane (8 ml). After
stirring overnight at ambient temperature, the mixture was
partitioned between water and ethyl acetate. The organic phase was
separated, washed with brine, dried with magnesium sulphate and
evaporated. The residue was purified by column chromatography
eluting with increasingly polar mixtures of methylene chloride and
methanol to give 2-(N-methyl-N-prop-2-yn-1-ylamino)ethanol (0.794
g, 56%).
[0420] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.2 (dd, 1H), 2.3 (s,
3H), 2.58 (dd, 2H), 3.35 (d, 2H), 3.6 (dd, 2H)
[0421] Diethyl azodicarboxylate (0.297 g, 1.71 mmol) was added to a
solution of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.3 g, 1.42
mmol), (prepared as described for the starting material in Example
4), triphenylphosphine (0.485 g, 1.85 mmol) and
2-(N-methyl-N-prop-2-yn-1-ylamino)ethanol (0.177 g, 1.56 mmol) in
methylene chloride (8 ml). The mixture was stirred for 2 hours at
ambient temperature and poured onto a column of silica and eluted
with increasingly polar mixtures of methylene chloride and ethyl
acetate followed by ethyl acetate to give
4-chloro-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazolin-
e (0.341 g, 78%).
[0422] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.33 (s, 3H), 2.87 (t,
2H), 3.17 (t, 1H), 3.44 (d, 2H), 4.02 (s, 3H), 4.33 (t, 2H), 7.41
(s, 1H), 7.51 (s, 1H), 8.89 (s, 1H)
EXAMPLE 7
##STR00056##
[0424] A solution of
7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazolin-
e (0.25 g, 0.543 mmol) and 1-acetylpiperazine (0.208 g, 1.63 mmol)
in DMF (4 ml) was stirred at 80.degree. C. for 2.5 hours. The
volatiles were removed under vacuum and the residue was purified by
column chromatography eluting with increasingly polar mixtures of
methylene chloride and methanol. The fractions containing the
expected product were combined and evaporated. The residue was
triturated under diethyl ether and the resulting solid was
filtered, washed with diethyl ether and dried under vacuum to give
7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)--
6-methoxyquinazoline (0.25 g, 0.543 mmol).
[0425] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (s, 3H), 2.0 (m,
2H), 2.4 (s, 3H), 2.4 (m, 4H), 2.55 (t, 2H), 3.45 (dd, 4H), 4.0 (s,
3H), 4.3 (t, 2H), 6.22 (s, 1H), 6.98 (dd, 1H), 7.15 (d, 1H), 7.4
(s, 1H), 7.62 (s, 1H), 8.48 (s, 1H), 10.98 (br s, 1H)
[0426] MS-ESI: 508 [M+H]+
[0427] The starting material was prepared as follows:
[0428] A mixture of
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (2.82 g, 0.01
mol), (prepared as described for the starting material in Example
4), thionyl chloride (40 ml) and DMF (0.28 ml) was stirred and
heated at reflux for 1 hour. The mixture was evaporated, the
residue was taken up in toluene and evaporated to dryness to give
7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (3.45
g).
[0429] 7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride
(3.35 g) was dissolved in methylene chloride (250 ml) and washed
with aqueous sodium hydrogen carbonate until the pH of the aqueous
solution was adjusted to pH8. The organic layer was washed with
brine, dried (MgSO.sub.4) and evaporated to give
7-benzyloxy-4-chloro-6-methoxyquinazoline free base (2.9 g,
96%).
[0430] A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline
free base (10 g, 33.2 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.9
g, 35.7 mmol), (prepared as described for the starting material in
Example 1), and potassium carbonate (9.2 g, 66.6 mmol) in NMP (100
ml) was stirred at 95.degree. C. for 1 hour. After cooling, the
mixture was partitioned between ethyl acetate and aqueous sodium
hydrogen carbonate. The organic layer was separated, washed with
brine and dried over magnesium sulphate and evaporated under
vacuum. The residue was triturated under acetonitrile and the
suspension was cooled. The precipitate was filtered and dried under
vacuum to give
7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline
(8.2 g, 57%).
[0431] .sup.1H NMR Spectrum: (DMSOd.sub.6): 2.4 (s, 3H), 4.0 (s,
3H), 5.35 (s, 2H), 6.22 (s, 1H), 6.95 (dd, 1H), 7.15 (d, 1H),
7.3-7.55 (m, 6H), 7.51 (s, 1H), 8.5 (s, 1H)
[0432] A suspension of
7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline
(8.2 g, 19.1 mmol), ammonium formate (12 g, 190 mmol) in DMF (50
ml) containing 10% palladium on carbon (2 g) was stirred at ambient
temperature for 1.5 hours. The mixture was diluted with ethyl
acetate and filtered over diatomaceous earth. A solid precipitated
out of the filtrate. The solid was filtered off. The filtrate was
washed with aqueous sodium hydrogen carbonate, followed by brine
and dried over magnesium sulphate. The volatiles were removed under
vacuum. The residual solid was combined with the solid previously
isolated from the filtrate and was then triturated with
acetonitrile under cooling. The precipitate was filtered, washed
with acetonitrile followed by diethyl ether and dried under vacuum
to give
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(6.48 g, quant.).
[0433] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (s, 3H), 3.98 (s,
3H), 6.22 (s, 1H), 6.95 (dd, 1H), 7.15 (d, 1H), 7.2 (s, 1H), 7.58
(s, 1H), 8.38 (s, 1H)
[0434] Diethyl azodicarboxylate (557 .mu.l, 3.53 mmol) was added to
a solution of
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(1 g, 2.95 mmol), triphenylphosphine (1.15 g, 4.42 mmol) and
3-bromo-1-propanol (293 .mu.l, 3.24 mmol) in methylene chloride (25
ml). The mixture was stirred at ambient temperature for 1 hour and
the residue was purified by column chromatography eluting with
increasingly polar mixtures of methylene chloride and methanol. The
fractions containing the expected product were combined and
evaporated. The residue was triturated under diethyl ether and the
solid was filtered, washed with diethyl ether and evaporated to
give
7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazolin-
e (1.35 g, 100%).
[0435] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (m, 2H), 2.45 (s,
3H), 3.75 (dd, 2H), 4.05 (s, 3H), 4.35 (dd, 2H), 6.25 (s, 1H), 7.0
(dd, 1H), 7.2 (d, 1H), 7.45 (s, 1H), 7.65 (s, 1H), 8.55 (s, 1H),
9.0 (br s, 1H)
[0436] MS-ESI: 460-462 [M+H]+
[0437] Alternatively
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline may be prepared as follows:
##STR00057##
[0438]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazo-
line (14 g, 41.3 mmol), (prepared as described for the starting
material in this example hereinbefore),
3-(4-acetylpiperazin-1-yl)propan-1-ol (9.2 g, 49.5 mmol) and
triphenylphosphine (12.9 g, 49.5 mmol) were stirred together in
methylene chloride (210 ml). Diisopropyl azodicarboxylate (9.75 ml,
49.5 mmol) was added dropwise and an ice/water bath was used to
keep the temperature of the reaction mixture between 15 and
18.degree. C. After the end of addition the reaction mixture was
allowed to warm to ambient temperature and stirred for 3 hours. The
mixture was filtered and concentrated under reduced pressure and
the resulting viscous oil dissolved in acetone (280 ml) and stirred
for 45 minutes. The solid that formed was filtered off and dried
under vacuum. The solid was purified by chromatography eluting with
methylene chloride/methanol (saturated with ammonia) (96/4) to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline (12.5 g, 60%) as a white solid.
[0439] MS and NMR details are given hereinbefore.
[0440] The starting material was prepared as follows:
[0441] 1-Acetylpiperazine (15.0 g, 117 mmol) was dissolved in
acetonitrile (200 ml) and potassium carbonate (40.4 g, 293 mmol)
was added followed by 3-bromo-1-propanol (10.6 ml, 117 mmol). The
mixture was heated at reflux for 2.5 hours, cooled, filtered and
concentrated under reduced pressure. The resulting viscous oil was
cooled in ice for 3 hours and the crystalline product that formed
was suspended in diethyl ether and filtered off. The hydroscopic
solid was dried under vacuum (P.sub.2O.sub.5) overnight to give
3-(4-acetylpiperazin-1-yl)propan-1-ol (17.3 g, 90%) as a pale
yellow solid.
[0442] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.75 (m, 2H); 2.08 (s,
3H); 2.51 (m, 4H); 2.65 (t, 2H); 3.47 (br t, 2H); 3.64 (br t, 2H);
3.82 (t, 2H)
[0443] MS-ESI: 187 [M+H]+
[0444] Alternatively
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline may be prepared as follows:
##STR00058##
[0445] A mixture of
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(20.0 g, 52.3 mmol), 4-fluoro-5-hydroxy-2-methylindole (10.5 g,
63.3 mmol), (prepared as described for the starting material in
Example 1), and cesium carbonate (34.4 g, 106 mmol) in acetone (500
ml) was heated at reflux for 4 hours. The mixture was cooled and
allowed to stand overnight. The mixture was filtered and the solid
suspended in water and re-filtered and dried under vacuum. The
solid was purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (95/5) to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline (20.4 g, 77%) as a white solid.
[0446] MS and NMR details are given hereinbefore.
[0447] The starting material was prepared as follows:
[0448] 4-Chloro-7-hydroxy-6-methoxyquinazoline (3 g, 14.2 mmol),
(prepared as described for the starting material in Example 4),
3-(4-acetylpiperazin-1-yl)propan-1-ol (3.2 g, 17.1 mmol), (prepared
as described for the starting material in this example
hereinbefore), and triphenylphosphine (4.5 g, 17.1 mmol) were
stirred together in dichloromethane (140 ml). Diisopropyl
azodicarboxylate (3.4 ml, 17.1 mmol) was added dropwise and an
ice/water bath used to keep the temperature of the reaction mixture
below 10.degree. C. After the addition, the reaction mixture was
allowed to warm to ambient temperature and stirred overnight. The
mixture was concentrated under reduced pressure. Column
chromatography of the residue (2:1 iso-hexane:ethyl acetate then
3%-5% methanol/dichloromethane) gave
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(3.96 g, 74%) as a white solid.
[0449] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (m, 5H); 2.34 (m,
2H); 2.40 (m, 2H); 2.46 (t, 2H); 3.43 (m, 4H); 4.01 (s, 3H); 4.29
(t, 2H); 7.40 (s, 1H); 7.46 (s, 1H); 8.87 (s, 1H)
[0450] MS-ESI 379.1 and 381.1 [MH].sup.+
[0451] Alternatively
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline may be prepared as follows:
##STR00059##
[0452]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazo-
line (250 mg, 0.74 mmol), (prepared as described for the starting
material in this example hereinbefore), and potassium carbonate
(112 mg, 0.81 mmol) were stirred together in N-methylpyrrolidinone
(3 ml). 1-Acetyl-4-(3-chloropropoxy)piperazine (166 mg, 0.81 mmol)
in N-methylpyrrolidinone (1 ml) was added and the mixture heated at
90.degree. C. for 3 hours. The mixture was cooled, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (97/3) to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl-
)oxy]-6-methoxyquinazoline (268 mg, 71%) as a white solid.
[0453] MS and NMR details are given hereinbefore.
[0454] The starting material was prepared as follows:
[0455] A mixture of 1-acetylpiperazine (1.0 g, 7.8 mmol),
1-bromo-3-chloropropene (772 .mu.l, 7.8 mmol) and potassium
carbonate (2.7 g, 19.5 mmol) in acetonitrile (150 ml) was heated at
reflux for 2 hours. The mixture was cooled, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography eluting with methylene chloride/methanol
(98/2) to give 1-acetyl-4-(3-chloropropoxy)piperazine (656 mg, 41%)
as a colourless oil.
[0456] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.95 (m. 2H); 2.08 (s,
3H); 2.42 (m, 4H), 2.51 (t, 2H); 3.46 (t, 2H); 3.61 (t, 4H)
EXAMPLE 8
##STR00060##
[0458] A solution of
6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazolin-
e (0.3 g, 0.652 mmol) and 1-(methylsulphonyl)piperazine (0.322 g,
1.95 mmol), (prepared as described for the starting material in
Example 2), in DMF (4 ml) was stirred at 80.degree. C. for 2.5
hours. The volatiles were removed under vacuum and the residue was
purified by column chromatography eluting with increasingly polar
mixtures of methylene chloride and methanol. The fractions
containing the expected product were combined and evaporated. The
residue was triturated under diethyl ether and the resulting solid
was filtered, washed with diethyl ether and dried under vacuum to
give
4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline (0.08 g, 23%).
[0459] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CF.sub.3COOD) 2.3 (m,
2H), 2.4 (s, 3H), 3.0 (s, 3H), 3.1-3.3 (m, 4H), 3.4 (dd, 2H), 3.7
(d, 2H), 3.8 (d, 2H), 4.1 (s, 3H), 4.4 (dd, 2H), 6.25 (s, 0.2H,
partly exchanged), 7.0 (dd, 1H), 7.2 (d, 1H), 7.55 (s, 1H), 7.82
(s, 1H), 9.1 (s, 1H)
[0460] MS-ESI: 544 [M+H]+
[0461] The starting material was prepared as follows
[0462] Diethyl azodicarboxylate (0.847 g, 4.86 mmol) was added to a
solution of
4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline
(1.5 g, 4.42 mmol), (prepared as described for the starting
material in Example 1), triphenylphosphine (1.74 g, 6.63 mmol) and
3-bromo-1-propanol (0.923 g, 6.63 mmol) in methylene chloride.
After stirring for 1 hour at ambient temperature,
triphenylphosphine (1.16 g) and DEAD (0.770 g) was added. After
stirring for 30 minutes, the volatiles were removed under vacuum
and the residue was purified by column chromatography eluting with
increasingly polar mixtures of methylene chloride and ethyl acetate
to give
6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquina-
zoline (1.5 g, 73%).
[0463] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.4 (m, 2H), 2.45 (s,
3H), 3.75 (dd, 2H), 4.05 (s, 3H), 4.32 (dd, 2H), 6.25 (s, 1H), 7.02
(dd, 2H), 7.18 (d, 1H), 7.42 (s, 1H), 7.7 (s, 1H) 8.55 (s, 1H)
[0464] MS-ESI: 460-462 [M+H]+
EXAMPLE 9
##STR00061##
[0466] Using an analogous procedure to that described for the
preparation of Example
8,7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoh-
ne (0.25 g, 0.54 mmol), (prepared as described for the starting
material in Example 7), was reacted with
1-methylsulphonylpiperazine (0.268 g, 163 mmol), (prepared as
described for the starting material in Example 2), in DMF to give
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiper-
azin-1-yl)propoxy)quinazoline (0.14 g, 47%).
[0467] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.35 (m,
2H), 2.4 (s, 3H), 3.02 (s, 3H), 3.1-3.3 (m, 4H), 3.4 (dd, 2H), 3.7
(d, 2H), 3.8 (d, 2H), 4.08 (s, 3H), 4.4 (dd, 2H), 6.25 (s, 0.2H,
partly exchanged), 7.0 (dd, 1H), 7.2 (d, 1H), 7.58 (s, 1H), 7.82
(s, 1H), 9.1 (s, 1H)
[0468] MS-ESI: 544 [M+H]+
EXAMPLE 10
##STR00062##
[0470] Diethyl azodicarboxylate (117 .mu.l, 0.738 mmol) was added
dropwise to a solution of
4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2 g,
0.615 mmol), triphenylphosphine (0.242 g, 0.92 mmol) and
3-(4-acetylpiperazin-1-yl)propan-1-ol (0.137 g, 0.738 mmol),
(prepared as described for the starting material in Example 1 or
Example 7), in methylene chloride (5 ml). After stirring at ambient
temperature for 1 hour, triphenylphosphine (0.032 g),
3-(4-acetylpiperazin-1-yl)propan-1-ol (0.022 g) and diethyl
azodicarboxylate (20 .mu.l) were added. The mixture was stirred for
1 hour at ambient temperature and evaporated under vacuum. The
residue was purified by column chromatography, eluting with
increasingly polar mixtures of methylene chloride and ethyl acetate
followed by methylene chloride and methanol. The fractions
containing the expected product were combined and evaporated. The
residue was repurified by preparative LC/MS eluting with
increasingly polar mixtures of acetonitrile and water (containing
1% acetic acid). The fractions containing the expected product were
combined and evaporated. The residue was triturated under diethyl
ether and pentane and the residue was filtered, washed with diethyl
ether and dried under vacuum to give
6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxy-
quinazoline (0.057 g, 19%).
[0471] .sup.1H NMR Spectrum: (DMSOd.sub.6, CF.sub.3COOD) 2.05 (s,
3H), 2.3 (m, 2H), 2.9-3.1 (m, 2H), 3.15 (m, 1H), 3.35 (dd, 2H),
3.45 (m, 1H), 3.6 (d, 2H), 4.05 (m, 1H), 4.1 (s, 3H), 4.4 (dd, 2H),
4.5 (d, 1H), 6.55 (d, 1H), 7.15 (dd, 1H), 7.38 (d, 1H), 7.5 (d,
1H), 7.58 (s, 1H), 7.85 (s, 1H), 9.12 (s, 1H)
[0472] MS-ESI: 494 [M+H]+
[0473] The starting material was prepared as follows:
[0474] A mixture of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.88
g, 2.9 mmol), (EP1153920 production examples 28-30),
4-fluoro-5-hydroxyindole (0.53 g, 3.5 mmol) and potassium carbonate
(0.607 g, 4.39 mmol) in DMF (18 ml) was stirred at 95.degree. C.
for 2 hours. After cooling, the mixture was filtered and the
volatiles were removed under vacuum. The residue was purified by
column chromatography eluting with increasingly polar mixtures of
methylene chloride and ethyl acetate to give
6-benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.8 g,
67%).
[0475] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.05 (s, 3H), 5.35 (s,
2H), 6.6 (s, 1H), 7.1 (dd, 1H), 7.35 (d, 1H), 7.35-7.5 (m, 5H),
7.55 (d, 2H), 7.8 (s, 1H), 8.55 (s, 1H), 11.5 (br s, 1H)
[0476] MS-ESI: [M+H]+ 416
[0477] 6-Benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline
(0.75 g, 1.8 mmol), ammonium formate (1.14 g, 18 mmol) and 10%
palladium on carbon (115 mg) in DMF (8 ml) containing water (1.5
ml) was stirred at ambient temperature for 2.5 hours. The mixture
was filtered over diatomaceous earth and the filtrate was
evaporated. The residue was triturated under diethyl ether,
filtered, washed with water, followed by diethyl ether and dried
overnight over P.sub.2O.sub.5 to give
4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.471 g,
80%).
[0478] .sup.1H NMR Spectrum: (DMSOd.sub.6) 4.02 (s, 3H), 6.55 (s,
1H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.4 (s, 1H), 7.5 (dd, 1H), 7.6 (s,
1H), 8.48 (s, 1H)
[0479] MS-ESI: 326 [M+H]+
[0480] 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 heated at reflux 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%).
[0481] .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)
[0482] 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
5-cyanomethyl-2-fluoro-4-nitrobenzyloxybenzene (1.2 g, 60%).
[0483] .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)
[0484] 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).
4-fluoro-5-hydroxyindole
[0485] .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 (br s,
1H)
6-fluoro-5-hydroxyindole
[0486] .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 11
##STR00063##
[0488]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-y-
lmethoxy)quinazoline (150 mg, 0.34 mmol) was suspended in methylene
chloride (5 ml), and diisopropylethylamine (72 .mu.l, 0.41 mmol)
and acetyl chloride (29 .mu.l, 0.41 mmol) were added. The mixture
was stirred for half an hour at ambient temperature, washed with
saturated sodium hydrogen carbonate solution, dried (MgSO.sub.4)
and concentrated under reduced pressure. The solid was suspended in
methanol and filtered off to give
7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-
-yl)oxy]-6-methoxyquinazoline (117 mg, 71%).
[0489] MS-ESI: 479.5 [MH].sup.+
[0490] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.22 (m, 2H); 1.83 (m,
2H); 1.99 (s, 3H); 2.13 (m, 1H); 2.40 (s, 3H); 2.58 (m, 1H); 3.06
(m, 1H), 3.85 (m, 1H); 3.98 (s, 3H); 4.08 (d, 2H); 4.40 (m, 1H);
6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.38 (s, 1H); 7.59 (s,
1H); 8.48 (s, 1H); 11.29 (br s, 1H)
[0491] The starting material was prepared as follows:
[0492] While maintaining the temperature in the range 0-5.degree.
C., a solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in
ethyl acetate (75 ml) was added in portions to a solution of ethyl
4-piperidinecarboxylate (30 g, 0.19 mol) in ethyl acetate (150ml)
cooled at 5.degree. C. After stirring for 48 hours at ambient
temperature, the mixture was poured onto water (300 ml). The
organic layer was separated, washed successively with water (200
ml), 0.1N aqueous hydrochloric acid (200 ml), saturated sodium
hydrogen carbonate (200 ml) and brine (200 ml), dried (MgSO.sub.4)
and evaporated to give ethyl
4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 98%).
[0493] .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)
[0494] A solution of 1M lithium aluminium hydride in THF (133 ml,
0.133 mol) was added in portions to a solution of ethyl
4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48 g, 0.19 mol)
in dry THF (180 ml) cooled at 0.degree. C. After stirring at
0.degree. C. for 2 hours, water (30 ml) was added followed by 2N
sodium hydroxide (10 ml). The precipitate was removed by filtration
through diatomaceous earth and washed with ethyl acetate. The
filtrate was washed with water, brine, dried (MgSO.sub.4) and
evaporated to give
1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (36.3 g,
89%).
[0495] MS (EI): 215 [M.]+
[0496] .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)
[0497] Diisopropyl azodicarboxylate (139 .mu.l, 0.71 mmol) was
added to a mixture of
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(200 mg, 0.59 mmol), (prepared as described for the starting
material in Example 7), triphenylphosphine (186 mg, 0.71 mmol) and
1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate), (152 mg,
0.71 mmol) in methylene chloride (3 ml), cooled in an ice/water
bath. The mixture was allowed to warm to ambient temperature and
was stirred overnight. The mixture was concentrated under reduced
pressure and the residue purified by column chromatography, eluting
with 1% methanol/methylene chloride and 0.1% triethylamine to give
tert-butyl
4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)-
methyl]piperidine-1-carboxylate (293 mg containing 13.5 mol %
triphenylphospine oxide, 86%).
[0498] MS-ESI: 537.6 [MH].sup.+
[0499] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.22 (m, 2H); 1.39 (s,
9H); 1.78 (m, 2H); 2.04 (m, 1H); 2.40 (s, 3H); 2.76 (m, 2H); 3.97
(m, 5H); 4.07 (d, 2H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 2H);
7.37 (s, 1H); 7.69 .mu.m, 3.3H (1H+Ph.sub.3PO)]; 8.47 (s, 1H);
11.29 (br s, 1H) tert-Butyl 4-[(4-[(4-fluoro-2-methyl-
H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxy-
late [285 mg (containing 13.5% triphenylphospine oxide), 0.49 mmol]
was dissolved in 4M hydrogen chloride in dioxane (5 ml) and stirred
at ambient temperature for 3 hours. The solvent was removed under
reduced pressure and the solid suspended in methylene chloride and
filtered off. The solid was dissolved in methanol and absorbed onto
an Isolute SCX column which was washed through with methanol and
then the product eluted with 7N ammonia in methanol. Concentration
of the fractions gave
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmetho-
xy)quinazoline (185 mg, 86%).
[0500] MS-ESI: 437.5 [MH].sup.+
[0501] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.34 (m, 2H); 1.85-2.20
(m, 3H); 2.45 (s, 3H); 2.68 (m, 2H); 3.15 (m, 2H); 4.05 (m, 5H);
6.32 (s, 1H); 6.97 (t, 1H); 7.11 (d, 1H); 7.30 (s, 1H) 7.63 (s,
1H); 8.58 (s, 1H); 9.08 (br s, 1H)
EXAMPLE 12
##STR00064##
[0503] Using an analogous procedure to that described for the
preparation of Example 11,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-y-
lmethoxy]quinazoline (120 mg, 0.28 mmol) was reacted with acetyl
chloride (24 .mu.l, 0.34 mmol). The crude product was purified by
column chromatography eluting with methanol/methylene chloride
(2/98) to give
7-[(2S)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline (76 mg, 58%).
[0504] MS-ESI: 465.6[MH].sup.+
[0505] .sup.1H NMR Spectrum: (100.degree. C., DMSOd.sub.6) 2.02 (m,
7H); 2.41 (s, 3H); 3.50 (m, 2H); 4.00 (s, 3H), 4.29 (m, 3H); 6.22
(s, 1H); 6.95 (t, 1H); 7.14 (d, 1H); 7.43 (s, 1H); 7.63 (s, 1H);
8.47 (s, 1H); 11.02 (br s, 1H)
[0506] The starting material was prepared as follows:
[0507] Using an analogous procedure to that described for the
preparation of the starting material in Example 11, tert-butyl
(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (142 mg, 0.71 mmol)
was reacted with
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(200 mg, 0.59 mmol), (prepared as described for the starting
material in Example 7), and the product purified by column
chromatography, eluting with methanol/methylene chloride (1/9)
containing 0.1% triethylamime to give tert-butyl
(2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-y-
loxy)methyl]pyrrolidine 1-carboxylate (178 mg, 58%).
[0508] MS-ESI: 523.3 [MH].sup.+
[0509] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H); 1.80 (m,
1H); 1.98 (m, 3H); 2.40 (s, 3H); 3.98 (s, 3H); 4.19 (m, 3H); 6.22
(s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.43 (br s, 1H); 7.59 (s, 1H);
8.48 (s, 1H); 11.29 (br s, 1H)
[0510] Using an analogous procedure to that described for the
preparation of the starting material in Example 11, tert-butyl
(2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-y-
loxy)methyl]pyrrolidine-1-carboxylate (170 mg, 0.33 mmol) was
reacted with hydrogen chloride in dioxane. The solid was dissolved
in methanol and absorbed onto an Isolute SCX column which was
washed through with methanol and then the product was eluted with
7N ammonia in methanol to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidi-
n-2-ylmethoxy]quinazoline (128 mg, 93%).
[0511] MS-ESI: 423.5 [MH].sup.+
[0512] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.53 (m, 1H); 1.71 (m,
2H); 1.88 (m, 1H); 2.40 (s, 3H); 2.84 (m, 2H); 3.52 (m, 1H); 3.98
(s, 3H); 4.04 (d, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H);
7.37 (s, 1H); 7.59 (s, 1H); 8.47 (s, 1H); 11.30 (br s, 1H)
EXAMPLE 13
##STR00065##
[0514] Using an analogous procedure to that described for the
preparation of Example 11,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-y-
lmethoxy]quinazoline (160 mg, 0.38 mmol) was reacted with acetyl
chloride (32 .mu.l, 0.46 mmol). The crude product was purified by
column chromatography eluting with methanol/methylene chloride
(2/98) to give
7-[(2R)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5--
yl)oxy]-6-methoxyquinazoline (82 mg, 46%).
[0515] MS-ESI: 465.6[MH].sup.+
[0516] .sup.1H NMR Spectrum: (100.degree. C., DMSO-d.sub.6) 2.02
(m, 7H); 2.41 (s, 3H); 3.50 (m, 2H); 4.00 (s, 3H), 4.29 (m, 3H);
6.22 (s, 1H); 6.95 (t, 1H); 7.14 (d, 1H); 7.43 (s, 1H); 7.63 (s,
1H); 8.47 (s, 1H); 11.02 (br s, 1H)
[0517] The starting material was prepared as follows:
[0518] Using an analogous procedure to that described for the
preparation of the starting material in Example 11, tert-butyl
(2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.48 g, 7.37 mmol)
was reacted with
4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(1.0 g, 2.95 mmol), (prepared as described for the starting
material in Example 7), and the product purified by column
chromatography, eluting with methanol/methylene chloride (1/9)
containing 0.1% triethylamine to give tert-butyl
(2R)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-y-
loxy)methyl]pyrrolidine-1-carboxylate (970 mg, 62%).
[0519] MS-ESI: 523.3 [MH].sup.+
[0520] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (s, 9H); 1.80 (m,
1H); 1.98 (m, 3H); 2.40 (s, 3H); 3.98 (s, 3H); 4.19 (m, 3H); 6.22
(s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.43 (br s, 1H); 7.59 (s, 1H);
8.48 (s, 1H); 11.29 (br s, 1H)
[0521] Using an analogous procedure to that described for the
preparation of the starting material in Example 11, tert-butyl
(2R)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-y-
loxy)methyl]pyrrolidine-1-carboxylate (960 mg, 1.84 mmol) was
reacted with hydrogen chloride in dioxane. The solid was dissolved
in methanol and absorbed onto an Isolute SCX column which was
washed through with methanol and then the product was eluted with
7N ammonia in methanol to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidi-
n-2-ylmethoxy]quinazoline (480 mg, 62%).
[0522] MS-ESI: 423.5 [MH].sup.+
[0523] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.53 (m, 1H); 1.71 (m,
2H); 1.88 (m, 1H); 2.40 (s, 3H); 2.84 (m, 2H); 3.52 (m, 1H); 3.98
(s, 3H); 4.04 (d, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H);
7.37 (s, 1H); 7.59 (s, 1H); 8.47 (s, 1H); 11.30 (br s, 1H)
EXAMPLE 14
##STR00066##
[0525]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-y-
lmethoxy)quinazoline (180 mg, 0.41 mmol), (prepared as described
for the starting material in Example 11), was suspended in
tetrahydrofuran (15 ml), and diisopropylethylamine (108.11, 0.45
mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (98 mg,
0.62 mmol) were added. The mixture was heated at reflux for 1.5
hours. Diisopropylethylamine (36 .mu.l, 0.21 mmol) and
2,2,2-trifluoroethyl trifluoromethanesulphonate (45 mg, 0.21 mmol)
were added and the mixture was heated at reflux for a further 2
hours. The mixture was concentrated under reduced pressure and
column chromatography of the residue, eluting with 1%
methanol/methylene chloride gave a sticky solid. This was
triturated with diethyl ether and filtered to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroe-
thyl)piperidin-4-ylmethoxy]quinazoline (93 mg, 44%).
[0526] MS-ESI: 519.1 [MH].sup.+
[0527] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.40 (m, 2H); 1.80 (m,
3H); 2.36 (m, 5H); 2.95 (br d, 2H); 3.14 (m, 2H); 3.98 (s, 3H);
4.06 (d, 2H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.36 (s,
1H); 7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
EXAMPLE 15
##STR00067##
[0529] Using an analogous procedure to that described for the
preparation of Example 14,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpro-
poxy)quinazoline (250 mg, 0.54 mmol) was reacted with
2,2,2-trifluoroethyl trifluoromethanesulphonate (128 mg, 0.59 mmol)
and purified by column chromatography, eluting with 5%
methanol/methylene chloride to give a sticky solid. The sticky
solid was dissolved in methanol and absorbed onto an Isolute SCX
column. The column was washed with methanol and eluted with 7N
ammonia in methanol. The product was triturated in ether/isohexane
and filtered to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluo-
roethyl)piperazin-1-yl]propoxy}quinazoline (130 mg, 44%).
[0530] MS-ESI: 548.6 [MH].sup.+
[0531] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95 (m, 2H); 2.40 (m,
9H); 2.62 (m, 4H); 3.12 (q, 2H); 3.97 (s, 3H); 4.22 (t, 2H); 6.22
(s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.36 (s, 1H); 7.58 (s, 1H);
8.47 (s, 1H); 11.29 (br s, 1H)
[0532] The starting material was prepared as follows:
[0533] A mixture of 1-tert-butoxycarbonylpiperazine (1.0 g, 5.37
mmol), 3-bromo-1-propanol (0.49 ml, 5.37 mmol) and potassium
carbonate (1.86 g, 13.4 mmol) was heated at reflux in acetonitrile
(10 ml) for 1.5 hours. The mixture was concentrated under reduced
pressure and column chromatography of the residue, eluting with 2%
methanol/methylene chloride, gave
1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (1.2 g,
91%).
[0534] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.46 (s, 9H); 1.74 (m,
2H); 2.46 (m, 4H); 2.61 (t, 2H); 3.43 (m, 4H); 3.80 (t, 2H)
[0535] Using an analogous procedure to that described for the
preparation of the starting material in Example 11,
1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (432 mg, 1.77
mmol) was reacted with
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(500 mg, 1.47 mmol), (prepared as described for the starting
material in Example 7). The product was purified by column
chromatography, eluting with 2%-5% methanol/methylene chloride to
give tert-butyl
4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ylox-
y)propyl]piperazine-1-carboxylate (582 mg, 70%).
[0536] LC-MS (ESI) 1.67 min, 100%, 566.7 [MH].sup.+
[0537] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.38 (s, 9H); 1.97 (m,
2H); 2.24-2.35 (m, 6H); 2.46 (s, 3H); 3.31 (m, 4H); 3.97 (s, 3H);
4.24 (t, 2H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.37 (s,
1H); 7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
[0538] Using an analogous procedure to that described for the
preparation of the starting material in Example 11, tert-butyl
4-[3-(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ylox-
y)propyl]piperazine-1-carboxylate was reacted with hydrogen
chloride in dioxane. The crude product was absorbed onto an Isolute
SCX column, washing with methanol and eluting with 7N ammonia in
methanol to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpro-
poxy)quinazoline (96%) as a pale orange foam.
[0539] MS-ESI 466.5 [MH].sup.+
[0540] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.96 (m, 2H); 2.30 (m,
4H); 2.40 (m, 5H); 2.69 (m, 4H), 3.97 (s, 3H); 4.23 (t, 2H); 6.22
(s, 1H); 6.96 (t, 1H); 7.13 (d, 1H); 7.37 (1H, s); 7.58 (s, 1H);
8.49 (s, 1H); 11.32 (br s, 1H)
EXAMPLE 16
##STR00068##
[0542] Using an analogous procedure to that described for the
preparation of Example 14, 2,2,2-trifluoroethyl
trifluoromethanesulphonate was reacted with
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(2-piperazin-1-yleth-
oxy)quinazoline. The product was purified by column chromatography,
eluting with 5% methanol/methylene chloride to give a sticky solid.
The sticky solid was dissolved in methanol and absorbed onto an
Isolute SCX column, washed with methanol and eluted with 7N ammonia
in methanol. The product was concentrated from ether to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{3-[4-(2,2,2-trifluo-
roethyl)piperazin-1-yl]ethoxy}quinazoline.
[0543] MS-ESI: 534.2 [MH].sup.+
[0544] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H); 2.55 (m,
4H); 2.63 (m, 4H); 2.79 (t, 2H); 3.13 (q, 2H); 3.97 (s, 3H); 4.29
(t, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.41 (s, 1H);
7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
EXAMPLE 17
##STR00069##
[0546] A mixture of
7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquina-
zoline (150 mg, 0.36 mmol), 1-(2-fluoroethyl)piperazine
di-trifluoroacetic acid salt (240 mg, 0.67 mmol) and
diisopropylethylamine (293 .mu.l, 1.68 mmol) in
N,N-dimethylformamide (3 ml) was stirred overnight at ambient
temperature. The mixture was diluted with ethyl acetate, washed
with brine (.times.2), dried (MgSO.sub.4) and concentrated under
reduced pressure. Column chromatography of the residue, eluting
with 4% methanol/methylene chloride gave
7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-4-[(4-fluoro-2-methyl-1H-in-
dol-5-yl)oxy]-6-methoxyquinazoline (50 mg, 30%).
[0547] MS-ESI: 498.6 [MH].sup.+
[0548] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.42 (s, 3H); 2.64 (t,
1H); 2.81 (t, 2H); 4.00 (s, 3H); 4.32 (t, 2H); 4.47 (t, 1H); 4.59
(t, 1H); 6.25 (s, 1H); 6.99 (t, 1H); 7.17 (d, 1H); 7.44 (s, 1H);
7.61 (s, 1H); 8.50 (s, 1H); 11.32 (br s, 1H)
[0549] The starting material was prepared as follows:
[0550] A suspension of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(530 mg, 1.56 mmol), (prepared as described for the starting
material in Example 7), in methylene chloride (15 ml) was treated
with triphenylphosphine (570 mg, 2.18 mmol), 2-bromoethanol (300
mg, 2.40 mmol) and diisopropyl azodicarboxylate (380 mg, 1.88 mmol)
and the mixture stirred at ambient temperature for 2 hours. The
crude reaction mixture was loaded onto a silica column and eluted
using ethyl acetate as solvent. The relevant fractions were
combined and evaporated under vacuum to give a residue, which was
triturated with ether, filtered and dried. This gave
7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-me-
thoxyquinazoline as a white solid (546 mg, 78%).
[0551] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 3.90 (t,
2H), 3.99 (s, 3H), 4.56 (t, 2H), 6.21 (s, 1H), 6.97 (t, 1H), 7.16
(d, 1H), 7.42 (s, 1H), 7.62 (s, 1H), 8.49 (s, 1H) and 11.29 (s, 1H)
MS (ESI): 446 and 448 (MH).sup.+
[0552] A mixture of 1-(tert-butoxycarbonyl)piperazine (5 g),
1-bromo-2-fluoroethane (5.11 g), potassium carbonate (9.26 g) and
acetonitrile (60 ml) was stirred and heated to 60.degree. C. for 4
hours. The reaction mixture was cooled to ambient temperature and
filtered and the filtrate was evaporated. The residue was purified
by column chromatography on silica using increasingly polar
mixtures of isohexane and ethyl acetate as eluent. There was thus
obtained 4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine as a
solid (3.7 g).
[0553] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D)
1.37 (s, 9H), 2.34-2.4 (m, 4H), 2.56 (t, 1H), 2.67 (t, 1H),
3.25-3.34 (m, 4H), 4.42 (t, 1H), 4.58 (t, 1H)
[0554] Trifluoroacetic acid (20 ml) was added to a mixture of
4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine (3.7 g),
triethylsilane (8 ml) and methylene chloride (100 ml) and the
resultant mixture was stirred at ambient temperature for 1.5 hours.
The mixture was evaporated and the residue was triturated under
diethyl ether. The solid so obtained was isolated, washed with
diethyl ether and dried to give 1-(2-fluoroethyl)piperazine
trifluoroacetic acid salt (6.0 g) as a solid.
[0555] .sup.1H NMR Spectrum: (DMSOd.sub.6 and CD.sub.3CO.sub.2D)
3.0-3.31 (m, 10H), 4.59 (m, 1H), 4.75 (m, 1H)
EXAMPLE 18
##STR00070##
[0557] A mixture of
7-[2-(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methylindol-5-yloxy)q-
uinazoline (165 mg, 0.38 mmol) and 1-acetylpiperazine (129 mg,
1.01mmol) in N,N-dimethylformamide (4 ml) was stirred overnight at
ambient temperature. The mixture was diluted with ethyl acetate,
washed with brine (.times.2), dried (MgSO.sub.4) and concentrated
under reduced pressure. Column chromatography of the residue,
eluting with 5% 7N ammonia in methanol/methylene chloride gave
7-{2-[2-(4-acetylpiperazin-1-yl)ethoxy]ethoxy}-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline (130 mg, 72%).
[0558] MS-ESI: 538.6 [MH].sup.+
[0559] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.94 (s, 3H); 2.38 (m,
7H); 3.37 (m, 4H); 3.63 (t, 2H); 3.82 (br t, 2H); 3.98 (s, 3H);
4.33 (br t; 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.41 (s,
1H); 7.60 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
[0560] The starting material was prepared as follows:
[0561] Using an analogous procedure to that described for the
preparation of the starting material in Example 11,
2-(2-bromoethoxy)ethanol, (600 mg, 3.54 mmol) (J. Org. Chem., 7697,
58, 1993), was reacted with
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(1.0 g, 2.95 mmol), (prepared as described for the starting
material in Example 7). The crude product was purified by column
chromatography, eluting with methanol/methylene chloride (1/98
followed by 2/98) to give the expected product contaminated by
triphenylphosphine oxide. This was crystallised from methanol to
give
7-[2-(2-bromoethoxy)ethoxy]-6-methoxy-4-(4-fluoro-2-methylindol-5-yloxy)q-
uinazoline (675 mg, 47%).
[0562] MS-ESI: 492.4 [MH].sup.+
[0563] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H); 3.63 (t,
2H); 3.85 (t, 2H); 3.90 (br t, 2H), 3.98 (s, 3H); 4.34 (br t, 2H);
6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.41 (s, 1H); 7.60 (s,
1H); 8.48 (s, 1H); 11.29 (br s, 1H)
EXAMPLE 19
##STR00071##
[0565] Diisopropylethylamine (72 .mu.l, 0.41 mmol) and isobutyryl
chloride (44 mg, 0.41 mmol), in methylene chloride (0.5 ml) were
added to a suspension of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmetho-
xy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the
starting material in Example 11), in methylene chloride (4 ml).
After a few minutes all the material had gone into solution. The
mixture was stirred for 3 hours at ambient temperature, washed with
saturated sodium hydrogen carbonate solution, dried (MgSO.sub.4)
and concentrated under reduced pressure. Column chromatography of
the residue, eluting with 2% methanol/methylene chloride gave
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)m-
ethoxy]-6-methoxyquinazoline (90 mg, 52%).
[0566] MS-ESI: 507.5 [MH].sup.+
[0567] .sup.1H NMR Spectrum: (DMSOd.sub.6) 0.99 (d, 6H); 1.20 (m,
2H); 1.85 (br t, 2H); 2.13 (m, 1H); 2.40 (s, 3H); 2.58 (br t, 1H);
2.87 (m, 1H); 3.07 (br t, 1H); 3.98 (m, 4H); 4.08 (br d, 2H); 4.44
(br d, 1H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.37 (s, 1H);
7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
EXAMPLE 20
##STR00072##
[0569] Using an analogous procedure to that described for the
preparation of Example 19,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-y-
lmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described
for the starting material in Example 12), was reacted with
isobutyryl chloride (45 .mu.l, 0.43 mmol). The product was purified
by column chromatography, eluting with methanol/methylene chloride
(2/98) to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2S)-1-isobutyrylpyrrolidin--
2-yl]methoxy}-6-methoxyquinazoline (95 mg, 54%).
[0570] MS-ESI: 493.2 [MH].sup.+
[0571] .sup.1H NMR Spectrum: (100.degree. C., DMSOd.sub.6) 1.03 (m,
6H); 2.02 (m, 4H); 2.41 (s, 3H); 2.72 (m, 1H); 3.54 (m, 2H); 3.99
(s, 3H); 4.26 (m, 2H); 4.39 (m, 1H); 6.22 (s, 1H); 6.95 (t, 1H);
7.14 (d, 1H), 7.44 (s, 1H); 7.62 (s, 1H); 8.46 (s, 1H); 11.02 (br
s, 1H)
EXAMPLE 21
##STR00073##
[0573] Using an analogous procedure to that described for the
preparation of Example 19,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-y-
lmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described
for the starting material in Example 13), was reacted with
isobutyryl chloride (48 .mu.l, 0.45 mmol). The product was purified
by column chromatography, eluting with methanol/methylene chloride
(2/98) to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2R)-1-isobutyrylpyrrolidin--
2-yl]methoxy}-6-methoxyquinazoline (120 mg, 64%).
[0574] MS-ESI: 493.2 [MH].sup.+
[0575] .sup.1H NMR Spectrum: (100.degree. C., DMSOd.sub.6) 1.03 (m,
6H); 2.02 (m, 4H); 2.41 (s, 3H); 2.72 (m, 1H); 3.54 (m, 2H); 3.99
(s, 3H); 4.26 (m, 2H); 4.39 (m, 1H); 6.22 (s, 1H); 6.95 (t, 1H);
7.14 (d, 1H), 7.44 (s, 1H); 7.62 (s, 1H); 8.46 (s, 1H); 11.02 (br
s, 1H)
EXAMPLE 22
##STR00074##
[0577] Diisopropylethylamine (72 .mu.l, 0.41 mmol) and
methanesulphonyl chloride (32 .mu.l, 0.41 mmol) were added to a
suspension of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmetho-
xy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the
starting material in Example 11), in methylene chloride (4 ml).
After a few minutes all the material had gone into solution. The
mixture was stirred for 3 hours at ambient temperature, washed with
saturated sodium hydrogen carbonate solution, dried (MgSO.sub.4)
and concentrated under reduced pressure. The solid was suspended in
methanol and filtered to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[1-(methylsulf-
onyl)piperidin-4-yl]methoxy}quinazoline (83 mg, 47%).
[0578] MS-ESI: 515.5 [MH].sup.+
[0579] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.41 (m, 2H); 1.95 (m,
3H); 2.40 (s, 3H); 2.77 (br t, 2H); 2.85 (s, 3H); 3.60 (br t, 2H);
3.98 (s, 3H); 4.12 (br d, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d,
1H); 7.39 (s, 1H); 5.59 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
EXAMPLE 23
##STR00075##
[0581] Using an analogous procedure to that described for the
preparation of Example 22,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-y-
lmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described
for the starting material in Example 12), was reacted with
methanesulphonyl chloride (33 .mu.l, 0.43 mmol). The product was
purified by column chromatography, eluting with methanol/methylene
chloride (2/98) to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2S)-1-(methylsulf-
onyl)pyrrolidin-2-yl]methoxy}quinazoline (105 mg, 59%).
[0582] MS-ESI: 501.6 [MH].sup.+
[0583] .sup.1H NMR Spectrum: (100.degree. C., DMSOd.sub.6) 2.02 (m,
4H); 2.41 (s, 3H); 3.38 (br t, 2H); 4.00 (s, 3H); 4.19 (m, 2H);
4.30 (dd, 1H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.40 (s,
1H); 7.64 (s, 1H); 8.47 (s, 1H); 11.02 (br s, 1H)
EXAMPLE 24
##STR00076##
[0585] Using an analogous procedure to that described for the
preparation of Example 22,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-y-
lmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described
for the starting material in Example 13), was reacted with
methanesulphonyl chloride (35 .mu.l, 0.45 mmol). The product was
purified by column chromatography, eluting with methanol/methylene
chloride (2/98) to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-1-(methylsulf-
onyl)pyrrolidin-2-yl]methoxy}quinazoline (108 mg, 57%).
[0586] MS-ESI: 501.6 [MH].sup.+
[0587] .sup.1H NMR Spectrum: (100.degree. C., DMSOd.sub.6) 2.02 (m,
4H); 2.41 (s, 3H); 3.38 (br t, 2H); 4.00 (s, 3H); 4.19 (m, 2H);
4.30 (dd, 1H); 6.22 (s, 1H); 6.96 (t, 1H); 7.14 (d, 1H); 7.40 (s,
1H); 7.64 (s, 1H); 8.47 (s, 1H); 11.02 (br s, 1H)
EXAMPLE 25
##STR00077##
[0589] A mixture of
7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(288 mg, 0.76 mmol), 5-hydroxy-7-azaindole (113 mg, 0.84 mmol),
(prepared as described for the starting material in Example 2), and
potassium carbonate (116 mg, 0.84 mmol) in DMA (8 ml) was stirred
at 85.degree. C. for 3 hours and allowed to cool to ambient
temperature. The mixture was filtered, the filtrate evaporated
under vacuum and the residue purified by column chromatography
eluting with methylene chloride/methanol (saturated with ammonia)
(100/8/1). The volatiles were removed under vacuum to give a white
solid which was triturated with diethyl ether, filtered and dried
to give
7-[3-(4-allylpiperazin-1-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquin-
azoline (280 mg, 77%).
[0590] MS-ESI: 475 [MH].sup.+
[0591] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.14 (m, 2H); 2.53 (m,
8H); 2.59 (t, 2H), 3.03 (d, 2H); 4.07 (s, 3H); 4.29 (t, 2H); 5.20
(m, 2H); 5.89 (m, 1H); 6.55 (m, 1H); 7.35 (s, 1H); 7.40 (m, 1H);
7.61 (s, 1H); 7.86 (d, 1H); 8.30 (d, 1H); 8.60 (s, 1H); 9.68 (s,
1H).
[0592] The starting material was prepared as follows:
[0593] To a suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline
(300 mg, 1.43 mmol), (prepared as described for the starting
material in Example 4), in methylene chloride (15 ml) was added
triphenylphosphine (522 mg, 2.0 mmol),
3-(4-allylpiperazin-1-yl)propan-1-ol (288 mg, 1.57 mmol), (DE
2755707), and diisopropyl azodicarboxylate (336 .mu.l, 1.71 mmol)
and the mixture stirred at ambient temperature for 2 hours. The
crude reaction mixture was loaded directly onto a silica
chromatography column and eluted with methylene chloride/methanol
(95/5). The volatile solvents were removed under vacuum to give
7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazohne
as an oil which crystallised on standing (480 mg, 89%).
[0594] MS-ESI: 377-379 [MH].sup.+
[0595] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.12 (m, 2H); 2.51 (m,
8H); 2.57 (t, 2H); 3.01 (d, 2H); 4.05 (s, 3H); 4.27 (t, 2H); 5.16
(m, 2H); 5.87 (m, 1H); 7.34 (s, 1H); 7.38 (s, 1H); 8.85 (s, 1H)
EXAMPLE 26
##STR00078##
[0597] 1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and
potassium carbonate (258 mg, 1.87 mmol) were added to a solution of
7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazol-
ine (144 mg, 0.31 mmol), (prepared as described for the starting
material in Example 7), in DMA (3.6 ml). The reaction mixture was
stirred at 85.degree. C. overnight before being filtered. The
filtrate was concentrated under vacuum and the crude product was
purified by column chromatography eluting with increasingly polar
mixtures of ammonia/methanol in methylene chloride (1 to 7%). A
second purification by column chromatography eluting with a mixture
of methanol in methylene chloride (1/9) gave
4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-{3-[4-(2-propynyl)pipera-
zin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).
[0598] MS-ESI: 504 [MH].sup.+
[0599] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.96 (m, 2H); 2.39 (s,
3H); 2.42 (m, 2H); 2.45 (m, 4H); 3.09 (t, 1H); 3.22 (d, 2H); 3.28
(m, 4H); 3.97 (s, 3H); 4.22 (t, 2H); 6.22 (s, 1H); 6.96 (t, 1H);
7.14 (d, 1H); 7.36 (s, 1H); 7.58 (s, 1H); 8.47 (s, 1H); 11.29 (br
s, 1H)
[0600] The starting material was prepared as follows:
[0601] Potassium carbonate (1.04 g, 7.5 mmol) and propargyl bromide
(654 mg, 5.5 mmol) were added to a solution of
tert-butyl-1-piperazinecarboxylate (931 mg, 5.0 mmol) in acetone (5
ml). The reaction mixture was heated at 60.degree. C. for 1 hour,
and then filtered to remove the inorganics. The solvent was removed
under vacuum to give a crude product which was purified by column
chromatography (10-30% ethyl acetate/hexane) yielding
4-propargylpiperazine-1-carboxylic acid tert-butyl ester (894 mg,
80%).
[0602] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.46 (s, 9H); 2.25 (t,
1H); 2.51 (t, 4H); 3.31 (d, 2H); 3.47 (t, 4H)
[0603] Trifluoroacetic acid (5 ml, mmol) was added to a solution of
4-propargylpiperazine-1-carboxylic acid tert-butyl ester (559 mg,
2.5 mmol) in methylene chloride (2 ml). The reaction mixture was
stirred at ambient temperature for 40 minutes before the solvent
was removed under high vacuum. The residue was azeotroped with
ethanol yielding 1-prop-2-yn-1-ylpiperazine di-trifluoroacetic salt
(865 mg, 98%) as a white solid.
[0604] MS-EI 125 [MH].sup.+
[0605] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.91 (t, 4H); 3.20 (t,
4H); 3.45 (t, 1H); 3.64 (d, 2H); 8.88 (br s, 1H)
EXAMPLE 27
##STR00079##
[0607] Diisopropyl azodicarboxylate (230 .mu.l, 1.17 mmol) was
added dropwise to a solution of
3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (203 mg, 1.07 mmol),
triphenylphosphine (357 mg, 1.36 mmol) and
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(330 mg, 0.97 mmol), (prepared as described for the starting
material in Example 7), in dichloromethane (8.5 ml). The reaction
mixture was stirred at ambient temperature for 1.5 hours and then
loaded directly onto a silica column, eluting with a mixture of
methanol in methylene chloride (11/89) to give
7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline (413 mg, 83%) as a white
solid.
[0608] MS-ESI: 512 [MH].sup.+
[0609] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.96 (m, 2H); 2.40 (s,
3H); 2.43 (m, 4H); 2.45 (m, 4H); 2.48 (m, 2H); 2.58 (dt, 2H); 3.97
(s, 3H); 4.23 (t, 2H); 4.50 (dt, 2H); 6.22 (s, 1H); 6.97 (t, 1H);
7.14 (d, 1H); 7.36 (s, 1H); 7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br
s, 1H)
[0610] The starting material was prepared as follows:
[0611] Potassium carbonate (1.85 g, 13.4 mmol) and
1-bromo-2-fluoroethane (440 .mu.l, 5.9 mmol) were added to a
solution of tert-butyl-1-piperazinecarboxylate (1 g, 5.4 mmol) in
acetonitrile (12 ml). The reaction mixture was stirred at
65.degree. C. for 3.5 hours after which time more
1-bromo-2-fluoroethane (160 .mu.l, 2.1 mmol) was added. The
reaction was heated for a further 3 hours then filtered to remove
the inorganic solids. The filtrate was concentrated and the crude
product was purified using column chromatography eluting with ethyl
acetate to give 4-(2-fluoroethyl)-piperazine-1-carboxylic acid
tert-butyl ester (714 mg, 57%).
[0612] MS-ESI: 233 [MH].sup.+
[0613] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.46 (s, 9H); 2.50 (t,
4H); 2.70 (dt, 2H); 3.45 (t, 4H); 4.57 (dt, 2H)
[0614] Trifluoroacetic acid (3 ml, 17.5 mmol) was added to a
solution of 4-(2-fluoroethyl)-piperazine-1-carboxylic acid
tert-butyl ester (350 mg, 1.5 mmol) in methylene chloride (12 ml).
The reaction mixture was stirred at ambient temperature for 40
minutes, before the solvent was evaporated under high vacuum. The
residue was azeotroped with toluene to give
1-(2-fluoroethyl)-piperazine diTFA salt (377 mg, 96%).
[0615] MS-EI: 133 [MH].sup.+
[0616] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.06 (s, 4H); 3.17 (m,
2H); 3.25 (m, 4H); 4.67 (dt, 2H); 9.03 (br s, 1H)
3-Bromopropan-1-ol (581 mg, 4.18 mmol) and potassium carbonate
(2.88 g, 20.9 mmol) were added to a solution of
1-(2-fluoroethyl)-piperazine diTFA salt (1.5 g, 4.18 mmol) in
acetonitrile (11 ml). The reaction mixture was stirred at
85.degree. C. for 4 hours and then loaded directly onto a column
and eluted with a mixture of methanol in methylene chloride (7/93)
to give 3-[4-(2-fluoroethyl)piperazin-1-yl]propan-1-ol (721 mg,
91%).
[0617] MS-EI: 191 [MH].sup.+
[0618] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.72 (m, 2H); 2.58 (m,
8H) 2.62 (m, 2H); 2.73 (t, 2H); 3.79 (t, 2H); 4.55 (dt, 2H)
EXAMPLE 28
##STR00080##
[0620] A mixture of
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline
(12.24 g, 33.5 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.54 g,
33.5 mmol), (prepared as described for the starting material in
Example 1), and potassium carbonate (4.64 g, 33.5 mmol) was heated
in N,N-dimethylacetamide (150 ml) at 85.degree. C. for 4 hours.
4-Fluoro-5-hydroxy-2-methylindole (33 mg, 0.2 mmol) and potassium
carbonate (108 mg, 57%) were added and the mixture heated for a
further 1 hour at 85.degree. C. and then stirred at ambient
temperature overnight. The mixture was filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography eluting with methylene chloride/methanol (95/5) to
give a white solid which was suspended in acetone (150 ml) and
heated at reflux for 1 hour. After cooling the mixture was filtered
and the solid dried in air to give
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline (10 g, 60%) as a white solid.
[0621] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.00 (s, 3H); 2.42 (s,
3H); 2.52 (t, 2H); 2.56 (br t, 2H); 2.85 (t, 2H); 3.45 (m, 4H);
4.00 (s, 3H); 4.35 (t, 2H); 6.25 (s, 1H), 6.99 (t, 1H); 7.17 (d,
1H); 7.45 (s, 1H); 7.62 (s, 1H); 8.51 (s, 1H); 11.32 (br s, 1H)
[0622] MS-ESI: 494.3 [M+H].sup.+
[0623] The starting material was prepared as follows
[0624] A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (222
mg, 1.05 mmol), (prepared as described for the starting material in
Example 4), in methylene chloride (12 ml) was treated with
triphenylphosphine (389 mg, 1.48 mmol),
2-(4-acetylpiperazin-1-yl)ethanol (200 mg, 1.16 mmol) and
diisopropyl azodicarboxylate (255 mg, 1.26 mmol) and the mixture
stirred at ambient temperature for 2.5 hours. The crude reaction
mixture was loaded onto a silica column and eluted using methylene
chloride/methanol (saturated with ammonia) (92/8). The relevant
fractions were combined and evaporated under vacuum to give a
residue, which was triturated with acetone, filtered and dried.
This gave
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline
as a white solid (240 mg, 62%).
[0625] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.97 (s, 3H), 2.50 (m,
4H), 2.82 (t, 2H), 3.41 (m, 4H), 3.98 (s, 3H), 4.32 (t, 2H), 7.38
(s, 1H), 7.48 (s, 1H), 8.85 (s, 1H)
[0626] MS-ESI: 365 (MH).sup.+
[0627] Alternatively
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline may be prepared as follows:
##STR00081##
[0628] A mixture of
7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquina-
zoline (310 mg of a sample containing triphenylphosphine oxide
(approx. 12% w/w), 0.61 mmol) and 1-acetylpiperazine (258 mg, 2.02
mmol) in N,N-dimethylformamide (5 ml) was stirred at ambient
temperature overnight and then concentrated under reduced pressure.
The residue was purified by column chromatography eluting with
methylene chloride/methanol (95/5) to give
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol--
5-yl)oxy]-6-methoxyquinazoline (202 mg, 67%) as a white solid.
[0629] MS and NMR details are given hereinbefore.
[0630] The starting material was prepared as follows:
[0631] A suspension of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(530 mg, 1.56 mmol), (prepared as described for the starting
material in Example 7), in methylene chloride (15 ml) was treated
with triphenylphosphine (570 mg, 2.18 mmol), 2-bromoethanol (300
mg, 2.40 mmol) and diisopropyl azodicarboxylate (380 mg, 1.88 mmol)
and the mixture stirred at ambient temperature for 2 hours. The
crude reaction mixture was loaded onto a silica column and eluted
using ethyl acetate as solvent. The relevant fractions were
combined and evaporated under vacuum to give a residue, which was
triturated with ether, filtered and dried. This gave
7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-me-
thoxyquinazoline as a white solid (546 mg, 78%).
[0632] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 3.90 (t,
2H), 3.99 (s, 3H), 4.56 (t, 2H), 6.21 (s, 1H), 6.97 (t, 1H), 7.16
(d, 1H), 7.42 (s, 1H), 7.62 (s, 1H), 8.49 (s, 1H), 11.29 (s,
1H)
[0633] MS (ESI): 446 and 448 (MH).sup.+
[0634] Alternatively
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline may be prepared as follows:
##STR00082##
[0635]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazo-
line (300 mg, 0.88 mmol), (prepared as described for the starting
material in Example 7), 2-(4-acetylpiperazin-1-yl)ethanol (183 mg,
1.06 mmol) and triphenylphosphine (278 mg, 1.06 mmol) were stirred
together in dichloromethane (10 ml) and the mixture cooled in an
ice/water bath. Diisopropyl azodicarboxylate (209 .mu.l, 1.06 mmol)
was added and the mixture stirred for 1.5 hours. A further one mole
equivalent of 2-(4-acetylpiperazin-1-yl)ethanol (172 mg, 1 mmol),
triphenylphosphine (262 mg, 1 mmol) and diisopropyl
azodicarboxylate (197 .mu.l, 1 mmol) were added and the mixture
stirred for a further 1 hour. The volatiles were removed under
vacuum and the residue was purified by column chromatography
eluting with methylene chloride/methanol (95/5) to give a crude
solid that was further purified by preparative HPLC to give
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline (75 mg, 17%).
[0636] MS and NMR details are given hereinbefore.
[0637] The starting material was prepared as follows:
[0638] A mixture of 1-acetylpiperazine (2.5 g, 19.5 mmol),
2-bromoethanol (1.38 ml, 19.5 mmol) and potassium carbonate (6.7 g,
48.8 mmol) in acetonitrile (30 ml) was heated at reflux for 3
hours. The mixture was cooled, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
eluting with methylene chloride/methanol (9/1) to give
2-(4-acetylpiperazin-1-yl)ethanol (1.89 g, 56%) as a colourless
oil.
[0639] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.09 (s, 3H); 2.50 (m,
4H); 2.57 (t, 2H); 3.48 (t, 2H); 3.63 (m, 4H)
[0640] Alternatively
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline may be prepared as follows:
[0641] A mixture of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline
(250 mg, 0.74 mmol), 1-acetyl-4-(2-chloroethyl)piperazine (144 mg,
0.81mmol) and potassium carbonate (112 mg, 0.81 mmol) in
N-methylpyrrolidinone (6 ml) was heated at 90.degree. C. for 2
hours. The mixture was cooled and water added. After 30 minutes the
solid was filtered off and dried under vacuum. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (96/4) to give
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)-
oxy]-6-methoxyquinazoline (310 mg, 58%) as a white solid.
[0642] MS and NMR details are given hereinbefore.
[0643] The starting material was prepared as follows:
[0644] 2-(4-Acetylpiperazin-1-yl)ethanol (500 mg, 2.90 mmol),
(prepared as described for the starting material in this example
hereinbefore), was dissolved in methylene chloride (10 ml) and
triethylamine (445 .mu.l, 3.19 mmol) and 4-toluenesulphonyl
chloride (609 mg, 3.19 mmol) were added and the mixture was stirred
at ambient temperature overnight. The mixture was washed with
brine, dried (MgSO.sub.4) and concentrated under reduced pressure.
The residue was purified by column chromatography eluting with
methylene chloride/methanol (98/2) to give
1-acetyl-4-(2-chloroethyl)piperazine (300 mg, 54%) as an oil.
[0645] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.08 (s, 3H); 2.48 (br t,
2H); 2.52 (br t, 2H); 2.75 (t, 2H); 3.48 (br t, 2H); 3.59 (t, 2H);
3.63 (br t, 2H)
EXAMPLE 29
##STR00083##
[0647] A mixture of
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(235 mg, 0.62 mmol), (prepared as described for the starting
material in Example 7), 5-hydroxyindazole (100 mg, 0.75 mmol) and
cesium carbonate (303 mg, 0.93 mmol) in acetone (15 ml) was heated
at reflux for 1.25 hours. The mixture was cooled, filtered and the
filtrate concentrated under reduced pressure. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (96/4). The residue was
further purified by preparative HPLC to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indazol-5-yloxy)-6-methoxyqui-
nazoline (127 mg, 43%) as a white foam.
[0648] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (m, 5H); 2.33 (m,
2H); 2.39 (m, 2H); 2.48 (t, 2H); 3.42 (m, 4H); 3.97 (s, 3H); 4.24
(t, 2H); 7.26 (dd, 1H); 7.36 (s, 1H); 7.60 (m, 2H); 7.65 (d, 1H);
8.07 (s, 1H); 8.48 (s, 1H); 13.15 (br s, 1H)
[0649] MS-ESI: 477.6 [M+H].sup.+
[0650] The starting material was prepared as follows:
[0651] 5-Methoxyindazole (1.7 g, 11.5 mmol), (Tetrahedron, 1994,
50, 3529), was dissolved in methylene chloride (35 ml) and cooled
in an ice/water bath. Boron tribromide (57.4 ml of a 1M solution in
methylene chloride, 57.4 mmol) was added over 10 minutes and then
the mixture allowed to warm to ambient temperature. The mixture was
stirred for 2 hours and then re-cooled in an ice/water bath. 2N
Sodium hydroxide was slowly added until pH8. The precipitated solid
was filtered off and dried under vacuum at 60.degree. C. overnight.
The residue was purified by column chromatography eluting with
methylene chloride/methanol (95/5) to give 5-hydroxyindazole (1.0
g, 65%) as a brown solid.
[0652] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.87 (dd, 1H); 6.95 (d,
1H); 7.32 (d, 1H); 7.81 (s, 1H); 8.99 (s, 1H); 12.69 (s, 1H)
[0653] MS-ESI: 135 [M+H].sup.+
EXAMPLE 30
##STR00084##
[0655] A mixture of
7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200
mg, 0.47 mmol), (WO 00/47212 A1, Example 314), and
1-acetylpiperazine (180 mg, 1.40 mmol) in N,N-dimethylformamide (4
ml) was stirred at ambient temperature for 3 hours. The mixture was
diluted with ethyl acetate and washed with brine (.times.2), dried
(MgSO.sub.4) and concentrated under reduced pressure. Column
chromatography of the residue (5% methanol/dichloromethane) gave
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indol-5-yloxy)-6-methoxyquina-
zoline (109 mg, 49%) as a white solid.
[0656] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.97 (m, 5H); 2.32 (m,
2H); 2.39 (m, 2H); 2.48 (t, 2H); 3.42 (m, 4H); 3.97 (s, 3H); 4.24
(t, 2H); 6.43 (s, 1H); 6.96 (dd, 1H); 7.35 (s, 1H); 7.42 (m, 3H);
7.58 (s, 1H); 8.46 (s, 1H); 11.17 (br s, 1H)
[0657] MS-ESI: 476.6 [MH].sup.+
EXAMPLE 31
##STR00085##
[0659]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolid-
in-2-ylmethoxy]quinazoline (60 mg, 0.14 mmol), (prepared as
described for the starting material in Example 12), was dissolved
in pyridine (3 .mu.l) and cooled to 0.degree. C. Trichloroacetyl
isocyanate (17 .mu.l, 0.14 mmol) was added and the mixture stirred
for 2 hours. The solvent was removed under reduced pressure and the
residue dissolved in 7N ammonia in methanol and stirred at ambient
temperature overnight and then at 50.degree. C. for 2 hours. The
solvent was removed under reduced pressure. Column chromatography
of the residue (2% to 5% methanol/dichloromethane) gave
7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-
-5-yl)oxy]-6-methoxyquinazoline (40 mg, 69%) as a yellow solid.
[0660] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.80-2.50 (m, 4H); 2.40
(s, 3H); 3.25 (m, 2H); 3.99 (s, 3H); 4.17 (m, 3H); 5.85 (s, 2H);
6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H); 7.44 (s, 1H); 7.59 (s,
1H); 8.47 (s, 1H); 11.29 (br s, 1H)
[0661] MS-ESI: 466.5 [MH].sup.+
EXAMPLE 32
##STR00086##
[0663]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-
-ylpropoxy)quinazoline (240 mg, 0.52 mmol), (prepared as described
for the starting material in Example 15), was dissolved in pyridine
(5 ml) and cooled to 0.degree. C. Trichloroacetyl isocyanate (61
.mu.l, 0.52 mmol) was added and the mixture stirred at ambient
temperature for 1 hour. The mixture was concentrated under reduced
pressure and the residue dissolved in 7N ammonia in methanol and
stirred at 45.degree. C. for 2.5 hours. Aqueous ammonia (1 ml) was
added and the mixture was stirred at 60.degree. C. for 1.5 hours
and then at ambient temperature overnight. The solvent was removed
under reduced pressure. Column chromatography of the residue using
methylne chloride/methanol (90/10) followed by methylene
chloride/methanol (saturated with ammonia) (90/10) gave a solid
which was suspended in methanol and filtered to give
7-{3-[4-carbamoylpiperazin-1-yl]propoxy}-4-[(4-fluoro-2-methyl-1H-indol-5-
-yl)oxy]-6-methoxyquinazoline (120 mg, 46%) as a pale yellow
solid.
[0664] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (m, 2H); 2.32 (m,
4H); 2.40 (s, 3H); 2.48 (t, 2H); 3.28 (m, 4H); 3.97 (s, 3H); 4.24
(t, 2H); 5.88 (s, 2H); 6.22 (s, 1H); 6.97 (t, 1H); 7.14 (d, 1H);
7.37 (s, 1H); 7.58 (s, 1H); 8.48 (s, 1H); 11.29 (br s, 1H)
[0665] MS-ESI: 509.6 [MH].sup.+
EXAMPLE 33
##STR00087##
[0667] A mixture of
6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline
(235 mg, 0.62 mmol), 5-hydroxyindazole (100 mg, 0.75 mmol),
(prepared as described for the starting material in Example 29),
and cesium carbonate (303 mg, 0.93 mmol) in acetone (20 ml) was
heated at reflux for 2 hours. The mixture was filtered and the
filtrate concentrated under reduced pressure. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (95/5) to give
6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indazol-5-yloxy)-7-methoxyqui-
nazoline (200 mg, 68%) as a pale green solid.
[0668] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95 (s, 3H); 2.00 (m,
2H); 2.34 (br t, 2H); 2.41 (br t, 2H); 2.4 (t, 2H); 2.5 (m, 2H);
3.42 (m, 4H); 4.01 (s, 3H); 4.25 (t, 2H); 7.29 (dd, 1H); 7.39 (s,
1H); 7.63 (m, 2H); 7.68 (d, 1H); 8.09 (s, 1H); 8.51 (s, 1H); 13.18
(br s, 1H)
[0669] MS-ESI: 477.6 [MH].sup.+
[0670] The starting material was prepared as follows:
[0671] 6-Acetoxy-4-chloro-7-methoxyquinazoline (10.0 g, 39.6 mmol),
(WO 01/04102, Table VI examples), was added in portions to a
stirred 7N methanolic ammonia solution (220 ml) and the mixture
cooled to 10.degree. C. in an ice/water bath. Initially the solid
dissolved to give a yellow solution which then deposited a yellow
precipitate. After stirring for one hour the precipitate was
filtered off, washed with diethyl ether and dried thoroughly under
high vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65
g, 67.8%).
[0672] .sup.1H NMR Spectrum: (DMSOd.sub.6) 3.96 (s, 3H); 7.25 (s,
1H); 7.31 (s, 1H); 8.68 (s, 1H)
[0673] MS-ESI: 211 [M+H].sup.+
[0674] Diethyl azodicarboxylate (991 mg, 5.7 mmol) was added
dropwise to a solution of 4-chloro-6-hydroxy-7-methoxyquinazoline
(1 g, 4.75 mmol), 3-(4-acetylpiperazin-1-yl)propan-1-ol (972 mg,
5.22 mmol), (prepared as described for the starting material in
Example 1 or Example 7), and triphenylphosphine (1.74 g, 6.65 mmol)
in methylene chloride (25 ml). The mixture was stirred at ambient
temperature for 2 hours. The solution was poured onto silica and
eluted with methylene chloride, followed by methylene
chloride/methanol (97/3 followed by 92/8). The fractions containing
the expected product were combined and evaporated to give
6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline
(1.3 g, 72%). NMR Spectrum: (DMSOd.sub.6) 2.0 (s, 3H), 2.05 (m,
2H), 2.35 (m, 2H), 2.4 (m, 2H), 2.5 (m, 2H), 2.45 (m, 4H), 4.02 (s,
3H), 4.2 (m, 2H), 7.4 (s, 1H), 7.5 (s, 1H), 8.9 (s, 1H)
[0675] MS-ESI: 379 [M+H]+
EXAMPLE 34
##STR00088##
[0677]
4-(7-Azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazo-
line (200 mg, 0.46 mmol) was dissolved in pyridine (5 ml) and
cooled to 0.degree. C. Trichloroacetyl isocyanate (551, 0.46 mmol)
was added and the mixture stirred at ambient temperature for 3
hours. The mixture was concentrated under reduced pressure and the
residue dissolved in 7N ammonia in methanol and stirred at ambient
temperature for 20 hours. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
eluting with methylene chloride/methanol (90/10) to give
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-carbamoylpiperazin-1-yl)-
propoxy]quinazoline (95 mg, 43%) as a white solid.
[0678] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.01 (m, 2H); 2.35 (br
t, 4H); 2.48 (t, 2H); 3.3 (m, 4H); 4.01 (s, 3H); 4.27 (t, 2H); 5.91
(s, 2H); 6.50 (dd, 1H); 7.40 (s, 1H); 7.57 (t, 1H); 7.64 (s, 1H);
7.93 (d, 1H); 8.20 (d, 1H); 8.51 (s, 1H); 11.78 (br s, 1H)
[0679] MS-ESI: 478.6 [MH].sup.+
[0680] The starting material was prepared as follows
[0681] 4-Chloro-7-hydroxy-6-methoxyquinazoline (1.7 g, 0.08 mmol),
(prepared as described for the starting material in Example 4),
tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (2.17 g,
8.89 mmol), (prepared as described for the starting material in
Example 15), and triphenylphosphine (2.97 g, 11.3 mmol) were added
to dichloromethane (42.5 ml). Diisopropyl azodicarboxylate (1.91
mw, 9.70 mmol) was added and the reaction mixture stirred at
ambient temperature for 1.5 hours and then concentrated under
reduced pressure. The residue was purified by column chromatography
eluting with methylene chloride/methanol (95/5 followed by 92/8) to
give the product containing a single impurity. A second column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (96/4) gave tert-butyl
4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxyl-
ate (3.0 g, 99%) as a white solid.
[0682] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.46 (s, 9H); 2.12 (m,
2H); 2.42 (t, 4H); 2.57 (t, 2H); 3.44 (t, 4H); 4.05 (s, 3H); 4.29
(t, 2H); 7.35 (s, 1H); 7.38 (s, 1H); 8.85 (s, 1H)
[0683] MS-ESI: 437.1, 439.0 [MH].sup.+
[0684] tert-Butyl
4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxyl-
ate (2.0 g, 4.42 mmol) was dissolved in N,N-dimethylacetamide (60
ml) and 5-hydroxy-7-azaindole (651 mg, 4.86 mmol), (prepared as
described for the starting material in Example 2), and potassium
carbonate (671 mg, 4.86 mmol) added. The reaction mixture was
heated at 85.degree. C. for 3 hours. The mixture was cooled,
filtered and concentrated under reduced pressure. Column
chromatography of the residue (8-10% methanol/dichloromethane) gave
4-(7-azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]propox-
y}-6-methoxyquinazoline (2.0 g, 85%) as a white solid.
[0685] .sup.1H NMR Spectrum: (CDCl.sub.3) 1.47 (s, 9H); 2.14 (m,
2H); 2.44 (t, 4H); 2.59 (t, 2H); 3.45 (t, 4H); 4.07 (s, 3H); 4.29
(t, 2H); 6.55 (m, 1H); 7.36 (s, 1H); 7.41 (m, 1H); 7.61 (s, 1H);
7.86 (d, 1H); 8.30 (d, 1H); 8.61 (s, 1H); 9.80 (br s, 1H)
[0686] MS-ESI: 535.0 [MH].sup.+
[0687]
4-(7-Azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-
propoxy}-6-methoxyquinazoline (1.9 g, 3.55 mmol) was suspended in
dichloromethane (60 ml) and trifluoroacetic acid (2 ml) added
dropwise. All solid dissolved at this point giving an orange
solution which was stirred for 3 hours at ambient temperature. More
trifluoroacetic acid (4 ml) was added and the mixture stirred
overnight. The mixture was concentrated under reduced pressure and
the residue concentrated from dichloromethane (.times.3) and
toluene to remove trifluoroacetic acid. The residue was dissolved
in methanol, placed on an Isolute SCX column, washed with methanol
and then eluted with 7N ammonia in methanol. The product was then
purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (95/5 followed by 93/7)
to give
4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazol-
ine (660 mg, 43%) as a white foam.
[0688] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.95 (m, 2H); 2.30 (m,
4H); 2.41 (t, 2H); 2.68 (t, 4H); 3.97 (s, 3H), 4.22 (t, 2H); 6.46
(d, 2H); 7.36 (s, 1H); 7.55 (d, 1H); 7.60 (s, 1H); 7.90 (d, 1H);
8.17 (d, 1H); 8.48 (s, 1H); 11.76 (br s, 1H)
[0689] MS-ESI: 435.6 [MH].sup.+
EXAMPLE 35
##STR00089##
[0691] A mixture of
4-chloro-7-[3-(2,5-dioxoimidazolidin-1-yl)propoxy]-6-methoxyquinazoline
(200 mg, 0.57 mmol), 4-fluoro-5-hydroxy-2-methylindole (113 mg,
0.68 mmol), (prepared as described for the starting material in
Example 1), and caesium carbonate (279 mg, 0.86 mmol) in acetone
(15 ml) was heated at reflux for 4 hours. The mixture was cooled,
filtered and the filtrate concentrated under reduced pressure. The
residue was purified by column chromatography eluting with
methylene chloride/methanol (97/3 followed by 95/5) to give
7-{3-[2,5-dioxo-4-(1-hydroxy-1-methylethyl)imidazolidin-1-yl]propoxy}-4-[-
(4-fluoro-2-methyl-1H-indol-5-yloxy]-6-methoxyquinazoline (87 mg,
28%) as a brown foam.
[0692] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.17 (s, 3H); 1.22 (s,
3H); 2.06 (m, 2H); 2.42 (s, 3H); 3.57 (t, 2H); 3.84 (d, 1H); 4.01
(s, 3H); 4.21 (t, 2H); 4.78 (s, 1H); 6.25 (s, 1H); 6.99 (t, 1H);
7.16 (d, 1H); 7.33 (s, 1H); 7.62 (s, 1H); 8.19 (s, 1H); 8.50 (s,
1H); 11.32 (br s, 1H)
[0693] MS-ESI: 538.6 [M+H]+
[0694] The starting material was prepared as follows:
[0695] Imidazolidine-2,4-dione (1.0 g, 9.99 mmol),
3-benzyloxypropan-1-ol (1.9 ml, 12.0 mmol) and triphenylphosphine
(3.1 g, 12.0 mmol) were stirred in methylene chloride (20 ml) and
cooled to 0.degree. C. Diisopropyl azodicarboxylate (2.36 .mu.t,
12.0 mmol) in dichloromethane (5 ml) was slowly added and the
mixture stirred at ambient temperature overnight. The mixture was
washed with water, dried (MgSO.sub.4) and concentrated under
reduced pressure. The residue was purified by column chromatography
eluting with methylene chloride/methanol (98/2) to give
3-(3-benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 53%,
containing 7% w/w triphenylphosphine oxide) as a pale yellow
solid.
[0696] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.76 (m, 2H); 3.40 (m,
4H); 3.83 (d, 2H); 4.41 (s, 2H); 7.31 (m, 5H); 7.94 (br s, 1H)
[0697] 3-(3-Benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 5.26
mmol) was dissolved in methanol (15 ml) and the system purged with
nitrogen. 10% Palladium on carbon (130 mg, 10% by mass) and a few
drops of glacial acetic acid were added and the mixture stirred
under a hydrogen atmosphere (1 atmosphere) for 3 days. The mixture
was filtered and concentrated under reduced pressure. The residue
was purified by column chromatography eluting with methylene
chloride/methanol (98/2 to 95/5) to give
3-(3-hydroxypropyl)imidazolidine-2,4-dione (606 mg, 73%) as a
viscous oil which crystallised on standing.
[0698] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65 (m, 2H); 3.39 (m,
4H); 3.88 (s, 2H); 4.44 (t, 1H), 7.96 (br s, 1H)
[0699] A mixture of 4-chloro-7-hydroxy-6-methoxyquinazoline (665
mg, 3.16 mmol), (prepared as described for the starting material in
Example 4), 3-(3-hydroxypropyl)imidazolidine-2,4-dione (600 mg,
3.79 mmol) and triphenylphosphine in dichloromethane (15 ml) was
stirred and cooled to 0.degree. C. Diisopropyl azodicarboxylate
(747 .mu.l, 3.79 mmol) in dichloromethane (5 ml) was added and the
mixture stirred at ambient temperature for 3 hours. Initially all
material went into solution but later a precipitate formed. The
mixture was concentrated and the solid residue suspended in
methanol, filtered and dried in air to give
4-chloro-7-[3-(2,5-dioxoimidazolidin-1-yl)propoxy]-6-methoxyquinazoline
(765 mg, 69%) as a pale yellow solid.
[0700] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.09 (m, 2H); 3.58 (t,
2H); 3.88 (d, 2H); 4.02 (s, 3H); 4.25 (t, 2H); 7.39 (s, 1H), 7.41
(s, 1H); 7.99 (br s, 1H); 8.87 (s, 1H)
[0701] MS-ESI: 351.5 and 353.5 [MH].sup.+
EXAMPLE 36
##STR00090##
[0703] A mixture of
4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (260
mg, 0.80 mmol), (prepared as described for the starting material in
Example 10), 2-(4-acetylpiperazin-1-yl)ethanol (165 mg, 0.96 mmol),
(prepared as described for the starting material in Example 28),
and triphenylphosphine (252 mg, 0.96 mmol) in dichloromethane (15
ml) was stirred and cooled in an ice/water bath. Diisopropyl
azodicarboxylate (189 .mu.l, 0.96 mmol) was added. The mixture was
stirred for 3 hours and then a further 0.5 mole equivalent of
2-(4-acetylpiperazin-1-yl)ethanol, triphenylphosphine and
diisopropyl azodicarboxylate were added. The mixture was stirred
for a further 1 hour and then concentrated under reduced pressure.
The residue was purified by column chromatography eluting with
methylene chloride/methanol (95/5) to give
6-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-me-
thoxyquinazoline (260 mg, 68%) as a white solid.
[0704] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.98 (s, 3H); 2.45 (m,
2H); 2.55 (m, 2H); 2.83 (t, 2H); 3.43 (m, 4H); 4.00 (s, 3H); 4.33
(t, 2H); 6.55 (s, 1H); 7.09 (t, 1H); 7.30 (d, 1H); 7.41 (s, 1H);
7.48 (t, 1H); 7.70 (s, 1H); 8.51 (s, 1H); 11.52 (br s, 1H)
[0705] MS-ESI: 480.1 [MH].sup.+
EXAMPLE 37
##STR00091##
[0707]
4-[(4-Fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-ylmethoxy)-
quinazoline (210 mg, 0.50 mmol) was suspended in dichloromethane (7
ml) and diisopropylethylamine (104 .mu.l, 0.60 mmol) and acetyl
chloride (42 .mu.l, 0.60 mmol) were added. All solid material went
into solution. The mixture was stirred at ambient temperature
overnight. The mixture was washed with brine, followed by saturated
aqueous sodium hydrogen carbonate, dried (MgSO.sub.4) and
concentrated under reduced pressure. The residue was purified by
column chromatography eluting with methylene chloride/methanol
(98/2) to give
6-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-met-
hoxyquinazoline (146 mg, 63%) as a white foam.
[0708] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.14-1.36 (m, 2H); 1.85
(m, 2H); 2.01 (s, 3H); 2.12 (m, 1H); 2.61 (br t, 1H); 3.09 (br t,
1H); 3.87 (br d, 1H); 4.01 (s, 3H); 4.09 (d, 2H); 4.41 (br d, 1H);
6.55 (s, 1H); 7.09 (t, 1H); 7.30 (d, 1H); 7.41 (s, 1H); 7.47 (t,
1H); 7.63 (s, 1H); 8.51 (s, 1H); 11.49 (br s, 1H)
[0709] MS-ESI: 465.1 [MH].sup.+
[0710] The starting material was prepared as follows:
[0711] A mixture of
4-[(4-fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (250
mg, 0.77 mmol), (prepared as described for the starting material in
Example 10), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate
(199 mg, 0.92 mmol), (prepared as described for the starting
material in Example 11), and triphenylphosphine (242 mg, 0.92 mmol)
in dichloromethane (15 ml) was stirred and cooled to 0.degree. C.
Diisopropyl azodicarboxylate (182 .mu.l, 0.92 mmol) in
dichloromethane (2 ml) was added. The mixture was stirred for 3
hours and then a further 0.5 mole equivalent of tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate, triphenylphosphine and
diisopropyl azodicarboxylate added. The mixture was stirred for 1
hour and then concentrated under reduced pressure. The residue was
purified by column chromatography eluting with ethyl acetate/hexane
(1/1) followed by methylene chloride/methanol (99/1) to give
6-[1-(tert-butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-1H-indol-5--
yl)oxy]-7-methoxyquinazoline (306 mg containing 10% w/w
triphenylphosphine oxide) which was used without further
purification in the next step.
[0712] MS-ESI: 523.1 [MH].sup.+
[0713]
6-[1-(tert-Butoxycarbonyl)piperidin-4-yl]methoxy-4-[(4-fluoro-1H-in-
dol-5-yl)oxy]-7-methoxyquinazoline (306 mg containing 10% w/w
triphenylphosphine oxide) was dissolved in 1,4-dioxane (5 ml) and
4M hydrogen chloride in 1,4-dioxane (5 ml) was added. The mixture
was stirred at ambient temperature for 2.5 hours and then
concentrated under reduced pressure. The residue was dissolved in
methanol and adsorbed onto an Isolute SCX column, washed with
methanol and then eluted with 7N ammonia in methanol to give
4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-ylmethoxy)quinaz-
oline (215 mg, 66% over two steps).
[0714] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.24 (m, 2H); 1.75 (br
d, 2H); 1.93 (m, 1H); 2.98 (br d, 2H); 4.01 (m, 5H); 6.55 (s, 1H);
7.09 (t, 1H), 7.30 (d, 1H); 7.40 (s, 1H); 7.47 (t, 1H), 7.61 (s,
1H); 8.50 (s, 1H); 11.50 (s, 1H)
[0715] MS-ESI: 423.1 [MH].sup.+
EXAMPLE 38
##STR00092##
[0717]
4-[(4-Fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-yloxy)quin-
azoline (215 mg, 0.53 mmol) was suspended in dichloromethane (10
ml) and diisopropylethylamine (110 .mu.l, 0.63 mmol) and acetyl
chloride (45 .mu.l, 0.63 mmol) were added. The mixture was stirred
at ambient temperature for 3 hours. The mixture was washed with
brine, followed by aqueous sodium hydrogen carbonate, dried
(MgSO.sub.4) and concentrated under reduced pressure. The residue
was purified by column chromatography eluting with methylene
chloride/methanol (98/2) to give
6-[(1-acetylpiperidin-4-yl)oxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-
quinazoline (128 mg, 54%) as a white foam.
[0718] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.67 (m, 1H); 1.79 (m,
1H), 2.09 (m, 5H); 3.35 (m, 1H); 3.47 (m, 1H); 3.76 (m, 1H); 3.93
(m, 1H); 4.06 (s, 3H); 5.00 (m, 1H); 6.61 (s, 1H); 7.16 (t, 1H);
7.63 (d, 1H); 7.49 (s, 1H); 7.53 (t, 1H); 7.82 (s, 1H); 8.57 (s,
1H); 11.55 (br s, 1H)
[0719] MS-ESI: 451.1 [MH].sup.+
[0720] The starting material was prepared as follows:
[0721]
4-[(4-Fluoro-1H-indol-5-yl)oxy]-6-hydroxy-7-methoxyquinazoline (700
mg, 2.15 mmol), (prepared as described for the starting material in
Example 10), tert-butyl 4-hydroxypiperidine-1-carboxylate (520 mg,
2.58 mmol) and triphenylphosphine (677 mg, 2.58 mmol) were stirred
in dichloromethane (20 ml) and cooled to 0.degree. C. Diisopropyl
azodicarboxylate (508111, 2.58 mmol) in dichloromethane (3 ml) was
added and the mixture stirred at ambient temperature overnight. The
mixture was filtered and concentrated under reduced pressure. The
residue was purified by column chromatography eluting with ethyl
acetate/isohexane (1/1) followed by methylene chloride/methanol
(99/1) to give
6-[(1-tert-butoxycarbonyl)piperidin-4-yloxy]-4-[(4-fluoro-1H-indol-5-yl)o-
xy]-7-methoxyquinazoline (933 mg containing 35% w/w
triphenylphosphine oxide) which was used directly in the next step
without further purification.
[0722] MS-ESI: 509.2 [MH].sup.+
[0723]
6-[(1-tert-Butoxycarbonyl)piperidin-4-yloxy]-4-[(4-fluoro-1H-indol--
5-yl)oxy]-7-methoxyquinazoline (933 mg containing 35% w/w
triphenylphosphine oxide) was dissolved in 1,4-dioxane (5 ml) and
4M hydrogen chloride in 1,4-dioxane (10 ml) was added. The mixture
was stirred at ambient temperature for 1 hour and then concentrated
under reduced pressure. The residue was dissolved in methanol and
adsorbed onto an Isolute SCX column, washed with methanol and then
eluted with 7N ammonia in methanol to give
4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-yloxy)quinazolin-
e (430 mg, 49% over two steps), approximately 86% pure. Used
without further purification.
[0724] MS-ESI: 409.1 [MH].sup.+
EXAMPLE 39
##STR00093##
[0726]
4-[(4-Fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-yloxy)quin-
azoline (215 mg, 0.53 mmol), (prepared as described for the
starting material in Example 38), was suspended in dichloromethane
(10 ml) and diisopropylethylamine (110 .mu.l, 0.63 mmol) and
methane sulphonyl chloride (49 .mu.l, 0.63 mmol) were added. All
solid material went into solution. The mixture was stirred at
ambient temperature for 3 hours. The mixture was washed with brine,
followed by aqueous sodium hydrogen carbonate, dried (MgSO.sub.4)
and concentrated under reduced pressure. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(98/2) to give
4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-{[1-(methylsulphonyl)piperidi-
n-4-yl]oxy}quinazoline (168 mg, 66%) as a white foam.
[0727] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.85 (m, 2H); 2.12 (m,
2H); 2.91 (s, 3H); 3.19 (m, 2H); 3.43 (m, 2H); 4.02 (s, 3H); 4.87
(m, 1H); 6.55 (s, 1H); 7.10 (t, 1H); 7.30 (d, 1H); 7.44 (s, 1H);
7.47 (t, 1H); 7.76 (s, 1H); 8.52 (s, 1H); 11.49 (s, 1H)
[0728] MS-ESI: 487.1 [MH].sup.+
EXAMPLE 40
##STR00094##
[0730] A stirred solution of
7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquina-
zoline (250 mg, 0.56 mmol), (prepared as described for the starting
material in Example 17), in DMF (2.5 ml) was treated with
N-methylpropargylamine (116 mg, 1.68 mmol) and stirred at ambient
temperature overnight. The solvent was evaporated under vacuum and
the residue purified by column chromatography eluting with
methylene chloride/methanol (saturated with ammonia) (92/8). The
relevant fractions were combined and evaporated under vacuum to
give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{2-[N-methyl-N-(2-pr-
opynyl)amino]ethoxy}quinazoline as a white solid. (165 mg,
68%).
[0731] .sup.1H NMR Spectrum: (DMSOd.sub.6): 2.32 (s, 3H), 2.40 (s,
3H), 2.86 (t, 2H), 3.14 (s, 1H), 3.42 (d, 2H), 3.98 (s, 3H), 4.30
(t, 2H), 6.21 (s, 1H), 6.96 (t, 1H), 7.14 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.50 (s, 1H), and 11.29 (s, 1H)
[0732] MS-ESI: 435 [M+H}.sup.+
EXAMPLE 41
##STR00095##
[0734] A mixture of
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazohne
(224 mg, 0.61 mmol), (prepared as described for the starting
material in Example 28), 5-hydroxy-7-azaindole (91 mg, 0.68 mmol),
(prepared as described for the starting material in Example 2), and
potassium carbonate (94 mg, 0.68 mmol) in DMA (5 ml) was stirred at
85.degree. C. for 2 hours, allowed to cool to ambient temperature
and the solvent evaporated under vacuum. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (95/5) to give a white solid. This was
triturated with acetone, filtered and dried to give
7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquin-
azoline (227 mg, 80%)
[0735] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.03 (s, 3H), 2.57 (m,
4H), 2.91 (t, 2H), 3.43 (t, 2H), 3.59 (t, 2H), 3.99 (s, 3H), 4.29
(t, 2H), 6.48 (m, 1H), 7.27 (s, 1H), 7.33 (t, 1H), 7.55 (s, 1H),
7.78 (d, 1H), 8.22 (d, 1H), 8.54 (s, 1H) and 9.59 (s, 1H)
[0736] MS-ESI: 463 [M+H].sup.+
EXAMPLE 42
##STR00096##
[0738] A mixture of
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(190 mg, 0.50 mmol), (prepared as described for the starting
material in Example 4), 5-hydroxy-2-methylindole (81 mg, 0.55
mmol), (WO 00/47212, Example 48), and potassium carbonate (76 mg,
0.55 mmol) in DMA (6 ml) was stirred at 85.degree. C. for 3 hours,
allowed to cool to ambient temperature and the solvent evaporated
under vacuum. The residue was purified by column chromatography
eluting with methylene chloride/methanol (saturated with ammonia)
(92/8) to give a white solid. This was triturated with a mixture of
ether and acetone, filtered and dried to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-6-methoxy-4-[(2-methyl-1H-indol-5-y-
l)oxy]quinazoline (130 mg, 53%).
[0739] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.02 (s, 3H), 2.09 (m,
2H), 2.39 (s, 3H), 2.41 (m, 4H), 2.54 (t, 2H), 3.40 (m, 2H), 3.57
(m, 2H), 3.98 (s, 3H), 4.22 (t, 2H), 6.17 (s, 1H), 6.90 (dd, 1H),
7.24 (m, 3H), 7.56 (s, 1H), 8.00 (br s, 1H) and 8.52 (s, 1H)
[0740] MS-ESI: 490 [M+H].sup.+
EXAMPLE 43
##STR00097##
[0742] A mixture of
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline
(190 mg, 0.50 mmol), (prepared as described for the starting
material in Example 4), 4-fluoro-5-hydroxyindole (83 mg, 0.55
mmol), (WO 00/47212, Example 242), and potassium carbonate (76 mg,
0.55 mmol) in DMA (6 ml) was stirred at 85.degree. C. for 3 hours,
allowed to cool to ambient temperature and the solvent evaporated
under vacuum. The residue was purified by column chromatography
eluting with methylene chloride/methanol (saturated with ammonia)
(92/8) to give a white solid. This was triturated with acetone,
filtered and dried to give
7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-6-m-
ethoxyquinazoline (75 mg, 30%).
[0743] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.03 (s, 3H), 2.06 (m,
2H), 2.40 (m, 4H), 2.53 (t, 2H), 3.40 (m, 2H), 3.58 (m, 2H), 4.00
(s, 3H), 4.22 (t, 2H), 6.60 (m, 1H), 7.05 (m, 1H), 7.17 (m, 2H),
7.30 (s, 1H), 7.58 (s, 1H), 8.44 (br s, 1H) and 8.56 (s, 1H)
[0744] MS-ESI: 494 [M+H].sup.+
EXAMPLE 44
##STR00098##
[0746] A mixture of
4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline
(87 mg, 0.2 mmol), (prepared as described for the starting material
in Example 34), iodoacetamide (41 mg, 0.22 mmol) and
N,N-diisopropylethylamine (26 mg, 0.22 mmol) in acetonitrile (5 ml)
was stirred at reflux for 1 hour and allowed to cool to ambient
temperature. The crude reaction mixture was loaded onto a silica
column and eluted using methylene chloride/methanol (saturated with
ammonia) (92/8) solvent. The relevant fractions were combined and
evaporated under vacuum to give a residue which was triturated with
acetone, filtered and dried to give
4-(7-azaindol-5-yloxy)-7-[3-(4-carbamoylmethyl)piperazin-1-yl)pro-
poxy]-6-methoxyquinazoline (62 mg, 63%).
[0747] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.07 (m, 2H), 2.51 (m,
10H), 2.96 (s, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 5.57 (br s, 1H),
6.48 (m, 1H), 6.96 (br s, 1H), 7.28 (s, 1H), 7.33 (m, 1H), 7.54 (s,
1H), 7.78 (d, 1H); 8.21 (d, 1H); 8.53 (s, 1H) and 9.37 (s, 1H)
[0748] MS-ESI: 492 [M+H].sup.+
EXAMPLE 45
##STR00099##
[0750] A mixture of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpro-
poxy)quinazoline (370 mg, 0.8 mmol), (prepared as described for the
starting material in Example 15), iodoacetamide (162 mg, 0.88 mmol)
and N,N-diisopropylethylamine (230 mg, 1.80 mmol) in acetonitrile
(10 ml) was stirred at reflux for 1 hour and allowed to cool to
ambient temperature. The solvent was removed under vacuum and the
residue purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (92/8) solvent. The
relevant fractions were combined and evaporated under vacuum to
give a solid which was triturated with acetone, filtered and dried
to give
7-[3-(4-carbamoylmethylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-i-
ndol-5-yl)oxy]-6-methoxyquinazoline (132 mg, 32%).
[0751] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.06 (m, 2H), 2.39 (s,
3H), 2.51 (m, 10H), 2.95 (s, 2H), 3.99 (s, 3H), 4.21 (t, 2H), 5.33
(br s, 1H), 6.28 (m, 1H), 6.93 (m, 2H), 7.03 (d, 1H), 7.27 (s, 1H),
7.56 (s, 1H), 8.05 (br s, 1H), 8.53 (s, 1H)
[0752] MS-ESI: 523 [M+H].sup.+
EXAMPLE 46
##STR00100##
[0754] A solution of
4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazol-
ine (240 mg, 0.63 mmol) in DMA (5 ml) was treated with potassium
carbonate (96 mg, 0.69 mmol) and 5-hydroxy-2-methylindole (102 mg,
0.69 mmol), (WO 00/47212, Example 48), and stirred at 85.degree. C.
for 4 hours. The mixture was cooled and the solvent evaporated
under vacuum to give a residue which was purified by column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (92/8). Evaporation of the relevant fractions gave an
oil which crystallised on trituration with ether to give
7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxy-4-[(2-methyl-1H--
indol-5-yl)oxy]quinazoline (150 mg, 48%).
[0755] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.06 (m, 2H), 2.39 (s,
3H), 2.51 (m, 10H), 2.60 (t, 1H), 2.67 (t, 1H), 3.97 (s, 3H), 4.20
(t, 2H), 4.44 (t, 1H), 4.56 (t, 1H), 6.17 (s, 1H), 6.90 (m, 1H),
7.26 (m, 3H), 7.54 (s, 1H), 7.92 (br s, 1H), 8.53 (s, 1H)
[0756] MS-ESI: 494 [M+H].sup.+
[0757] The starting material was prepared as follows:--
[0758] A suspension of 4-chloro-7-hydroxy-6-methoxyquinazohne (202
mg, 0.96 mmol), (prepared as described for the starting material in
Example 4), in methylene chloride (10 ml) was treated with
triphenylphosphine (352 mg, 1.35 mmol),
3-[4-(2-fluoroethyl)piperazin-1-yl)propan-1-ol (200 mg, 1.06 mmol),
(prepared as described for the starting material in Example 27),
and diisopropyl azodicarboxylate (226 mg, 1.15 mmol) and the
mixture stirred at ambient temperature for 2 hours. The crude
reaction mixture was loaded onto a silica column and eluted using
methylene chloride/methanol (95/5). The relevant fractions were
combined and evaporated under vacuum to give
4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazol-
ine (208 mg, 57%) as a white solid.
[0759] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.12 (t, 2H), 2.57 (m,
10H), 2.66 (t, 1H), 2.75 (t, 1H), 4.05 (s, 3H), 4.28 (t, 2H), 4.49
(t, 1H), 4.65 (t, 1H), 7.35 (s, 1H), 7.38 (s, 1H), 8.85 (s, 1H)
[0760] MS-ESI: 383 [M+H].sup.+
EXAMPLE 47
##STR00101##
[0762] 8-Chloro[1,3]dioxolo[4,5-g]quinazoline (100 mg, 0.48 mmol),
(WO 9749688), was dissolved in dimethylacetamide (2.5 ml).
5-Hydroxy-7-azaindole (71 mg, 0.53 mmol), (prepared as described
for the starting material in Example 2), and potassium carbonate
(73 mg, 0.53 mmol) were added and the mixture heated to 85.degree.
C. for 3 hours. The reaction mixture was cooled, filtered and
concentrated. The resulting residue was purified by column
chromatography eluting with methylene chloride/methanol (91/9) to
yield 4-(7-azaindol-5-yloxy)-6,7-methylenedioxyquinazoline (92 mg,
63%).
[0763] .sup.1H NMR Spectrum: (DMSOd.sub.6) 6.30 (s, 2H), 6.45 (d,
1H), 7.35 (s, 1H), 7.55 (t, 1H), 7.65 (s, 1H), 7.90 (d, 1H), 8.15
(d, 1H), 8.45 (s, 1H), 11.75 (br s, 1H)
[0764] MS-ESI: 307 [M+H]+
EXAMPLE 48
##STR00102##
[0766]
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-
-ylmethoxy]quinazoline (200 mg, 0.5 mmol) was dissolved in
dimethylformamide (2 ml) and added to a solution of
1-prop-2-yn-1-ylpiperazine di-trifluoracetic acid salt (535 mg, 1.5
mmol), (prepared as described for the starting material in Example
26), and potassium carbonate (414 mg, 3 mmol) in dimethylformamide
(3 ml). The reaction was heated to 60.degree. C. and left
overnight. The reaction mixture was cooled, filtered and
concentrated. The resulting residue was purified by column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (94/6) to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{(2R)-2-hydroxy-3-[4-prop-2-yn-
-1-ylpiperazin-1-yl]propoxy}-6-methoxyquinazoline (200 mg,
76%).
[0767] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.35 (s, 3H), 2.40 (m,
10H), 3.05 (t, 1H), 3.20 (d, 2H), 4.00 (s, 3H), 4.05 (m, 2H), 4.20
(m, 1H), 4.90 (d, 1H), 6.20 (s, 1H), 6.95 (dd, 1H), 7.15 (d, 1H),
7.40 (s, 1H), 7.60 (s, 1H), 8.45 (s, 1H), 11.30 (br s, 1H)
[0768] MS-ESI: 520 [M+H]+
[0769] The starting material was prepared as follows:
[0770]
4-(4-Fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline
(339 mg, 1 mmol), (prepared as described for the starting material
in Example 7), was dissolved in dimethylacetamide (5 ml) under
nitrogen. (2R) Glycidyl tosylate (285 mg, 1.25 mmol) and potassium
carbonate (345 mg, 2.5 mmol) were added and the reaction stirred at
ambient temperature for 2.5 hours, then warmed to 40.degree. C. and
left overnight. The solvent was removed under vacuum and the
residue partitioned between water and dichloromethane. The organic
phase was washed with brine and dried (Na.sub.2SO.sub.4). The
residue was purified by column chromatography, eluting with
methylene chloride/methanol (97/3) to give
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmet-
hoxy]quinazoline (339 mg, 85%).
[0771] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.40 (s, 3H), 2.75 (m,
1H), 2.90 (m, 1H), 3.40 (m, 1H), 4.00 (s, 3H), 4.05 (m, 1H), 4.60
(m, 1H), 6.20 (s, 1H), 6.95 (dd, 1H), 7.15 (d, 1H), 7.40 (s, 1H),
7.60 (s, 1H), 8.45 (s, 1H), 11.30 (br s, 1H)
[0772] MS-ESI: 396 [M+H]+.
EXAMPLE 49
##STR00103##
[0774]
4-Chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyqui-
nazoline (172 mg, 0.47 mmol) was dissolved in dimethylacetamide (5
ml). 5-Hydroxy-7-azaindole (69 mg, 0.51 mmol), (prepared as
described for the starting material in Example 2), and potassium
carbonate (71 mg, 0.51 mmol) were added and the mixture heated to
85.degree. C. for 4 hours. The reaction mixture was cooled,
filtered and concentrated. The resulting residue was purified by
column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (94/6). The fractions containing the
expected product were evaporated under vacuum and the residue was
suspended in acetone, filtered and dried under vacuum to give
4-(7-azaindol-5-yloxy)-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-me-
thoxyquinazoline (123 mg, 56%).
[0775] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.60 (m, 4H), 2.65 (m,
4H), 2.75 (t, 2H), 3.00 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 4.50
(t, 1H), 4.65 (t, 1H), 6.55 (d, 1H), 7.35 (s, 1H), 7.40 (t, 1H),
7.60 (s, 1H), 7.85 (d, 1H), 8.30 (d, 1H), 8.60 (s, 1H), 9.70 (br s,
1H)
[0776] MS-ESI: 467 [M+H]+
[0777] The starting material was prepared as follows:
[0778] 1-(2-Fluoroethyl)piperazine diTFA salt (464 mg, 1.29 mmol),
(prepared as described for the starting material in Example 27),
was dissolved in acetonitrile (3.5 ml). Potassium carbonate (889
mg, 6.44 mmol) and 2-bromoethanol (95 .mu.l, 1.34 mmol) were added
and the mixture heated to 85.degree. C. and left overnight. More
bromoethanol (95 .mu.l, 1.34 mmol) was added and the reaction
mixture heated at 85.degree. C. for a further 2 hours. The reaction
mixture was cooled, filtered and concentrated. The residue was
purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (92/8) to give
2-[4-(2-fluoroethyl)piperazin-1-yl]ethanol (151 mg, 66%).
[0779] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.60 (m, 10H), 2.65 (t,
1H), 2.75 (t, 1H), 3.60 (t, 2H), 4.45 (t, 1H), 4.65 (t, 1H)
[0780] MS-ESI: 177 [M+H]+
[0781] 4-Chloro-7-hydroxy-6-methoxyquinazoline (146 mg, 0.69 mmol),
(prepared as described for the starting material in Example 4), was
suspended in dichloromethane (7.5 ml). Triphenylphosphine (254 mg,
0.97 mmol) and 2-[4-(2-fluoroethyl)piperazin-1-yl]ethanol (134 mg,
0.76 mmol) were added. Diisopropyl azodicarboxylate (165 .mu.l,
0.83 mmol) was then added dropwise. The reaction mixture was
stirred for 2.25 hours at ambient temperature and then loaded
directly onto a silica column and eluted with methylene
chloride/methanol (92/8) to give
4-chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoli-
ne (172 mg, 67%).
[0782] .sup.1H NMR Spectrum: (CDCl.sub.3) 2.65 (10H, m), 2.95 (2H,
t), 4.05 (3H, s), 4.30 (2H, t), 4.50 (1H, t), 4.65 (1H, t), 7.30
(1H, s), 7.40 (1H, s), 8.85 (1H, s)
[0783] MS-ESI: 369 and 371 [M+H]+
EXAMPLE 50
##STR00104##
[0785]
4-Chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]qui-
nazoline (300 mg, 0.8 mmol) was dissolved in dimethylacetamide (10
ml). 5-Hydroxy-7-azaindole (118 mg, 0.88 mmol), (prepared as
described for the starting material in Example 2), and potassium
carbonate (122 mg, 0.88 mmol) were added and the mixture heated to
85.degree. C. for 1.5 hours. The reaction mixture was cooled,
filtered and concentrated. The resulting residue was preabsorbed on
silica and eluted with methylene chloride/methanol (saturated with
ammonia) (90/10) to give
4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)pro-
poxy]quinazoline (288 mg, 76%).
[0786] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.95 (m, 2H), 2.45 (m,
10H), 3.10 (t, 1H), 3.25 (d, 2H), 4.00 (s, 3H), 4.20 (t, 2H), 6.45
(d, 1H), 7.35 (s, 1H), 7.55 (t, 1H), 7.60 (s, 1H), 7.90 (d, 1H),
8.20 (d, 1H), 8.50 (s, 1H), 11.75 (br s, 1H)
[0787] MS-ES: 473 (M.sup.+H)+
[0788] The starting material was prepared as follows:
[0789] 1-Prop-2-yn-1-ylpiperazine diTFA salt (704 mg, 2 mmol),
(prepared as described for the starting material in Example 26),
was dissolved in acetonitrile (5 ml). Potassium carbonate (1.38 g,
10 mmol) and 3-bromopropan-1-ol (180 .mu.L, 2 mmol) were added and
the mixture heated to 85.degree. C. for 6.5 hours. The reaction
mixture was cooled, filtered and concentrated to give an oil. This
was triturated with diethyl ether to give a white solid, which was
partitioned between dichloromethane and water. The organic phase
was then dried (MgSO.sub.4) and concentrated to give
3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (286 mg, 79%).
[0790] .sup.1H NMR Spectrum (CDCl.sub.3) 1.70 (m, 2H), 2.25 (t,
1H), 2.60 (m, 10H), 3.25 (d, 2H), 3.80 (t, 2H)
[0791] MS-ESI: 183 [M+H]+
[0792] 4-Chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.42 mmol),
(prepared as described for the starting material in Example 4), was
suspended in dichloromethane (15 ml). Triphenylphosphine (523 mg, 2
mmol) and 3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (267 mg,
1.46 mmol) were added. Diisopropyl azadicarboxylate (340 .mu.l,
1.71 mmol) was then added dropwise. The reaction mixture was
stirred for 1.25 hours at ambient temperature and then loaded
directly onto a silica column, and eluted with methylene
chloride/methanol (90/8 followed by 90/10) to give
4-chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoli-
ne (409 mg, 77%).
[0793] .sup.1H NMR Spectrum: (DMSO-d.sub.6) 1.95 (m, 2H), 2.45 (m,
10H), 3.10 (t, 1H), 3.20 (d, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.35
(s, 1H), 7.40 (s, 1H), 8.80 (s, 1H)
[0794] MS-ESI: 375 and 377 [M+H]+
EXAMPLE 51
##STR00105##
[0796] A mixture of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmet-
hoxy]quinazoline (200 mg, 0.506 mmol), (prepared as described for
the starting material in Example 48), and
1,4-dioxa-8-azaspiro[4.5]decane (195 .mu.l, 1.52 mmol) in DMF (3
ml) was stirred at 70.degree. C. urder argon for 3 hours. The
volatiles were removed under vacuum and the residue was purified by
column chromatography eluting with methylene chloride/methanol
(95/5 followed by 90/10). The fractions containing the expected
product were combined and evaporated to dryness. The residue was
triturated with diethyl ether, filtered and dried under vacuum to
give
7-{(2R)-3-[(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)]-2-hydroxypropoxy}-4-[(4-f-
luoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (190 mg,
70%).
[0797] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.65 (t, 4H); 2.43 (s,
3H); 2.49-2.64 (m, 6H); 3.87 (s, 4H); 4.01 (s, 3H); 4.05 (br s;
1H); 4.13 (dd, 1H); 4.26 (dd, 1H); 4.97 (d, 1H); 6.26 (s, 1H); 7.01
(dd, 1H); 7.18 (d, 1H); 7.44 (s, 1H); 7.63 (s, 1H); 8.52 (s, 1H);
11.31 (s, 1H)
[0798] MS-ESI: 539.5 [M+H]+
EXAMPLE 52
##STR00106##
[0800] Using an analogous procedure to that described for the
preparation of Example 51,
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmet-
hoxy]quinazoline (200 mg, 0.506 mmol), (prepared as described for
the starting material in Example 48), was reacted with
1-acetylpiperazine (195 mg, 1.51 mmol) to give
7-{(2R)-3-[4-acetylpiperazin-1-yl]-2-hydroxypropoxy}-4-[(4-fluoro-2-methy-
l-1H-indol-5-yl)oxy]-6-methoxyquinazoline (175 mg, 66%).
[0801] .sup.1H NMR Spectrum: (DMSOd.sub.6) 2.00 (s, 3H); 2.43 (s,
3H); 2.35-2.60 (m, 6H); 3.40-3.52 (m, 4H); 4.02 (s, 3H); 4.11 (br
s, 1H); 4.15 (dd, 1H); 4.27 (dd, 1H); 5.05 (d, 1H); 6.26 (s, 1H);
7.01 (dd, 1H); 7.18 (d, 1H); 7.46 (s, 1H); 7.63 (s, 1H); 8.52 (s,
1H); 11.36 (s, 1H)
[0802] MS-ESI: 524.5 [M+H]+
EXAMPLE 53
##STR00107##
[0804]
4-[(4-Fluoro-2-methyl-1H-indol)-5-yloxy]-6-methoxy-7-(piperidin-4-y-
lmethoxy)quinazoline (500 mg, 1.15 mmol), (prepared as described
for the starting material in Example 11), N,N-dimethylglycine (142
mg, 1.37 mmol) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (523 mg, 1.37 mmol) were stirred in
N,N-dimethylformamide (4 ml) and N,N-diisopropylethylamine (399
.quadrature.l, 2.29 mmol) was added. The mixture was stirred for 1
hour, diluted with ethyl acetate, washed with brine followed by 2N
aqueous sodium hydroxide. The organic layer was dried (MgSO.sub.4)
and concentrated under reduced pressure. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia) (98/2) to give
7-[1-(N,N-dimethylaminoacetyl)piperidin-4-ylmethoxy]-4-[(4-fluoro-2-methy-
l-1H-indol)-5-yloxy]-6-methoxyquinazoline (455 mg, 76%) as a white
foam.
[0805] MS-ESI: 522.1 [MH].sup.+
[0806] .sup.1H NMR Spectrum: (DMSOd.sub.6) 1.33 (m, 2H); 1.87 (br
d, 2H); 2.22 (m, 7H); 2.44 (s, 3H); 2.65 (br t, 1H); 3.10 (m, 3H);
4.02 (s, 3H); 4.12 (m, 3H); 4.43 (br d, 1H); 6.27 (s, 1H); 7.01 (t,
1H); 7.18 (d, 1H); 7.42 (s, 1H); 7.63 (s, 1H); 8.52 (s, 1H); 11.34
(br s, 1H)
EXAMPLE 54
[0807] 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-00002 (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur
182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste)
2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50
Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)
Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25
Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose
Ph.Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml)
Compound X 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M
Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400
4.5% w/v Water for injection to 100% (f) Injection II 10 mg/ml)
Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium
hydroxide solution 15.0% v/v Water for injection to 100% (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 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.
* * * * *