U.S. patent application number 12/147250 was filed with the patent office on 2008-10-30 for 4-anilino quinazoline derivatives as antiproliferative agents.
This patent application is currently assigned to Astrazeneca AB. Invention is credited to Robert Hugh Bradbury, Laurent Francois Andre Hennequin, Jason Grant Kettle.
Application Number | 20080269487 12/147250 |
Document ID | / |
Family ID | 28678580 |
Filed Date | 2008-10-30 |
United States Patent
Application |
20080269487 |
Kind Code |
A1 |
Bradbury; Robert Hugh ; et
al. |
October 30, 2008 |
4-ANILINO QUINAZOLINE DERIVATIVES AS ANTIPROLIFERATIVE AGENTS
Abstract
The invention concerns quinazoline derivatives of Formula (I)
wherein each of Q.sup.1, Z, R.sup.1 and Q.sup.2 have any of the
meanings defined in the description; processes for their
preparation, pharmaceutical compositions containing them and their
use in the manufacture of a medicament for use as an
antiproliferative agent in the prevention or treatment of tumours
which are sensitive to inhibition of erbB receptor tyrosine
kinases. ##STR00001##
Inventors: |
Bradbury; Robert Hugh;
(Cheshire, GB) ; Hennequin; Laurent Francois Andre;
(Cheshire, GB) ; Kettle; Jason Grant; (Cheshire,
GB) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Astrazeneca AB
|
Family ID: |
28678580 |
Appl. No.: |
12/147250 |
Filed: |
June 26, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10508675 |
Sep 22, 2004 |
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PCT/GB03/01306 |
Mar 26, 2003 |
|
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12147250 |
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Current U.S.
Class: |
544/283 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 43/00 20180101; A61P 35/00 20180101; C07D 403/12 20130101;
A61P 17/06 20180101; A61P 13/08 20180101; A61P 9/10 20180101; C07D
401/12 20130101 |
Class at
Publication: |
544/283 |
International
Class: |
C07D 401/02 20060101
C07D401/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2002 |
GB |
0207323.7 |
Dec 24, 2002 |
GB |
0230086.1 |
Jan 28, 2003 |
GB |
0301916.3 |
Claims
1-22. (canceled)
23.
6-{[1-(carbamoylmethyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilin-
o)-7-methoxyquinazoline and/or a pharmaceutically acceptable salt
thereof.
Description
[0001] The invention concerns certain novel quinazoline
derivatives, or pharmaceutically-acceptable salts thereof, which
possess anti-tumour activity and are accordingly useful in methods
of treatment of the human or animal body. The invention also
concerns processes for the manufacture of said quinazoline
derivatives, to pharmaceutical compositions containing them and to
their use in therapeutic methods, for example in the manufacture of
medicaments for use in the prevention or treatment of solid tumour
disease in a warm-blooded animal such as man.
[0002] Many of the current treatment regimes for diseases resulting
from the abnormal regulation of cellular proliferation such as
psoriasis and cancer, utilise compounds that inhibit DNA synthesis
and cellular proliferation. To date, compounds used in such
treatments are generally toxic to cells however their enhanced
effects on rapidly dividing cells such as tumour cells can be
beneficial. Alternative approaches to these cytotoxic anti-tumour
agents are currently being developed, for example selective
inhibitors of cell signalling pathways. These types of inhibitors
are likely to have the potential to display an enhanced selectivity
of action against tumour cells and so are likely to reduce the
probability of the therapy possessing unwanted side effects.
[0003] Eukaryotic cells are continually responding to many diverse
extracellular signals that enable communication between cells
within an organism. These signals regulate a wide variety of
physical responses in the cell including proliferation,
differentiation, apoptosis and motility. The extracellular signals
take the form of a diverse variety of soluble factors including
growth factors as well as paracrine and endocrine factors. By
binding to specific transmembrane receptors, these ligands
integrate the extracellular signal to the intracellular signalling
pathways, therefore transducing the signal across the plasma
membrane and allowing the individual cell to respond to its
extracellular signals. Many of these signal transduction processes
utilise the reversible process of the phosphorylation of proteins
that are involved in the promotion of these diverse cellular
responses. The phosphorylation status of target proteins is
regulated by specific kinases and phosphatases that are responsible
for the regulation of about one third of all proteins encoded by
the mammalian genome. As phosphorylation is such an important
regulatory mechanism in the signal transduction process, it is
therefore not surprising that aberrations in these intracellular
pathways result in abnormal cell growth and differentiation and so
promote cellular transformation (reviewed in Cohen et al, Curr Opin
Chem. Biol. 1999, 3, 459-465).
[0004] It has been widely shown that a number of these tyrosine
kinases are mutated to constitutively active forms and/or when
over-expressed result in the transformation of a variety of human
cells. These mutated and over-expressed forms of the kinase are
present in a large proportion of human tumours (reviewed in
Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133,
F217-F248). As tyrosine kinases play fundamental roles in the
proliferation and differentiation of a variety of tissues, much
focus has centred on these enzymes in the development of novel
anti-cancer therapies. This family of enzymes is divided into two
groups--receptor and non-receptor tyrosine kinases e.g. EGF
Receptors and the SRC family respectively. From the results of a
large number of studies including the Human Genome Project, about
90 tyrosine kinase have been identified in the human genome, of
this 58 are of the receptor type and 32 are of the non-receptor
type. These can be compartmentalised in to 20 receptor tyrosine
kinase and 10 non-receptor tyrosine kinase sub-families (Robinson
et al, Oncogene, 2000, 19, 5548-5557).
[0005] The receptor tyrosine kinases are of particular importance
in the transmission of mitogenic signals that initiate cellular
replication. These large glycoproteins, which span the plasma
membrane of the cell possess an extracellular binding domain for
their specific ligands (such as Epidermal Growth Factor (EGF) for
the EGF Receptor). Binding of ligand results in the activation of
the receptor's kinase enzymatic activity that is encoded by the
intracellular portion of the receptor. This activity phosphorylates
key tyrosine amino acids in target proteins, resulting in the
transduction of proliferative signals across the plasma membrane of
the cell.
[0006] It is known that the erbB family of receptor tyrosine
kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently
involved in driving the proliferation and survival of tumour cells
(reviewed in Olayioye et al., EMBO J., 2000, 19, 3159). One
mechanism in which this can be accomplished is by overexpression of
the receptor at the protein level, generally as a result of gene
amplification. This has been observed in many common human cancers
(reviewed in Klapper et ah. Adv. Cancer Res., 2000, 77, 25) such as
breast cancer (Sainsbury et al., Brit. J. Cancer. 1988, 58, 458;
Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al. Science,
1989, 244, 707; Klijn et al. Breast Cancer Res. Treat., 1994, 29,
73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol.,
1995, 19, 183), non-small cell lung cancers (NSCLCs) including
adenocarcinomas (Cerny et al., Brit. J. Cancer. 1986, 54, 265;
Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer
Research. 1993, 53, 2379; Brabender et al. Clin. Cancer Res., 2001,
7, 1850) as well as other cancers of the lung (Hendler et al.,
Cancer Cells, 1989, 7, 347; Ohsaki et. al., Oncol. Rep. 2000, 7,
603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al.,
Clin. Cancer Res. 2001, 1, 1957, Zhau et. al., Mol. Carcinog., 3,
254), oesophageal cancer (Mukaida et al., Cancel 1991, 68, 142),
gastrointestinal cancer such as colon, rectal or stomach cancer
(Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al.,
Gastroenterology. 2000, 112, 1103; Ross et al. Cancer Invest. 2001,
19, 554), cancer of the prostate (Visakorpi et al., Histochem. J.
1992, 24, 481; Kumar et al., 2000, 32, 73; Scher et al. J. Natl.
Cancer Inst. 2000, 92, 1866), leukaemia Konaka et al., Cell, 1984,
37, 1035, Martin-Subero et al. Cancer Genet Cytogenet, 2001, 127,
174), ovarian (Hellstrom et al., Cancer Res., 2001, 61, 2420), head
and neck (Shiga et al., Head Neck. 2000, 22, 599) or pancreatic
cancer (Ovotny et al., Neoplasma, 2001, 48, 188). As more human
tumour tissues are tested for expression of the erbB family of
receptor tyrosine kinases it is expected that their widespread
prevalence and importance will be further enhanced in the
future.
[0007] As a consequence of the mis-regulation of one or more of
these receptors, it is widely believed that many tumours become
clinically more aggressive and so correlate with a poorer prognosis
for the patient (Brabender et al., Clin. Cancer Res., 2001, 7,
1850; Ross et al. Cancer Investigation, 2001, 19, 554, Yu et al.,
Bioessays. 2000, 22.7, 673). In addition to these clinical
findings, a wealth of pre-clinical information suggests that the
erbB family of receptor tyrosine kinases are involved in cellular
transformation. This includes the observations that many tumour
cell lines overexpress one or more of the erbB receptors and that
EGFR or erbB2 when transfected into non-tumour cells have the
ability to transform these cells. This tumorigenic potential has
been further verified as transgenic mice that overexpress erbB2
spontaneously develop tumours in the mammary gland. In addition to
this, a number of pre-clinical studies have demonstrated that
anti-proliferative effects can be induced by knocking out one or
more erbB activities by small molecule inhibitors, dominant
negatives or inhibitory antibodies (reviewed in Mendelsohn et al.
Oncogene, 2000, 19, 6550). Thus it has been recognised that
inhibitors of these receptor tyrosine kinases should be of value as
a 50 selective inhibitor of the proliferation of mammalian cancer
cells (Yaish et al. Science, 1988, 242, 933, Kolibaba et al,
Biochimica et Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi et
al, 2000, Oncogene, 9, 5690-5701; Mendelsohn et al, 2000, Oncogene,
19, 6550-6565). In addition to this pre-clinical data, findings
using inhibitory antibodies against EGFR and erbB2 (c-225 and
trastuzumab respectively) have proven to be beneficial in the
clinic for the treatment of selected solid tumours (reviewed in
Mendelsohn et al., 2000, Oncogene, 19, 6550-6565).
[0008] Amplification and/or activity of members of the erbB type
receptor tyrosine kinases have been detected and so have been
implicated to play a role in a number of non-malignant
proliferative disorders such as psoriasis (Ben-Bassat, Curr. Pharm.
Des., 2000, 6, 933; Elder et al., Science, 1989, 243, 811), benign
prostatic hyperplasia (BPH) (Kumar et al. Int. Urol. Nephrol. 2000,
32, 73), atherosclerosis and restenosis (Bokemeyer et al. Kidney
Int., 2000, 58, 549). It is therefore expected that inhibitors of
erbB type receptor tyrosine kinases will be useful in the treatment
of these and other non-malignant disorders of excessive cellular
proliferation.
[0009] European patent application EP 566 226 discloses certain
4-anilinoquinazolines that are receptor tyrosine kinase
inhibitors.
[0010] International patent applications WO 96/33977, WO 96/33978,
WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994
disclose that certain quinazoline derivatives which bear an anilino
substituent at the 4-position and a substituent at the 6- and/or
7-position possess receptor tyrosine kinase inhibitory
activity.
[0011] European patent application EP 837 063 discloses aryl
substituted 4-aminoquinazoline derivatives carrying moiety
containing an aryl or heteroaryl group at the 6- or 7-position on
the quinazoline ring. The compounds are stated to be useful for
treating hyperproliferative disorders.
[0012] International patent applications WO 97/30035 and WO
98/13354 disclose certain 4-anilinoquinazolines substituted at the
7-position are vascular endothelial-growth factor receptor tyrosine
kinase inhibitors,
[0013] WO 00/55141 discloses 6,7-substituted 4-aminoquinazoline
compounds characterised in that the substituents at the 6- and/or
7-position carry an ester linked moiety (RO-CO).
[0014] WO 00/56720 discloses 6,7-dialkoxy-4-anilinoquinazoline
compounds for the treatment of cancer or allergic reactions.
[0015] WO 02/41882 discloses 4-anilinoquinazoline compounds
substituted at the 6- and/or 7-position by a substituted
pyrrolidinyl-alkoxy or piperidinyl-alkoxy group.
[0016] None of the prior art discloses
4-(2,3-dihalogenoanilino)quinazoline compounds.
[0017] We have now surprisingly found that certain
4-(2,3-dihalogenoanilino)quinazoline derivatives possess potent
anti-tumour activity. Without wishing to imply that the compounds
disclosed in the present invention possess pharmacological activity
only by virtue of an effect on a single biological process, it is
believed that the compounds provide an anti-tumour effect by way of
inhibition of one or more of the erbB family of receptor tyrosine
kinases that are involved in the signal transduction steps which
lead to the proliferation of tumour cells. In particular, it is
believed that the compounds of the present invention provide an
anti-tumour effect by way of inhibition of EGFR and/or erbB2
receptor tyrosine kinases.
[0018] Generally the compounds of the present invention possess
potent inhibitory activity against the erbB receptor tyrosine
kinase family, for example by inhibition of EGFR and/or erbB2
and/or erbB4 receptor tyrosine kinases, whilst possessing less
potent inhibitory activity against other kinases. Furthermore,
certain compounds of the present invention possess substantially
better potency against the EGFR over that of the erbB2 tyrosine
kinase. The invention also includes compounds that are active
against all or a combination of EGFR, erbB2 and erbB4 receptor
tyrosine kinases, thus potentially providing treatments for
conditions mediated by one or more of these receptor tyrosine
kinases.
[0019] Generally the compounds of the present invention exhibit
favourable physical properties such as a high solubility whilst
retaining high antiproliferative activity. Furthermore, many of the
compounds according to the present invention are inactive or only
weakly active in a hERG assay.
[0020] According to a first aspect of the invention there is
provided a quinazoline derivative of the Formula I:
##STR00002##
wherein: G.sup.1 and G.sup.2 each independently is halogeno;
X.sup.1 is a direct bond or O; R.sup.1 is selected from hydrogen
and (1-6C)alkyl, wherein the (1-6C)alkyl group is optionally
substituted by one or more substituents, which may be the same or
different, selected from hydroxy and halogeno, and/or a substituent
selected from amino, nitro, carboxy, cyano, halogeno, (1-6C)alkoxy,
hydroxy(1-6C)alkoxy, (2-6C)alkenyl, (2-8C)alkynyl,
<1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, carbamoyl,
N-(1-6C)alkylcarbamoyl, N,N di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, <2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, H, N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino and
N-(1-6C)alkyl-(1-6C)alkanesulfonylamino; X.sup.2 is a direct bond
or [CR.sup.2R.sup.3].sub.m, wherein m is an integer from 1 to 6,
and each of R.sup.2 and R.sup.3 independently is selected from
hydrogen, hydroxy, (1-4C)alkyl and hydroxy(1-4C)alkyl; Q.sup.1 is
(3-7C)cycloalkyl or heterocyclyl, wherein Q.sup.1 optionally bears
1, 2 or 3 substituents, which may be the same or different,
selected from halogeno, trifluoromethyl, trifluoromethoxy, cyano,
nitro, hydroxy, amino, carboxy, carbamoyl, acryloyl, (1-6C)alkyl,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (2-6C)alkenylthio,
(2-6C)alkynylthio, (1-6C)alkylsulfinyl, (2-6C)alkenylsulfinyl,
(2-6C)alkynylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl,
(2-6C)alkenylsulfonyl, (1-6C)alkylamino, di-[(2-6C)alkyl]amino,
(1-6C)alkoxycarbonyl; N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl, or from a group of the
formula:
Q.sup.2-X.sup.3
wherein X.sup.3 is CO and Q.sup.2 is heterocyclyl,
[0021] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from halogeno,
hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0022] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno, hydroxy and (1-6C)alkyl and/or
optionally a substituent selected from cyano, nitro, carboxy,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy,
(1-4C)alkoxy(1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,
hydroxy(1-4C)alkoxy and (1-2C)alkoxy(1-4C)alkoxy,
[0023] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from halogeno,
hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally
bear on any available ring nitrogen a substituent (provided the
ring is not thereby quaternised) selected from (1-4C)alkyl,
(2-4C)alkanoyl and (1-4C)alkylsulfonyl, and wherein any (1-4C)alkyl
or (2-4C)alkanoyl group present as a substituent on the ring formed
by R.sup.a and R.sup.b together with the nitrogen atom to which
they are attached, optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
(1-4C)alkyl and (1-4C)alkoxy;
[0024] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears 1 or 2 oxo (.dbd.O) or
thioxo (.dbd.S) substituents;
or a pharmaceutically acceptable salt thereof.
[0025] According to a further aspect of the present invention there
is provided a quinazoline derivative of the Formula I wherein each
of R.sup.1, G.sup.1, G.sup.2, X.sup.5 and X.sup.2 has any of the
meanings defined hereinbefore; and
Q.sup.1 is (3-7C)cycloalkyl or heterocyclyl, wherein Q.sup.1
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6)alkylthio,
(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (2-6C)alkenylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl, (2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl, or from a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is heterocyclyl,
[0026] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from (1-4C)alkyl,
(2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0027] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno, hydroxy and (1-6C)alkyl and/or
optionally a substituent selected from cyano, nitro, carboxy,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy,
(2-6C)alkanoyl, (2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein
R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is hydrogen or
(1-4C)alkyl,
[0028] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from
(1-4C)alkyl, and may optionally bear on any available ring nitrogen
a substituent (provided the ring is not thereby quaternised)
selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl;
[0029] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears 1 or 2 oxo (.dbd.O) or
thioxo (.dbd.S) substituents;
or a pharmaceutically acceptable salt thereof.
[0030] According to a further aspect of the present invention there
is provided a quinazoline derivative of the Formula I wherein each
of R.sup.3, G.sup.1, G.sup.2, X.sup.1 and X.sup.2 has any of the
meanings defined hereinbefore; and
[0031] Q.sup.1 is (3-7C)cycloalkyl or heterocyclyl, wherein Q.sup.1
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
(1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,
(1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl,
[0032] wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-6C)alkynyl and
(2-6C)alkanoyl group within Q.sup.1 optionally bears one or more
substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno, hydroxy and (1-6C)alkyl and/or
optionally a substituent selected from cyano, nitro, carboxy,
(2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy and
NR.sup.aR.sup.b wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl,
[0033] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring;
[0034] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2 group optionally bears 1 or 2oxo (.dbd.O) or thioxo
(.dbd.S) substituents;
or a pharmaceutically acceptable salt thereof.
[0035] According to a further aspect of the present invention there
is provided a quinazoline derivative of the Formula I wherein each
of R.sup.1, G.sup.1, G.sup.2, X.sup.1 and X.sup.2 has any of the
meanings defined hereinbefore; and
Q.sup.1 is a non-aromatic saturated or partially saturated 3 to 7
(for example 4, 5 or 6) membered monocyclic heterocyclyl ring with
1 ring nitrogen heteroatom and optionally 1 or 2 heteroatoms
selected from nitrogen and sulfur, which ring is linked to the
group X.sup.2--O-- by a ring carbon atom, and wherein Q.sup.1
optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl,
trifluoromethoxy, cyano, nitro, hydroxy, amino, carbamoyl,
acryloyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy,
(2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio,
(2-6C)alkenylthio, (2-6C)alkynyl thio, (1-6C)alkylsulfinyl,
(2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl, (1-6C)alkylsulfamoyl,
(2-6C)alkenylsulfonyl, (2-6C)alkenylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, (2-6C)alkanoyl,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl (1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl and
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of
the formula:
Q.sup.3-X.sup.3
wherein X.sup.3 is CO and Q.sup.2 is a heterocyclyl group selected
from morpholino and a 4, 5 or 6-membered monocyclic heterocyclyl
group containing 1 nitrogen heteroatom and optionally 1 or 2
heteroatoms selected from sulfur and nitrogen,
[0036] and wherein Q.sup.3 optionally bears 1 or 2 substituents,
which may be the same or different, selected from halogeno,
hydroxy, (1-4C)alkyl, <2-4C)alkanoyl and
(1-4C)alkylsulfonyl,
[0037] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno, hydroxy and (1-6C)alkyl and/or
optionally a substituent selected from cyano, nitro, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, hydroxy(1-6C)alkoxy,
(1-4C)alkoxy(1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,
hydroxy(1-4C)alkoxy and <1-2C)alkoxy(1-4C)alkoxy,
[0038] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from halogeno,
hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally
bear on any available ring nitrogen a substituent (provided the
ring is not thereby quaternised) selected from (1-4C)alkyl,
(2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0039] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy;
[0040] and wherein any heterocyclyl group within the
Q.sup.5-.times.2- group optionally bears 1 or 2oxo (.dbd.O) or
thioxo (.dbd.S) substituents;
[0041] provided that when X.sup.2 is [CH.sub.2].sub.m, m is an
integer from 1 to 6, and Q.sup.1 is a pyrrolidinyl or piperidinyl
group substituted at the 1-position by a (2-4C)alkyl or
(2-5C)alkanoyl group, then the (2-4C)alkyl or (2-5C)alkanoyl group
at the 1-position on Q.sup.1 is not substituted by a
2-oxo-morpholino group;
or a pharmaceutically acceptable salt thereof.
[0042] In this specification the generic term "alkyl" includes both
straight-chain and branched-chain alkyl groups such as propyl,
isopropyl and tert-butyl, and (3-7C)cycloalkyl groups such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
However references to individual alkyl groups such as "propyl" are
specific for the straight-chain version only, references to
individual branched-chain alkyl groups such as "isopropyl" are
specific for the branched-chain version only and references to
individual cycloalkyl groups such as "cyclopentyl" are specific for
that 5-membered ring only. An analogous convention applies to other
generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy,
cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes
methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and
di-[(1-6C)alkyl]amino includes dimethylamino, diethylamino,
N-cyclobutyl-N-methyl amino and N-cyclohexyl-N-ethylamino.
[0043] It is to be understood that, insofar as certain of the
compounds of Formula I defined above may exist in optically active
or racemic forms by virtue of one or more asymmetrically
substituted carbon and/or sulfur atoms, and accordingly may exist
in, and be isolated as enantiomerically pure, a mixture of
diastereoisomers or as a racemate. The present invention includes
in its definition any racemic, optically-active, enantiomerically
pure, mixture of diastereoisomers, stereoisomeric form of the
compound of Formula (I), or mixtures thereof, which possesses the
above-mentioned activity. The synthesis of optically active forms
may be carried out by standard techniques of organic chemistry well
known in the art, for example by synthesis from optically active
starting materials or by resolution of a racemic form. Similarly,
the above-mentioned activity may be evaluated using the standard
laboratory techniques referred to hereinafter.
[0044] The invention relates to all tautomeric forms of the
compounds of the Formula I that possess antiproliferative
activity.
[0045] It is also to be understood that certain compounds of the
Formula I may 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 possess
antiproliferative activity.
[0046] It is also to be understood that certain compounds of the
Formula I may exhibit polymorphism, and that the invention
encompasses all such forms which possess antiproliferative
activity.
[0047] Suitable values for the generic radicals referred to above
include those set out below.
[0048] A suitable value for Q.sup.1 when it is (3-7C)cycloalkyl is,
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl or bicyclo[2.2.1]heptyl.
[0049] When Q.sup.1 or Q.sup.2 is heterocyclyl it is a non-aromatic
saturated (i.e. with the maximum degree of saturation) or partially
saturated (i.e. ring systems retaining some, but not the full,
degree of unsaturation) 3 to 10 membered monocyclic ring with up to
five heteroatoms selected from oxygen, nitrogen and sulfur (but not
containing any O--O, O--S or S--S bonds), and linked via a ring
carbon atom, or a ring nitrogen atom (provided the ring is not
thereby quaternised). Suitable values for Q.sup.1 or Q.sup.2
include for example, oxiranyl, oxetanyl, azetidinyl,
tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, oxazepanyl,
pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl,
1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, more
specifically including for example, tetrahydrofuran-3-yl,
tetrahydrofuran-2-yl-, tetrahydropyran-4-yl, tetrahydrothien-3-yl,
tetrahydrothiopyran-4-yl, pyrrolidin-3-yl, pyrrolidin-2-yl,
3-pyrrolin-3-yl-, morpholino,
1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino,
piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, homopiperidin-3-yl,
homopiperidin-4-yl, piperazin-1-yl, 1,4-oxazepanyl, or
1,2,3,6-tetrahydropyridin-4-yl. A nitrogen or sulfur atom within a
heterocyclyl group may be oxidized to give the corresponding N or S
oxide(s), for example 1,1-dioxotetrahydrothienyl,
1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or
1-oxotetrahydrothiopyranyl. A suitable value for such a group which
bears 1 or 2 oxo or thioxo substituents is, for example,
2-oxopyrrolidinyl, 2-oxopiperazinyl, 2-thioxopyrrolidinyl,
2-oxopiperidinyl, 2,5-dioxopyrrolidinyl or
2,6-dioxopiperidinyl.
[0050] Particular values for Q.sup.1 and Q.sup.2 include, for
example, non-aromatic saturated or partially saturated 3 to 7
membered monocyclic heterocyclyl rings with 1 ring nitrogen or
sulfur heteroatom and optionally 1 or 2 heteroatoms selected from
nitrogen, oxygen and sulfur. Examples of such rings include
azetidinyl, oxazepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl,
tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothienyl, tetrahydrothiopyranyl or thiomorpholinyl.
[0051] Further particular values for Q.sup.1 include, for example,
non-aromatic saturated or partially saturated 3 to 7 membered
monocyclic heterocyclyl rings with 1 ring nitrogen heteroatom and
optionally 1 or 2 heteroatoms selected from nitrogen and sulfur,
which rings are linked to X.sup.2--O by a ring carbon atom, such
as, for example, azetidinyl, pyrrolinyl pyrrolidinyl,
tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl,
piperazinyl, homopiperazinyl, dihydropyridinyl,
tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl,
tetrahydrothiopyranyl or thiomorpholinyl More particularly Q.sup.1
is a non-aromatic saturated or partially saturated 4, 5 or 6
membered monocyclic heterocyclyl ring with 1 or 2 ring nitrogen
heteroatom(s), which ring is linked to the group X.sup.2--O-- by a
ring carbon atom, more particularly pyrrolidin-3-yl,
pyrrolidin-2-yl, 3-pyrrolin-3-yl-, piperidin-4-yl, piperidin-3-yl,
piperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl,
piperazin-2-yl, piperazin-3-yl, or 1,2,3,6-tetrahydropyridin-4-yl A
nitrogen atom within a heterocyclyl group may be oxidized to give
the corresponding N oxide.
[0052] Particular values for Q.sup.2 include, for example,
morpholino, or 4, 5 or 6 membered heterocyclyl rings containing 1
nitrogen atom and optionally 1 or 2 heteroatoms selected from
nitrogen and sulfur such as piperazinyl, pyrrolidinyl, piperidinyl,
particularly pyrrolidin-1-yl, pyrrolidin-2-yl, piperazin-1-yl or
piperidino.
[0053] When R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5or 6 membered ring, the ring is
a saturated or partially saturated non-aromatic heterocyclyl ring
containing 1 nitrogen and optionally 1 or 2 heteroatoms selected
from oxygen, sulfur and nitrogen (but not containing any O--O, O--S
or S--S bonds), and wherein the ring so formed is linked via a ring
nitrogen atom to the group to which the ring is attached. The ring
may optionally bear 1 or 2 substituents on an available ring carbon
atom as hereinbefore defined (for example selected from
(1-4C)alkyl), and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) as hereinbefore defined (for example selected from
(1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl). Suitable
values for R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring include, for
example, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl,
piperidino, piperazin-1-yl and morpholino.
[0054] Suitable values for any of the R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.4, R.sup.a, R.sup.b, G.sup.1, G.sup.2 or for various
groups within Q.sup.1 as defined hereinbefore or hereafter in this
specification include:--
TABLE-US-00001 for halogeno fluoro, chloro, bromo and iodo; for
(1-6C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, pentyl
and hexyl; for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl and
tert-butyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy
and butoxy; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and
but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;
for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy:
ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio: methylthio,
ethylthio and propylthio; for (2-6C)alkenylthio: vinylthio and
allylthio; for (2-6C)alkynylthio: ethynlythio and 2-propynylthio
for (1-6C)alkylsulfinyl: methylsulfinyl and ethylsulfinyl; for
(2-6C)alkenylsulfinyl: vinylsulfinyl and allylsulfinyl; for
(2-6C)alkynylsulfinyl: ethynylsulfinyl and 2-propynylsulfinyl for
(1-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for
(2-6C)alkenylsulfonyl: vinylsulfonyl and allylsulfonyl; for
(2-6C)alkynylsulfonyl: ethynylsulfonyl and 2-propynylsulfonyl; for
(1-6C)alkylamino: methylamino, ethylamino, propylamino,
isopropylamino and butylamino; for di-[(1-6C)alkyl]amino:
dimethylamino, diethylamino, N-ethyl- N-methylamino and
diisopropylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for
N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl,
N-propylcarbamoyl and N-isopropylcarbamoyl; for
N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-
N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl:
acetyl, propionyl and isobutyryl; for (2-6C)alkanoyloxy: acetoxy
and propionyloxy; for (2-6C)alkanoylamino: acetamido and
propionamido; for N-(1-6C)alkyl-(2-6C)alkanoylamino:
N-methylacetamido and N-methylpropionamido; for
N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl, N-ethylsulfamoyl and
N-isopropylsulfamoyl; for N,N-di-[(1-6C)alkyl]sulfamoyl:
N,N-dimethylsulfamoyl and N-methyl-N-ethylsulfamoyl; for
(1-6C)alkanesulfonylamino: methanesulfonylamino and
ethanesulfonylamino; for N-(1-6C)alkyl-(1-6C)alkanesulfonylamino:
N-methylmethanesulfonylamino and N-methylethanesulfonylamino; for
amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and
3-aminopropyl; for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl,
ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl,
2-ethylaminoethyl and 3-methylaminopropyl; for
di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl,
diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and
3-dimethylaminopropyl; for halogeno-(1-6C)alkyl: chloromethyl,
2-chloroethyl, 1-chloroethyl and 3-chloropropyl; for
hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl
and 3-hydroxypropyl; for hydroxy-(1-6C)alkoxy: hydroxymethoxy,
2-hydroxyethoxy, 1-hydroxyethoxy and 3-hydroxypropoxy; for
(1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl,
1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and
3-cyanopropyl; for amino(2-6C)alkanoyl: aminoacetyl and
2-aminopropionyl; for (1-6C)alkylamino-(2-6C)alkanoyl:
methylaminoacetyl and 3-(methylamino)propionyl; for
N,N-di-[(1-6C)alkyl]amino-(2-6C)alkanoyl: di-methylaminoacetyl and
3-(di-methylamino)propionyl; for (2-6C)alkanoylamino-(1-6C)alkyl:
acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; for
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl:
N-methylacetamidomethyl, N-methylpropionamidomethyl,
2-(N-methylacetamido)ethyl and 2-(N-methylpropionamido)ethyl; for
(1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl,
ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and
2-methoxycarbonylaminoethyl; for carbamoyl(1-6C)alkyl:
carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and
3-carbamoylpropyl; for N-(1-6C)alkylcarbamoyl(1-6C)alkyl:
N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl,
N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl,
2-(N-methylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl; for
N,Ndi-(1-6C)alkylcarbamoyl(1-6C)alkyl: N,N-dimethylcarbamoylmethyl,
N,N-diethylcarbamoylmethyl, N methyl,N-ethylcarbamoylmethyl, 1-
(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)ethyl,
2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl and
3-(N,N-dimethylcarbamoyl)propyl; for sulfamoyl(1-6C)alkyl:
sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and
3-sulfamoylpropyl; for N-(1-6C)alkylsulfamoyl(1-6C)alkyl:
N-methylsulfamoylmethyl, N-ethylsulfamoylmethyl,
N-propylsulfamoylmethyl, 1-(N-methylsulfamoyl)ethyl,
2-(N-methylsulfamoyl)ethyl and 3-(N-methylsulfamoyl)propyl; for
N,Ndi-(1-6C)alkylsulfamoyl(1-6C)alkyl: N,N-dimethylsulfamoylmethyl,
N,N-diethylsulfamoylmethyl, N methyl,N-ethylsulfamoylmethyl, 1-
(N,N-dimethylsulfamoyl)ethyl, 1-(N,N-diethylsulfamoyl)ethyl,
2-(N,N-dimethylsulfamoyl)ethyl, 2-(N,N-diethylsulfamoyl)ethyl and
3-(N,N-dimethylsulfamoyl)propyl; for (2-6C)alkanoyl(1-6C)alkyl:
acetylmethyl, propionylmethyl, 2-acetylethyl and 2-propionylethyl;
for (2-6C)alkanoyloxy(1-6C)alkyl: acetoxymethyl,
propionyloxymethyl, 2-acetoxyethyl and 3-acetoxypropyl; for
(1-6C)alkoxy(1-6C)alkylS(O).sub.q: 2-methoxyethylsulfonyl,
2-methoxyethylsulpinyl and 2-methoxyethylthio; for
amino(1-6C)alkylS(O).sub.q: 2-aminoethylsulfonyl,
2-aminoethylsulfinyl and 2-aminoethylthio; for
N-(1-6C)alkylamino(1-6C)alkylS(O).sub.q:
2-(methylamino)ethylsulfonyl, 2-(ethylamino)ethylsulfinyl and
2-(methylamino)ethylthio; and for
N,N-di[(1-6C)alkyl]amino(1-6C)alkylS(O).sub.q:
2-(dimethylamino)ethylsulfonyl, 3-(dimethylamino)propylsulfonyl,
2-(di-ethylamino)ethylsulfinyl and
2-(N-methyl-N-ethylamino)ethylthio.
[0055] A suitable value for a (1-3C)alkylenedioxy group which may
be present as a substituent on the ring formed by R.sup.a and
R.sup.b together with the nitrogen atom to which they are attached
is, for example, methylenedioxy, ethylidenedioxy,
isopropylidenedioxy or ethylenedioxy and the oxygen atoms thereof
occupy adjacent ring positions. For example when R.sup.a and
R.sup.b together with the nitrogen atom to which they are attached
form a pyrrolidin-1-yl ring the ring may substituted with a
methylenedioxy group to give a 3,4-methylenedioxypyrrolidin-1-yl
group.
[0056] As defined hereinbefore, a (1-6C)alkyl, (2-8C)alkenyl,
(2-6C)alkynyl or (2-6C)alkanoyl group within Q.sup.1 may be
substituted by, for example, a group such as hydroxy,
(2-8C)alkenyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy or
NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are as hereinbefore
defined. For example when Q.sup.1 is substituted by an acetyl
group, the acetyl group may itself be substituted with a
di-[(1-6C)alkyl]amino group to form for example a
di-methylaminoacetyl or N-methyl-N-ethylamino-acetyl group on
Q.sup.1, or an acetyl group may be substituted with a (2-6C)alkenyl
group to give an alkenoyl group, for example an acetyl group
substituted by an allyl group to give but-3-enoyl. Similarly when,
for example Q.sup.1 is substituted by a (1-6C)alkyl sulfonyl group
such as propylsulfonyl, the (1-6C)alkyl group may t be substituted
with, for example, a dimethylamino group to give a dimethyl
amino-(1-6C)alkyl sulfonyl group such as
3-(dimethylamino)propylsulfonyl. By way of a further example, when
Q.sup.1 is substituted by a N-methylcarbamoyl group, the methyl
group may, for example be substituted by a (2-6C)alkenyl or
(2-6C)alkynyl group to give, for example a N-alkylcarbamoyl or
N-(2-propynyl)carbamoyl group.
[0057] It is to be understood that when, R.sup.1 is a group
(1-6C)alkyl substituted by, for example amino to give for example a
2-aminoethyl group, it is the (1-6C)alkyl group that is attached to
the group X.sup.1 (or the quinazoline ring when X.sup.3 is a direct
bond). An analogous convention applies to the other groups defined
herein. For example, when Q.sup.1 is carries a (1-6C)alkyl group
substituted by (1-6C)alkoxy to give a (1-6C)alkoxy(1-6C)alkyl
substituent, it is the (1-6C)alkyl that is linked to Q.sup.1.
[0058] It is to be understood that when X.sup.3 is CO, it is a
carbonyl group.
[0059] When it is stated herein that "any heterocyclyl group within
the Q.sup.1-X.sup.2- group optionally bears 1 or 2 oxo (.dbd.O) or
thioxo (.dbd.S) substituents", the oxo and/or thioxo groups may be
present on any heterocyclyl group within Q.sup.1 including
heterocyclyl groups represented by Q.sup.1 itself, by Q.sup.2 and
when R.sup.a and R.sup.b together with the nitrogen atom to which
they are attached form a 4, 5 or 6 membered heterocyclyl ring.
[0060] When in this specification reference is made to a
(1-4C)alkyl group it is to be understood that such groups refer to
alkyl groups containing up to 4 carbon atoms. A skilled person will
realise that representative examples of such groups are those
listed above under (1-6C)alkyl that contain up to 4 carbon atoms,
such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
Similarly, reference to a (1-3C)alkyl group refers to alkyl groups
containing up to 3 carbon atoms such as methyl, ethyl, propyl and
isopropyl. A similar convention is adopted for the other groups
listed above such as (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and
(2-4C)alkanoyl.
[0061] In the compound of Formula I hydrogen atoms are present at
the 2, 5 and 8 positions on the quinazoline ring.
[0062] A suitable pharmaceutically-acceptable salt of a compound of
the Formula I is, for example, an acid-addition salt of a compound
of the Formula I, for example an acid-addition salt with an
inorganic or organic acid such as hydrochloric, hydrobromic,
sulfuric, trifluoroacetic, citric or maleic acid; or, for example,
a salt of a compound of the Formula I which is sufficiently acidic,
for example an alkali or alkaline earth metal salt such as a
calcium or magnesium salt, or an ammonium salt, or a salt with an
organic base such as methylamine, dimethylamine, trimethylamine,
piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0063] Particular novel compounds of the invention include, for
example, quinazoline derivatives of the Formula I, or
pharmaceutically-acceptable salts thereof, wherein, unless
otherwise stated, each of m, R.sup.1, R.sup.2, R.sup.3, Q.sup.1,
Q.sup.2, X.sup.1, X.sup.2, m, G.sup.1 and G.sup.2 has any of the
meanings defined hereinbefore or in paragraphs (a) to (qqq)
hereinafter:--
(a) Q.sup.1 is a non-aromatic saturated or partially saturated 3 to
7 membered monocyclic heterocyclyl ring with 1, 2 or 3 heteroatoms
selected from oxygen, nitrogen and sulfur, linked to the group
X.sup.2--O by a ring carbon or a ring nitrogen (provided that the
ring is not thereby quaternized), and wherein any available
nitrogen in Q.sup.1 optionally bears a substituent (where such
substitution does not result in quaternization) selected from
trifluoromethyl, cyano, carbamoyl, trifluoromethyl, (1-6C)alkyl,
(2-8C)alkenyl, (2-6C)alkynyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsulfonyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl
(2-6C)alkanoyl oxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl,
[0064] wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and
(2-6C)alkanoyl group within an optional substituent on an available
nitrogen is optionally substituted by one or more substituents,
which maybe the same or different, selected from fluoro, chloro,
hydroxy and (1-4C)alkyl, and/or optionally a substituent selected
from cyano, nitro, carboxy, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or(1-4C)alkyl,
[0065] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 (suitably 1) substituents selected from halogeno,
trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,
N-(1-6C)alkyl(2-6C)alkanoylamino, hydroxy(1-6C)alkyl,
cyano(1-6C)alkyl, amino(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl,
di-[(1-6C)alkyl]amino(1-6C)alkyl and (1-6C)alkoxy(1-6C)alkyl,
[0066] and wherein Q.sup.1 optionally bears 1 or 2 oxo or thioxo
substituents;
(b) Q.sup.1 is a non-aromatic saturated, or partially saturated 3
to 7 membered monocyclic heterocyclyl ring with 1, 2 or 3
heteroatoms selected from oxygen, nitrogen and sulfur, linked to
the group X.sup.2--O by a ring carbon, and wherein any available
nitrogen in Q.sup.1 optionally bears a substituent (where such
substitution does not result in quaternization) selected from
trifluoromethyl, cyano, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsulfonyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
carbamoyl(1-6)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl (2-6C)alkanoyl(1-6C)alkyl,
(2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl and
(1-6C)alkoxycarbonyl(1-6C)alkyl,
[0067] wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl and
(2-6C)alkanoyl group within an optional substituent on an available
nitrogen is optionally substituted by one or more substituents,
which maybe the same or different, selected from fluoro, chloro,
hydroxy and (1-4C)alkyl, and/or optionally a substituent selected
from cyano, nitro, carboxy, (1-4C)alkoxy, hydroxy(1-4C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or(1-4C)alkyl,
[0068] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 (suitably 1) substituents selected from halogeno,
trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,
(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, hydroxy(1-6C)alkyl,
cyano(1-6C)alkyl, amino(1-6C)alkyl, (1-6C)alkylamino(1-6C)alkyl,
di-[(1-6C)alkyl]amino(1-6C)alkyl and (1-6C)alkoxy(1-6C)alkyl,
and wherein Q.sup.1 optionally bears 1 or 2 oxo or thioxo
substituents; (c) Q.sup.1 is a non-aromatic saturated or partially
saturated 3 to 7 membered monocyclic heterocyclyl ring with 1
nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from
oxygen, nitrogen and sulfur, which ring is linked to the group
X.sup.2--O-- by a carbon atom in the ring,
[0069] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, carbamoyl,
trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
hydroxy(1-6C)alkyl, to cyano(1-6C)alkyl, amino(1-6C)alkyl,
(1-6C)alkylamino(1-6C)alkyl, di-[<1-6C)alkyl]amino(1-6C)alkyl,
amino(2-6C)alkanoyl, (1-6C)alkylamino-(2-6C)alkanoyl,
N,N-di-[(1-6C)alkyl]amino-(2-6C)alkanoyl, (1-6C)alkoxy(1-6C)alkyl,
hydroxy(1-6C)alkoxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(3-6)alkyl]carbamoyl(1-6C)alkyl, (2-6C)alkanoyl(1-6C)alkyl,
(2-6C)alkanoyloxy(1-6C)alkyl, (2-6C)alkanoylamino(1-6C)alkyl,
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl,
(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkylS(O).sub.q
(wherein q is 0, 1 or 2), amino(1-6C)alkylS(O).sub.q (wherein q is
0, 1 or 2), N-(1-6C)alkylamino(1-6C)alkylS(O).sub.q (wherein q is
0, 1 or 2) and N,N-di-[(1-6C)alkyl]amino(1-6C)alkylS(O).sub.q
(wherein q is 0, 1 or 2),
[0070] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from cyano, nitro, hydroxy,
amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy(1-6C)alkyl,
cyano(1-6C)alkyl, amino(1-6C)alkyl) (1-6C)alkylamino(1-6C)alkyl,
di-[(1-6C)alkyl]amino(1-6C)alkyl and (1-6C)alkoxy(1-6C)alkyl,
and wherein any (1-6C)alkyl, (2-8C)alkenyl, <2-8C)alkynyl or
(2-6C)alkanoyl group in Q.sup.1 optionally bears 1 or 2
substituents which may be the same or different selected from
fluoro and chloro, and wherein Q.sup.1 optionally bears 1 or 2 oxo
substituents; (d) Q.sup.1 is a non-aromatic saturated 3 to 7
membered monocyclic heterocyclyl ring with 1 nitrogen heteroatom
and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen
and sulfur, which ring is linked to the group X.sup.2--O-- by a
carbon atom in the ring, and wherein the nitrogen atom of any NH
group in Q.sup.1 optionally bears a substituent as hereinbefore
defined in (c) and any ring carbon in Q.sup.1 is optionally
substituted as hereinbefore defined in (c) and wherein Q.sup.1
optionally bears 1 or 2 oxo substituents; (e) Q.sup.1 is a
non-aromatic partially saturated 3 to 7 membered monocyclic
heterocyclyl ring with a single carbon-carbon double bond, 1
nitrogen heteroatom and optionally 1 or 2 heteroatoms selected from
oxygen, nitrogen and sulfur, which ring is linked to the group
X.sup.2--O-- by one of the ring carbon atoms carrying said
carbon-carbon double bond (for example 3-pyrrolin-3-yl or
1,2,3,6-tetrahydropyridin-4-yl), and wherein the nitrogen atom of
any NH group in Q.sup.1 optionally bears a substituent as
hereinbefore defined in (c) and any ring carbon in Q.sup.1 is
optionally substituted as hereinbefore defined in (c), and wherein
Q.sup.1 optionally bears 1 or 2 oxo substituents; (f) Q.sup.1 is
selected from cyclobutyl, cyclopentyl and cyclohexyl optionally
substituted by 1or 2 substituents selected from (1-6C)alkyl,
(2-8C)alkenyl, (2-8C)alkynyl and (1-6C)alkoxy; (g) Q.sup.1 is
selected from Q.sup.1 is a non-aromatic saturated 5 or 6 membered
monocyclic heterocyclyl ring with 1 nitrogen heteroatom and
optionally 1 or 2 (suitably 1) heteroatoms selected from oxygen and
nitrogen, which ring is linked to the group X.sup.2--O-- by a
carbon atom in the ring,
[0071] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, carbamoyl,
(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkylsulfonyl,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,
(2-4C)alkanoyl, sulfamoyl, N-(1-4C)alkylsulfamoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, cyano(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(1-4C)alkoxy(1-3C)alkylS(O).sub.q (wherein q is 0, 1or particularly
2), amino(1-3C)alkylS(O).sub.q (wherein q is 0, 1 or particularly
2), N-(1-4C)alkylamino(1-3C)alkylS(O).sub.q (wherein q is 0, 1 or
particularly 2) and N,N-di[(1-4)alkyl]amino(1-3C)alkylS(O).sub.q
(wherein q is 0, 1 or particularly 2),
[0072] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from cyano, oxo, amino,
carboxy, carbamoyl, (1-4C)alkyl, (2-6C)alkenyl and
(2-6C)alkynyl,
[0073] and wherein any (1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or
(2-4C)alkanoyl group in Q.sup.1 optionally bears 1 or 2
substituents which may be the same or different selected from
fluoro and chloro;
(h) Q.sup.1 is selected from cyclopropyl, cyclopentyl, cyclohexyl,
oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl,
1,3-dioxolan-(2, 4 or 5-yl), 3- or 4-tetrahydropyranyl, 3- or
4-oxepanyl, 1-, 2- or 3-pyrrolidinyl, 2-pyrrolin-2-yl,
2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholino, morpholin-2-yl,
morpholin-3-yl, thiomorpholino, thiomorpholin-2-yl,
thiomorpholin-3-yl, piperidino, piperidin-2-yl, piped din-3-yl,
piperidin-4-yl, 1-,2-,3- or 4-homopiperidinyl, piperazin-1-yl,
piperazin-2-yl, 1,1-tetrahydropyridinyl,
1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-5-yl,
1,2,3,6-tetrahydropyridin-6-yl, homopiperazinyl, azetidin-3-yl,
tetrahydrothien-3-yl, 1,1-dioxotetrahydrothien-3-yl,
1-oxotetrahydrothien-3-yl, tetrahydrothiopyran-3-yl,
tetrahydrothiopyran-4-yl, 1-oxotetrahydrothiopyran-3-yl,
1,1-dioxotetrahydrothiopyran-3-yl, 1-oxotetrahydrothiopyran-4-yl
and 1,1-dioxotetrahydrothiopyran-4-yl,
[0074] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, (1-4C)alkyl,
cyano(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylsulfonyl,
trifluoromethyl, carbamoyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N,N-di-[(1-4C)alkyl]sulfamoyl
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(1-4C)alkoxy(1-3C)alkylsulfonylamino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino(1-3C)alkylsulfonyl and
N,N-di-[(1-4)alkyl]amino(1-3C)alkylsulfonyl, and Q.sup.1 optionally
bears on any available carbon atom in the ring 1 or 2 substituents
selected from oxo and (1-4C)alkyl,
[0075] and wherein any (1-4C)alkyl group in Q.sup.1 optionally
bears 1 or 2 fluoro substituents;
(i) Q.sup.1 is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,
2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholin-2-yl,
morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,
piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-, 3- or
4-homopiperidinyl, piperazin-1-yl, 2-oxopiperazin-1-yl,
3-oxopiperazin-1-yl, piperazin-2-yl,
1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl,
1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl,
2,3,4,6 or 7-homopiperazinyl, azetidin-3-yl,
[0076] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, (1-4C)alkyl,
cyano(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylsulfonyl,
trifluoromethyl, carbamoyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N,N-di-[(1-4C)alkyl]sulfamoyl,
amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(1-4C)alkoxy(1-3C)alkylsulfonyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino(1-3C)alkylsulfonyl and
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl, 3 and Q.sup.1
optionally bears on any available carbon atom in the ring 1 or 2
substituents selected from (1-4C) alkyl and oxo,
[0077] and wherein any (1-4C)alkyl group in Q.sup.1 optionally
bears 1 or 2 fluoro substituents;
(j) Q.sup.1 is selected from pyrrolidin-2-yl, pyrrolidin-3-yl,
piperidin-2-yl, piperidin-3-yl and piperidin-4-yl,
[0078] and wherein the nitrogen atom of any NH group in Q.sup.3
optionally bears a substituent selected from cyano, cyanomethyl,
methyl, ethyl, carbamoyl, carbamoylmethyl, 2-methoxyethyl,
methylsulfonyl and ethylsulfonyl (particularly methylsulfonyl and
carbamoylmethyl),
[0079] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from methyl, ethyl and
oxo;
(k) X.sup.2 is a direct bond; (l) X.sup.2 is
[CR.sup.2R.sup.3].sub.m, wherein m is 1 or 2 and R.sup.2 and
R.sup.3 are hydrogen; (m) X.sup.2 is a direct bond or CH.sub.2; (n)
Q.sup.1-X.sup.2 is selected from pyrrolidin-2-yl,
pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl,
3-pyrrolidin-2-ylpropyl, pyrrolidin-3-yl, pyrrolidin-3-ylmethyl,
2-pyrrolidin-3-ylethyl, 3-pyrrolidin-3-ylpropyl, 2-pyrrolin-2-yl,
2-pyrrolin-2-ylmethyl, 2-pyrrolin-3-yl)pyrrolin-3-ylmethyl,
3-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholin-2-yl,
morpholin-2-ylmethyl, 2-morpholin-2-ylethyl, morpholin-3-yl,
morpholin-3-ylmethyl, 2-morpholin-3-ylethyl, thiomorpholinomethyl,
thiomorpholin-2-yl, thiomorpholin-2-ylmethyl,
2-thiomorpholin-2-ylethyl, thiomorpholin-3-yl
thiomorpholin-3-ylmethyl, 2-thiomorpholin-3-ylethyl,
piperidinomethyl, 2-piperidinoethyl, piperidin-2-yl,
piperidin-2-ylmethyl, 2-piperidin-2-ylethyl,
3-piperidin-2-ylpropyl, piperidin-3-yl, piperidin-3-ylmethyl,
2-piperidin-3-ylethyl, 3-piperidin-3-ylpropyl, piperidin-4-yl,
piperidin-4-ylmethyl, 2-piperidin-4-ylethyl,
3-piperidin-4-ylpropyl, piperazin-1-ylmethyl,
2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl,
2-oxopiperazin-1-ylmethyl, 2-(2-oxopiperazin-1-ylethyl,
3-(2-oxopiperazin-1-yl)propyl, 3-oxopiperazin-1-ylmethyl,
2-(3-oxopiperazin-1-yl)ethyl, 3-(3-oxopiperazin-1-yl)propyl,
piperazin-2-yl, piperazin-2-ylmethyl, 2-piperazin-2-ylethyl and
3-piperazin-2-ylpropyl, and wherein the nitrogen atom of any NH
group in Q.sup.1 optionally bears a substituent selected from
cyano, cyanomethyl, 2-cyanoethyl, methyl, ethyl, 2-methoxyethyl,
2-ethoxyethyl, methylsulfonyl, trifluoromethyl, carbamoyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-di-methylcarbamoyl,
N,N-di-ethylcarbamoyl, acetyl, propionyl, sulfamoyl,
N-methylsulfamoyl, N-ethylsulfamoyl, N,N-di-methylsulfamoyl,
N,N-di-ethylcarbamoyl, 3-aminopropionyl, 3-(methylamino)propionyl,
3-(di-methylamino)propionyl, carbamoylmethyl, 2-carbamoylethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N,N-di-methylcarbamoylmethyl, 2-(N,N-di-methylcarbamoyl)ethyl,
methoxymethylsulfonyl, 2-methoxyethylsulfonyl,
2-aminoethylsulfonyl, 2-(N-methylamino)ethylsulfonyl and
2-(N,N-di-methylamino)ethylsulfonyl; (o) Q.sup.1-X.sup.3 is
selected from piperidin-4-yl and piperidin-4-ylmethyl, wherein the
nitrogen atom in the piperidinyl ring optionally bears a
substituent selected from cyano, cyanomethyl, methyl, ethyl,
carbamoyl, carbamoylmethyl, 2-methoxyethyl, methylsulfonyl and
ethylsulfonyl; (p) Q.sup.1-X.sup.2 is selected from
1-carbamoylmethylpiperidin-4-yl and 1-methylsulfonylpiperidin-4-yl;
(q) R.sup.1-X.sup.1 is selected from hydrogen, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkoxy; (r) R.sup.1-X.sup.1 is selected from
hydrogen, methoxy, ethoxy and 2-methoxyethoxy; (s) R.sup.1: X.sup.1
is methoxy; (t) G.sup.1 and G.sup.2 each independently is selected
from fluoro and chloro; (u) G.sup.1 is fluoro and G.sup.2 is
chloro; (v) Q.sup.1 is a non-aromatic saturated 5 or 6 membered
monocyclic heterocyclyl ring with 1 nitrogen heteroatom and
optionally 1 or 2 additional heteroatoms selected from oxygen, 3
nitrogen and sulfur, which ring is linked to the group X.sup.2--O--
by a carbon atom in the ring, and wherein Q.sup.1 bears 1 or 2
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,
amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkenylsulfonyl, (1-6C)alkylamino, di-[(1-6)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl (1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl and
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of
the formula:
Q.sup.2-X.sup.3
wherein X.sup.3 is CO and Q.sup.2 is a saturated 5 or 6 membered
monocyclic heterocyclyl ring with 1 nitrogen heteroatom and
optionally 1 or 2 additional heteroatoms selected from oxygen,
nitrogen and sulfur, which ring is linked to the group X.sup.3 by a
nitrogen atom in the ring, and wherein Q.sup.2 optionally bears 1
or 2 substituents, selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl,
[0080] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno and hydroxy and/or optionally a
substituent selected from cyano, nitro, carboxy, (2-8C)alkenyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein
R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is hydrogen or
(1-4C)alkyl,
[0081] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from
(1-4C)alkyl, and may optionally bear on any available ring nitrogen
a substituent (provided the ring is not thereby quaternised)
selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl;
and wherein any heterocyclyl group within the Q.sup.1-X.sup.2-
group optionally bears 1 or 2 oxo (.dbd.O) or thioxo (.dbd.S)
substituents; (w) Q.sup.1 is a non-aromatic saturated 5 or 6
membered monocyclic heterocyclyl ring with 1 nitrogen heteroatom
and optionally 1 or 2 additional heteroatoms selected from oxygen,
nitrogen and sulfur, which ring is linked to the group X.sup.2--O--
by a carbon atom in the ring, and wherein Q.sup.1 bears 1 or 2
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,
amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkenylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6)alkyl-(2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl (1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl and
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of
the formula:
Q.sup.2-X.sup.3
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
piperidino, piperazin-1-yl and morpholino, and wherein Q.sup.2
optionally bears 1 or 2 substituents, selected from (1-4C)alkyl,
(2-6C)alkanoyl and (1-4C)alkylsulfonyl,
[0082] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which may be the same or
different selected from halogeno and hydroxy and/or optionally a
substituent selected from cyano, nitro, carboxy, (2-8C)alkenyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein
R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is hydrogen or
(1-4C)alkyl,
[0083] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from
(1-4C)alkyl, and may optionally bear on any available ring nitrogen
a substituent (provided the ring is not thereby quaternised)
selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl;
and wherein any heterocyclyl group within the Q.sup.1-X.sup.2-
group optionally bears 1 or 2 oxo (.dbd.O) or thioxo (.dbd.S)
substituents; (x) Q.sup.1 is a non-aromatic saturated 5 or 6
membered monocyclic heterocyclyl ring with 1 nitrogen heteroatom
and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen
and sulfur, which ring is linked to the group X.sup.2--O-- by a
carbon atom in the ring, and wherein Q.sup.1 bears 1 or 2
substituents, which may be the same or different, selected from
halogeno, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,
amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy,
(1-6C)alkylthio, (1-6C)alkysulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkenylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl, (2-6C)alkanoylamino, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino,
carbamoyl(1-6C)alkyl, (2-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl and
N-(1-6)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino,
[0084] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl
and (2-6C)alkanoyl group within Q.sup.1 optionally bears one or
more substituents (for example 1, 2 or 3) which maybe the same or
different selected from halogeno and hydroxy and/or optionally a
substituent selected from cyano, nitro, carboxy, (2-6C)alkenyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein
R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is hydrogen or
(1-4C)alkyl,
[0085] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from
(1-4C)alkyl, and may optionally bear on any available ring nitrogen
a substituent (provided the ring is not thereby quaternised)
selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl;
[0086] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears 1 or 2 oxo (.dbd.O) or
thioxo (.dbd.S) substituents;
(y) Q.sup.1 is a fully saturated 5 or 6 membered monocyclic
heterocyclyl ring with 1 nitrogen heteroatom and optionally 1 or 2
heteroatoms selected from oxygen, nitrogen and sulfur, which ring
is linked to the group X.sup.2--O-- by a carbon atom in the ring,
and wherein Q.sup.1 bears 1 or 2 substituents, which may be the
same or different, selected from carbamoyl, (1-6C)alkyl,
(1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di[(1-6C)alkyl]sulfamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl and
(2-6C)alkanoyl(1-6C)alkyl, or a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino,
[0087] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
Q.sup.1 optionally bears a substituent selected from hydroxy,
(2-6C)alkanoyl, (2-6C)alkanoyloxy and NR.sup.aR.sup.b, wherein
R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is (1-4C)alkyl,
[0088] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a pyrrolidin-1-yl, piperidino,
piperazin-1-yl or morpholino ring, which ring optionally bears 1 or
2 substituents, which maybe the same or different, selected from
(1-4C)alkyl;
[0089] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears 1 or 2oxo (.dbd.O)
substituents; and
[0090] X.sup.2 is a direct bond or CH.sub.2;
(z) Q.sup.1 is a fully saturated 5 or 6 membered monocyclic
heterocyclyl ring with 1 nitrogen heteroatom and optionally 1
additional heteroatom selected from oxygen, nitrogen and sulfur,
which ring is linked to the group X.sup.2--O-- by a carbon atom in
the ring, and wherein the nitrogen atom of any NH group in Q.sup.1
bears a substituent selected from carbamoyl, (1-4C)alkyl,
(1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,
(2-4C)alkanoyl, sulfamoyl, N-(1-4C)alkylsulfamoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(2-4C)alkanoyl(1-3C)alkyl, hydroxy(2-4C)alkanoyl,
amino(2-4C)alkanoyl,
(1-4C)alkylamino(2-4C)alkanoyl)N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl,
piperazin-1-yl-(2-4C)alkanoyl and morpholino-(2-4C)alkanoyl;
[0091] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears an oxo (.dbd.O)
substituent; and
[0092] X.sup.2 is a direct bond or CH.sub.2;
(aa) Q.sup.1 is a fully saturated 5 or 6 membered monocyclic
heterocyclyl ring with 1 nitrogen heteroatom and optionally 1
additional heteroatom selected from oxygen, nitrogen and sulfur,
which ring is linked to the group X.sup.2--O-- by a carbon atom in
the ring, and wherein Q.sup.1 bears one substituent on a ring
carbon atom selected from carbamoyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl (2-4C)alkanoyl,
amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
pyrrolidin-1-yl-(2-4C)alkanoyl piperidino-(2-4C)alkanoyl,
piperazin-1-yl-(2-4C)alkanoyl and morpholino(2-4C)alkanoyl, or a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino,
[0093] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from (1-4C)alkyl,
[0094] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears an oxo (.dbd.O)
substituent; and
[0095] X.sup.2 is a direct bond or CH.sub.2;
(bb) Q.sup.1 is selected from pyrrolidinyl and piperidinyl linked
to the group X.sup.2--O-- by a ring carbon atom and wherein the
pyrrolidinyl or piperidinyl group is substituted by 1 or 2 groups
selected from carbamoyl, (1-4C)alkyl, (1-4C)alkylsulfonyl,
(1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl,
N,N-m-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N,N-di-[(1-4C)alkyl]sulfamoyl,
carbamoyl(1-3C)alkyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(2-4C)alkanoyl(1-3C)alkyl, hydroxy(2-4C)alkanoyl,
amino(2-4C)alkanoyl(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl,
piperazin-1-yl-(2-4C)alkanoyl, morpholino-(2-4C)alkanoyl and a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino;
[0096] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears an oxo (.dbd.O)
substituent; and
[0097] X.sup.2 is a direct bond or CH.sub.2;
(cc) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl,
pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl
and piperidin-4-ylmethyl, and wherein a pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 carries one or two substituents selected
from (1-4C)alkyl, (1-4C)alkylsulfonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl,
N-di-[(1-4C)alkyl]sulfamoyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl, hydroxy(2-4C)alkanoyl,
N-(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl,
N-(1-4)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4)alkyl]amino(1-3C)alksulfonyl
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl,
morpholino-(2-4C)alkanoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidine
1-yl, morpholino and piperidino; (dd) Q.sup.1-X.sup.2 is selected
from pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl,
piperidin-3-ylmethyl and piperidin-4-ylmethyl, and wherein a
pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 carries one or
two substituents selected from (1-4C)alkyl, (1-4C)alkylsulfonyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl, hydroxy(2-4C)alkanoyl,
N-(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl,
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl)
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl and
morpholino-(2-4C)alkanoyl or a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino; (ee)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl, piperidin-3-yl,
piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein a pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 substituted on a ring nitrogen by a
substituent selected from methyl, ethyl, methylsulfonyl,
ethylsulfonyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, acetyl, propionyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, N,N-dimethylcarbamoylmethyl,
2-(N,N-dimethylcarbamoyl)ethyl, N,N-diethylcarbamoylmethyl,
2-(N,N-diethylcarbamoyl)ethyl, hydroxyacetyl, 2-hydroxypropionyl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-di-methylamino)propionyl,
N,N-diethylaminoacetyl), 2-(N,N-diethylamino)propionyl,
N-methyl-N-ethylaminoacetyl, 2-(N-methyl-N-ethylamino)propionyl,
acetoxyacetyl, 2-(acetoxy)propionyl,
2-(N-methylamino)ethylsulfonyl, 2-(N-ethylamino)ethylsulfonyl,
2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl, 3-(N-methylamino)propyl
sulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)priopionyl, piperidinoacetyl,
2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl and
a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino; (ff)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl, piperidin-3-yl,
piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein a pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 is substituted on a ring nitrogen by a
substituent selected from methyl, ethyl, methylsulfonyl,
N,N-dimethylcarbamoyl, acetyl, hydroxyacetyl, N-methylaminoacetyl,
N,N-dimethylaminoacetyl, 3-(N-di-methylamino)propylsulfonyl,
pyrrolidin-1-ylacetyl, piperidinoacetyl, 2-piperidinopropionyl and
morpholinoacetyl; (gg) Q.sup.1-X.sup.2 is selected from
pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl,
piperidin-3-ylmethyl and piperidin-4-ylmethyl, and wherein the
pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 is carries one
substituent in an ortho position to the ring nitrogen in the
pyrrolidinyl or piperidinyl group selected from carbamoyl,
N-(1-4C)alkylcarbamoyl, N)N-di-[(1-4C)alkyl]carbamoyl, and a group
of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
piperidino and morpholino;
[0098] and wherein the ring nitrogen in the pyrrolidinyl or
piperidinyl group in Q.sup.1 optionally bears a substituent
selected from (1-4C)alkyl;
(hh) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl, and wherein the
pyrrolidinyl group carries one substituent in the 5-position
selected from N,N-di-[(1-4C)alkyl]carbamoyl and a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino, and wherein the
pyrrolidinyl group optionally bears a substituent at the 1-position
selected from (1-4C)alkyl (as will be realised this embodiment
covers, for example, a group where Q.sup.1-X.sup.2 is a
pyrrolidin-3-yl group of the formula:
##STR00003##
wherein X is the substituent at the 5-position and references in
the Examples herein to for example, a
2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yl at the 6-position on the
quinazoline ring is an example of such a group); (ii)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl, piperidin-3-yl,
piperidin-4-yl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein the pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 is carries one substituent on a ring
carbon atom selected from N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, and a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino, and wherein the
ring nitrogen in the pyrrolidinyl or piperidinyl group in Q.sup.3
optionally bears a substituent selected from methyl and ethyl; (jj)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl, and wherein the
pyrrolidinyl group carries a N,N-dimethylcarbamoyl substituent in
the 5- position;
(kk) X.sup.2 is CH.sub.2;
[0099] (ll) Q.sup.1 is a non-aromatic saturated or partially
saturated 4, 5 or 6 membered monocyclic heterocyclyl ring with 1 or
2 ring nitrogen heteroatom(s), which ring is linked to the group
X.sup.2--O-- by a ring carbon atom, and wherein Q.sup.1 optionally
bears 1 or 2 substituents, which may be the same or different,
selected from halogeno, cyano, nitro, hydroxy, carbamoyl, acryloyl,
(1-6C)alkyl, (1-6C)alkylthio, (2-6C)alkenylthio, (2-6C)alkynylthio,
(1-6C)alkylsulfonyl, (2-6C)alkenylsulfinyl, (2-6C)alkynylsulfinyl
(1-6C)alkylsulfonyl, (26C)alkenylsulfonyl, (2-6C)alkynylsulfinyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
(2-6C)alkanoyl, sulfamoyl, N-(1-6C)alkylsulfamoyl,
N,N-di-[(1-6C)alkyl]sulfamoyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl and
N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl, or from a group of
the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is a heterocyclyl group selected
from morpholino, piperidinyl, piperazinyl and pyrrolidinyl (which
piperidinyl, piperazinyl or pyrrolidinyl may be linked to X.sup.3
by a ring carbon or a ring nitrogen),
[0100] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from halogeno,
hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0101] and wherein any (1-6C)alkyl, or (2-6C)alkanoyl group within
Q.sup.1 optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, hydroxy and (1-6C)alkyl
and/or optionally a substituent selected from cyano, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, and (1-4C)alkoxy,
[0102] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring which does
not contain oxygen, which ring optionally bears 1 or 2
substituents, which may be the same or different, on an available
ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and
(1-3C)alkylenedioxy, and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl,
[0103] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy;
[0104] and wherein any heterocyclyl group within the
Q.sup.5-.times.2- group optionally bears 1 or 2oxo (.dbd.O) or
thioxo (.dbd.S) substituents;
(mm) Q.sup.1 is selected from pyrrolidinyl and piperidinyl linked
to the group X.sup.2--O-- by a ring carbon atom and wherein the
pyrrolidinyl or piperidinyl group is optionally substituted by 1 or
2 groups selected from halogeno, cyano, hydroxy, carbamoyl,
(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl,
(1-6C)alkylsulfonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl and
(2-6C)alkanoyl(1-6C)alkyl, or from a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q'' is a heterocyclyl group selected from
morpholino, piperidino, piperazin-1-yl, pyrrolidin-1-yl and
pyrrolidin-2-yl,
[0105] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from halogeno,
hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkylsulfonyl,
[0106] and wherein any (1-6C)alkyl, or (2-6C)alkanoyl group within
Q.sup.1 optionally bears 1 or 2 substituents, which may be the same
or different, selected from halogeno, hydroxy and (1-6C)alkyl
and/or optionally a substituent selected from cyano, (2-8C)alkenyl,
(2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkanoyl, (2-6C)alkanoyloxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, and (1-4C)alkoxy,
[0107] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a ring selected from pyrrolidin-1-yl,
piperidino and piperazin-1-yl, which ring optionally bears 1 or 2
substituents, which may be the same or different, on an available
ring carbon atom selected from halogeno, hydroxy, (1-4C)alkyl and
methylenedioxy, and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) selected from (1-4C)alkyl, (2-4C)alkanoyl and
(1-4C)alkylsulfonyl,
[0108] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy,
[0109] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy,
[0110] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears 1 or 2oxo (.dbd.O)
substituents;
(nn) Q.sup.1 is selected from pyrrolidinyl and piperidinyl linked
to the group X.sup.2--O-- by a ring carbon atom and wherein the
pyrrolidinyl or piperidinyl group is substituted by 1 or 2 groups
selected from carbamoyl, (1-4C)alkyl, (1-4C)alkylsulfonyl,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,
(2-4C)alkanoyl, sulfamoyl, N-(1-4C)alkylsulfamoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, carbamoyl-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl, (2C)alkanoyl(1-3C)alkyl,
amino(2-4C)alkanoyl, (1-4)alkylamino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl,
3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl,
morpholino-(2-4C)alkanoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
pyrrolidin-2-yl, morpholino and piperidino,
[0111] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and halogeno
(particularly chloro and more particularly fluoro),
[0112] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0113] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro),
[0114] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears an oxo (.dbd.O)
substituent; and
[0115] X.sup.2 is a direct bond;
(oo) Q.sup.1 is selected from pyrrolidinyl and piperidinyl linked
to the group X.sup.2--O-- by a ring carbon atom and wherein the
pyrrolidinyl or piperidinyl group is substituted by 1 or 2 groups,
which may be the same or different, selected from carbamoyl,
(1-4C)alkyl, (1-4C)alkylsulfonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N,N-di-[(1-4C)alkyl]sulfamoyl,
carbamoyl(1-3C)alkyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(2-4C)alkanoyl(1-3C)alkyl]amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl,
3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl and a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
pyrrolidin-2-yl and piperidino,
[0116] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl piperidino
or piperazin-1-yl group within a substituent on Q.sup.1 or which is
represented by Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy,
(1-4C)alkyl, (2-4C)alkanoyl and halogeno (particularly chloro and
more particularly fluoro),
[0117] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0118] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro),
[0119] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally bears an oxo (.dbd.O)
substituent; and
[0120] X.sup.2 is CH.sub.2;
(pp) Q.sup.1 is selected from pyrrolidinyl and piperidinyl linked
to the group X.sup.2--O-- by a ring carbon atom and wherein the
pyrrolidinyl or piperidinyl group is substituted by 1 or 2 groups,
which may be the same or different, selected from carbamoyl,
(1-4C)alkyl, (1-4C)alkylsulfonyl, N-(1-4C)alkylcarbamoyl,
(2-4C)alkanoyl, sulfamoyl, N-(1-4C)alkylsulfamoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(2-4C)alkanoyl(1-3C)alkyl, amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkyl sulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
[0121] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0122] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro),
[0123] X.sup.2 is a direct bond or CH.sub.2;
(qq) Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl,
pyrrolidin-3-yl, (3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl,
pyrrolidin-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, piperidin-4-yl, piperidin-4-ylmethyl,
piperidin-3-yl, (3R)-piperidin-3-yl and (3S)-piperidin-3-yl,
wherein Q.sup.3 is substituted by 1 or 2 groups, which may be the
same or different, selected from carbamoyl, (1-4C)alkyl,
(1-4C)alkylsulfonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N-di-[(1-4C)alkyl]sulfamoyl,
carbamoyl(1-3C)alkyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3G)alkyl,
(2-4C)alkanoyl(1-3C)alkyl, amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl
3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl,
morpholino-(2-4C)alkanoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
pyrrolidin-2-yl, morpholino and piperidino,
[0124] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and halogeno
(particularly chloro and more particularly fluoro),
[0125] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0126] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro),
and wherein any heterocyclyl group within the Q.sup.1-X.sup.2-
group optionally bears an oxo (.dbd.O) substituent; (rr)
Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl,
pyrrolidin-3-yl, (3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl,
pyrrolidin-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, piperidin-4-yl, piperidin-3-yl,
(3R)-piperidin-3-yl and (3S)-piperidin-3-yl, wherein the
pyrrolidinyl or piperidinyl group in Q.sup.1 is substituted at the
1-position by a substituent selected from (1-4C)alkyl,
(1-4C)alkylsulfonyl, (2-4C)alkanoyl, (2-4C)alkanoyl(1-3C)alkyl,
amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
N,N-di-[(1-4)alkyl]amino(1-3C) alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl
3,4-methylenedioxypyrrolidin-1-yl(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl and a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is pyrrolidin-2-yl,
[0127] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino
or piperazin-1-yl group within a substituent on Q.sup.1 or which is
represented by Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy, oxo,
(1-4C)alkyl, (2-4C)alkanoyl and halogeno (particularly chloro and
more particularly fluoro),
[0128] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl, and
wherein any (1-4C)alkyl group in a substituent on Q.sup.1
optionally bears one or two substituents, which may be the same or
different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro);
(ss) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-4-yl,
piperidin-3-yl, (3R)-piperidin-3-yl and (3S)-piperidin-3-yl,
wherein Q.sup.1 is substituted at the 1-position by a group
selected from (1-4C)alkyl, (1-4C)alkylsulfonyl, (2-4C)alkanoyl,
(2-4C)alkanoyl(1-3C)alkyl, amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl, amino(1-3C)alkylsulfonyl,
N-(1-4C)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl,
3,4-methylenedioxypyrrolidino-1-yl-(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl,
morpholino-(2-4C)alkanoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is pyrrolidin-2-yl,
[0129] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and halogeno
(particularly chloro and more particularly fluoro),
[0130] and wherein any (2-4C)alkanoyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy and (1-3C)alkyl,
[0131] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, (1-4C)alkoxy and halogeno
(particularly chloro and more particularly fluoro),
and wherein any heterocyclyl group within the Q.sup.1-X.sup.2-
group optionally bears an oxo (.dbd.O) substituent; (tt)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, (2R)-piperidin-2-ylmethyl,
(2S)-piperidin-2-ylmethyl, piperidin-3-ylmethyl,
(3R)-piperidin-3-ylmethyl, (3S)-piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein the pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 is substituted on a ring nitrogen by a
substituent selected from methyl, ethyl, isopropyl, isobutyl,
cyclopropylmethyl, methylsulfonyl, ethylsulfonyl,
N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl,
N-cyclopropylmethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, acetyl, propionyl,
isobutyryl-methylsulfamoyl, N-ethylsulfamoyl, N-isopropylsulfamoyl,
N-cyclopropylmethylsulfamoyl, N,N-dimethylsulfamoyl,
N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbamoylmethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N-ethylcarbamoylmethyl, 2-(N-ethylcarbamoyl)ethyl,
N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,
N,N-diethylcarbamoylmethyl, 2-(N,N-diethylcarbamoyl)ethyl,
hydroxyacetyl, 2-hydroxypropionyl, N-methylaminoacetyl,
N-ethylaminoacetyl, 2-(N-methylamino)propionyl,
2-(N-ethylamino)propionyl, N,N-dimethylaminoacetyl,
2-(N,N-di-methylamino)propionyl, N,N-diethylaminoacetyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxyacetyl,
2-(acetoxy)propionyl, 2-(N-methylamino)ethylsulfonyl,
2-(N-methylamino)ethylsulfonyl,
2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl,
3-(N-methylamino)propylsulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propyl sulfonyl,
3-<N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, piperazin-1-ylacetyl,
2-piperazin-1-yl)propionyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from morpholino,
pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and
piperazin-1-yl,
[0132] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,
[0133] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0134] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(uu) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, 3
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, (2R)-piperidin-2-ylmethyl,
(2S)-piperidin-2-ylmethyl, piperidin-3-ylmethyl,
(3R)-piperidin-3-ylmethyl, (3S)-piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein the pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 is substituted on a ring nitrogen by a
substituent selected from, acetyl, propionyl, isobutyryl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-di-methylamino)propionyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxyacetyl,
2-(acetoxy)propionyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, piperazin-1-yl-acetyl and
2-piperazin-1-yl-propionyl,
[0135] and wherein any pyrrolidin-1-yl, piperidino or
piperazin-1-yl group within a substituent on Q.sup.1 or which is
represented by Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy, oxo,
methyl, ethyl, acetyl and fluoro,
[0136] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0137] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(vv) Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl,
pyrrolidin-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, and wherein the pyrrolidinyl group in
Q.sup.1-X.sup.2 is substituted on a ring nitrogen by a substituent
selected from methyl, ethyl, isopropyl, isobutyl, cyclopropyl
methyl, methylsulfonyl, ethylsulfonyl, N-methylcarbamoyl,
N-ethylcarbamoyl, N-isopropylcarbamoyl,
N-cyclopropylmethylcarbamoyl, N,N-dimethyl carbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, acetyl, propionyl,
isobutyryl, N-methylsulfamoyl, N-ethylsulfamoyl,
N-isopropylsulfamoyl, N-cyclopropylmethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbamoylmethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N-ethylcarbamoylmethyl, 2-(N-ethylcarbamoyl)ethyl,
N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,
N,N-diethylcarbamoylmethyl, 2-(N,N-diethylcarbamoyl)ethyl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-methylamino)propionyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxyacetyl,
2-(acetoxy)propionyl, 2-(N-methylamino)ethylsulfonyl,
2-(N-ethylamino)ethylsulfonyl, 2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl 3-(N-methylamino)propylsulfonyl,
3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, piperazin-1-ylacetyl,
2-piperazin-1-ylpropionyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from morpholino,
pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and
piperazin-1-yl,
[0138] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,
[0139] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0140] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(ww) Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl)pyrrolidin-3-ylmethyl,
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl, and wherein
the pyrrolidinyl group in Q.sup.1-X.sup.2 is substituted on the
ring nitrogen by a substituent selected from methyl, ethyl,
isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl,
ethylsulfonyl, N-methylcarbamoyl, N-ethylcarbamoyl,
N-isopropylcarbamoyl, N-cyclopropylmethylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-dimethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, acetyl, propionyl, isobutyryl,
N-methylsulfamoyl, N-ethylsulfamoyl, N-isopropylsulfamoyl,
N-cyclopropylmethylsulfamoyl, N,N-dimethylsulfamoyl,
N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbamoylmethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N-ethylcarbamoylmethyl, 2-(N-ethylcarbamoyl)ethyl,
N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,
N,N-diethylcarbamoylmethyl, 2-(N,N-diethylcarbamoyl)ethyl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-di-methylamino)propionyl,
N,N-diethylaminoacetyl, 2-(N,N-diethylamino)propionyl,
N-methyl-N-ethylaminoacetyl, 2-(N-methyl-N-ethylamino)propionyl,
acetoxyacetyl, 2-(acetoxy)propionyl,
2-(N-methylamino)ethylsulfonyl, 2-(N-ethylamino)ethylsulfonyl,
2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl,
3-(N-methylamino)propylsulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl piperazin-1-ylacetyl,
2-piperazin-1-ylpropionyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidino and piperazin-1-yl,
[0141] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino
or piperazin-1-yl group within a substituent on Q.sup.1 or which is
represented by Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy, oxo,
methyl, ethyl, acetyl and fluoro,
[0142] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which maybe the same or different, selected from hydroxy and
methyl,
[0143] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.3 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(xx) Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl,
pyrrolidin-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, and wherein the pyrrolidinyl group in
Q.sup.1-X.sup.2 is substituted on a ring nitrogen by a substituent
selected from morpholinoacetyl and 2-morpholinopropionyl which
substituent optionally bears one or two substituents, which may be
the same or different, selected from hydroxy, oxo, methyl, ethyl
and fluoro; (yy) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl and piperidin-4-yl, and
wherein a pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 is
substituted on a ring nitrogen by a substituent selected from
methyl, ethyl, isopropyl, isobutyl, cyclopropylmethyl,
methylsulfonyl, ethylsulfonyl, acetyl, propionyl, isobutyryl,
carbamoylmethyl, N-methylcarbamoylmethyl,
2-(N-methylcarbamoyl)ethyl, N-ethylcarbamoylmethyl,
2-(N-ethylcarbamoyl)ethyl, N,N-dimethylcarbamoylmethyl,
2-(N,N-dimethylcarbamoyl)ethyl, N,N-diethylcarbamoylmethyl,
2-(N,N-diethylcarbamoyl)ethyl, N-methylaminoacetyl,
N-ethylaminoacetyl, 2-(N-methylamino)propionyl,
2-(N-ethylamino)propionyl, N,N-dimethylaminoacetyl,
2-(N,N-methylamino)propionyl, N,N-diethylaminoacetyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxy acetyl,
2-(acetoxy)propionyl, 2-(N-methylamino)ethylsulfonyl,
2-(N-ethylamino)ethylsulfonyl, 2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl,
3-(N-methylamino)propylsulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl,
piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from morpholino,
pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and
piperazin-1-yl,
[0144] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,
[0145] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0146] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(zz) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrolidin-3-yl, (3S)-pyrrolidin-3-yl, and wherein the
pyrrolidinyl group in Q.sup.1-X.sup.2 is substituted on a ring
nitrogen by a substituent selected from methyl, ethyl, isopropyl,
isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl,
propionyl, isobutyryl, carbamoylmethyl, N-methylcarbamoylmethyl,
2-(N-methylcarbamoyl)ethyl, N-ethylcarbamoylmethyl,
2-(N-ethylcarbamoyl)ethyl, N-dimethylcarbamoylmethyl,
2-(N,N-dimethylcarbamoyl)ethyl, N,N-diethylcarbamoylmethyl,
2-(N,N-diethylcarbamoyl)ethyl, N-methyl aminoacetyl,
N-ethylaminoacetyl, 2-(N-methylamino)propionyl,
2-(N-ethylamino)propionyl), N,N-dimethylaminoacetyl,
2-(N,N-di-methylamino)propionyl, N,N-diethyl aminoacetyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxyacetyl,
2-(acetoxy)propionyl, 2-(N-methylamino)ethylsulfonyl,
2-(N-ethylamino)ethylsulfonyl, 2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl, 3-(N-methylamino)propylsulfony,
3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-methylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl,
piperazin-1-ylacetyl, 2-piperazin-1-ylpropiony-1 and a group of the
formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from morpholino,
pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and
piperazin-1-yl,
[0147] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,
[0148] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0149] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(aaa) Q.sup.1-X.sup.2 is selected from piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl and piperidin-4-yl, and
wherein the piperidinyl group in Q.sup.1-X.sup.2 is substituted on
the ring nitrogen by a substituent selected from methyl, ethyl,
isopropyl, isobutyl, cyclopropylmethyl, methylsulfonyl,
ethylsulfonyl, acetyl, propionyl, isobutyryl, carbamoylmethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N-ethylcarbamoylmethyl, 2-(N-ethylcarbamoyl)ethyl,
N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,
N,N-diethylcarbamoylmethyl, 2-(N,N-diethylcarbamoyl)ethyl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-dimethylamino)propionyl,
N,N-diethylaminoacetyl, 2-(N,N-diethylamino)propionyl,
N-methyl-N-ethylaminoacetyl, 2-(N-methyl-N-ethylamino)propionyl,
acetoxyacetyl, 2-(acetoxy)propionyl,
2-(N-methylamino)ethylsulfonyl, 2-(K-ethylamino)ethylsulfonyl,
2-(N,N-di-methylamino)ethylsulfanyl,
2-(N,N-di-ethylamino)ethylsulfonyl,
3-(N-methylamino)propylsulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-yl acetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl, morpholinoacetyl, 2-morpholinopropionyl,
piperazin-1-ylacetyl, 2-piperazin-1-ylpropionyl and a group of the
formula;
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from morpholino,
pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino and
piperazin-1-yl,
[0150] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl,
morpholino, piperidino or piperazin-1-yl group within a substituent
on Q.sup.1 or which is represented by Q.sup.2 optionally bears one
or two substituents, which may be the same or different, selected
from hydroxy, oxo, methyl, ethyl, acetyl, fluoro and chloro,
[0151] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0152] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(bbb) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, pyrolidin-3-ylmethyl,
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, (2R)-piperidin-2-ylmethyl,
(2S)-piperidin-2-ylmethyl, piperidin-3-ylmethyl,
(3R)-piperidin-3-ylmethyl, (3S)-piperidin-3-ylmethyl and
piperidin-4-ylmethyl; (ccc) Q.sup.1-X.sup.2 is selected from
pyrrolidin-3-yl, (3R)-pyrrolidin-3-yl and (3S)-pyrrolidin-3-yl;
(ddd) Q.sup.1-X.sup.2 is selected from piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl and piperidin-4-yl; (eee)
Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl-3 (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidinyl-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, (2R)-piperidin-2-ylmethyl,
(2S)-piperidin-2-ylmethyl, piperidin-3-ylmethyl,
(3R)-piperidin-3-ylmethyl, (3S)-piperidin-3-ylmethyl and
piperidin-4-ylmethyl,
[0153] and wherein the pyrrolidinyl or piperidinyl group in
Q.sup.1-X.sup.2 is substituted on the ring nitrogen by a
substituent selected from N-methylcarbamoyl, N-ethylcarbamoyl,
N-isopropylcarbamoyl, N-cyclopropylmethylcarbamoyl,
N,N-dimethylcarbamoyl,
[0154] > N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl,
N-methylsulfamoyl, N-ethylsulfamoyl, N-isopropylsulfamoyl,
N-cyclopropylmethylsulfamoyl N-dimethylsulfamoyl,
N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbamoylmethyl,
N-methylcarbamoylmethyl, 2-(N-methylcarbamoyl)ethyl,
N-ethylcarbamoylmethyl, 2-(N-ethylcarbamoyl)ethyl,
N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 3
N,N-diethylcarbamoylmethyl, 2-(N,N-diethylcarbamoyl)ethyl,
N-methylaminoacetyl, N-ethylaminoacetyl,
2-(N-methylamino)propionyl, 2-(N-ethylamino)propionyl,
N,N-dimethylaminoacetyl, 2-(N,N-di-methylamino)propionyl,
2-(N,N-diethylamino)propionyl, N-methyl-N-ethylaminoacetyl,
2-(N-methyl-N-ethylamino)propionyl, acetoxyacetyl,
2-(acetoxy)propionyl, 2-(N-methylamino)ethylsulfonyl,
2-(N-ethylamino)ethylsulfonyl, 2-(N,N-di-methylamino)ethylsulfonyl,
2-(N,N-di-ethylamino)ethylsulfonyl,
3-(N-methylamino)propylsulfonyl, 3-(N-ethylamino)propylsulfonyl,
3-(N,N-di-methylamino)propylsulfonyl,
3-(N,N-di-ethylamino)propylsulfonyl, pyrrolidin-1-ylacetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl piperazin-1-ylacetyl,
2-piperazin-1-ylpropionyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
pyrrolidin-2-yl, piperidino and piperazin-1-yl,
[0155] and wherein any pyrrolidin-1-yl, pyrrolidin-2-yl, piperidino
or piperazin-1-yl group within a substituent on Q.sup.1 or which is
represented by Q.sup.2 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy, oxo,
methyl, ethyl, acetyl, fluoro and chloro,
[0156] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(fff) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,
(3R)-pyrrolidin-3-ylmethyl, (3S)-pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, (2R)-piperidin-2-ylmethyl,
(2S)-piperidin-2-ylmethyl, piperidin-3-ylmethyl,
(3R)-piperidin-3-ylmethyl, (3S)-piperidin-3-ylmethyl and
piperidin-4-ylmethyl,
[0157] and wherein the pyrrolidinyl or piperidinyl group in
Q.sup.1-X.sup.2 is substituted on the ring nitrogen by a
substituent selected from pyrrolidin-1-yl acetyl,
2-(pyrrolidin-1-yl)propionyl,
3,4-methylenedioxypyrrolidin-1-ylacetyl,
2-(3,4-methylenedioxypyrrolidin-1-yl)propionyl, piperidinoacetyl,
2-piperidinopropionyl piperazin-1-ylacetyl and
2-piperazin-1-ylpropionyl
[0158] and wherein any pyrrolidin-1-yl, piperidino or
piperazin-1-yl group within a substituent on Q.sup.1 optionally
bears one or two substituents, which may be the same or different,
selected from hydroxy, oxo, methyl, ethyl, acetyl and fluoro,
[0159] and wherein any acetyl, propionyl or isobutyryl group in a
substituent on Q.sup.1 optionally bears one or two substituents,
which may be the same or different, selected from hydroxy and
methyl,
[0160] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which may be the
same or different, selected from hydroxy, methoxy, fluoro,
chloro;
(ggg) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)-pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, 3 piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, and piperidin-4-ylmethyl, and wherein
the pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 is
optionally substituted on the ring nitrogen by a substituent
selected from methyl, acetyl, carbamoylmethyl, N-methylaminoacetyl,
N,N-dimethylaminoacetyl, 3-(N,N-di-methylamino)propylsulfonyl and
pyrrolidin-1-ylacetyl,
[0161] and wherein any pyrrolidin-1-yl, group within a substituent
on Q.sup.1 optionally bears one or two substituents, which may be
the same or different, selected from hydroxy, oxo, methyl, ethyl,
acetyl and fluoro,
[0162] and wherein any (1-4C)alkyl group in a substituent on
Q.sup.1 optionally bears one or two substituents, which maybe the
same or different, selected from hydroxy, methoxy, fluoro,
chloro,
[0163] and wherein any acetyl group in a substituent on Q.sup.1
optionally bears a hydroxy substituent;
(hhh) Q.sup.1-X.sup.2 is selected from pyrrolidin-3-yl,
(3R)pyrrolidin-3-yl, (3S)-pyrrolidin-3-yl, piperidin-3-yl,
(3R)-piperidin-3-yl, (3S)-piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl,
(2S)-pyrrolidin-2-ylmethyl, and piperidin-4-ylmethyl, and wherein
the pyrrolidinyl or piperidinyl group in Q.sup.3-X.sup.2 is
substituted on the ring nitrogen by a substituent selected from
methyl, acetyl, hydroxyacetyl, carbamoylmethyl,
N-methylaminoacetyl, N,N-dimethylaminoacetyl and
pyrrolidin-1-ylacetyl; (iii) Q.sup.1-X.sup.2 is selected from
piperidin-4-yl, pyrrolidin-2-ylmethyl, (2R)-pyrrolidin-2-ylmethyl
and (2S)-pyrrolidin-2-ylmethyl, and wherein the pyrrolidinyl or
piperidinyl group in Q.sup.1-X.sup.2 is substituted on the ring
nitrogen by a substituent selected from acetyl, hydroxyacetyl,
N,N-dimethylaminoacetyl and pyrrolidin-1-ylacetyl; (jjj)
Q.sup.1-X.sup.2 is selected from pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl and (2S)-pyrrolidin-2-ylmethyl, and
wherein the pyrrolidinyl in Q.sup.3-X.sup.2 is substituted on the
ring nitrogen by a substituent selected from N-methylaminoacetyl,
N,N-dimethylaminoacetyl and pyrrolidin-1-ylacetyl; (kkk)
Q.sup.1-X.sup.2 is a group of the formula A:
##STR00004##
wherein:
[0164] R.sup.4 is selected from carbamoyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is a heterocyclyl group selected
from a 4, 5 or 6-membered monocyclic heterocyclyl group containing
1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected
from sulfur, oxygen and nitrogen,
[0165] and wherein Q.sup.2 is attached to X.sup.3 by a ring
nitrogen atom,
[0166] and wherein Q.sup.2 optionally bears one or more
substituents (for example 1, 2 or 3), which may be the same or
different, selected from halogeno, hydroxy, (1-4C)alkyl and
(2-4C)alkanoyl,
[0167] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.4 optionally bears one or more substituents (for example 1, 2
or 3) which may be the same or different selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl and
(1-6C)alkoxy,
[0168] R.sup.5 is selected from hydrogen, (1-6C)alkyl,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkanoyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl
and(2-6C)alkanoyl(1-6C)alkyl,
[0169] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.5 optionally bears one or more substituents (for example 1, 2
or 3), which may be the same or different, selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-6C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, nitro and (1-4C)alkoxy,
[0170] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from halogeno,
hydroxy, (1-4C)alkyl and (1-3C)alkylenedioxy, and may optionally
bear on any available ring nitrogen a substituent (provided the
ring is not thereby quaternised) selected from (1-4C)alkyl and
(2-4C)alkanoyl,
[0171] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents(for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy,
[0172] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2 group optionally bears 1 or 2oxo (.dbd.O) or thioxo
(.dbd.S) substituents;
(lll) Q.sup.1-X.sup.2 is a group of the formula A as defined in
(kkk) above wherein: R.sup.4 is selected from carbamoyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and a group
of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino, piperidino and piperazin-1-yl
[0173] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from halogeno,
hydroxy, (1-4C)alkyl, oxo and (2-4C)alkanoyl,
[0174] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.4 optionally bears one or more substituents (for example 1, 2
or 3) which may be the same or different selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl and
(1-6C)alkoxy,
[0175] R.sup.5 is selected from hydrogen, (1-6C)alkyl,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkanoyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl
and(2-6C)alkanoyl(1-6C)alkyl,
[0176] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.5 optionally bears one or more substituents (for example 1, 2
or 3) which may be the same or different selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, nitro and (1-4C)alkoxy,
[0177] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a ring selected from pyrrolidin-1-yl,
piperidino, morpholino and piperazin-1-yl, which ring optionally
bears 1 or 2 substituents, which may be the same or different, on
an available ring carbon atom selected from halogeno, hydroxy,
(1-4C)alkyl and oxo, and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) selected from (1-4C)alkyl and (2-4C)alkanoyl,
[0178] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents(for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy;
(mmm) Q.sup.1-X.sup.2 is a group of the formula A as defined in
(kkk) above wherein: R.sup.4 is selected from carbamoyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and to a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino, piperidino and piperazin-1-yl
[0179] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from fluoro, chloro,
hydroxy, methyl, oxo and acetyl,
[0180] and wherein any (1-6C)alkyl group within R.sup.4 optionally
bears one or more substituents (for example 1, 2 or 3) which may be
the same or different selected from fluoro, chloro and hydroxy
and/or optionally a substituent selected from cyano, nitro, vinyl,
ethynyl and methoxy,
[0181] R.sup.5 is selected from hydrogen, (1-4C)alkyl,
(1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl,
(2-4C)alkanoyl, carbamoyl(1-4C)alkyl,
N-(1-4C)alkylcarbamoyl(1-4C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-4C)alkyl, sulfamoyl(1-4C)alkyl,
N-(1-4C)alkylsulfamoyl(1-4C)alkyl,
N,N-di-[(1-4C)alkyl]sulfamoyl(1-4C)alkyl and
(2-4C)alkanoyl(1-4C)alkyl,
[0182] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group within
R.sup.3 optionally bears one or more substituents (for example 1, 2
or 3), which may be the same or different, selected from fluoro,
chloro, hydroxy, methyl and ethyl and/or optionally a substituent
selected from cyano, nitro, vinyl, ethynyl, methoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3), which may be the same or different, selected
from fluoro, chloro and hydroxy and/or optionally a substituent
selected from cyano, nitro and methoxy,
[0183] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a ring selected from pyrrolidin-1-yl,
piperidino, morpholino and piperazin-1-yl, which ring optionally
bears 1 or 2 substituents, which may be the same or different, on
an available ring carbon atom selected from halogeno, hydroxy,
methyl, ethyl and oxo, and may optionally bear on any available
ring nitrogen a substituent (provided the ring is not thereby
quaternised) selected from methyl, ethyl and acetyl;
(nnn) Q.sup.1-X.sup.2 is a group of the formula A as defined in
(kkk) above wherein: R.sup.4 is selected from carbamoyl,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl and a group
of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino, piperidino and piperazin-1-yl,
[0184] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from fluoro, chloro,
hydroxy, methyl, oxo and acetyl,
[0185] and wherein any (1-4C)alkyl group within R.sup.4 optionally
bears 1 or 2 substituents, which may be the same or different,
selected from fluoro, chloro and hydroxy and/or optionally a
substituent selected from cyano, nitro, vinyl, ethynyl and
methoxy,
[0186] R.sup.5 is selected from hydrogen, methyl, ethyl, isopropyl,
isobutyl, cyclopropylmethyl, methylsulfonyl, ethylsulfonyl, acetyl,
propionyl, isobutyryl, carbamoylmethyl,
N-(1-4C)alkylcarbamoylmethyl, N,N-di-[(1-4C)alkyl]carbamoylmethyl,
sulfamoylmethyl, N-(1-4C)alkylsulfamoylmethyl and
N,N-di-[(1-4C)alkyl]sulfamoylmethyl
[0187] and wherein any (1-4C)alkyl, acetyl, propionyl or isobutyryl
group within R.sup.5 optionally bears 1 or 2 substituents, which
may be the same or different, selected from fluoro, chloro and
hydroxy, methyl and ethyl and/or optionally a substituent selected
from cyano, nitro, vinyl, ethynyl, methoxy and NR.sup.aR.sup.b,
wherein R.sup.a is hydrogen or (1-4C)alkyl and R.sup.b is hydrogen
or (1-4C)alkyl, and wherein any (1-4C)alkyl in R.sup.a or R.sup.b
optionally bears 1 or 2 substituents, which may be the same or
different, selected from fluoro, chloro and hydroxy and/or
optionally a substituent selected from cyano, nitro and
methoxy,
[0188] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a ring selected from pyrrolidin-1-yl,
piperidino, morpholino and piperazin-1-yl, which ring optionally
bears 1 or 2 substituents, which may be the same or different, on
an available ring carbon atom selected from halogeno, hydroxy,
methyl, and oxo, and may optionally bear on any available ring
nitrogen a substituent (provided the ring is not thereby
quaternised) selected from methyl and acetyl;
(ooo) Q.sup.1-X.sup.2 is a group of the formula A as defined in
(kkk) above wherein:
[0189] R.sup.4 is selected from N,N-di-[(1-4C)alkyl]carbamoyl and a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-j-yl,
morpholino and piperidino,
[0190] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from fluoro, chloro,
hydroxy, methyl and oxo,
[0191] and wherein any (1-4C)alkyl group within R.sup.4 optionally
bears 1 or 2 substituents, which may be the same or different,
selected from fluoro, chloro and hydroxy and/or optionally a
substituent selected from methoxy,
[0192] R.sup.5 is selected from hydrogen, methyl, ethyl, isopropyl,
isobutyl and cyclopropylmethyl,
[0193] and wherein any (1-4C)alkyl group within R.sup.5 optionally
bears 1 or 2 substituents, which may be the same or different,
selected from fluoro, chloro and hydroxy, and/or optionally a
substituent selected from methoxy;
(ppp) Q.sup.1-X.sup.2 is a group of the formula A as defined in
(kkk) above wherein: R.sup.4 is selected from
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino (particularly
R.sup.4 is N,N-dimethylcarbamoyl),
[0194] R.sup.5 is selected from hydrogen, methyl and ethyl
(particularly R.sup.5 is hydrogen or methyl, more particularly
methyl);
(qqq) R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1-X.sup.1 optionally bears 1, 2 or 3 substituents, which may
be the same or different, selected from hydroxy, fluoro and chloro,
for example R.sup.1-X.sup.1 is selected from methoxy, ethoxy,
isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy,
2-methoxyethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or
3-hydroxy-3-methylbutoxy.
[0195] As will be realised the group represented by formula A in
paragraphs (kkk) to (ppp) above contains two chiral centres on the
pyrrolidinyl ring. As mentioned hereinbefore the present invention
encompasses all stereoisomers of the group of formula A, for
example the (2R,4R), (2S,4S), (2R,4S) and (2S,4R) isomers.
[0196] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen, (1-6C)alkoxy and
(1-6C)alkoxy(1-6C)alkoxy, wherein any (1-6C)alkoxy group in
R.sup.1-X.sup.3- optionally bears one or more hydroxy substituent
(suitably 1 or 2) and/or a substituent selected from amino,
(1-4C)alkylamino, di-[(1-4C)alkyl]amino, carbamoyl,
N-(1-4C)alkylcarbamoyl and N,N-di-[(1-4C)alkyl]carbamoyl,
sulfamoyl, N-(1-4C)alkylsulfamoyl and
N,N-di-[(1-4C)alkyl]sulfamoyl; X.sup.2 is a direct bond or
[CR.sup.2R.sup.3].sub.m, wherein m is 1, 2 or 3 (particularly 1 or
2, more particularly 1), and R.sup.2 and R.sup.3 each independently
is hydrogen, methyl, ethyl or hydroxy (preferably hydrogen);
Q.sup.1 is a non-aromatic saturated or partially saturated 3 to 7
membered monocyclic heterocyclyl ring with 1 nitrogen heteroatom
and optionally 1 or 2 heteroatoms selected from oxygen, nitrogen
and sulfur, which ring is linked to the group X.sup.2--O-- by a
carbon atom in the ring,
[0197] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, carbamoyl,
trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl,
hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, amino(1-6C)alkyl,
(1-6C)alkylamino(1-6C)alkyl,
di-[(1-6C)alkyl)amino(1-6C)alkyl]amino(2-6C)alkanoyl,
(1-6C)alkylamino-(2-6C)alkanoyl,
N,N-di[(1-6C)alkyl]amino-(2-6C)alkanoyl, (1-6C)alkoxy(1-6C)alkyl,
hydroxy(1-6C)alkoxy(1-6C)alkyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl,
(2-6C)alkanoyl(1-6C)alkyl, (2-6C)alkanoyloxy(1-6C)alkyl,
(2-6C)alkanoylamino(1-6C)alkyl,
N,N-(1-6C)alkyl-(2-6C)alkanoylamino(1-6C)alkyl,
(1-6C)alkoxycarbonyl(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkylS(O).sub.q
(wherein q is 0, 1 or 2), amino(1-6C)alkylS(O).sub.q (wherein q is
0, 1 or 2), N-(1-6C)alkylamino(1-6C)alkylS(O).sub.q (wherein q is
0, 1 or 2) and N,N-di[(1-6C)alkyl]amino(1-6C)alkylS(O).sub.q
(wherein q is 0, 1 or 2),
[0198] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from (1-4C)alkyl,
(2-6C)alkenyl, (2-6C)alkynyl and oxo,
[0199] and wherein any (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl or
(2-6C)alkanoyl group in Q.sup.3 optionally bears 1 or 2
substituents which may be the same or different selected from
fluoro and chloro; and
G.sup.1 and G.sup.2 each independently is selected from fluoro,
chloro and bromo (particularly G.sup.1 is fluoro and G.sup.2
chloro); or a pharmaceutically acceptable salt thereof.
[0200] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen, methoxy, ethoxy and
2-methoxyethoxy; X.sup.2 is a direct bond or [CH.sub.2].sub.m,
wherein m is 1 or 2 (suitably 1); Q.sup.1 is a non-aromatic
saturated 5 or 6 membered monocyclic heterocyclyl ring with 1
nitrogen heteroatom and optionally 1 or 2 (suitably 1) heteroatoms
selected from oxygen and nitrogen, which ring is linked to the
group X.sup.2--O-- by a carbon atom in the ring,
[0201] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, carbamoyl,
(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkylsulfonyl,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,
(2-4C)alkanoyl, sulfamoyl, N-(1-4C)alkylsulfamoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, cyano(1-4C)alkyl,
(1-4C)alkoxy(1-4C)alkyl, amino(2-4C)alkanoyl,
(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl,
(1-4C)alkoxy(1-3C)alkylS(O).sub.q (wherein q is 0, 1 or suitably
2), amino(1-3C)alkylS(O).sub.q (wherein q is 0, 1 or suitably 2),
N-(1-4C)alkylamino(1-3C)alkylS(O).sub.q (wherein q is 0, 1 or
suitably 2) and N,N-di[(1-4)alkyl]amino(1-3C)alkylS(O).sub.q
(wherein q is 0, 1 or suitably 2),
[0202] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from oxo, (1-4C)alkyl,
(2-6C)alkenyl and (2-6C)alkynyl,
[0203] and wherein any (1-4C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl
in Q.sup.1 optionally bears 1 or 2 substituents which may be the
same or different selected from fluoro and chloro; and G.sup.1 and
G.sup.2 each independently is selected from fluoro, chloro and
bromo (particularly G.sup.1 is fluoro and G.sup.2 chloro);
or a pharmaceutically acceptable salt thereof.
[0204] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen, methoxy, ethoxy and
2-methoxyethoxy; X.sup.2 is a direct bond or CH.sub.2; Q.sup.1 is
selected from pyrrolidin-2-yl, pyrrolidin-3-yl, 2-pyrrolin-2-yl,
2-pyrrolin-3-yl, 3-pyrrolin-3-yl, morpholin-2-yl, morpholin-3-yl,
thiomorpholin-2-yl, thiomorpholin-3-yl, piperidin-2-yl,
piperidin-3-yl, piped din-4-yl, 2-3- or 4-homopiperidinyl,
piperazin-1-yl, 2-oxopiperazin-1-yl, 3-oxopiperazin-1-yl,
piperazin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl,
1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-5-yl,
1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,6 or 7-homopiperazinyl and
azetidin-3-yl,
[0205] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, (1-4C)alkyl,
cyano(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylsulfonyl,
trifluoromethyl, carbamoyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl, sulfamoyl,
N-(1-4C)alkylsulfamoyl, N,N-di-[(1-4C)alkyl]sulfamoyl,
amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl, carbamoyl(1-3C)alkyl,
N-(1-4C)alkylcarbamoyl(1-3C)alkyl, (1-4C)alkoxy(1-3C)alkylsulfonyl,
amino(1-3C)alkylsulfonyl, N-(1-4C)alkylamino(1-3C)alkylsulfonyl and
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl, and Q.sup.1 optionally
bears on any available carbon atom in the ring 1 or 2 substituents
selected from (1-4C)alkyl and oxo,
[0206] and wherein any (1-4C)alkyl group in Q.sup.1 optionally
bears 1 or 2 fluoro substituents (to give for example 2-fluoroethyl
or 2,2-difluoroethyl); and
G.sup.1 and G.sup.2 each independently is selected from fluoro and
chloro (particularly G.sup.1 is fluoro and G.sup.2 chloro); or a
pharmaceutically acceptable salt thereof,
[0207] Suitable values for Q.sup.1X.sup.2 in this embodiment
include, for example, 1-methyl pyrrolidin-3-yl, piperidin-4-yl,
piperidin-4-ylmethyl, 1-methylpiperidin-4-yl,
1-methylpiperidin-4-ylmethyl, 1-(2-methoxyethyl)piperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-ylmethyl,
1-methylsulfonylpiperidin-4-yl,
1-methylsulfonylpiperidin-4-ylmethyl, 1-cyanopiperidin-4-yl,
1-cyanopiperidin-4-ylmethyl, 1-cyanomethylpiperidin-4-yl,
1-cyanomethylpiperidin-4-ylmethyl, 1-carbamoylmethylpiperidin-4-yl,
1-carbamoylmethylpiperidin-4-ylmethyl.
[0208] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen and methoxy; X.sup.2 is
a direct bond; Q.sup.1 is selected from pyrrolidin-2-yl,
pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl and
piperidin-4-yl,
[0209] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from cyano, cyanomethyl,
methyl, ethyl, carbamoyl, carbamoylmethyl, 2-methoxyethyl,
methylsulfonyl and ethylsulfonyl (suitably methylsulfonyl and
carbamoylmethyl)>
[0210] and Q.sup.1 optionally bears on any available carbon atom in
the ring 1 or 2 substituents selected from methyl, ethyl and oxo;
and
G.sup.1 and G.sup.2 each independently is selected from fluoro,
chloro and bromo (particularly G.sup.1 is fluoro and G.sup.2
chloro); or a pharmaceutically acceptable salt thereof.
[0211] Suitable values for Q.sup.1X.sup.2 in this embodiment
include, for example, piperidin-4-yl, 1-methylpiperidin-4-yl,
1-(2-methoxyethyl)piperidin-4-yl, 1-methylsulfonylpiperidin-4-yl,
1-cyanopiperidin-4-yl, 1-cyanomethylpiperidin-4-yl and
1-carbamoylmethylpiperidin-4-yl.
[0212] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen, (1-4C)alkoxy and
(1-4C)alkoxy(1-4C)alkoxy (particularly hydrogen and methoxy);
X.sup.2 is a direct bond or CH.sub.2; Q.sup.1 is a fully saturated
5 or 6 membered monocyclic heterocyclyl ring with 1 nitrogen
heteroatom and optionally 1 additional heteroatom selected from
oxygen, nitrogen and sulfur, which ring is linked to the group
X.sup.2--O by a carbon atom in the ring, and wherein Q.sup.1 bears
one substituent on a ring carbon atom selected from carbamoyl,
N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,
carbamoyl(1-3C)alkyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N-di-[(1-4C)alkyl]carbamoyl(1-3C)alkyl, (2-4)alkanoyl,
amino(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl,
piperazin-1-yl-(2-4C)alkanoyl and morpholino-(2-4C)alkanoyl, or a
group of the formula:
Q.sup.2-X.sup.3
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino,
[0213] and wherein the nitrogen atom of any NH group in Q.sup.1
optionally bears a substituent selected from (1-4C)alkyl,
[0214] and wherein any heterocyclyl group within the
Q.sup.1-X.sup.2- group optionally hears an oxo (.dbd.O)
substituent; and
G.sup.1 and G.sup.2 each independently is selected from fluoro and
chloro (particularly G.sup.1 is fluoro and G.sup.2 chloro); or a
pharmaceutically acceptable salt thereof.
[0215] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen and (1-4C)alkoxy
(particularly hydrogen and methoxy); Q.sup.1-X.sup.2 is selected
from pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, 3 pyrrolidin-3-ylmethyl,
piperidin-2-ylmethyl, piperidin-3-ylmethyl and
piperidin-4-ylmethyl, and wherein a pyrrolidinyl or piperidinyl
group in Q.sup.1-X.sup.2 carries one or two substituents selected
from (1-4C)alkyl, (1-4C)alkylsulfonyl, N-(1-4C)alkylcarbamoyl,
N,N-di-[(1-4C)alkyl]carbamoyl, (2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]sulfamoyl, N-(1-4C)alkylcarbamoyl(1-3C)alkyl,
N,N-di[(1-4C)alkyl]carbamoyl(1-3C)alkyl, hydroxy(2-4C)alkanoyl,
N-(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl
(2-4C)alkanoyloxy-(2-4C)alkanoyl,
N-(1-4)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4C)alkyl]amino(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl,
morpholino-(2-4C)alkanoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino; and G.sup.1 and G.sup.2 each
independently is selected from fluoro and chloro (particularly
G.sup.1 is fluoro and G.sup.2 chloro); or a pharmaceutically
acceptable salt thereof,
[0216] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen and (1-4C)alkoxy
(particularly methoxy); Q.sup.1-X.sup.2 is selected from
pyrrolidin-3-yl, pyrrolidin-2-ylmethyl and pyrrolidin-3-ylmethyl,
and wherein the pyrrolidinyl group carries one substituent in the
5-position selected from N,N-di-[(1-4C)alkyl]carbamoyl and a group
of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino, and wherein the
pyrrolidinyl group optionally bears a substituent at the 1-position
selected from(1-4C)alkyl; G.sup.1 is fluoro; and G.sup.2 is chloro;
or a pharmaceutically acceptable salt thereof.
[0217] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1- is selected from hydrogen and (1-4C)alkoxy
(particularly methoxy); Q.sup.1-X.sup.2 is selected from
pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,
pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl,
piperidin-3-ylmethyl and piperidin-4-ylmethyl, and wherein a
pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 carries a
substituent at the 1-position selected from (1-4C)alkyl,
(1-4C)alkylsulfonyl, (2-4C)alkanoyl, hydroxy(2-4C)alkanoyl,
N-(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl,
N,N-di[(1-4C)alkyl]amino(1-3C)alkylsulfonyl;
pyrrolidin-1-yl-(2-4C)alkanoyl, piperidino-(2-4C)alkanoyl and
morpholino-(2-4C)alkanoyl or a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is morpholino; G.sup.1 is fluoro;
and G.sup.2 is chloro; or a pharmaceutically acceptable salt
thereof.
[0218] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1X.sup.1 optionally bears 1, 2 or 3 substituents, which may
be the same or different, selected from hydroxy, fluoro, chloro
(for example R.sup.1-X.sup.1 is selected from hydrogen, methoxy,
ethoxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, a particular
value for R.sup.1-X.sup.1 being hydrogen or (1-4C)alkoxy, more
particularly (1-4C)alkoxy, such as methoxy); Q.sup.1-X.sup.2 is
selected from pyrrolidin-3-yl, (3R)-pyrrolidin-3-yl,
(3S)-pyrrolidin-3-yl, piperidin-3-yl, (3R)-piperidin-3-yl,
(3S)-piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl,
pyrrolidin-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl,
(2R)-piperidin-2-ylmethyl, (2S)-piperidin-2-ylmethyl,
piperidin-3-ylmethyl, (3R)-piperidin-3-ylmethyl, (3S)-methyl,
(3S)-piperidin-3-ylmethyl and piperidin-4-ylmethyl, and wherein the
pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 carries a
substituent at the 1 position selected from (1-4C)alkyl,
(1-4C)alkylsulfonyl, (2-4C)alkanoyl, carbamoyl(1-3C)alkyl,
N-(1-4)alkylcarbamoyl hydroxy(2-4C)alkanoyl,
N,N-(1-4C)alkylamino-(2-4C)alkanoyl,
N,N-di-[(1-4C)alkyl]amino-(2-4C)alkanoyl,
(2-4C)alkanoyloxy-(2-4C)alkanoyl
N-(1-4)alkylamino-(1-3C)alkylsulfonyl,
N,N-di[(1-4)alkyl]amino(1-3C)alkylsulfonyl,
pyrrolidin-1-yl-(2-4C)alkanoyl,
3,4-methylenedioxypyrrolidin-1-yl-(2-4C)alkanoyl,
piperidino-(2-4C)alkanoyl, piperazin-1-yl-(2-4C)alkanoyl and a
group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-2-yl,
and wherein any pyrrolidinyl, piperidino or piperazin-1-yl within a
substituent on Q.sup.1 optionally bears one or two substituents
selected from fluoro, chloro, hydroxy, oxo, methyl and acetyl;
G.sup.1 is fluoro; and G.sup.2 is chloro; or a pharmaceutically
acceptable salt thereof.
[0219] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1-X.sup.1 optionally bears 1, 2 or 3 substituents, which may
be the same or different, selected from hydroxy, fluoro, chloro
(for example R.sup.1-X.sup.1 is selected from hydrogen, methoxy,
ethoxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, a particular
value for R.sup.1-X.sup.1 being hydrogen or (1-4C)alkoxy, more
particularly (1-4C)alkoxy such as methoxy); Q.sup.1-X.sup.2 is
selected from pyrrolidin-3-yl, (3R)-pyrrolidin-3-yl,
(3S)-pyrrolidin-3-yl, piperidin-3-yl, (3R)-piperidin-3-yl,
(3S)-piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-ylmethyl,
(2R)-pyrrolidin-2-ylmethyl, (2S)-pyrrolidin-2-ylmethyl, pyrrol)
din-3-ylmethyl, (3R)-pyrrolidin-3-ylmethyl,
(3S)-pyrrolidin-3-ylmethyl, piperidin-2-ylmethyl,
(2R)-piperidin-2-ylmethyl, (2S)-piperidin-2-ylmethyl,
piperidin-3-ylmethyl, (3R)-piperidin-3-ylmethyl,
(3S)-piperidin-3-ylmethyl and piperidin-4-ylmethyl, and wherein the
pyrrolidinyl or piperidinyl group in Q.sup.1-X.sup.2 carries a
substituent at the 1 position selected from morpholino
(2-4C)alkanoyl; G.sup.1 is fluoro; and G.sup.2 is chloro; or a
pharmaceutically acceptable salt thereof.
[0220] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1X.sup.1 optionally bears 1, 2 or 3 substituents, which may
be the same or different, selected from hydroxy, fluoro, chloro
(for example R.sup.1-X.sup.1 is selected from hydrogen, methoxy,
ethoxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, a particular
value for R.sup.1-X.sup.1 being hydrogen or (1-4C)alkoxy, more
particularly (1-4C)alkoxy such as methoxy); Q.sup.1-X.sup.2 is a
group of the formula A:
##STR00005##
wherein:
[0221] R.sup.4 is selected from carbamoyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl and a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is a heterocyclyl group selected
from a 4, 5 or 6-membered monocyclic heterocyclyl group containing
1 nitrogen heteroatom and optionally 1 or 2 heteroatoms selected
from sulfur, oxygen and nitrogen,
[0222] and wherein Q.sup.2 is attached to X.sup.3 by a ring
nitrogen atom,
[0223] and wherein Q.sup.2 optionally bears one or more
substituents (for example 1, 2 or 3), which may be the same or
different, selected from halogeno, hydroxy, (1-4C)alkyl, oxo and
(2-4C)alkanoyl,
[0224] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.4 optionally bears one or more substituents (for example 1, 2
or 3) which may be the same or different selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl and
(1-6C)alkoxy,
[0225] R.sup.5 is selected from hydrogen, (1-6C)alkyl,
(1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl,
(2-6C)alkanoyl, carbamoyl(1-6C)alkyl,
N-(1-6C)alkylcarbamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl(1-6C)alkyl, sulfamoyl(1-6C)alkyl,
N-(1-6C)alkylsulfamoyl(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]sulfamoyl(1-6C)alkyl and
(2-6C)alkanoyl(1-6C)alkyl,
[0226] and wherein any (1-6C)alkyl or (2-6C)alkanoyl group within
R.sup.5 optionally bears one or more substituents (for example 1, 2
or 3) which may be the same or different selected from halogeno,
hydroxy and (1-6C)alkyl and/or optionally a substituent selected
from cyano, nitro, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy and
NR.sup.aR.sup.b, wherein R.sup.a is hydrogen or (1-4C)alkyl and
R.sup.b is hydrogen or (1-4C)alkyl, and wherein any (1-4C)alkyl in
R.sup.a or R.sup.b optionally bears one or more substituents (for
example 1, 2 or 3) which may be the same or different selected from
halogeno and hydroxy and/or optionally a substituent selected from
cyano, nitro and (1-4C)alkoxy,
[0227] or R.sup.a and R.sup.b together with the nitrogen atom to
which they are attached form a 4, 5 or 6 membered ring, which
optionally bears 1 or 2 substituents, which may be the same or
different, on an available ring carbon atom selected from halogeno,
hydroxy, (1-4C)alkyl, (1-3C)alkylenedioxy and oxo, and may
optionally bear on any available ring nitrogen a substituent
(provided the ring is not thereby quaternised) selected from
(1-4C)alkyl and (2-4C)alkanoyl,
[0228] and wherein any (1-4C)alkyl or (2-4C)alkanoyl group present
as a substituent on the ring formed by R.sup.a and R.sup.b together
with the nitrogen atom to which they are attached optionally bears
one or more substituents (for example 1, 2 or 3), which may be the
same or different, selected from halogeno and hydroxy and/or
optionally a substituent selected from (1-4C)alkyl and
(1-4C)alkoxy;
G.sup.1 is fluoro; and G.sup.2 is chloro; or a pharmaceutically
acceptable salt thereof.
[0229] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
[0230] R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1X.sup.1 optionally bears 1, 2 or 3 substituents, which may
be the same or different, selected from hydroxy, fluoro, chloro
(for example R.sup.1-X.sup.1 is selected from hydrogen, methoxy,
ethoxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy,
2-fluoroethoxy, 2-methoxyethoxy, 2,2-difluoroethoxy,
2,2,2-trifluoroethoxy or 3-hydroxy-3-methylbutoxy, a particular
value for R.sup.1-X.sup.1 being hydrogen or (1-4C)alkoxy, more
particularly (1-4C)alkoxy such as methoxy);
Q.sup.1-X.sup.2 is a group of the formula A:
##STR00006##
wherein: R.sup.4 is selected from N,N-di-[(1-4C)alkyl]carbamoyl and
a group of the formula:
Q.sup.2-X.sup.3-
wherein X.sup.3 is CO and Q.sup.2 is selected from pyrrolidin-1-yl,
morpholino and piperidino (for example R.sup.4 is
N,N-dimethylcarbamoyl or morpholinocarbonyl, particularly R.sup.4
is N,N-dimethylcarbamoyl),
[0231] and wherein Q.sup.2 optionally bears 1 or 2 substituents,
which may be the same or different, selected from fluoro, chloro,
hydroxy, methyl and oxo,
[0232] and wherein any (1-4C)alkyl group within R.sup.4 optionally
bears 1 or 2 substituents, which may be the same or different,
selected from fluoro, chloro and hydroxy and/or optionally a
substituent selected from methoxy,
[0233] R.sup.5 is selected from hydrogen, methyl, ethyl, isopropyl,
isobutyl and cycloproplymethyl,
and wherein any (1-4C)alkyl group within R.sup.5 optionally bears 1
or 2 substituents, which may be the same or different, selected
from fluoro, chloro and hydroxy, and/or optionally a substituent
selected from methoxy; G.sup.1 is fluoro; and G.sup.2 is chloro; or
a pharmaceutically acceptable salt thereof.
[0234] A further embodiment of the invention is a quinazoline
derivative of the Formula I wherein:
R.sup.1-X.sup.1 is selected from hydrogen, (1-6C)alkoxy and
(1-4C)alkoxy(1-6C)alkoxy, and wherein any (1-6C)alkoxy group within
R.sup.1X.sup.1 optionally bears 1, 2 or 3 substituents, which maybe
the same or different, selected from hydroxy, fluoro, chloro (for
example R.sup.1-X.sup.1 is selected from hydrogen, methoxy, ethoxy,
isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy,
2-methoxyethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or
3-hydroxy-3-methylbutoxy, a particular value for R.sup.1-X.sup.1
being hydrogen or (1-4C)alkoxy, more particularly (1-4C)alkoxy such
as methoxy); Q.sup.1-X.sup.2 is selected from
(2S,4R)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yl,
(2R,4S)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yl,
(2R,4R)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yl,
(2S,4S)-2-(N,N-dimethylcarbamoyl)-1-methylpyrrolidin-4-yl,
(2S,4R)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yl,
(2R,4S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yl,
(2R,4R)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yl and
(2S,4S)-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yl; G.sup.1 is
fluoro; and G.sup.2 is chloro; or a pharmaceutically acceptable
salt thereof.
[0235] A preferred compound of the invention is, for example, a
quinazoline derivative of the Formula I selected from: [0236]
4-(3-Chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-7--
methoxyquinazoline; and [0237]
6-{[1-(carbamoylmethyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-
-methoxyquinazoline; or a pharmaceutically acceptable acid addition
salt thereof.
[0238] Another preferred compound of the invention is, for example,
a quinazoline derivative of the Formula I selected from: [0239]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]qu-
inazoline; [0240]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline-
; [0241]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy-
]quinazoline; [0242]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpiperidin-4-yl)oxy]qui-
nazoline; [0243]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpiperidin-4-yl)methoxy-
]quinazolin; [0244]
4-(3Chloro-2-fluoroanilino)-7-methoxy-6-[2-(1-methylpiperidin-4-yl)ethoxy-
]quinazoline; [0245]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4--
yl]oxy}quinazoline; [0246]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4--
yl]methoxy}quinazoline; [0247]
4-(3-Chloro-2-fluoroanilino)-6-{[1-(2-methylsulfonyl)piperidin-4-yl]-meth-
oxy}-7-methoxyquinazoline; [0248]
6-{[1-(carbamoylmethyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilin-
o)-7-methoxyquinazoline; [0249]
4-(3-Chloro-2-fluoroanilino)-6-{[(cyanomethyl)piperidin-4-yl]oxy}-7-metho-
xyquinazoline; [0250]
4-(3-Chloro-2-fluoroanilino)-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}-7-
-methoxyquinazoline; and [0251]
4-(3-Chloro-2-fluoroanilino)-6-[(1-cyanopiperidin-4-yl)methoxy]-7-methoxy-
quinazoline; or a pharmaceutically acceptable acid addition salt
thereof.
[0252] Another preferred compound of the invention is, for example,
a quinazoline derivative of the Formula I selected from: [0253]
6-(1-acetylpiperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquina-
zoline; [0254]
4-(3-chloro-2-fluoroanilino)-6-[1-(N,N-dimethylaminoacetyl)piperidin-4-yl-
oxy]-7-methoxyquinazoline; [0255]
6-[1-(N,N-dimethylsulfamoyl)piperidin-4-yloxy]-4-(3-chloro-2-fluoroanilin-
o)-7-methoxyquinazoline; [0256]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(morpholinoacetyl)piperidin-4-
-yloxy]quinazoline; [0257]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperi-
din-4-yloxy]quinazoline; [0258]
4-(3-chloro-2-fluoroanilino)-6-{1-[3-(dimethylamino)propylsulfonyl]piperi-
din-4-yloxy}-7-methoxyquinazoline; [0259]
4-(3-chloro-2-fluoroanilino)-6-[1-(methylsulfonyl)piperidin-3-yl]oxy]-7-m-
ethoxyquinazoline; [0260]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl)piperidin-3-yloxy]-
-7-methoxyquinazoline; [0261]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)piperidin-3-yloxy]-
-7-methoxyquinazoline; [0262]
6-(1-acetylpiperidin-3-yloxy)-4-(3-chloro-2-flouroanilino)-7-methoxyquina-
zoline; [0263]
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)pyrrolid-
in-4-yloxy]-7-methoxyquinazoline; [0264]
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)-1-methy-
lpyrrolidin-4-yloxy]-7-methoxyquinazoline; [0265]
4-(3-chloro-2-fluoroanilino)-6-[1-(N,N-dimethylaminoacetyl)piperidin-3-yl-
oxy]-7-methoxyquinazoline; [0266]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(N,N-dimethylaminoacetyl)piperidin-
-3-yloxy]-7-methoxyquinazoline; [0267]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(N,N-dimethylaminoacetyl)piperidin-
-3-yloxy]-7-methoxyquinazoline; [0268]
4-(3-chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-3-yloxy]-7-met-
hoxyquinazoline; [0269]
6-[1-(acetoxyacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-met-
hoxyquinazoline; [0270]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yloxy-
]-7-methoxyquinazoline; [0271]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yloxy-
]-7-methoxyquinazoline; [0272]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylsulfonylpyrrolidi-
n-2-yl]methoxy}quinazoline; [0273]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-1-methylsulfonylpyrrolidi-
n-2-yl]methoxy}quinazoline; [0274]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(methylsulfonyl)pyrrolidin-3-
-yl]methoxy}quinazoline; [0275]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-methylpyrrolidin-3-yloxy]-7-methox-
yquinazoline; [0276]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-methylpyrrolidin-3-yloxy]-7-methox-
yquinazoline; [0277]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylpyrrolidin-2-yl]m-
ethoxy}quinazoline; [0278]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)methox-
y]quinazoline; [0279]
6-[(3R)-1-acetylpyrrolidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methox-
yquinazoline; [0280] 6{[(2S>
1-acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyqu-
inazoline; [0281]
6-{[(2R)-1-acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7--
methoxyquinazoline; [0282]
6-[(1-acetylpyrrolidin-3-yl)methoxy]-4-(3-chloro-2-fluoroanilino)-7-metho-
xyquinazolin; [0283]
4-(3-chloro)-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(N,N-dimethylsulfamoyl)-
pyrrolidin-3-yloxy]quinazoline; [0284]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(morpholinoacetyl)pyrro-
lidin-2-yl]methoxy}quinazoline; [0285]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolid-
in-2-yl]methoxy}quinazoline; [0286]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline;
[0287]
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-2-(N,N-dimethylcarbamoyl)--
1-methylpyrrolidin-4-yloxy]-7-methoxyquinazoline; [0288]
4-(3-chloro-2-fluoroanilino)-6-[(2R,4S)-2-(N,N-dimethylcarbamoyl)-1-methy-
lpyrrolidin-4-yloxy]-7-methoxyquinazoline; [0289]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N-methylaminoacetyl)py-
rrolidin-2-yl]methoxy}quinazoline; [0290]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N-dimethylaminoacetyl)-
pyrrolidin-2-yl]methoxy}quinazoline; [0291]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(pyrrolidin-1-ylacetyl)-
pyrrolidin-2-yl]methoxy}quinazoline; [0292]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2RS,4R)-1-methyl-2-(morpholino-
carbonyl)-pyrrolidin-4-yloxy]quinazoline; [0293]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine; [0294]
6-[(3LS)-1-acetylpiperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methox-
yquinazoline; [0295]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(methylsulfonyl)piperidi-
n-3-yloxy]quinazoline; [0296]
4-(3-chloro-2-fluoroanilino)-6-{(3S)-1-[(dimethylamino)acetyl]piperidin-3-
-yloxy}-7-methoxyquinazoline;
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperi-
din-3-yloxy]quinazoline; [0297]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(pyrrolidin-1-ylacetyl)p-
iperidin-3-yloxy]quinazoline; [0298]
4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-y-
lacetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazoline; [0299]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(1-methylpiperazin-4-yl-
acetyl)pyrrolidin-2-yl]methoxy}quinazoline; [0300]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(1-methylpiperazin-4-yl-
acetyl)pyrrolidin-2-yl]methoxy}quinazoline; [0301]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(hydroxyacetyl)pyrrolidin-3-yloxy]-
-7-methoxyquinazoline; [0302]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(2-hydroxyisobutyryl)py-
rrolidin-2-yl]methoxy}quinazoline; [0303]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylpyrrolidin-2-ylca-
rbonyl]piperidin-3-yloxy}quinazoline; [0304]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(N,N-dimethylcarbamoylmethyl)-
piperidin-3-3 yloxy]quinazoline; [0305]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-diflouropyrolidin-1--yla-
cetyl)piperidin-3-yloxy]quinazoline; [0306]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1--
yl]acetyl]piperidin-3-yloxy}quinazoline; [0307]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(4-methyl-3-oxopiperazin-1-y-
l)acetyl]piperidin-3-yloxy}quinazoline; [0308]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(4-acetylpiperazin-1-1-yl)ac-
etyl]piperidin-3-yloxy}quinazoline; and [0309]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6{[(2R)-1-methylpyrrolidin-2-yl]me-
thoxy}quinazoline; or a pharmaceutically acceptable salt
thereof.
Synthesis of Quinazoline Derivatives of the Formula I
[0310] A further aspect the present invention provides a process
for preparing a quinazoline derivative of Formula I or a
pharmaceutically-acceptable salt thereof. It will be appreciated
that during certain of the following processes certain substituents
may require protection to prevent their undesired reaction. The
skilled chemist will appreciate when such protection is required,
and how such protecting groups may be put in place, and later
removed.
[0311] For examples of protecting groups see one of the many
general texts on the subject, for example, `Protective Groups in
Organic Synthesis` by Theodora Green (publisher John Wiley &.
Sons). Protecting groups may be removed by any convenient method as
described in the literature or known to the skilled chemist as
appropriate for the removal of the protecting group in question,
such methods being chosen so as to effect removal of the protecting
group with minimum disturbance of groups elsewhere in the
molecule.
[0312] Thus, if reactants include, for example, groups such as
amino, carboxy or hydroxy it may be desirable to protect the group
in some of the reactions mentioned herein.
[0313] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or r-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a r-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulfuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0314] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium, sodium hydroxide or ammonia. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0315] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
Resins may also be used as a protecting group.
[0316] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
[0317] A quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, may be prepared by any
process known to be applicable to the preparation of
chemically-related compounds. Such processes, when used to prepare
a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, are provided as a further
feature of the invention and are illustrated by the following
representative examples. Necessary starting materials may be
obtained by standard procedures of organic chemistry (see, for
example, Advanced Organic Chemistry (Wiley-Interscience), Jerry
March). 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. Information on the preparation of necessary
starting materials or related compounds (which may be adapted to
form necessary starting materials) may also be found in the
following patent and Application Publications, the contents of the
relevant process sections of which are hereby incorporated herein
by reference: WO94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO
96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994,
WO01/66099, U.S. Pat. No. 5,252,586, EP 520 722, EP 566 226, EP 602
851 and EP 635 507.
[0318] The present invention also provides that quinazoline
derivatives of the Formula I, or pharmaceutically acceptable salts
thereof, can be prepared by a process (a) to (h) as follows
(wherein the variables are as defined above unless otherwise
stated):
Process (a) By reacting a compound of the Formula II:
##STR00007##
wherein R.sup.1, X.sup.1, G.sup.1 and G.sup.2 have any of the
meanings defined hereinbefore except that any functional group is
protected if necessary, with a compound of the Formula III:
Q.sup.1-X.sup.2-Lg Formula in
wherein Q.sup.1, X.sup.2 have any of the meanings defined
hereinbefore except that any functional group is protected if
necessary and Lg is a displaceable group, wherein the reaction is
conveniently performed in the presence of a suitable base,
[0319] and whereafter any protecting group that is present is
removed by conventional means.
[0320] A convenient displaceable group Lg is, for example, a
halogeno, alkanesulfonyloxy or arylsulfonyloxy group, for example a
chloro, bromo, methanesulfonyloxy, 4-nitrobenzenesulfonyloxy or
toluene-4-sulfonyloxy group (suitably a methanesulfonyloxy,
4-nitrobenzenesulfonyloxy or toluene-4-sulfonyloxy group).
[0321] The reaction is advantageously carried out in the presence
of base. A suitable base is, for example, an organic amine base
such as, for example, pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, N-methylmorpholine or
diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal or
alkaline earth metal carbonate or hydroxide, for example sodium
carbonate, potassium carbonate, cesium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide. Alternatively
such a base is, for example, an alkali metal hydride, for example
sodium hydride, an alkali metal or alkaline earth metal amide, for
example sodium amide or sodium bis(trimethylsilyl)amide, or a
sufficiently basic alkali metal halide, for example cesium fluoride
or sodium iodide. The reaction is suitably effected in the presence
of an inert solvent or diluent, for example an alkanol or ester
such as methanol, ethanol, 2-propanol or ethyl acetate, a
halogenated solvent such as methylene chloride, trichloromethane or
carbon tetrachloride, an ether such as tetrahydrofuran or
1,4-dioxan, an aromatic hydrocarbon solvent such as toluene, or
(suitably) a dipolar aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
dimethylsulfoxide. The reaction is conveniently effected at a
temperature in the range, for example, 10 to 150.degree. C. (or the
boiling point of the solvent), suitably in the range 20 to
90.degree. C.
[0322] When X.sup.2 is a direct bond a particularly suitable base
is cesium fluoride. This reaction is suitably performed in an inert
dipolar aprotic solvent such as N,N-dimethylacetamide or
N,N-dimethylformamide. The reaction is suitably carried out at a
temperature of from 25 to 85.degree. C.
Process (b) By modifying a substituent in or introducing a
substituent into another quinazoline derivative of Formula I or a
pharmaceutically acceptable salt thereof, as hereinbefore defined
except that any functional group is protected if necessary, and
whereafter any protecting group that is present is removed by
conventional means.
[0323] Methods for converting substituents into other substituents
are known in the art. For example an alkylthio group may be
oxidised to an alkylsulfinyl or alkylsulfonyl group, a cyano group
reduced to an amino group, a nitro group reduced to an amino group,
a hydroxy group alkylated to a methoxy group, a carbonyl group
converted to a thiocarbonyl group (eg. using Lawsson's reagent), a
bromo group converted to an alkylthio group, an amino group may be
acylated to give an alkanoylamino group (for example by reaction
with a suitable acid chloride or acid anhydride) or an alkanoyloxy
group may be hydrolysed to a hydroxy group (for example an
acetyloxyacetyl group may be converted to a hydroxyacetyl group)
Conveniently, one R.sup.1 group may be converted into another
R.sup.1 group as a final step in the preparation of a compound of
the Formula I. IT is also possible to introduce a substituent onto
the group Q.sup.1 as a final step in the preparation of a compound
of the Formula I. For example when the compound of Formula I
contains primary or secondary amino group, for example an NH group
in the ring Q.sup.1,a substituent may be added to the nitrogen atom
of the primary or secondary amino group by reacting the compound of
the Formula I containing a primary or secondary amino group with a
compound of the formula R-Lg, wherein Lg is a displaceable group
(for example halogeno such as chloro or bromo) and R is the
required substituent (for example (1-6C)alkyl, (2-6C)alkanoyl,
cyano, cyano(1-6C)alkyl, (1-6C)alkylsulfonyl, carbamoyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
carbamoyl(1-6C)alkyl, N-(1-6C)alkylcarbamoyl(1-6C)alkyl, sulfamoyl,
N-(1-6C)alkylsulfamoyl, N,N-<31-[(1-6C)alkyl]sulfamoyl or a
group Q.sup.2-X.sup.3-, wherein Q.sup.2-X.sup.3-are as hereinbefore
defined, which groups may be optionally substituted as hereinbefore
defined). The reactions described above are conveniently performed
in the presence of a suitable base (such as those described above
in process (a), for example potassium carbonate, sodium iodide or
di-isopropylethylamine) and conveniently in the presence of an
inert solvent or diluent (for example the inert solvents and
diluents described in process (a) such as N,N-dimethylacetamide,
methanol, ethanol or methylene chloride). Conveniently, when
Q.sup.1 carries, for example an (2-6C)alkanoyl or
(1-6C)alkylsulfonyl group, which is substituted by a group
NR.sup.aR.sup.b, as hereinbefore defined, the NR.sup.aR.sup.b group
may be introduced by reaction of a compound of the Formula I
wherein Q.sup.1 carries a group of the formula Lg-(2-6C)alkanoyl or
Lg-(1-6C)alkylsulfonyl, wherein Lg is a suitable displaceable group
such as chloro, with a compound of the formula NHR.sup.aR.sup.b;
wherein the reaction is conveniently performed in the presence of a
suitable base and optionally in a suitable inert solvent or
diluent. For example a pyrrolidin-1-ylacetyl group on Q.sup.1 may
be prepared by reacting a compound of the Formula I wherein Q.sup.1
is substituted by a chloroacetyl group with pyrrolidine, analogous
procedures may be used to prepare substituents on Q.sup.1 such as
morpholinoacetyl, N-methylaminoacetyl, N,N-dimethylaminoacetyl.
Similarly, for example a 3-(N,N-dimethylamino)propylsulfonyl
substituent on Q.sup.1 may be prepared by reacting a compound of
the Formula I wherein Q.sup.1 carries a 3-chloropropylsulfonyl
substituent with di-methylamine. Further examples of modifying or
converting substituents into other substituents are well known to
those skilled in the art and further methods are contained in the
accompanying non-limiting Examples.
Process (c) By removal of a protecting group from a quinazoline
derivative of Formula I, or a pharmaceutically acceptable salt
thereof.
[0324] Suitable methods for removal of protecting groups are well
known and are discussed herein. For example for the production of
those compounds of the Formula I wherein Q.sup.1 or R.sup.1
contains a primary or secondary amino group, the cleavage of the
corresponding compound of Formula I wherein Q.sup.1 or R.sup.1
contains a protected primary or secondary amino group.
[0325] Suitable protecting groups for an amino group are, for
example, any of the protecting groups disclosed hereinbefore for an
amino group. Suitable methods for the cleavage of such amino
protecting groups are also disclosed hereinbefore. In particular, a
suitable protecting group is a lower alkoxycarbonyl group such as a
tert-butoxycarbonyl group which may be cleaved under conventional
reaction conditions such as under acid-catalysed hydrolysis, for
example in the presence of trifluoroacetic acid.
Process (d) By reacting a compound of the Formula II as
hereinbefore defined with a compound of the Formula II as defined
hereinbefore except Lg is OH under Mitsunobu conditions, and
whereafter any protecting group that is present is removed by
conventional means.
[0326] Suitable Mitsunobu conditions include, for example, reaction
in the presence of a suitable tertiary phosphine and a
di-alkylazodicarboxylate in an organic solvent such as THF, or
suitably dichloromethane and in the temperature range 0.degree.
C.-60.degree. C., but suitably at ambient temperature. A suitable
tertiary phosphine includes for example tri-n-butylphosphine or
suitably tri-phenylphosphine. A suitable di-alkylazodicarboxylate
includes for example diethyl azodicarboxylate (DEAD) or suitably
di-tert-butyl azodicarboxylate. Details of Mitsunobu reactions are
contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction,
D. L. Hughes, Organic Reactions, 1992, Vol. 42, 335-656 and
Progress in the Mitsunobu Reaction, D. L. Hughes, Organic
Preparations and Procedures International, 1996, Vol. 28, 127->
164.
Process (e) For the preparation of those compounds of the Formula I
wherein R.sup.1-X.sup.1 is a hydroxy group by the cleavage of a
quinazoline derivative of the Formula I wherein R.sup.1-X.sup.1 is
a (1-6C)alkoxy group.
[0327] The cleavage reaction may conveniently be carried out by any
of the many procedures known for such a transformation. The
cleavage reaction of a compound of the Formula I wherein R.sup.1 is
a (1-6C)alkoxy group may be carried out, for example, by treatment
of the quinazoline derivative with an alkali metal
(1-6C)alkylsulfide such as sodium ethanethiolate or, for example,
by treatment with an alkali metal diarylphosphide such as lithium
diphenylphosphide. Alternatively the cleavage reaction may
conveniently be carried out, for example, by treatment of the
quinazoline derivative with a boron or aluminium trihalide such as
boron tribromide, or by reaction with an organic or inorganic acid,
for example trifluoroacetic acid. Such reactions are suitably
carried out in the presence of a suitable inert solvent or diluent
as defined hereinbefore. A preferred cleavage reaction is the
treatment of a quinazoline derivative of the Formula I with
pyridine hydrochloride. The cleavage reactions are suitably carried
out at a temperature in the range, for example, of from 10 to
150.degree. C., for example from 25 to 80.degree. C.
Process (f) For the preparation of those compounds of the Formula I
wherein X.sup.1 is O, by the reaction of a compound of the Formula
IV (a compound of Formula I wherein R.sup.1-X.sup.1 is OH):
##STR00008##
wherein Q.sup.1, X.sup.2, G.sup.1 and G.sup.2 have any of the
meanings defined hereinbefore except that any functional group is
protected if necessary, with a compound of the formula R.sup.1-Lg,
wherein R.sup.1 has any of the meanings defined hereinbefore,
except that any functional group is protected if necessary and Lg
is a displaceable group, wherein the reaction is conveniently
performed in the presence of a suitable base;
[0328] and whereafter any protecting group that is present is
removed by conventional means. Suitable displaceable groups, Lg,
are as hereinbefore defined for process a, for example chloro or
bromo. The reaction is suitably performed in the presence of a
suitable base. Suitable solvents, diluents and bases include, for
example those hereinbefore described in relation to process
(a).
Process (g)
[0329] For the preparation of those compounds of the Formula I
wherein Q.sup.1 or R.sup.1 contains a (1-6C)alkoxy or substituted
(1-6C)alkoxy group or a (1-6C)alkylamino or substituted
(1-6C)alkylamino group, the alkylation, conveniently in the
presence of a suitable base as defined hereinbefore for process a,
of a quinazoline derivative of the Formula I wherein Q.sup.1 or
R.sup.1 contains a hydroxy group or a primary or secondary amino
group as appropriate.
[0330] A suitable alkylating agent is, for example, any agent known
in the art for the alkylation of hydroxy to alkoxy or substituted
alkoxy, or for the alkylation of amino to alkylamino or substituted
alkylamino, for example an alkyl or substituted alkyl halide, for
example a (1-6C)alkyl chloride, bromide or iodide or a substituted
(1-6C)alkyl chloride, bromide or iodide, conveniently in the
presence of a suitable base as defined hereinbefore, in a suitable
inert solvent or diluent as defined hereinbefore and at a
temperature in the range, for example, 10 to 140.degree. C.,
conveniently at or near ambient temperature. An analogous procedure
may be used to introduce optionally substituted (2-6C)alkanoyloxy,
(2-6C)alkanoylamino and (1-6C)alkanesulfonylamino groups into
Q.sup.1 or R.sup.1.
[0331] Conveniently for the production of those compounds of the
Formula I wherein Q.sup.1 or R.sup.1 contains a (1-6C)alkylamino or
substituted (1-6C)alkylamino group, a reductive animation reaction
may be employed using formaldehyde or a (2-6C)alkanolaldehyde (for
example acetaldehyde or propionaldehyde). For example, for the
production of those compounds of the Formula I wherein Q.sup.1 or
R.sup.1 contains an N-methyl group, the corresponding compound
containing a N--H group may be reacted with formaldehyde in the
presence of a suitable reducing agent. A suitable reducing agent
is, for example, a hydride reducing agent, for example formic acid,
an alkali metal aluminium hydride such as lithium aluminium
hydride, or, suitably, an alkali metal borohydride such as sodium
borohydride, sodium cyanoborohydride, sodium triethylborohydride,
sodium trimethoxyborohydride and sodium triacetoxyborohydride. The
reaction is conveniently performed in a suitable inert solvent or
diluent, for example tetrahydrofuran and diethyl ether for the more
powerful reducing agents such as lithium aluminium hydride, and,
for example, methylene chloride or a protic solvent such as
methanol and ethanol for the less powerful reducing agents such as
sodium triacetoxyborohydride and sodium cyanoborohydride. When the
reducing agent is formic acid the reaction is conveniently carried
out using an aqueous solution of the formic acid. The reaction is
performed at a temperature in the range, for example, 10 to
100.degree. C., such as 70 to 90.degree. C. or, conveniently, at or
near ambient temperature. Conveniently, when the reducing agent is
formic acid, protecting groups such as tert-butoxycarbonyl on the
NH group to be alkylated (for example present from the synthesis of
the starting material) may be removed in-situ during the
reaction.
Process (h)
[0332] For the preparation of those compounds of the Formula I
wherein R.sup.1 is substituted by a group T, wherein T is selected
from (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoylamino,
(1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl, the
reaction of a compound of the formula V:
##STR00009##
wherein Q.sup.1, X.sup.1, X.sup.2, R.sup.1, G.sup.1 and G.sup.2
have any of the meanings defined hereinbefore except that any
functional group is protected if necessary and Lg is a displaceable
group (for example chloro or bromo) with a compound of the formula
TH, wherein T is as defined above except that any functional group
is protected if necessary;
[0333] and whereafter any protecting group that is present is
removed by conventional means. The reaction is conveniently carried
out in the presence of a suitable base. The reaction may
conveniently be performed in a suitable inert solvent of diluent.
Suitable bases, solvents and diluents are for example those
described under process (a). The reaction is suitable performed at
a temperature of for example, from 10 to 150.degree. C., for
example 30 to 60.degree. C.
[0334] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halogeno group.
Process (i)
[0335] By reacting a compound of the formula VI:
##STR00010##
wherein R.sup.1, X.sup.1, X.sup.2, Q.sup.1 have any of the meanings
defined hereinbefore except that any functional group is protected
if necessary and Lg is a displaceable group as hereinbefore
defined, with an aniline of the formula VII:
##STR00011##
wherein G.sup.1 and G.sup.2 have any of the meanings defined
hereinbefore except that any functional group is protected if
necessary, and wherein the reaction is conveniently performed in
the presence of a suitable acid,
[0336] and whereafter any protecting group that is present is
removed by conventional means.
[0337] Suitable displaceable groups represented by Lg are as
hereinbefore defined, in particular halogeno such as chloro.
[0338] The reaction is conveniently carried out in the presence of
a suitable inert solvent or diluent, for example an alcohol or
ester such as methanol, ethanol, isopropanol or ethyl acetate, a
halogenated solvent such as methylene chloride, chloroform or
carbon tetrachloride, an ether such as tetrahydrofuran or
1,4-dioxane, an aromatic solvent such as toluene, or a dipolar
aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N methylpyrrolidin-2-one acetonitrile or
dimethylsulfoxide. The reaction is conveniently carried out at a
temperature in the range, for example, 10 to 250.degree. C.,
conveniently in the range 40 to 120.degree. C. or where a solvent
or diluent is used at the reflux temperature. Conveniently, the
compound of formula VI may is reacted with a compound of the
formula VII in the presence of a protic solvent such as
isopropanol, conveniently in the presence of an acid, for example
hydrogen chloride gas in diethyl ether or dioxane, or hydrochloric
acid, for example a 4 M solution of hydrogen chloride in dioxane,
under the conditions described above. Alternatively, this reaction
may be conveniently carried out in an aprotic solvent, such as
dioxane or a dipolar aprotic solvent such as N,N-dimethylacetamide
or acetonitrile in the presence of an acid, for example hydrogen
chloride gas in diethyl ether or dioxane, or hydrochloric acid. The
compound of the formula VI, wherein Lg is halogeno, may be reacted
with a compound of the formula VI in the absence of an acid. In
this reaction displacement of the halogeno leaving group Lg results
in the formation of the acid HLg in-situ and auto-catalysis of the
reaction. Conveniently the reaction is carried out in a suitable
inert organic solvent, for example isopropanol, dioxane or
N,N-dimethylacetamide. Suitable conditions for this reaction are as
described above.
[0339] Alternatively, the compound of formula VI may is reacted
with a compound of the formula VII in the presence of a suitable
base. Suitable bases for this reaction are as hereinbefore defined
under Process (a). This reaction is conveniently performed in an
inert solvent or diluent, for example those mentioned above in
relation to this process (i);
Process (j)
[0340] For the preparation of those compounds of the Formula I
wherein Q.sup.1 carries a substituted carbamoyl group (such as
N,N-di-[(1-6C)alkyl]carbamoyl) or a group Q.sup.2-X.sup.3-, wherein
Q.sup.2 is a nitrogen containing heterocyclyl group linked to
X.sup.3 by a ring nitrogen and X.sup.3 is as CO; the coupling of a
compound of the Formula I, as hereinbefore defined, except any
functional group is protected if necessary, and wherein Q.sup.1
carries a carboxy group, with a primary or secondary amine or a
group of the formula Q.sup.2H, wherein Q.sup.2H is a heterocyclic
group containing an NH group; and whereafter any protecting group
that is present is removed conventional means.
[0341] The coupling reaction is conveniently carried out in the
presence of a suitable coupling agent, such as a carbodiimide (for
example 1-[3-(Dimethylamino)propy]-3-ethylcarbodiimide), or a
suitable peptide coupling agent, for example
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate (HATU). The coupling reaction is conveniently
carried out in an inert solvent such as, for example, a halogenated
solvent such as methylene chloride, or a dipolar aprotic solvent
such as N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidinone. Suitably the coupling reaction is carried
out in the presence of a suitable base, such as an organic amine,
for example di-isopropylethylamine or 4-dimethylaminopyridine. The
coupling reaction is suitable performed at -25.degree. C. to
150.degree. C., conveniently at ambient temperature.
[0342] Persons skilled in the art will appreciate that, in order to
obtain compounds of the invention in an alternative and in some
occasions, more convenient manner, the individual process steps
mentioned hereinbefore may be performed in different order, and/or
the individual reactions may be performed at different stage in the
overall route (i.e. chemical transformations may be performed upon
different intermediates to those associated hereinbefore with a
particular reaction).
[0343] When a pharmaceutically-acceptable salt of a quinazoline
derivative of the Formula I is required, for example an
acid-addition salt, it may be obtained by, for example, reaction of
said quinazoline derivative with a suitable acid using a
conventional procedure. To facilitate isolation of the compound
during preparation, the compound may be prepared in the form of a
salt that is not a pharmaceutically acceptable salt. The resulting
salt can then be modified by conventional techniques to give a
pharmaceutically acceptable salt of the compound. Such techniques
include, for example ion exchange techniques or re-precipitation of
the compound in the presence of a pharmaceutically acceptable
counter ion. For example re-precipitation in the presence of a
suitable acid such as HCl to give a hydrochloride acid addition
salt.
[0344] As mentioned hereinbefore some of the compounds according to
the present invention may contain one of more chiral centers and
may therefore exist as stereoisomers (for example when Q.sup.1
contains a pyrrolidin-3-yl group). Stereoisomers may be separated
using conventional techniques, e.g. chromatography or fractional
crystallisation. The enantiomers may be isolated by separation of a
racemate for example by fractional crystallisation, resolution or
HPLC. The diastereomers may be isolated by separation by virtue of
the different physical properties of the diastereoisomers, for
example, by fractional crystallisation, HPLC or flash
chromatography. Alternatively particular stereoisomers may be made
by chiral synthesis from chiral starting materials under conditions
which will not cause racemisation or epimerisation, or by
derivatisation, with a chiral reagent. Examples of suitable chiral
synthesis and separation of isomers are described in the Examples.
When a specific stereoisomer is isolated it is suitably isolated
substantially free for other stereoisomers, for example containing
less than 20%, particularly less than 10% and more particularly
less than 5% by weight of other stereoisomers.
[0345] In the section above the expression "inert solvent" refers
to a solvent which does not react with the starting materials,
reagents, intermediates or products in a manner which adversely
affects the yield of the desired product.
[0346] Preparation of Starting Materials
[0347] Compounds of Formula II are commercially available or may be
prepared using conventional techniques or analogous processes to
those described in the prior art. In particular those patents and
applications listed hereinbefore, such as WO96/15118, WO 01/66099
and EP 566 226. For example, the compounds of Formula II may be
prepared in accordance with Reaction Scheme 1:
##STR00012##
wherein R.sup.1, X.sup.1, Lg, G.sup.1 and G.sup.2 are as
hereinbefore defined and Pg is a hydroxy protecting group. (i)
Reaction suitably in an inert protic solvent (such as an alkanol
for example iso-propanol), an aprotic solvent (such as dioxane) or
a dipolar aprotic solvent (such as N,N-dimethylacetamide) in the
presence of an acid, for example hydrogen chloride gas in diethyl
ether or dioxane, or hydrochloric acid, under analogous conditions
to those described above under process (i).
[0348] Alternatively the reaction may be carried out in one of the
above inert solvents conveniently in the presence of a base, for
example potassium carbonate. The above reactions are conveniently
carried out at a temperature in the range, for example, 0 to
150.degree. C., suitably at or near the reflux temperature of the
reaction solvent.
(ii) Cleavage of Pg may be performed under standard conditions for
such reactions. For example when Pg is an alkanoyl group such as
acetyl, it may be cleaved by heating in the presence of a
methanolic ammonia solution.
[0349] Compounds of formula VII are known or can be prepared using
known processes for the preparation of analogous compounds. If not
commercially available, compounds of the formula (VIII) may be
prepared by procedures which are selected from standard chemical
techniques, techniques which are analogous to the synthesis of
known, structurally similar compounds, or techniques which are
analogous to the procedures described in the Examples. For example,
standard chemical techniques are as described in Houben Weyl. By
way of example the compound of the formula VIII in which
R.sup.1-X.sup.1- is methoxy, Lg is chloro and Pg is acetyl may be
prepared using the process illustrated in Reaction Scheme 2:
##STR00013##
[0350] Reaction Scheme 2 may be generalised by the skilled man to
apply to compounds within the present specification which are not
specifically illustrated (for example to introduce a substituent
other than methoxy at the 7-position in the quinazoline ring).
[0351] Compounds of the Formula in are commercially available or
may be prepared using standard techniques, for example as
illustrated in U.S. Pat. No. 5,252,586 and WO 94/27965.
[0352] Compounds of the Formula IV may be prepared using process
(e) above, starting with a compound prepared, for example using
Process (a).
[0353] Compounds of the formula V may be prepared using, for
example process (a) or process (d) in which the group represented
by R.sup.1 is appropriately functionalised with a suitable
displaceable group Lg such as chloro or bromo.
[0354] Compounds of the formula VI may be prepared using
conventional methods well known in the art. For example the hydroxy
protecting group, Pg, in a compound of the formula VIII as
hereinbefore described in Reaction Scheme 1 is removed to give the
compound of the formula X:
##STR00014##
The protecting group Pg may be removed from the compound of formula
X using conventional techniques.
[0355] The compound of the formula X may then be coupled with a
compound of the Formula III as hereinbefore defined using analogous
conditions to those described In Process (a) or Process (d).
[0356] Certain novel intermediates utilised in the above processes
are provided as a further feature of the present invention together
with the process for their preparation.
[0357] According to a further feature of the present invention
there is provided the compounds of the formulae II and IX or a salt
thereof, (including pharmaceutically acceptable salts thereof), as
hereinbefore defined. Particularly compounds of the formula II and
IX wherein R.sup.1-X.sup.5 is hydrogen or (1-4C)alkoxy. More
particularly compounds of the formula II and IX wherein
R.sup.1-X.sup.1 is hydrogen or (1-4C)alkoxy, and G.sup.1 and
G.sup.2 are selected from fluoro and chloro.
Biological Assays
[0358] The following assays may be used to measure the effects of
the compounds of the present invention as inhibitors of the
erb-tyrosine kinases, as inhibitors in-vitro of the proliferation
of KB cells (human naso-pharangeal carcinoma cells) and as
inhibitors in vivo on the growth in nude mice of xenografts of LoVo
tumour cells (colorectal adenocarcinoma),
a) Protein Tyrosine Kinase Phosphorylation Assays
[0359] This test measures the ability of a test compound to inhibit
the phosphorylation of a tyrosine containing polypeptide substrate
by EGFR tyrosine kinase enzyme.
[0360] Recombinant intracellular fragments of EGFR, erbB2 and erbB4
(accession numbers X00588, X03363 and L0786S respectively) were
cloned and expressed in the bacuiovirus/Sf21 system. Lysates were
prepared from these cells by treatment with ice-cold lysis buffer
(20 mM N-2-hydroxyethylpiperizine-N'-2-ethanesulfonic acid (HEPES)
pH7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM
MgCl.sub.2, 1 mM ethylene glycol-bis(.beta.-aminoethyl ether)
N',N',N',N'-tetraacetic acid (EGTA), plus protease inhibitors and
then cleared by centrifugation.
[0361] Constitutive kinase activity of the recombinant protein was
determined by its ability to phosphorylate a synthetic peptide
(made up of a random co-polymer of Glutamic Acid, Alanine and
Tyrosine in the ratio of 6:3:1). Specifically, Maxisorb.TM. 96-well
immunoplates were coated with synthetic peptide (0.2 .mu.g of
peptide in a 100 .mu.l phosphate buffered saline (PBS) solution and
incubated at 4.degree. C. overnight). Plates were washed in PBS-T
(phosphate buffered saline with 0.5% Tween 20) then in 50 mM HEPES
pH 7.4 at room temperature to remove any excess unbound synthetic
peptide. EGFR, ErbB2 or ErbB4 tyrosine kinase activity was assessed
by incubation in peptide coated plates for 20 minutes at 22.degree.
C. in 100 mM HEPES pH 7.4, adenosine trisphosphate (ATP) at Km
concentration for the respective enzyme, 10 mM MnCl.sub.2, 0.1 mM
Na.sub.3VO.sub.4, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100
with test compound in DMSO (final concentration of 2.5%). Reactions
were terminated by the removal of the liquid components of the
assay followed by washing of the plates with PBS-T.
[0362] The immobilised phospho-peptide product of the reaction was
detected by immunological methods. Firstly, plates were incubated
for 90 minutes at room temperature with anti-phosphotyrosine
primary antibodies that were raised in the mouse (4G10 from Upstate
Biotechnology). Following extensive washing, plates were treated
with Horseradish Peroxidase (HRP) conjugated sheep anti-mouse
secondary antibody (NXA931 from Amersham) for 60 minutes at room
temperature. After further washing, HRP activity in each well of
the plate was measured colorimetrically using
22'-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt
crystals (ABTS.TM. from Roche) as a substrate.
[0363] Quantification of colour development and thus enzyme
activity was achieved by the measurement of absorbance at 405 nm on
a Molecular Devices ThermoMax microplate reader. Kinase inhibition
for a given compound was expressed as an IC.sub.50 value. This was
determined by calculation of the concentration of compound that was
required to give 50% inhibition of phosphorylation in this assay.
The range of phosphorylation was calculated from the positive
(vehicle plus ATP) and negative (vehicle minus ATP) control
values.
b) EGFR Driven KB Cell Proliferation Assay
[0364] This assay measures the ability of a test compound to
inhibit the proliferation of KB cells (human naso-pharangeal
carcinoma obtained from the American Type Culture Collection
(ATCC).
[0365] KB cells (human naso-pharangeal carcinoma obtained from the
ATCC were cultured in Dulbecco's modified Eagle's medium (DMEM)
containing 10% foetal calf serum, 2 mM glutamine and non-essential
amino acids at 37.degree. C. in a 7.5% CO.sub.2 air incubator.
Cells were harvested from the stock flasks using
Trypsin/ethylaminediaminetetraacetic acid (EDTA). Cell density was
measured using a haemocytometer and viability was calculated using
trypan blue solution before being seeded at a density of
1.25.times.10.sup.3 cells per well of a 96 well plate in DMEM
containing 2.5% charcoal stripped serum, 1 mM glutamine and
non-essential amino acids at 37.degree. C. in 7.5% CO.sub.2 and
allowed to settle for 4 hours.
[0366] Following adhesion to the plate, the cells are treated with
or without EGF (final concentration of 1 ng/ml) and with or without
compound at a range of concentrations in dimethylsulfoxide (DMSO)
(0.1% final) before incubation for 4 days. Following the incubation
period, cell numbers were determined by addition of 50 .mu.l of
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
(stock 5 mg/ml) for 2 hours. MTT solution was then tipped off, the
plate gently tapped dry and the cells dissolved upon the addition
of 100 .mu.l of DMSO.
[0367] Absorbance of the solubilised cells was read at 540 nm using
a Molecular Devices
[0368] ThermoMax microplate reader. Inhibition of proliferation was
expressed as an IC.sub.50 value. This was determined by calculation
of the concentration of compound that was required to give 50%
inhibition of proliferation. The range of proliferation was
calculated from the positive (vehicle plus EGF) and negative
(vehicle minus EGF) control values.
c) H16N-2 Cell Proliferation Assay
[0369] This assay measures the ability of a test compound to
inhibit heregulin fi or EGF driven proliferation of H16N-2 cells.
These non-neoplastic epithelial cells respond in a proliferative
manner to stimulation with either EGF or heregulin .beta. (Ram, G.
R. and Ethier, S. P.(1996) Cell Growth and Differentiation, 7,
551-561) were isolated human mammary tissue (Band, V. and Sager, R.
Tumour progression in breast cancer. In: J. S. Rhim and A.
Dritschilo (eds.), Neoplastic Transformation in human Cell Culture,
pp 169-178. Clifton, N.J.: Humana Press, 1991) and were obtained
from the Dana-Farber Cancer Institute, 44 Binney Street, Boston,
Mass. 02115.
[0370] H16N-2 cells were routinely cultured in culture medium (a
1:1 mix of Gibco F12 and Ham's .alpha.MEM media containing 1%
foetal calf serum, 10 mM HEPES, 1 .mu.g/ml Insulin, 12.5 ng/ml EGF,
2.8 .mu.M Hydrocortisone, 2 nM Estradiol 5 .mu.M Ascorbic Acid, 10
.mu.g/ml Transferrin, 0.1 mM Phosphoethanolamine, 15 nM Sodium
Selenite, 2 mM Glutamine, 10 nM Tri-iodo-thrynoine, 35 .mu.g/ml
Bovine pituitary Extract and 0.1 mM Ethanolamine) at 37.degree. C.
in a 7.5% CO.sub.2 air incubator. Cells were harvested from the
stock flasks using Trypsin/ethylaminediaminetetraacetic acid
(EDTA). Cell density was measured using a haemocytometer and
viability was calculated using trypan blue solution before being
seeded at a density of 1.0.times.10.sup.3 cells per well of a 96
well plate in the above media at 37.degree. C. in 7.5% CO.sub.2 and
allowed to settle for 72 hours.
[0371] Following this, the cells were starved of serum for 24 hours
upon the addition of starvation medium (a 1:1 mix of Gibco F12 and
Ham's .alpha.MEM media containing, 10 mM HEPES, 2 nM Estradiol, 5
.mu.M Ascorbic Acid, 10 .mu.g/ml Transferrin, 0.1 mM
Phosphoethanolamine, 15 nM Sodium Selenite, 2 mM Glutamine, and 0.1
mM Ethanolamine) and incubated at 37.degree. C. in 7.5% CO.sub.2.
The cells were then treated with or without compound at a range of
concentrations in dimethylsulphoxide (DMSO) (1% final) for two
hours before the addition of exogenous ligand (at a final
concentration of 100 ng/ml of heregulin 0 or 5 ng/ml of EGF) and
incubation with both ligand and compound for 4 days at 37.degree.
C. in 7.5% CO.sub.2Following the incubation period, cell numbers
were determined by removal of the media by aspiration and
incubating with 50 .mu.l of
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MIT)
(stock 5 mg/ml) for 2 hours. MTT solution was then removed by
aspiration, allowed to air dry and the cells dissolved upon the
addition of 100 .mu.l of DMSO.
[0372] Absorbance of this solubilised cells was read at 540 nm to
quantify cell biomass. Inhibition of proliferation was expressed as
an IC.sub.50 value. This was determined by calculation of the
concentration of compound that was required to give 50% inhibition
of proliferation. The range of proliferation was calculated from
the positive (vehicle plus ligand) and negative (vehicle minus
ligand) control values.
d) In vivo Xenograft Assay
[0373] This assay measures the ability of a test compound to
inhibit the growth of a LoVo tumour (colorectal adenocarcinoma
obtained from the ATCC) in Female Swiss athymic mice (Alderley
Park, nu/nu genotype).
[0374] Female Swiss athymic (nu/nu genotype) mice were bred and
maintained in Alderley Park in negative pressure Isolators (PFI
Systems Ltd.). Mice were housed in a barrier facility with 12 hr
light/dark cycles and provided with sterilised food and water ad
libitum. All procedures were performed on mice of at least 8 weeks
of age. LoVo tumour cell (colorectal adenocarcinoma obtained from
the ATCC) xenografts were established in the hind flank of donor
mice by sub cutaneous injections of 1.times.10.sup.7 freshly
cultured cells in 100 .mu.l of serum free media per animal. On day
5 post-implant, mice were randomised into groups of 7 prior to the
treatment with compound or vehicle control that was administered
once daily at 0.1 ml/10 g body weight. Tumour volume was assessed
twice weekly by bilateral Vernier calliper measurement, using the
formula (length.times.width).times.
(length.times.width).times.(.pi./6), where length was the longest
diameter across the tumour, and width was the corresponding
perpendicular. Growth inhibition from start of study was calculated
by comparison of the mean changes in tumour volume for the control
and treated groups, and statistical significance between the two
groups was evaluated using a Students t test.
e) hERG-Encoded Potassium Channel Inhibition Assay
[0375] 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.
[0376] 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
Aceutase (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.
[0377] 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 room 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.
[0378] 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.
[0379] 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.
[0380] The compositions, pH and osmolarity of the bath and pipette
solution are tabulated below.
TABLE-US-00002 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
[0381] The amplitude of the hERG-encoded potassium channel tail
current following the step from 440 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.
[0382] 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.
[0383] 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.
[0384] Although the pharmacological properties of the compounds of
the Formula I vary with structural change as expected, in general
activity possessed by compounds of the Formula I, may be
demonstrated at the following concentrations or doses in one or
more of the above tests (a), (b) and (c):--
TABLE-US-00003 Test (a): IC.sub.50 in the range, for example,
0.001-10 .mu.M; Test (b): IC.sub.50 in the range, for example,
0.001-10 .mu.M; Test (c): IC.sub.50 in the range, for example,
0.001-10 .mu.M; Test (d): activity in the range, for example, 1-200
mg/kg/day;
[0385] No physiologically unacceptable toxicity was observed in
Test (c) at the effective dose for compounds tested of the present
invention. Accordingly no untoward toxicological effects are
expected when a compound of Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
is administered at the dosage ranges defined hereinafter.
[0386] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a quinazoline
derivative of the Formula I, or a pharmaceutically-acceptable
thereof, as defined hereinbefore in association with a
pharmaceutically-acceptable diluent or carrier.
[0387] The compositions of the invention may be in a form suitable
for oral use (for example as tablets, lozenges, hard or soft
capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for
example as creams, ointments, gels, or aqueous or oily solutions or
suspensions), for administration by inhalation (for example as a
finely divided powder or a liquid aerosol), for administration by
insufflation (for example as a finely divided powder) or for
parenteral administration (for example as a sterile aqueous or oily
solution for intravenous, subcutaneous, intramuscular or
intramuscular dosing or as a suppository for rectal dosing).
[0388] The compositions of the invention may be obtained by
conventional procedures using conventional pharmaceutical
excipients, well known in the art. Thus, compositions intended for
oral use may contain, for example, one or more colouring,
sweetening, flavouring and/or preservative agents.
[0389] The amount of active ingredient that is combined with one or
more excipients to produce a single dosage form will necessarily
vary depending upon the host treated and the particular route of
administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from
0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg,
for example from 1 to 30 mg) compounded with an appropriate and
convenient amount of excipients which may vary from about 5 to
about 98 percent by weight of the total composition.
[0390] The size of the dose for therapeutic or prophylactic
purposes of a compound of the Formula I will naturally vary
according to the nature and severity of the conditions, the age and
sex of the animal or patient and the route of administration,
according to well known principles of medicine.
[0391] In using a compound of the Formula I for therapeutic or
prophylactic purposes it will generally be administered so that a
daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body
weight is received, given if required in divided doses. In general
lower doses will be administered when a parenteral route is
employed. Thus, for example, for intravenous administration, a dose
in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will
generally be used. Similarly, for administration by inhalation, a
dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight
will be used. Oral administration is however preferred,
particularly in tablet form. Typically, unit dosage forms will
contain about 0.5 mg to 0.5 g of a compound of this invention.
[0392] We have found that the compounds of the present invention
possess anti-proliferative properties such as anti-cancer
properties that are believed to arise from their erbB family
receptor tyrosine kinase inhibitory activity, particularly
inhibition of the EGF receptor (erbB1) tyrosine kinase.
Furthermore, certain of the compounds according to the present
invention possess substantially better potency against the EGF
receptor tyrosine kinase, than against other tyrosine kinase
enzymes, for example erbB2. Such compounds possess sufficient
potency against the EGF receptor tyrosine kinase that they may be
used in an amount sufficient to inhibit EGF receptor tyrosine
kinase whilst demonstrating little, or significantly lower,
activity against other tyrosine kinase enzymes such as erbB2. Such
compounds are likely to be useful for the selective inhibition of
EGF receptor tyrosine kinase and are likely to be useful for the
effective treatment of, for example EGF driven tumours.
[0393] Accordingly, the compounds of the present invention are
expected to be useful in the treatment of diseases or medical
conditions mediated alone or in part by erbB receptor tyrosine
kinases (especially EGF receptor tyrosine kinase), i.e. the
compounds may be used to produce an erbB receptor tyrosine kinase
inhibitory effect in a warm-blooded animal in need of such
treatment. Thus the compounds of the present invention provide a
method for the treatment of malignant cells characterised by
inhibition of one or more of the erbB family of receptor tyrosine
kinases. Particularly the compounds of the invention may be used to
produce an anti-proliferative and/or pro-apoptotic and/or
anti-invasive effect mediated alone or in part by the inhibition of
erbB receptor tyrosine kinases. Particularly, the compounds of the
present invention are expected to be useful in the prevention or
treatment of those tumours that are sensitive to inhibition of one
or more of the erbB receptor tyrosine kinases, such as EGF and/or
erbB2 and/or erbB4 receptor tyrosine kinases (especially EGF
receptor tyrosine kinase) that are involved in the signal
transduction steps which drive proliferation and survival of these
tumour cells. Accordingly the compounds of the present invention
are expected to be useful in the treatment of psoriasis, benign
prostatic hyperplasia (BPH), atherosclerosis and restenosis and/or
cancer by providing an anti-proliferative effect, particularly in
the treatment of erbB receptor tyrosine kinase sensitive cancers.
Such benign or malignant tumours may affect any tissue and include
non-solid tumours such as leukaemia, multiple myeloma or lymphoma,
and also solid tumours, for example bile duct, bone, bladder,
brain/CNS, breast, colorectal, endometrial, gastric, head and neck,
hepatic, lung, neuronal, oesophageal, ovarian, pancreatic,
prostate, renal, skin, testicular, thyroid, uterine and vulval
cancers.
[0394] According to this aspect of the invention there is provided
a compound of the Formula I, or a pharmaceutically acceptable salt
thereof, for use as a medicament.
[0395] According to a further aspect of the invention there is
provided a compound of the Formula I, or a pharmaceutically
acceptable salt thereof, for use in the production of an
anti-proliferative effect in a warm-blooded animal such as man.
[0396] Thus according to this aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in the production of an
anti-proliferative effect in a warm-blooded animal such as man.
[0397] According to a further feature of this aspect of the
invention there is provided a method for producing an
anti-proliferative effect in a warm-blooded animal, such as man, in
need of such treatment which comprises administering to said animal
an effective amount of a quinazoline derivative of the Formula I,
or a pharmaceutically acceptable salt thereof, as hereinbefore
defined.
[0398] According to a further aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in the prevention or
treatment of those tumours which are sensitive to inhibition of
erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or
erbB4 (especially EGFR), that are involved in the signal
transduction steps which lead to the proliferation of tumour
cells.
[0399] According to a further feature of this aspect of the
invention there is provided a method for the prevention or
treatment of those tumours which are sensitive to inhibition of one
or more of the erbB family of receptor tyrosine kinases, such as
EGFR and/or erbB2 and/or erbB4 (especially EGFR), that are involved
in the signal transduction steps which lead to the proliferation
and/or survival of tumour cells which comprises administering to
said animal an effective amount of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore.
[0400] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in the prevention
or treatment of those tumours which are sensitive to inhibition of
erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or
erbB4 (especially EGFR), that are involved in the signal
transduction steps which lead to the proliferation of tumour
cells.
[0401] According to a further aspect of the invention there is
provided the use of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined hereinbefore
in the manufacture of a medicament for use in providing a EGFR
and/or erbB2 and/or erbB4 (especially a EGFR) tyrosine kinase
inhibitory effect.
[0402] According to a further feature of this aspect of the
invention there is provided a method for providing a EGFR and/or an
erbB2 and or an erbB4 (especially a EGFR) tyrosine kinase
inhibitory effect which comprises administering to said animal an
effective amount of a quinazoline derivative of the Formula I, or a
pharmaceutically-acceptable salt thereof, as defined
hereinbefore.
[0403] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in providing a
EGFR and/or erbB2 and/or erbB4 (especially a EGFR) tyrosine kinase
inhibitory effect.
[0404] According to a further feature of the present invention
there is provided the use of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore in the manufacture of a medicament for use in
providing a selective EGFR tyrosine kinase inhibitory effect.
[0405] According to a further feature of this aspect of the
invention there is provided a method for providing a selective EGFR
tyrosine kinase inhibitory effect which comprises administering to
said animal an effective amount of a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, as
defined hereinbefore.
[0406] According to a further feature of this aspect of the
invention there is provided a compound of the Formula I, or a
pharmaceutically acceptable salt thereof, for use in providing a
selective EGFR tyrosine kinase inhibitory effect.
[0407] By "a selective EGFR kinase inhibitory effect" is meant that
the quinazoline derivative of Formula I is more potent against EGF
receptor tyrosine kinase than it is against other kinases. In
particular some of the compounds according to the invention are
more potent against EGF receptor kinase than it is against other
tyrosine kinases such as other erbB so receptor tyrosine kinases
such erbB2. For example a selective EGFR kinase inhibitor according
to the invention is at least 5 times, preferably at least 10 times
more potent against erbB2 receptor tyrosine kinase driven
proliferation than it is against EGFR tyrosine kinase driven
proliferation, as determined from the relative IC.sub.50 values in
a suitable assay (for example the H116N-2 assay described
above).
[0408] According to a further aspect of the present invention there
is provided the use of a quinazoline derivative of the Formula I,
or a pharmaceutically-acceptable salt thereof, as defined
hereinbefore in the manufacture of a medicament for use in the
treatment of a cancer (for example a cancer selected from
leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder,
brain/CNS, breast, colorectal, endometrial, gastric, head and neck,
hepatic, lung, neuronal, oesophageal, ovarian, pancreatic,
prostate, renal, skin, testicular, thyroid, uterine and vulval
cancer).
[0409] According to a further feature of this aspect of the
invention there is provided a method for treating a cancer (for
example a cancer selected from leukaemia, multiple myeloma,
lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal,
endometrial, gastric, head and neck, hepatic, lung, neuronal,
oesophageal, ovarian, pancreatic, prostate, renal, skin,
testicular, thyroid, uterine and vulval cancer) in a warm-blooded
animal, such as man, in need of such treatment, which comprises
administering to said animal an effective amount of a quinazoline
derivative of the Formula I, or a pharmaceutically-acceptable salt
thereof, as defined hereinbefore.
[0410] According to a further aspect of the invention there is
provided a compound of the Formula I, or a pharmaceutically
acceptable salt thereof, for use in the treatment of a cancer (for
example selected from leukaemia, multiple myeloma, lymphoma, bile
duct, bone, bladder, brain/CNS, breast, colorectal, endometrial,
gastric, head and neck, hepatic, lung, neuronal, oesophageal,
ovarian, pancreatic, prostate, renal, skin, testicular, thyroid,
uterine and vulval cancer).
[0411] As mentioned above the size of the dose required for the
therapeutic or prophlyactic treatment of a particular disease will
necessarily be varied depending upon, amongst other things, the
host treated, the route of administration and the severity of the
illness being treated.
[0412] The anti-proliferative treatment defined hereinbefore may be
applied as a sole therapy or may involve, in addition to the
quinazoline derivative of the invention, conventional surgery or
radiotherapy or chemotherapy. Such chemotherapy may include one or
more of the following categories of anti-tumour agents:--
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside and hydroxyurea; antitumour antibiotics (for
example anthracyclines like adriamycin, bleomycin, doxorubicin,
daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and
mithramycin); antimitotic agents (for example vinca alkaloids like
vincristine, vinblastine, vindesine and vinorelbine and taxoids
like taxol and taxotere); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan and camptothecin); (ii) cytostatic agents such as
antioestrogens (for example tamoxifen, toremifene, raloxifene,
droloxifene and iodoxyfene), oestrogen receptor down regulators
(for example fulvestrant), antiandrogens (for example bicalutamide,
flutamide, nilutamide and cyproterone acetate), LHRH antagonists or
LHRH agonists (for example goserelin, leuprorelin and buserelin),
progestogens (for example megestrol acetate), aromatase inhibitors
(for example as anastrozole, letrozole, vorazole and exemestane)
and inhibitors of 5.alpha.-reductase such as finasteride; (iii)
agents which inhibit cancer cell invasion (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function); (iv) inhibitors
of growth factor function, for example such inhibitors include
growth factor antibodies, growth factor receptor antibodies (for
example the anti-erbb2 antibody trastuzumab [Herceptin.TM.] and the
anti-erbb1 antibody cetuxirnab [C225]), farnesyl transferase
inhibitors, tyrosine kinase inhibitors and serine/threonine kinase
inhibitors, for example other 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)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family; (v) antiangiogenic agents such
as those which inhibit the effects of vascular endothelial growth
factor, (for example the anti-vascular endothelial cell growth
factor antibody bevacizumab [Avastin.TM.], compounds such as those
disclosed in International Patent Applications WO 97/22596, WO
97/30035, WO 97/32856 and WO 98/13354) and compounds that work by
other mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin); (vi) vascular damaging
agents such as Combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO00/40529, WO
00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense
therapies, for example those which are directed to the targets
listed above, such as ISIS 2503, an anti-ras antisense; (viii) 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 (ix) 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.
[0413] Such conjoint treatment may be achieved by way of the
simultaneous, sequential or separate dosing of the individual
components of the treatment. Such combination products employ the
compounds of this invention within the dosage range described
hereinbefore and the other pharmaceutically-active agent within its
approved dosage range.
[0414] According to this aspect of the invention there is provided
a pharmaceutical product comprising a quinazoline derivative of the
Formula I as defined hereinbefore and an additional anti-tumour
agent as defined hereinbefore for the conjoint treatment of
cancer.
[0415] Although the compounds of the Formula I are primarily of
value as therapeutic agents for use in warm-blooded animals
(including man), they are also useful whenever it is required to
inhibit the effects of the erbB receptor tyrosine protein kinases.
Thus, they are useful as pharmacological standards for use in the
development of new biological tests and in the search for new
pharmacological agents.
[0416] The invention will now be illustrated by the following non
limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (.degree. C.);
operations were carried out at room or ambient temperature, that
is, at a temperature in the range of 18-25.degree. C.; (ii) organic
solutions were dried over anhydrous magnesium sulfate; evaporation
of solvent was carried out using a rotary evaporator under reduced
pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of
up to 60.degree. C.; (iii) chromatography means flash
chromatography on silica gel; thin layer chromatography (TLC) was
carried out on silica gel plates; (iv) in general, the course of
reactions was followed by TLC and/or analytical LCMS, and reaction
times are given for illustration only; (v) final products had
satisfactory proton nuclear magnetic resonance (NMR) spectra and/or
mass spectral data; (vi) yields are given for illustration only and
are not necessarily those which can be obtained by diligent process
development; preparations were repeated if more material was
required; (vii) when given, NMR data is in the form of delta values
for major diagnostic protons, given in parts per million (ppm)
relative to tetramethylsilane (TMS) as an internal standard,
determined at 300 MHz using perdeuterio dimethyl sulfoxide
(DMSO-d.sub.6) as solvent unless otherwise indicated; the following
abbreviations have been used: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; b, broad; (viii) chemical symbols have
their usual meanings; SI units and symbols are used; (ix) solvent
ratios are given in volume:volume (v/v) terms; and (x) mass spectra
(MS) were run with an electron energy of 70 electron volts in the
chemical ionization (CI) mode using a direct exposure probe and
ionization was effected by electrospray; values for m/z are given;
generally, only ions which indicate the parent mass are reported;
and unless otherwise stated, the mass ion quoted is
(MH.sup.+).sup.+; (xi) unless stated otherwise compounds containing
an asymmetrically substituted carbon and/or sulfur atom have not
been resolved; (xii) where a synthesis is described as being
analogous to that described in a previous example the amounts used
are the millimolar ratio equivalents to those used in the previous
example; (xvi) the following abbreviations have been used: DCM
dichloromethane;
DMF N,N-dimethylformamide;
DMA N,N-dimethylacetamide;
THF Tetrahydrofuran;
[0417] HATU 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate xvii) where a synthesis is described as leading
to an acid addition salt (e.g. HCl salt), the specific
stoichiometry of the salt was not confirmed. xviii) In Examples 1
to 15 and the Reference Examples unless otherwise stated, all NMR
data is reported on free-base material, with isolated salts
converted to the free-base form prior to characterisation.
EXAMPLE 1
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]qui-
nazoline
##STR00015##
[0419] To a suspension of
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
(Reference Example 2, 639 mg, 2.0 mmol) in DCM (30 ml) was added
1-methyl-3-pyrrolidinol (658 .mu.l, 6.0 mmol) and triphenyl
phosphine (1572 mg, 6.0 mmol). The suspension was cooled to
0.degree. C. under a nitrogen atmosphere. Di-tert-butyl
azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM
(20 ml), dropwise over the course of 15 minutes. The resulting
light brown solution was allowed to warm to room temperature and
was stirred overnight. The solution was evaporated, and the residue
purified by chromatography, eluting with 0 to 5% methanol in DCM.
The appropriate fractions were combined and evaporated, and the
crude product (230 mg) re-dissolved in 1:1 methanol/DCM (5 ml).
Ethereal HCl (1 M, 1.14 ml) was added, and the mixture evaporated.
Crystallisation from ethanol/diethyl ether gave the title product
as a hydrochloride salt in the form of a white crystalline solid
(154 mg, 16%: .sup.1H NMR (hydrochloride salt): 2.30 (m, 1H),
2.65-2.75 (m, 1H), 2.88 (s, 3H), 3.30-3.80 (m, 3H), 3.85-4.05 (m,
1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51
(dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8.72 (s, 1H), 8.81 (s, 1H);
Mass Spectrum: 403.3, 405.3.
EXAMPLE 2
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline
##STR00016##
[0421]
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoro-
anilino)-7-methoxyquinazoline (Reference Example 3; 350 mg, 0.70
mmol) was dissolved in trifluoroacetic acid (5 ml), and the
solution stood for 2 hours. The excess trifluoroacetic acid was
evaporated, and the residue was azeotroped twice with DCM. The
residue was purified by chromatography, eluting with 0 to 4% (7:1
MeOH/concentrated aqueous NH.sub.4OH) in DCM. Evaporation of the
appropriate fractions gave the product as an off-white solid (270
mg, 96%); .sup.1H NMR: 1.53-1.64 (m, 2H), 2.00-2.05 (m, 2H),
2.64-2.72 (m, 2H), 3.00-3.07 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H),
7.20 (s, 1H), 7.26 (ddd, 1H), 7.47 (dd, 1H), 7.50 (dd, 1H), 7.82
(s, 1H), 8.34 (s, 1H), 9.56 (s, 1H): Mass Spectrum: 403.2,
405.2
EXAMPLE 3
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinolin-
e
##STR00017##
[0423] The procedure described in Example 2 was repeated but using
6-{[(1-tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroan-
ilino)-7-methoxyquinazoline (Reference Example 4). The title
compound was obtained in 91% yield; .sup.1H NMR: 1.45-1.61 (m, 2H),
1.95-2.00 (m, 2H), 2.18 (m, 1H), 2.92 (m, 2H), 3.25-3.35 (m, 2H),
3.93 (s, 3H), 4.03 (d, 2H), 7.20 (s, 1H), 7.26 (dd, 1H), 7.46 (dd,
1H), 7.50 (dd, 1H), 7.89 (s, 1H), 8.36 (s, 1H), 8.72 (br. s, 1H),
9.74 (s, 1H); Mass Spectrum: 417.4, 419.
EXAMPLE 4
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-methylpiperidin-4-yl)oxy]quina-
zoline
##STR00018##
[0425]
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoro-
anilino)-7-methoxyquinazoline (Reference Example 3; 300 mg, 0.66
mmol) was dissolved in formic acid (10 ml). Aqueous formaldehyde
solution (40%, 1 ml) was added, and the mixture heated to
90.degree. C. for 3 hours. The mixture was evaporated, and the
residue dissolved in water (30 ml). The solution was adjusted to pH
8-9 by the addition of sodium hydroxide solution (1 M), causing
precipitation of a white solid; this was collected by filtration
and washed with water (20 ml). The crude product was purified by
chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated
aqueous NH.sub.4OH) in DCM. Evaporation of the appropriate
tractions followed by crystallisation of the residue from
acetonitrile gave the product as a white crystalline solid (55 mg,
20%); .sup.1H NMR: 1.66-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.14-2.22
(m, 2H), 2.18 (s, 3H), 2.65-2.70 (m, 2H), 3.92 (s, 3H), 4.51 (m,
1H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H),
7.78 (s, 1H), 8.34 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 417.2,
419.3
EXAMPLE 5
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpiperidin-4-yl)methoxy]-
quinazoline
##STR00019##
[0427] The procedure described in Example 4 was repeated using
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroan-
ilino)-7-methoxyquinazoline (reference example 4) to give the title
compound in 42% yield after crystallisation from methyl tert-butyl
ether; .sup.1H NMR: 1.28-1.42 (m, 2H), 1.79-1.95 (m, 5H), 2.17 (s,
3H), 2.80 (m, 2H), 3.95 (s, 3H), 3.98 (d, 2H), 7.20 (s, 1H), 7.28
(dd, 1H), 7.48 (dd, 1H), 7.52 (dd, 1H), 7.77 (s, 1H), 8.37 (s, 1H),
9.59 (s, 1H); Mass Spectrum: 431.1, 430.0
EXAMPLE 6
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[2-(1-methylpiperidin-4-yl)ethoxy-
]quinazoline
##STR00020##
[0429] The procedure described in Example 4 was repeated using
6-{[2-(1-tert-Butoxycarbonyl)piperidin-4-yl]ethoxy}(reference
example 5) to give the title compound in 60% yield after
crystallisation from methyl tert-butyl ether, .sup.1H NMR:
1.17-1.30 (m, 2H), 1.43 (m, 1H), 1.65-1.85 (m, 6H), 2.11 (s, 3H),
2.73 (m, 2H), 3.92 (s, 3H), 4.14 (t, 2H), 7.18 (s, 1H), 7.26 (ddd,
1H), 7.46 (dd, 1H), 7.51 (dd, 1H), 7.76 (s, 1H) 8.35 (s, 1H), 9.53
(s, 1H); Mass Spectrum: 445.5, 447.
EXAMPLE 7
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4-y-
l]oxy}quinazoline
##STR00021##
[0431]
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoro-
anilino)-7-methoxyquinazoline (Reference Example 3; 485 mg, 1.07
mmol) was dissolved in trifluoroacetic acid (10 ml), and the
solution stirred at ambient temperature for 2 hours. The excess
trifluoroacetic acid was evaporated, and the residue was azeotroped
twice with DCM. The residue was dissolved in DMA (25 ml); potassium
carbonate (887 mg, 6.42 mmol) and 1-bromo-2-methoxyethane (100
.mu.l, 1.07 mmol) were added. The mixture was stirred at ambient
temperature for 16 hours. Further potassium carbonate (444 mg, 3.21
mmol) and 1-bromo-2-methoxyethane (100 .mu.l, 1.07 mmol) were
added, and the mixture heated at 60.degree. C. for a further 4
hours. The solvent was evaporated; the residue was partitioned
between DCM (50 ml) and water (50 ml). The aqueous layer was
extracted with DCM (2.times.30 ml) and the extractions combined
with the DCM layer. The combined DCM fractions were filtered
through a silicone-treated filter paper and evaporated. The residue
was purified by chromatography, eluting with 0 to 2% (7:1
MeOH/concentrated aqueous NH.sub.4OH) in DCM. Evaporation of the
appropriate fractions followed by crystallisation of the residue
from acetonitrile gave the product as a white crystalline solid
(153 mg, 38%); .sup.1H NMR: 1.60-1.75 (m, 2H), 1.95-2.05> (m,
2H), 2.30 (m, 2H), 2.49 (t, 2H), 2.75-2.82 (m, 2H), 3.22 (s, 3H),
3.43 (t, 2H), 3.92 (s, 3H), 4.51 (m, 1H), 7.19 (s, 1H), 7.26 (ddd,
1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.78 (s, 1H), 8.34 (s, 1H), 9.53
(s, 1H); Mass Spectrum: 461.2, 463.2
EXAMPLE 8
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(2-methoxyethyl)piperidin-4-)
yl]methoxy}quinazoline
##STR00022##
[0433]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]q-
uinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5
ml). Potassium carbonate (138 mg, 1.00 mmol) and
1-bromo-2-methoxyethane (24 .mu.l, 0.25 mmol) were added. The
mixture was stirred at 60.degree. C. for 4 hours. Further potassium
carbonate (138 mg, 1.00 mmol) and 1-bromo-2-methoxyethane (24
.mu.l, 0.25 mmol) were added; heating was continued at 60.degree.
C. for a further 4 hours. The solvent was evaporated and the
residue was partitioned between DCM (20 ml) and water (20 ml). The
aqueous layer was extracted with DCM (2.times.10 ml) and the
extractions combined with the DCM layer. The combined DCM fractions
were filtered through a silicone-treated filter paper and
evaporated. The residue was purified by chromatography, eluting
with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH.sub.4OH) in DCM.
The appropriate fractions were combined and evaporated, and the
crude product (40 mg) re-dissolved in 1:1 methanol/DCM (5 ml).
Ethereal HCl (1 M, 0.5 ml) was added, and the mixture evaporated.
Crystallisation from iso-propanol/diethyl ether gave the title
product as a hydrochloride salt, a yellow solid (28 mg, 20%);
.sup.1H NMR (hydrochloride salt): 1.60-1.75 (m, 2H), 2.00-2.05 (m,
2H), 2.16 (m, 1H), 2.95-3.10 (m, 2H), 3.22 (t, 2H), 3.29 (s, 3H),
3.50-3.57 (m, 2H), 3.70 (t, 2H), 3.99 (s, 3H), 4.12 (d, 2H), 7.34
(dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H), 7.61 (dd, 1H), 8.46 (s, 1H),
8.78 (s, 1H), 10.08 (br. s, 1H): Mass Spectrum: 475.5, 477
EXAMPLE 9
4-(3-Chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl)piperidin-4-yl]oxy}-7-m-
ethoxyquinazoline
##STR00023##
[0435]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quina-
zoline (Example 2, 1360 mg, 3.38 mmol) was dissolved in DCM (40
ml), and diisopropylethylamine (882 .mu.l, 5.07 mmol) was added.
Methanesulfonyl chloride(392 .mu.l, 5.07 mmol) was added dropwise,
and the solution stirred for 16 hours at ambient temperature. The
solvent was evaporated, and the residue purified by chromatography,
eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH.sub.4OH) in
DCM. The appropriate fractions were combined and evaporated, and
the residue crystallised from ethyl acetate/hexane to give the
product as a white crystalline solid (650 mg, 40%); .sup.1H NMR:
1.80-1.90 (m, 2H), 2.04-2.13 (m, 2H), 2.91 (s, 3H), 3.10-3.20 (m,
2H), 3.34-3.44 (m, 2H), 3.93 (s, 3H), 4.67 (m, 1H), 7.22 (s, 1H),
7.27 (dd, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.86 (s, 1H), 8.37 (s,
1H), 9.55 (s, 1H); Mass Spectrum: 481.2, 483.1
EXAMPLE 10
4-(3-Chloro-2-fluoroanilino)-6-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}-
-7-methoxyquinazoline
##STR00024##
[0437] The procedure described in Example 9 was repeated using
4-(3-chloro-2-fluoroanilino)-7-methoxy-r>[(piperidin-4-yl)methoxy]quin-
azoline (Example 3). Thus was obtained the compound below in 71%
yield after trituration with diethyl ether. .sup.1H NMR: 1.31-1.47
(m, 2H), 1.90-2.07 (m, 3H), 2.76 (m, 2H), 2.85 (s, 3H), 3.56-3.67
(m, 2H), 3.93 (s, 3H), 4.01 (d, 2H), 7.19 (s, 1H), 7.26 (dd, 1H),
7.46 (dd, 1H), 7.50 (dd, 1H), 7.78 (s, 1H), 8.36 (s, 1H), 9.61, (s,
1H); Mass Spectrum: 495.4, 497.4
EXAMPLE 11
6-{[1-(carbamoylmethyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7--
methoxyquinazoline
##STR00025##
[0439]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quina-
zoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DCM (10 ml),
and diisopropylethylamine (45 .mu.l, 0.26 mmol) was added.
2-Bromoacetamide (36 mg, 0.26 mmol) was added, and the solution
stirred for 16 hours at ambient temperature. The solvent was
evaporated, and the residue purified by chromatography, eluting
with 0 to 3% (7:1 MeOH/concentrated aqueous NH.sub.4OH) in DCM. The
appropriate fractions were combined and evaporated, and the residue
crystallised from acetonitrile to give the product as a white
crystalline solid (48 mg, 60%); .sup.1H NMR: 1.70-1.84 (m, 2H),
1.98-2.09 (m, 2H), 2.38 (m, 2H), 2.70-2.80 (m, 2H), 2.89 (s, 2H),
3.92 (s, 3H), 4.54 (m, 1H), 7.08 (br. s, 2H), 7.20 (s, 1H), 7.26
(ddd, 1H), 7.47 (ddd, 1H), 7.51 (ddd, 1H), 7.80 (s, 1H), 8.35 (s,
1H), 9.53 (s, 1H); Mass Spectrum: 460.5, 462.4.
EXAMPLE 12
6-{[1-(Carbamoylmethyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilino-
)-7-methoxyquinazoline
##STR00026##
[0441] The procedure of Example 11 was repeated but using
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazo-
line (Example 3). The title compound was obtained in 44% yield
after crystallisation from acetonitrile; .sup.1H NMR: 1.34-1.50 (m,
2H), 1.77-1.90 (m, 3H), 2.05-2.20 (m, 2H), 2.80-2.95 (m, 4H), 3.93
(s, 3H), 3.97 (d, 2H), 7.04-7.16 (m, 2H), 7.19 (s, 1H), 7.26 (ddd,
1H), 7.46 (ddd, 1H), 7.50 (ddd, 1H), 7.76 (s, 1H), 8.35 (s, 1H).
9.58 (s, 1H): Mass Spectrum: 474.4, 476.4
EXAMPLE 13
4-(3-Chloro-2-fluoroanilino)-6-{[1-(cyanomethyl)piperidin-4-yl]oxy}-7-meth-
oxyquinazoline
##STR00027##
[0443]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quina-
zoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DMA (5 ml).
Potassium carbonate (96 mg, 0.70 mmol) and chloroacetonitrile (17
yd, 0.25 mmol) were added. The mixture was stirred at 60.degree. C.
for 4 hours. The solvent was evaporated and the residue was
partitioned between DCM (20 ml) and water (20 ml). The aqueous
layer was extracted with DCM (2.times.10 ml) and the 1 extractions
combined with the DCM layer. The combined DCM fractions were
filtered through a silicone-treated filter paper and evaporated.
The residue was purified by chromatography, eluting with 0 to 2%
(7:1 MeOH/concentrated aqueous NH.sub.4OH) in DCM. The appropriate
fractions were combined and evaporated, and the residue triturated
with diethyl ether, giving the product as a white solid (28 mg,
36%); .sup.1H NMR: 1.67-1.80 (m, 2H), 2.03-2.13 (m, 2H), 2.46 (m,
2H), 2.77-2.85 (m, 2H), 3.76 (s, 2H), 3.92 (s, 3H), 4.55 (m, 1H),
7.20 (s, 1H), 7.27 (dd, 1H), 7.47 (dd, 1H), 7.52 (dd, 1H), 7.80 (s,
1H), 8.35 (s, 1H), 9.54 (s, 1H); Mass Spectrum: 442.4, 444.4.
EXAMPLE 14
4-(3-Chloro-2-fluoroanilino)-6-{[1-(cyanomethyl)piperidin-4-yl]methoxy}-7--
methoxyquinazoline
##STR00028##
[0445]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]q-
uinazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DMA (5
ml). Potassium carbonate (138 mg, 1.00 mmol) and chloroacetonitrile
(17 .mu.l, 0.25 mmol) were added. The mixture was stirred at
60.degree. C. for 4 hours. Further potassium carbonate (138 mg,
1.00 mmol) and chloroacetonitrile (17 .mu.l, 0.25 mmol) were added,
and heating was continued at 60.degree. C. for a further 4 hours.
The solvent was evaporated and the residue was partitioned between
DCM (20 ml) and water (20 ml). The aqueous layer was extracted with
DCM (2.times.10 ml) and the extractions combined with the DCM
layer. The combined DCM fractions were filtered through a
silicone-treated filter paper and evaporated. The residue was
purified by chromatography, eluting with 0 to 2% (7:1
MeOH/concentrated aqueous NH.sub.4OH) in DCM. The appropriate
fractions were combined and evaporated. The residue was further
purified using reverse phase HPLC, eluting with 5 to 95%
acetonitrile in water containing 0.2% trifluoroacetic acid. The
appropriate fractions were combined; the acetonitrile was
evaporated from the solution, and the resulting aqueous solution
was adjusted to pH 8 using concentrated aqueous ammonia. The
resulting suspension was extracted twice with DCM, and the
extractions combined, filtered through a silicone-treated filter
paper, and evaporated. The residue was triturated with diethyl
ether to give the product as a white solid (10 mg, 9%); .sup.1H
NMR: 1.32-1.46 (m, 2H), 1.75-1.92 (m, 3H), 220 (m, 2H), 2.84 (m,
2H), 3.72 (s, 2H), 3.93 (s, 3H), 3.98 (d, 2H), 7.20 (s, 1H), 7.26
(dd, 1H), 7.47 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.36 (s, 1H),
9.59 (s, 1H); Mass Spectrum: 456.4, 458.4
EXAMPLE 15
4-(3-Chloro-2-fluoroanilino)-6-[(1-cyanopiperidin-4-yl)methoxy]-7-methoxyq-
uinazoline
##STR00029##
[0447]
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxyqu-
inazoline (Example 3, 104 mg, 0.25 mmol) was dissolved in DCM (10
ml), and diisopropylethylamine (48 .mu.l, 0.28 mmol) was added.
Cyanogen bromide solution (3 M in DCM, 92u], 0.28 mmol) was added,
and the solution stirred for 16 hours at ambient temperature. The
solvent was evaporated, and the residue purified by chromatography,
eluting with 0 to 2% (7:1 MeOH/concentrated aqueous NH.sub.4OH) in
DCM. The appropriate fractions were combined and evaporated, and
the residue triturated with diethyl ether to give the product as a
white solid (75 mg, 68%); .sup.1H NMR: 1.34-1.50 (m, 2H), 1.80-1.90
(m, 2H), 2.02 (m, 1H), 3.10 (m, 2H), 3.37-3.46 (m, 2H), 3.93 (s,
3H), 3.99 (d, 2H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.46 (dd, 1H), 7.46
(dd, 1H), 7.50 (dd, 1H), 7.77 (s, 1H), 8.36 (s, 1H), 9.57 (s, 1H);
Mass Spectrum: 442.4, 444.4.
EXAMPLE 16
6-(1-Acetylpiperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinaz-
oline
##STR00030##
[0449] Acetyl chloride (179 mg) was added to a solution of
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
dihydrochloride (1 g) and diisopropylethylamine (735 mg) in
methylene chloride that was cooled at 0.degree. C. and the mixture
was stirred for 2 hours and allowed to warm to room temperature.
The reaction mixture was adsorbed onto silica and the residue was
purified by column chromatography eluting with increasingly polar
mixtures of methylene chloride/methanol (100/0 to 90/10). The
fractions containing the desired product were combined and
evaporated under vacuum to give the title product as a colourless
foam (0.655 g); .sup.1H NMR Spectrum: (DMSO d.sub.6) 1.54-1.78 (m,
2H), 1.91-2.10 (m, 5H) 3.29-3.41 (m, 2H), 3.66-3.76 (m, 1H),
3.78-3.88 (m, 1H), 3.93 (s, 3H), 4.74 (m, 1H), 7.20 (s, 1H), 7.27
(t, 1H), 7.44-7.55 (m, 2H), 7.87 (s, 1H), 836 (s, 1H), 9.54 (s,
1H); Mass Spectrum: (M+H).sup.+445.
[0450] The
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyqui-
nazoline dihydrochloride starting material was prepared as
follows:
[0451] 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in
WO01/66099; 10.0 g, 39.6 mmole) was added in portions to a stirred
7 N methanolic ammonia solution (220 ml) cooled to 10.degree. C. in
an ice/water bath. After stirring for one hour the precipitate was
filtered, washed with diethylether and dried thoroughly under high
vacuum to give 4-chloro-6-hydroxy-7-methoxyquinazoline (5.65 g,
67.8%); .sup.1H NMR Spectrum: (DMSO d.sub.6) 3.96 (s, 3H); 7.25 (s,
1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum: (M+H).sup.+ 211
[0452] Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride
(20 ml) was added slowly to a stirred suspension of
4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g),
4-hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and
triphenylphosphine (10.5 g) in methylene chloride (100 ml) at
5.degree. C. under an atmosphere of nitrogen. The reaction mixture
was allowed to warm to room temperature for 16 hours. The reaction
mixture was then evaporated under vacuum and adsorbed onto silica
and the product was eluted with isohexane/ethyl
acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions
containing the desired product were combined and evaporated under
vacuum to give tert-butyl
4-[(4-chloro-7-methoxyquinazoline-6-yl)oxy]piperidinecarboxylate as
a white solid (10.3 g); .sup.1H NMR Spectrum: (DMSO d<j) 1.40
(s, 9H), 1.56-1.69 (m, 2H), 1.93-2.04 (m, 2H), 3.20-3.31 (m, 2H),
3.60-3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50
(s, 1H), 8.86 (s, 1H); Mass Spectrum: (M+H).sup.+ 394.
[0453] 4.0 M HCl in Dioxane (4.0 ml) was added to a suspension of
tert-butyl
4-[(4-chloro-7-methoxyquinazoline-6-yl)oxy]piperidine-1-carboxylate
(2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in isopropanol (50
ml). The reaction mixture was stirred and heated at 100.degree. C.
for 2 hours. The yellow precipitate was filtered hot and washed
with iso-propanol followed by diethylether and dried under vacuum
to give
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
as a di-hydrochloride salt (2.38 g); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.84-1.99 (m, 2H), 2.22-2.33 (m, 2H), 3.12-3.33 (m, 4H),
4.00 (s, 3H), 5.08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t,
1H), 7.62 (t, 1H), 8.80 (s, 1H), 8.84-8.94 (m, 2H), 8.99-9.11 (m,
1H); Mass Spectrum: (M+H).sup.+403.
EXAMPLE 17
4-(3-Chloro-2-fluoroanilino)-6-[1-(N,N-dimethylaminoacetyl)piperidin-4-ylo-
xy]methoxyquinazoline
##STR00031##
[0455] A suspension of
4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-meth-
oxyquinazoline (0.14 g) and sodium iodide (0.1 g) in an ethanolic
solution of dimethylamine (33%) (10 ml) was stirred at ambient
temperature for 2 hours. The mixture was evaporated under vacuum
and the residue dissolved in methylene chloride and purified by
column chromatography on silica eluting with increasingly polar
mixtures of methylene chloride/methanol (saturated with ammonia)
(100/0 to 85/15). The fractions containing the title product were
combined and evaporated under vacuum and the residue triturated
with diethyl ether and filtered to give the title product as a
crystalline solid (0.085 g); .sup.1H NMR Spectrum: (DMSO d.sub.6)
1.56-1.78 (m, 2H), 1.92-2.08 (m, 2H), 2.20 (s, 6H), 3.05-3.18 (m.
2H), 330-3.48 (m, 2H), 3.79-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m,
1H), 7.21 (s, 1H), 7.28 (t, 1H), 7.44-7.56 (m, 2H), 7.86 (s, 1H),
8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M+H).sup.+ 488.
[0456] The
4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-ylo-
xy]-7-methoxy quinazoline starting material was prepared as
follows:
[0457] Chloroacetyl chloride (135 mg) was added to a solution of
4-(3-chloro-2-fluoroanilino)-6-(piperidin-4-yloxy)-7-methoxyquinazoline
di-hydrochloride (500 mg) (Starting material for Example 16) and
diisopropylethylamine (368 mg) in methylene chloride (15 ml) that
was cooled at 0.degree. C. and the mixture was stirred for 2 hours
and allowed to warm to room temperature. The reaction mixture was
adsorbed onto silica and the residue purified by column
chromatography on silica eluting with increasingly polar mixtures
of methylene chloride/methanol (100/0 to 94/6). The fractions
containing the expected product were combined and were re-purified
by column chromatography on silica eluting with increasingly polar
mixtures of methylene chloride/methanol (100/0 to 96/4). The
fractions containing the expected product were combined and
evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-meth-
oxyquinazoline as a crystalline solid (033 g); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.60-1.83 (m, 2H), 1.94-2.10 (m, 2H),
3.36-3.46 (m, 2H), 3.67-3.86 (m, 2H), 3.94 (s, 3H) 4.40 (s, 2H),
4.77 (m, 1H), 7.22 (s, 1H), 7.27 (t, 1H), 7.46-7.55 (m, 2H), 7.89
(s, 1H), 8.38 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H).sup.+
479.
EXAMPLE 18
6-[1-(N,N-Dimethylsulfamoyl)piperidin-4-yloxy]-4-(3-chloro-2-fluoroanilino-
)-7-methoxyquinazoline
##STR00032##
[0459] Dimethylsulfamoyl chloride (90 mg) was added to a solution
of
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
dihydrochloride (250 mg)(starting material Example 16) and
diisopropylethylamine (184 mg) in methylene chloride (10 ml). The
reaction mixture was stirred for 16 hours at ambient temperature.
The reaction mixture was adsorbed onto silica and the residue was
purified by column chromatography on silica eluting with
increasingly polar mixtures of methylene chloride/methanol (100/0
to 95/5). The fractions containing the expected product were
combined and evaporated under vacuum and the residue triturated
with diethylether to give the title product as a white solid (0.23
g); .sup.1H NMR Spectrum: (DMSO c*) 1.72-1.86 (m, 2H), 2.00-2.12
(m, 2H), 2.76 (s, 6H); 3.12-3.23 (m, 2H), 3.40-3.51 (m, 2H), 3.94
(s, 3H), 4.68 (m, 1H), 7.19-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.85
(s, 1H), 8.37 (s, 1H), 9.52 (s, 1H); Mass Spectrum: (M+H).sup.+
510.
EXAMPLE 19
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(morpholinoacetyl)piperidin-4--
yloxy]quinazoline
##STR00033##
[0461] A suspension of
4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-meth-
oxyquinazoline (0.15 g)(starting material for Example 17) and
sodium iodide (0.02 g) in morpholine (5 ml) was stirred at ambient
temperature for 16 hours. The mixture was evaporated under vacuum
and the residue dissolved in methylene chloride/methanol. This was
adsorbed onto silica and purified by column chromatography on
silica eluting with increasingly polar mixtures of methylene
chloride/methanol (100/0 to 90/10). The fractions containing the
title product were combined and evaporated under vacuum. The
residue was triturated with diethylether, filtered and dried under
vacuum to give the title product as a beige crystalline solid
(0.105 g); .sup.1H NMR Spectrum: (DMSO d.sub.6 and CD.sub.3COOD)
1.57-1.80 (m, 2H), 1.91-2.12 (m, 2H), 2.40-2.51 (m, 4H), 3.14-3.48
(m, 4H), 3.52-3.61 (m, 4H), 3.81-3.90 (m, 2H)> 3.94 (s, 3H),
4.76 (m, 1H), 7.20-7.30 (m, 2H), 7.42-7.54 (m, 2H), 7.85 (s, 1H),
8.36 (s, 1H); Mass Spectrum: (M+H).sup.+ 530.
EXAMPLE 20
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperid-
in-4-yloxy]quinazoline
##STR00034##
[0463] A suspension of
4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-meth-
oxyquinazoline (0.15 g)(starting material used in Example 17) and
sodium iodide (0.02 g) in pyrrolidine (5 ml) was stirred at ambient
temperature for 16 hours. The mixture was evaporated under vacuum
and the residue dissolved in methylene chloride/methanol. This was
adsorbed onto silica and purified by column chromatography eluting
with increasingly polar mixtures of methylene chloride/methanol
(100/0 to 92/8). The fractions containing the title product were
combined and evaporated under vacuum and the residue triturated
with diethyl ether, filtered and dried under vacuum to give the
title product as a white crystalline solid. (0.085 g); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.57-1.77 (m, 6H), 1.92-2.09 (m, 2H),
3.20-3.48 (m, 8H), 3.80-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m, 1H),
7.2-7.31 (m, 2H), 7.45-7.55 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H),
9.53 (s, 1H); Mass Spectrum: (M+H).sup.+ 514.
EXAMPLE 21
4-(3-Chloro-2-fluoroanilino)-6-{1-[3-(dimethylamino)propylsulfonyl]piperid-
in-4-yloxy}-7-methoxyquinazoline
##STR00035##
[0465] A suspension of
4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-ylo-
xy}-7-methoxyquinazoline (0.15 g) and sodium iodide (0.03 g) in an
ethanolic solution of dimethylamine (33%) (15 ml) was stirred at
ambient temperature for 16 hours. The reaction mixture was adsorbed
onto silica and purified by column chromatography on silica eluting
with increasingly polar mixtures of methylene chloride/methanol
(saturated with ammonia) (100/0 to 88/12). The fractions containing
the title product were combined and evaporated under vacuum to give
the title product (0.105 g); .sup.1H NMR Spectrum: (DMSO d.sub.6)
1.75-1.87 (no, 4H), 2.0-2.11 (m, 2H), 2.12 (s, 6H), 2.30 (t, 2H),
3.05-3.14 (m, 2H), 3.17-3.29 (m, 2H), 3.40-3.50 (m, 2H), 3.93 (s,
3H), 4.69 (m, 1H), 7.22 (s, 1H), 7.28 (t, 1H), 7.44-7.55 (m, 2H),
7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum:
(M+H).sup.+ 552
[0466] The
4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piper-
idin-4-yloxy}-7-methoxyquinazoline starting material was prepared
as follows:
[0467] 3-chloropropanesulfonylchloride (174 mg) was added to a
solution of
6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
dihydrochloride (190 mg; starting material for Example 16) and
diisopropylethylamine (140 mg) in methylene chloride (5 ml) at
ambient temperature and the reaction mixture was stirred for 16
hours. The reaction mixture was adsorbed onto silica and the
residue was purified by column chromatography on silica eluting
with increasingly polar mixtures of methylene chloride/methanol
(100/0 to 94/6). The fractions containing the expected product were
combined and evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-{1-[3-chloropropylsulfonyl]piperidin-4-ylo-
xy}-7-methoxyquinazoline as a brown gum (0.15 g); Mass Spectrum:
(M+H).sup.+ 543.
EXAMPLE 22
4-(3-Chloro-2-fluoroanilino)-6-[1-(methylsulfonyl)piperidin-3-yloxy]-7-met-
hoxyquinazoline
##STR00036##
[0469] Methanesulfonyl chloride (42 mg) was added to a solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
(134 mg) and > diisopropylethylamine (65 mg) in methylene
chloride (5 ml) at ambient temperature. The reaction mixture was
stirred for 36 hours at ambient temperature. The reaction mixture
was adsorbed onto silica and the residue was purified by column
chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol(100/0 to 95/5). The fractions
containing the title product were combined and evaporated under
vacuum and the residue triturated with diethyl ether, filtered and
dried under vacuum to give the title product as a mixture of the 3R
and 3S isomers (0.10 g); .sup.1H NMR Spectrum: (DMSO d.sub.6 and
CD.sub.3COOD) 1.54-2.07 (m, 4H), 2.95 (s, 3H), 3.10-3.20 (m, 1H),
3.21-3.37 (m, 2H), 3.50-3.59 (m, 1H), 3.93 (s, 3H), 4.70 (m, 1H),
7.20-7.29 (m, 2H), 7.40-7.55 (m, 2H), 7.89 (s, 1H), 8.37 (s, 1H);
Mass Spectrum: (M+H).sup.+ 481.
[0470] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)qui-
nazoline starting material was prepared as follows:
[0471] 4-Nitrobenzenesulfonyl chloride (4.4 g) was added to a
stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate
(4.0 g) and pyridine (2.25 ml) in methylene chloride (80 ml) and
stirred at ambient temperature for 16 hours. The reaction mixture
was poured into saturated sodium bicarbonate solution. The organic
layer was separated, washed with brine and dried over sodium
sulfate. The solution was evaporated under vacuum and triturated
with diethylether and filtered to remove undesired solids. The
diethylether liquors were evaporated under vacuum and dissolved in
methylene chloride before purification by column chromatography on
silica eluting with ethyl acetate/isohexane(20/80). The fractions
containing the expected product were combined and evaporated under
vacuum to give tert-butyl
3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate as a yellow
crystalline solid (6.77 g); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.43
(s, 9H), 1.40-1.54 (m, 1H), 1.70-1.94 (m, 3H), 3.22-3.60 (m, 4H),
4.67 (m, 1H), 8.11 (s, 2H), 8.40 (s, 2H).
[0472] Dimethylformamide (23 ml) was added to
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline,
tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate
(1.93 g) and cesium fluoride (2.28 g). The reaction mixture was
then stirred at room temperature for 4 days. The reaction mixture
was evaporated under vacuum and partitioned between methylene
chloride and water. The solutions were filtered to remove insoluble
solids and the methylene chloride was washed with water and
saturated brine and adsorbed onto silica. The product was then
purified by column chromatography on silica eluting with
increasingly polar mixtures of methylene chloride/methanol (100/0
to 94/6). The fractions containing the required product were
combined and evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-
-methoxyquinazoline as a yellow gum (0.67 g); Mass Spectrum:
(M+H).sup.+ 503.
[0473] Trifluoroacetic acid (5 ml) was added to a solution of
4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-
-methoxyquinazoline (0.67 g) in methylene chloride (15 ml) and the
reaction mixture was stirred at ambient temperature for 1 hour. The
reaction mixture was evaporated under vacuum and the residue
dissolved in methylene chloride. The methylene chloride solution
was washed with a saturated solution of sodium bicarbonate, water,
brine, dried over MgSO.sub.4 and evaporated to give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
(0.28 g); Mass Spectrum: (M+H).sup.+ 403.
[0474] The
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
starting material used above was prepared as follows:
[0475] 6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in
WO01/66099; 10.0 g, 39.6 mmole) was suspended in acetonitrile (400
ml) and 3-chloro-2-fluoroaniline (6.05 g, 41.6 mmole) and hydrogen
chloride (4.0 M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were
added. The reaction mixture was refluxed for one hour and then
allowed to cool to ambient temperature. The resulting precipitate
was filtered off, washed with acetonitrile and diethylether to give
a white solid. This solid was added in portions to a stirred 7 N
methanolic ammonia solution (400 ml). The mixture was stirred for
two hours and the precipitate filtered, washed with acetonitrile
followed by diethylether and dried under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as a
white solid (12.1 g, 95%); .sup.1H NMR Spectrum: (DMSO d.sub.6)
3.95 (s, 3H); 7.18 (s, 1H); 7.20-7.25 (m, 1H); 7.39-7.44 (m, 1H);
7.47-7.52 (m, 1H); 7.65 (s, 1H); 8.31 (s, 1H); 9.45 (br.s, 1H):
Mass Spectrum: (M+H).sup.+ 320.
EXAMPLE 22.1
Resolution to
4-(3-Chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl)piperidin-3-yloxy]-
-7-methoxyquinazoline and
4-(3-Chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)piperidin-3-yloxy]-
-7-methoxyquinazoline
##STR00037##
[0477] The racemic mixture obtained in Example 22 (36 mg) was
resolved into the 3R and 3S enantiomers by chiral HPLC using the
following conditions:
TABLE-US-00004 Column 10 .mu.m Chiralpak AS (20 mm .times. 250 mm)
No. AS00CJ-IB004 Eluent Iso-hexane/ethanol (80/20) Oven Temperature
Ambient Flow 10 ml/min Wavelength 254 nm Sample Concentration 0.9
mg/ml in ethanol Run Time 110 mins
[0478] First eluted enantiomer (10.1 mg); .sup.1H NMR Spectrum:
(DMSO ds) 1.60-1.80 (m, 1H), 1.80-1.95 (m, 1H), 1.95-2.08 (m, 1H),
2.08-2.22 (m, 1H), 3.08 (s, 3H), 3.20-3.45 (m, 1H), 3.45-3.50 (m,
2H), 3.70 (dd, 1H), 4.05 (s, 3H), 4.70-4.90 (m, 1H), 7.30-7.50 (m,
2H), 7.50-7.70 (m, 2H), 8.02 (s, 1H), 8.50 (s, 1H), 9.50 (s, 1H);
Mass Spectrum: (M+H).sup.+ 481.
[0479] Second eluted enantiomer (18.7 mg); .sup.1H NMR Spectrum:
(DMSO d.sub.6) 1.60-1.80 (m, 1H), 1.80-1.95 (m, 1H), 1.95-2.08 (m,
1H), 2.08-2.22 (m, 1H), 3.08 (s, 3H), 3.20-3.45 (m, 1H), 3.45-3.50
(m, 2H), 3.70 (dd, 1H), 4.05 (s, 3H), 4.70-4.90 (m, 1H), 7.30-7.50
(m, 2H), 7.50-7.70 (m, 2H), 8.02 (s, 1H), 8.50 (s, 1H), 9.50 (s,
1H); Mass Spectrum: (M+H).sup.+ 481.
EXAMPLE 23
6-(1-Acetylpiperidin-3-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinaz-
oline
##STR00038##
[0481] Acetyl chloride (27 mg) was added to a solution of
4-(3-chloro-2-fluoroanilino)-6-(piperidin-3-yloxy)-7-methoxyquinazoline
(starting material described in Example 22; 134 mg) and
diisopropylethylamine (65 mg) in methylene chloride (5 ml) and the
reaction mixture was stirred at ambient temperature for 16 hours.
The reaction mixture was adsorbed onto silica and purified by
column chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol (100/0 to 95/5). The fractions
containing the required product were combined and evaporated to
give the title product (0.07 g); 3H NMR Spectrum: (DMSO d.sub.6 at
373K) 1.52-1.62 (m, 1H), 1.80-1.94 (m, 2H), 2.00 (s, 3H), 2.06-2.15
(m, 1H), 3.43-3.64 (m, 3H), 3.82-4.04 (m, 4H), 4.58 (m, 1H),
7.20-7.29 (m, 2H), 7.42 (t, 1H), 7.59 (t, 1H), 7.93 (s, 1H), 8.40
(s, 1H), 9.30 (s, 1H); Mass Spectrum: (M+H).sup.+ 445.
EXAMPLE 24
4-(3-Chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)pyrrolidi-
n-4-yloxy]-7-methoxy quinazoline
##STR00039##
[0483] Trifluoroacetic acid (5 ml) was added to a solution of
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(N,N-di-
methylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (0.17 g)
in methylene chloride (10 ml) and the reaction mixture was stirred
at ambient temperature for 2 hours. The reaction mixture was
evaporated under vacuum and the residue dissolved in methanol
saturated with ammonia)/methylene chloride, adsorbed onto silica
and purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride/methanol(saturated with
ammonia) (100/0 to 85/15). The fractions containing the required
product were combined and evaporated under vacuum to give the title
product as a colourless gum which crystallised on standing (0.13
g); .sup.1H NMR Spectrum: (DMSO ds and CD.sub.3COOD) 1.85-1.96 (m,
1H), 2.84-2.95 (m, 4H), 3.00 (s, 3H), 3.24-3.32 (m, 1H), 3.40-3.48
(m, 1H), 3.95 (s, 3H), 4.31 (m, 1H), 5.21 (m, 1H), 7.20-7.30 (m,
2H), 7.47-7.55 (m, 2H), 7.76 (s, 1H), 8.37 (s, 1H); Mass Spectrum:
(M+H).sup.+ 460.
[0484] The
4-(3-chloro-2-fluoroanilino)-6-[(2S,43)-1-(tert-butoxycarbonyl)-
-2-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline
starting material was prepared as follows:
[0485] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (2.48 g) was added to a stirred suspension of
N-tert-butoxycarbonyl-L-hydroxyproline (2.0 g),
4-(dimethylamino)pyridine (5.28 g) and dimethylamine hydrochloride
(1.4 g) in methylene chloride (100 ml) and the reaction mixture was
stirred at room temperature for 16 hours. The reaction mixture was
washed with citric acid (1.0 M), saturated sodium bicarbonate and
saturated brine before drying over magnesium sulfate. The product
was then purified by column chromatography on silica eluting with
increasingly polar mixtures of methylene chloride/methanol (100/0
to 90/10). The fractions containing the expected product were
combined and evaporated under vacuum to give
(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrol-
idine as a colourless gum (1.01 g); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.29-1.40 (m, 9H), 1.74-1.83 (m, 1H), 2.04-2.15 (m, 1H),
2.80-2.87 (m 3H), 3.03 (s, 3H), 3.26 (m, 1H), 3.40 (m, 1H), 4.28
(m, 1H), 4.64 (m, 1H), 4.95 (d, 1H).
[0486] 4-Nitrobenzenesulfonyl chloride (0.895 g) was added to a
stirred solution of
(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrol-
idine (0.993 g) and pyridine (0.6 g) in methylene chloride (10 ml)
and stirred at 4.degree. C. for 16 hours under an atmosphere of
nitrogen. The reaction mixture was washed with aqueous citric acid
(1.0 M), saturated sodium bicarbonate and dried over magnesium
sulfate. The product was then purified by column chromatography on
silica eluting with increasingly polar mixtures of methylene
chloride/methanol (100/0 to 95/5). The fractions containing the
required product were combined and evaporated under vacuum to give
(2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophen-
yl)sulfonyloxy]pyrrolidine as a yellow gum(0.685 g); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.30-1.36 (s, 9H), 1.98-2.07 (m, 1H);
2.37-2.48 (m, 1H); 2.83 (s, 3H), 3.00 (s, 3H), 3.45-3.55 (m, 2H),
4.70 (m, 1H), 5.23 (m, 1H), 8.21 (d, 2H), 8.47 (d, 2H).
[0487] Dimethylformamide (8 ml) was added to
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (0.489
g; prepared as described in the starting materials for Example 22),
(2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophen-
yl)sulfonyloxy]pyrrolidine (0.678 g) and cesium fluoride (0.697 g).
The reaction mixture was then stirred at room temperature for 16
hours. The reaction mixture was evaporated under vacuum and the
residue dissolved in methylene chloride/methanol and adsorbed onto
silica. The product was then purified by column chromatography
eluting with increasingly polar mixtures of methylene
chloride/methanol (100/0 to 90/10). The fractions containing the
expected product were combined and evaporated. The residue was
re-purified by column chromatography eluting with increasingly
polar mixtures of ethyl acetate/methanol (100/0 to 92/8). The
fractions containing the required product were combined and
evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-
-(N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as
a colourless gum which crystallised on standing (0.36 g); .sup.1H
NMR Spectrum: (DMSO d.sub.6 373K) 1.41 (s, 9H), 1.99 (m, 1H),
2.92-3.03 (m, 7H); 3.44 (m, 1H), 3.96 (s 3H), 4.14 (m, 1H), 4.70
(t, 1H), 5.10 (m, 1H), 7.22-7.30 (m, 2H), 7.44 (t, 1H), 7.62 (t,
1H), 7.84 (s, 1H), 8.40 (s, 1H), 9.30 (s, 1H); Mass Spectrum:
(M+H).sup.+ 560.
EXAMPLE 25
4-(3-Chloro-2-fluoroanilino)-6-[(2S,4S)-2-(N,N-dimethylcarbamoyl)-1-methyl-
pyrrolidin-4-yloxy]-7-methoxy quinazoline
##STR00040##
[0489]
4-(3-chloro-2-fluoroanilino)-6-[(2S,4S)-1-(tert-butoxycarbonyl)-2-(-
N,N-dimethylcarbamoyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline
(prepared as described in Example 24; 0.18 g), formic acid (0.31
ml) and formaldehyde (0.51 ml) were heated at 85.degree. C. for 6
hours. The reaction mixture was cooled and evaporated under vacuum.
The resulting residue was partitioned between methylene
chloride/n-propanol and saturated sodium bicarbonate. The organic
layer was dried over magnesium sulfate, adsorbed onto silica and
purified by column chromatography eluting with increasingly polar
mixtures of methylene chloride/methanol (100/0 to 90/10). The
fractions containing the desired product were combined and
evaporated under vacuum to yield a white crystalline solid. The
solid was washed with water, dissolved in methylene chloride and
dried over magnesium sulfate. The solvent was removed under vacuum
to give the title product (0.11 g); .sup.1H NMR Spectrum: (DMSO ds)
1.87 (t, 1H), 2.24 (s, 3H), 2.61-2.68 (m, 1H), 2.83 (s, 3H),
2.85-2.94 (m, 1H), 3.10 (s, 3H), 3.22-3.31 (m, 2H), 3.92 (s, 3H),
5.04 (m, 1H), 7.22 (s, 1H), 7.29 (t, 1H), 7.45-7.56 (m, 2H), 7.64
(s, 1H), 8.35 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H).sup.+
474.
EXAMPLE 26
4-(3-Chloro-2-fluoroanilino)-6-[-1-(N,N-dimethylaminoacetyl)piperidin-3-yl-
oxy]-7-methoxyquinazoline
##STR00041##
[0491]
6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)--
7-methoxyquinazoline (470 mg, 0.98 mmol) was treated with a 33%
solution of dimethylamine in ethanol (20 ml) and stirred at room
temperature for 3 hours. The solvent was evaporated under vacuum
and the residue-purified by column chromatography eluting with
methylene chloride/methanol (9/1). The fractions containing the
expected product were combined and evaporated under vacuum. The
residue was re-columned eluting with methylene chloride/methanol
(saturated with ammonia) (92/8). The fractions containing the
expected product were combined and evaporated to give the title
product (185 mg, 39%); .sup.1H NMR Spectrum: (DMSO d.sub.6 at
100.degree. C.) 1.40-1.65 (m, 1H); 1.75-1.95 (m, 2H); 2.00-2.30 (m,
7H); 3.05 (dd, 2H); 3.40-3.62 (m, 2H); 3.62-3.75 (m, 1H); 3.88 (dd,
1H); 3.95 (s, 3H); 4.45-4.65 (m, 1H); 7.15-7.30 (m, 2H); 7.30-7.47
(m, 1H); 7.50-7.7 (m, 1H); 7.88 (s, 1H); 8.40 (s, 1H); 9.25 (s,
1H); Mass Spectrum: (M+H).sup.+ 488.
[0492] The
6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanili-
no)-7-methoxyquinazoline material was prepared as follows:
--4-(3-chloro-2-fluoroaniline (430 mg, 1.07 mmol) (Prepared as
described in Example 22 under preparation of starring material),
chloroacetyl chloride (126 mg, 1.12 mmol) and
N,N-diisopropylethylamine (519 mg, 4.02 mmol) in methylene chloride
(15 ml) was stirred at room temperature for 2 hours. The solvent
was evaporated under vacuum and the residue purified by column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (92/8) solvent. Removal of the solvent under vacuum
gave
6-[1-(chloroacetyl)piperidin-3-yloxy]--4-(3-chloro-2-fluoroanilino)-7-met-
hoxyquinazoline as a yellow gum (470 mg). This material was used
without any further purification); Mass Spectrum: (M+H).sup.+
479.
EXAMPLE 26.1
Resolution to
4-(3-Chloro-2-fluoroanilino)-6-[(3/J)-1-(N-dimethylaminoacetyl)
piperidin-3-yloxy]-7-methoxyquinazoline and
4-(3-Chloro-2-fluoroanilino)-6-[(3S)-1-(N,N-dimethylaminoacetyl)piperidin-
-3-yloxy]-7-methoxyquinazoline
##STR00042##
[0494] The racemic mixture obtained in Example 26 (320 mg) was
resolved into the 3R and 3S enantiomers by chiral HPLC using the
following conditions:
TABLE-US-00005 Column Merck 50 mm 20 .mu.m Chiralpak AS VCSP No.
AS00SC- JG001 Eluent Iso-Hexane/EtOH 80/20 Oven Temperature Ambient
Flow 40 ml/min Wavelength 254 nm Sample Concentration 10 mg/ml in
EtOH/Acetonitrile 80/20 Run Time 110 mins
[0495] First eluted enantiomer (103 mg); Mass Spectrum: (M+H).sup.+
488.
[0496] Second eluted enantiomer (97 mg); Mass Spectrum: (M+H).sup.+
488.
EXAMPLE 27
6-[1-(Acetoxyacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-meth-
oxyquinazoline
##STR00043##
[0498] A suspension of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (1.0 g, 2.28 mmol; prepared as described in Example
45) in methylene chloride (30 ml) was treated with
N,N-diisopropylethylamine (L21 g, 9.33 mmol) and stirred at room
temperature for 30 minutes. The resulting solution was cooled to
0.degree. C. in a nitrogen atmosphere, acetoxyacetyl chloride (354
mg, 2.60 mmol) added and the mixture allowed to slowly warm to room
temperature with stirring. The solvent was evaporated under vacuum
and the residue purified by column chromatography eluting with
methylene chloride/methanol (saturated with ammonia) (98/2)
solvent. The fractions containing the expected product were
combined and evaporated under vacuum to give the title product (1.0
g, 87%); 3H NMR Spectrum: (DMSO d.sub.6 at 100.degree. C.)
1.50-1.60 (m, 1H), 1.80-1.93 (m, 2H), 2.03 (s, 3H); 2.04-2.10 (m,
1H); 3.40-3.60 (m, 3H); 3.78-3.86 (m, 1H); 3.97 (s, 3H); 4.52-4.60
(m, 1H); 4.75 (d, 2H); 7.20-7.28 (m, 2H); 7.38-7.44 (m, 1H);
7.54-7.64 (m, 1H); 7.88 (s, 1H); 8.40 (s, 1H); 9.22 (bs, 1H);
[0499] Mass Spectrum: (M+H).sup.+ 503
EXAMPLE 28
4-(3-Chloro-2-fluoroanilino)-6-[1-(hydroxyacetyl)piperidin-3-yloxy]-7-meth-
oxyquinazoline
##STR00044##
[0501]
6-[1-(acetoxyacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-
-7-methoxyquinazoline (930 mg, 1.85 mmol)(prepared as described in
Example 27) and potassium carbonate (385 mg, 2.79 mmol) in methanol
(50 ml) was stirred at room temperature for 3 hours. The solvent
was evaporated under vacuum and the residue purified by column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (92/8). The fractions containing the expected product
were combined and evaporated. The residue was triturated with
acetone, filtered and dried to give the title product (574 mg,
67%);
[0502] .sup.1H NMR Spectrum: (DMSO d.sub.6 at 100.degree. C.)
1.50-1.60 (m, 1H); 1.80-1.92 (m, 2H); 2.04-2.13 (m, 1H); 3.44-3.56
(m, 3H); 3.77-3.88 (m, 1H); 3.97 (s, 3H); 4.10 (d, 2H); 4.50-4.60
(m, 1H); 7.20-7.27 (m, 2H); 7.38-7.42 (m, 1H); 7.55-7.60 (m, 1H);
7.88 (s, 1H); 8.38 (s, 1H); 9.25 (bs, 1H); Mass Spectrum:
(M+H).sup.+ 461.
EXAMPLE 29
4-(3-Chloro-2-fluoroanilino)-6-[(3R)-1-(methylsulfonyl)pyrrolidin-3-yloxy]-
-7-methoxyquinazoline
##STR00045##
[0504]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyq-
uinazoline hydrochloride (0.21 g, 0.49 mmole) was dissolved in a
mixture of dichloromethane (4 ml), pyridine (1 ml) and
diisopropylethylamine (0.17 ml) under a nitrogen atmosphere.
Methanesulfonyl chloride (0.06 ml, 0.07 mmol) was added to the
stirred solution. After stirring 2 hours at room temperature, the
reaction mixture was partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
with brine, dried over anhydrous sodium sulfate, filtered and
evaporated. The residue was purified by column chromatography
eluting with methylene chloride/methanol (saturated with ammonia)
(96/4).
[0505] The fractions containing the expected product were combined
and evaporated under vacuum and the residual gum was triturated
with diethylether, filtered and dried under vacuum to give the
title product as a white solid (0.17 g, 74%); .sup.1H NMR Spectrum:
(DMSO d.sub.6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.33-3.45 (m, 2H);
3.5 (d, 1H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35
(m, 2H); 7.40-7.60 (m, 2H); 7.5 (m, 2H); 7.80 (s, 1H); 8.37 (s,
1H); 9.6 (s, 1H); Mass Spectrum: (M+H).sup.+ 467.
[0506] The
4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-meth-
oxyquinazoline hydrochloride starting material was prepared as
follows:
[0507] (3S)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (3.75 g, 20
mmole) was reacted with 4-nitrobenzenesulfonyl chloride using the
same methodology as described in the preparation of tert-butyl
3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate in Example
22 to give tert-butyl
(3S)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate as a
crystalline pale-brown solid (5.0 g, 67%); .sup.1H NMR Spectrum:
(CDCl.sub.3) 1.44 (s, 9H); 2.05-2.2 (m, 2H); 3.37-3.59 (m, 4H);
5.16-5.23 (m, 1H); 8.12 (d, 2H); 8.41 (d, 2H).
[0508] 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
(prepared as described in the starting materials used in Example
22; 4.0 g, 12.5 mmol) was mixed with tert-butyl
(3S)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate (4.7
g, 12.6 mmol) and cesium fluoride (5.7 g, 7.5 mmol). Dry
N,N-dimethylformamide (60 ml) was then added and the mixture
stirred at ambient temperature overnight. The mixture was diluted
with ethyl acetate and filtered. The filtrate was washed with
water, 50% aqueous brine then brine, dried over Na.sub.3SO.sub.4,
filtered and evaporated. The residue was purified by column
chromatography eluting with methylene chloride/methanol (saturated
with ammonia) (98/2). The fractions containing the expected product
were combined and evaporated to give
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3--
yloxy]-7-methoxyquinazoline as a dry foam (2.35 g, 38%: .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.39 (s, 9H); 2.10-2.30 (m, 2H); 3.35-3.50
(m, 3H); 3.64-3.71 (m, 1H); 3.92 (s, 3H); 5.12 (m, 1H); 7.21 (s,
1H); 7.23-7.27 (m, 1H); 7.44-7.55 (m, 2H); 7.80 (s, 1H); 837 (s,
1H); 9.61 (s, 1H); Mass Spectrum: (M+H).sup.+ 489.
[0509]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrroli-
din-3-yloxy]-7-methoxyquinazoline (2.3 g, 4.7 mmole) was dissolved
in acetonitrile (35 ml) and hydrogen chloride (4.0 M in
1,4-dioxane) (4.7 ml, 18.8 mmole) was added. The mixture was heated
to reflux for one hour. After cooling to room temperature, the
solid was filtered, washed with acetonitrile and diethylether, and
dried under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazo-
line hydrochloride as a white solid (1.9 g, 95%); .sup.1H NMR
Spectrum (DMSO d.sub.6) 2.17-2.29 (m, 1H); 2.34-2.44 (m, 1H);
3.1-3.3 (m, 3H); 3.72-3.84 (m, 1H); 4.00 (s, 3H); 5.44 (m, 1H);
7.31-7.38 (m, 1H); 7.45 (s, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m,
1H); 8.67 (s, 1H); 8.80 (s, 1H); 9.43 (br.s, 1H); 9.62 (br.s, 1H);
12.25 (br.s, 1H);
[0510] Mass Spectrum: (M-H).sup.+ 387.
EXAMPLE 30
4-(3-Chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yloxy]-
-7-methoxyquinazoline
[0511] Using a similar procedure to that described in Example 29,
4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-methoxyquinazo-
line hydrochloride (210 mg) was reacted with methane sulfonyl
chloride to give the title product (100 mg, 43%); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.38-3.52
(m, 3H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35 (m,
2H); 7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.58 (s, 1H);
Mass Spectrum: (M+H).sup.+ 467.
[0512] The
4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-meth-
oxyquinazoline hydrochloride starting material was prepared using a
similar process to that described for the preparation of the
starting materials in Example 29 as described below:
[0513] (R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (3.75 g, 20
mmole) was converted to tert-butyl
(3S)-3-[(4-nitrophenyl)sulfonyloxy]-pyrrolidine-1-carboxylate (2.21
g, 59%); .sup.1H NMR Spectrum: (DMSO ds) 1.44 (s, 9H); 2.05-2.25
(m, 2H); 3.37-3.59 (m, 4H); 5.20 (s, 1H); 8.11 (d, 2H); 8.41 (d,
2H).
[0514] 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
was reacted with tert-butyl
(3R)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate to
give
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3--
yloxy]-7-methoxyquinazoline as a dry foam (2.9 g, 95%); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.40 (s, 9H); 2.07-2.29 (m, 2H); 3.32-3.50
(m, 3H); 3.64-3.70 (dd, 1H); 3.92 (s, 3H); 5.08-5.18 (m, 1H); 7.21
(s, 1H); 7.23-7.30 (m, > 1H); 7.43-7.55 (m, 2H); 7.79 (s, 1H);
8.36 (s, 1H); 9.6 (s, 1H); Mass Spectrum: (M+H).sup.+ 489.
[0515]
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-butoxycarbonyl)pyrrolidin-3--
yloxy]-7-methoxyquinazoline was reacted with hydrogen chloride (4.0
M in 1,4-dioxane) to give
4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-methoxyquinazo-
line hydrochloride (1.94 g, 93%); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 2.18-2.28 (m, 1H); 2.35-2.45 (m, 1H); 3.27-3.46 (m, 3H);
3.73-3.82 (m, 1H); 3.99 (s, 3H); 5.41-5.47 (m, 1H); 7.31-7.37 (m,
1H); 7.44 (s, 1H); 7.47-7.54 (m, 1H); 7.58-7.64 (m, 1H); 8.66 (s,
1H); 8.80 (s, 1H); 9.42 (bs, 1H); 9.61 (bs, 1H); 12.24 (bs, 1H);
Mass Spectrum: (M+H).sup.+ 389.
EXAMPLE 31
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylsulfonylpyrrolidin-
-2-yl]methoxy)quinazoline
##STR00046##
[0517] Using a similar procedure to that described in Example 29,
4-(3-chloro-2-3
fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]-methoxy}quinazoline
hydrochloride (300 mg) was reacted with methane sulfonyl chloride
to give the title product (200 mg, 61%); .sup.1H NMR Spectrum:
(DMSO d.sub.6) 1.88-2.17 (m, 4H); 2.98 (s, 3H); 3.38 (m, 2H); 3.93
(s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.20 (s, 1H); 7.20-7.30 (m,
1H); 7.42-7.53 (m, 2H); 7.81 (s, 1H); 8.37 (s, 1H); 9.62 (s, 1H);
Mass Spectrum: (M+H).sup.+ 481.
[0518] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl-
]methoxy}quinazoline hydrochloride starting material was prepared
as described below:
[0519] 4-Chloro-6-hydroxy-7-methoxyquinazoline (prepared as
described in the preparation of starring materials for Example 16;
2.75 g, 13 mmol) was mixed with triphenylphosphine (5.13 g, 19.6
mmole) and
(2S)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (3.94 g,
19.6 mmole). Methylene chloride (85 ml) was added and the mixture
cooled under nitrogen in an ice/water bath. Di-tert-butyl
azodicarboxylate (4.51 g, 19.6 mmole) was dissolved in methylene
chloride (35 ml) and added dropwise such that the internal
temperature remained less than 10.degree. C. Once the addition was
complete the cooling bath was removed and the reaction mixture
stirred for 3 hours. The solvent was removed under vacuum and the
residue purified by column chromatography eluting with methylene
chloride/ethyl acetate(saturated with ammonia)(70/30) to give
4-chloro-7-methoxy-6-{[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy}-
quinazoline as a gum (6.15 g); Mass Spectrum: (M+H).sup.+ 394.
[0520] To a solution of
4-chloro-7-methoxy-6-{[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]methoxy}-
quinazoline in acetonitrile (120 ml), 3-chloro-2-fluoroaniline (1.4
ml, 12.7 mmole) and hydrogen chloride (4.0 M in 1,4-dioxane) (13
ml, 52 mmole) were added. This mixture was heated to reflux for one
hour. After cooling to ambient temperature the precipitate was
filtered off, washed with acetonitrile followed by diethylether and
dried under vacuum to give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-pyrrolidin-2-yl]methoxy}q-
uinazoline hydrochloride as a yellow solid (5.73 g, 100%); .sup.1H
NMR Spectrum: (DMSO de) 1.70-2.10 (m, 3H); 2.10-2.30 (m, 1H);
3.00-3.80 (m, 2H); 3.97-4.10 (m, 4H); 4.45-4.57 (m, 2H); 7.32-7.38
(m, 1H); 7.46 (S, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m, 1H); 8.65
(s, 1H); 8.81 (s, 1H); 9.31 (bs, 1H); 9.67 (bs, 1H); 12.09 (bs,
1H): Mass Spectrum: (M+H).sup.+ 403.
EXAMPLE 32
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-1-methylsulfonylpyrrolidin-
-2-yl]methoxy}quinazoline
##STR00047##
[0522] Using a similar process to that described in Example 29,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]qui-
nazoline hydrochloride (300 mg) was reacted with methane sulfonyl
chloride to give the title product (250 mg, 76%); .sup.1H NMR
Spectrum: (DMSO ds) 1.88-2.12 (m, 4H); 2.99 (s, 3H); 3.30-3.34 (m,
2H); 3.94 (s, 3H); 4.02 (m, 1H); 4.15 (m, 2H); 7.15-7.30 (m, 2H);
7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.62 (s, 1H);
[0523] Mass Spectrum: (M+H).sup.+ 481.
[0524] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylm-
ethoxy]quinazoline hydrochloride starting material was prepared
using an analogous process to that described for the preparation of
the starting material used in Example 31:
4-Chloro-7-methoxy-6-hydroxyquinazoline (2.78 g) was reacted with
(2R>1-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (3.98
g) to give
4-chloro-7-methoxy-6-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]m-
ethoxy}quinazoline (5.0 g, 100%); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.37 (s, 9H); 1.66-1.88 (m, 2H); 1.90-2.07 (m, 2H);
3.15-3.24 (m, 1H); 3.41-3.49 (m, 1H); 4.00 (s, 3H); 4.10-4.25 (m,
3H); 7.44 (d, 2H); 8.85 (s, 1H); Mass Spectrum: (M+H).sup.+
394.
[0525]
4-chloro-7-methoxy-6-{[(2R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-
methoxy}quinazoline was reacted with 3-chloro-2-fluoroaniline to
give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-pyrrolidin-2-yl]methoxy}q-
uinazoline hydrochloride (5.3 g 100%); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.70-1.84 (m, 1H); 1.87-1.97 (m, 1H); 1-99-2.08 (m, 1H);
2.17-2.28 (m, 1H); 3.18-3.27 (m, 2H); 3.98-4.10 (m, 4H); 4.45-4.57
(m, 2H); 7.32-7.38 (m, 1H); 7.47 (s, 1H); 7.49-7.55 (m, 1H);
7.59-7.65 (m, 1H); 8.66 (s, 1H); 8.81 (s, 1H); 9.30 (bs, 1H); 9.67
(bs, 1H); 12.09 (bs, 1H); Mass Spectrum: (M-HT 401.
EXAMPLE 33
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(methylsulfonyl)pyrrolidin-3--
yl]methoxy}quinazoline
##STR00048##
[0527] Using a similar procedure to that described in Example 29,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazol-
ine hydrochloride (300 mg) was reacted with methane sulfonyl
chloride to give the title product (200 mg, 67%); .sup.1H NMR
Spectrum: (DMSO d.sub.6+CD3COOD) 1.75-1.89 (m, 1H); 2.08-2.18 (m,
1H); 2.77-2.86 (m, 1H); 2.91 (s, 3H); 3.12-3.18 (m, 1H); 3.25-3.43
(m, 2H); 3.47-3.52 (m, 1H); 3.94 (s, 3H); 4.06-4.09 (m, 2H);
7.15-7.30 (m, 2H); 7.43-7.53 (m, 2H): 7.81 (s, 1H); 8.38 (s, 1H);
Mass Spectrum: (M+H).sup.+ 481.
[0528] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethox-
y)quinazoline hydrochloride starting material was prepared using an
analogous process to that described for the preparation of the
starting materials in Example 31 as follows:
[0529] 4-Chloro-7-methoxy-6-hydroxyquinazoline (2.5 g) was reacted
with 1-(tert-butoxycarbonyl)-3-(hydroxymethyl)pyrrolidine (3.58 g)
to give
4-chloro-7-methoxy-6-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methoxy}qui-
nazoline (5.36 g, 100%); .sup.1H NMR Spectrum: (DMSO d.sub.6) 1.39
(s, 9H); 1.45-1.79 (m, 2H); 1.97-2.08 (m, 1H); 2.65-2.74 (m, 1H);
2.91-3.17 (m, 2H); 3.40-3.52 (m, 1H); 4.01 (s, 3H); 4.15-4.22 (m,
2H); 7.42 (s, 1H); 7.45 (s, 1H); 8.86 (s, 1H); Mass Spectrum:
(M+H).sup.+ 394.
[0530]
4-chloro-7-methoxy-6-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]metho-
xy}quinazoline (4.5 g) was reacted with 3-chloro-2 fluoroaniline to
give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazol-
ine hydrochloride (5.45 g, 100%); .sup.1H NMR Spectrum: (DMSO de)
1.71-1.85 (m, 1H); 2.10-2.22 (m, 1H); 2.81-2.91 (m, 1H); 2.97-3.07
(m, 1H); 3.11-3.22 (m, 1H); 3.24-3.33 (m, 1H); 3.35-3.46 (m, 1H);
4.00 (s, 3H); 4.28-4.34 (m, 2H); 7.31-7.37 (m, 1H); 7.43 (s, 1H);
7.49-7.54 (m, 1H); 7.59-7.64 (m, 1H); 8.60 (s, 1H); 8.80 (s, 1H);
9.32 (bs, 2H); 12.05 (bs, 1H); Mass Spectrum: (M-H).sup.- 401.
EXAMPLE 34
4-(3-Chloro-2-fluoroanilino)-6-[(3R)-1-methylpyrrolidin-3-yloxy]-7-methoxy-
quinazoline
##STR00049##
[0532]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyq-
uinazoline hydrochloride (0.24 g, 0.56 mmole; prepared as described
in Example 29-preparation of starting materials) was dissolved in
formic acid (4 ml) and formaldehyde (37% w/v in water) (2 ml) was
added. The mixture was heated to 85.degree. C. for one hour and
then evaporated under
[0533] vacuum and azeotroped with toluene. The residue was
partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3. The organic layer was separated, washed with brine,
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatography eluting with methylene
chloride/methanol (saturated with ammonia) (94/6). The fractions
containing the expected product were combined, evaporated and the
residue triturated with isohexane/diethylether, filtered and dried
under vacuum to give the title product as a white solid (0.13 g;
59%); .sup.1H NMR Spectrum: (DMSO de) 1-70-1.9 (m, 1H); 2.27 (s,
3H); 2.30-2.50 (m, 2H); 2.55-2.75 (m, 2H); 2.91-3.00 (m, 1H); 3.91
(s, 3H); 4.90-5.10 (m, 1H); 7.18 (s, 1H); 7.20-7.35 (m, 1H);
7.40-7.58 (m, 2H); 7.64 (s, 1H); 8.35 (s, 1H); 9.57 (s, 1H); Mass
Spectrum: (M-H).sup.- 401.
EXAMPLE 35
4-(3-Chloro-2-fluoroanilino)-6-[(3S)-1-methylpyrrolidin-3-yloxy]-7-methoxy-
quinazoline
##STR00050##
[0535] 4
(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonylpyrrolidi-
n-3-yloxy]-7-methoxyquinazoline (0.30 g) was dissolved in formic
acid (5 ml) and formaldehyde (37% w/v in water) (2.5 ml) was added.
The mixture was heated to 85.degree. C. for one hour and then
evaporated under vacuum and azeotroped with toluene. The residue
was partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3. The organic layer was separated, washed with brine,
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride/methanol (saturated with
ammonia) (100/0 to 94/6). The fractions containing the expected
product were combined, evaporated and the residue triturated with
diethylether, filtered and dried under vacuum to give the title
product as a white solid (0.133 g; 35%); .sup.1H NMR Spectrum:
(DMSO-d.sub.6) 1.70-1.90 (m, 1H), 2.28 (s, 3H), 2.32-2.50 (m, 2H),
2.55-2.75 (m, 2H), 2.80-3.00 (m, 1H), 3.91 (s, 3H), 4.93-5.10 (m,
1H), 7.18 (s, 1H), 7.20-7.35 (m, 1H), 7.40-7.55 (m, 2H), 7.65 (s,
1H), 8.35 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H).sup.+
403.
[0536] The
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-tert-butoxycarbonylpyrro-
lidin-3-yloxy]-7-methoxyquinazoline starting material was prepared
as follows:
[0537] A solution of 4-nitrobenzenesulfonyl chloride (4.44 g) in
methylene chloride (50 ml) was added to a stirred solution of
tert-butyl 3-(R)-hydroxypyrrolidine-1-carboxylate (3.75 g) and
pyridine (2.5 ml) in methylene chloride (30 ml) at 10.degree. C.
and the mixture allowed to warm to ambient temperature with
stirring. The reaction mixture was poured into saturated sodium
bicarbonate solution. The organic layer was separated, washed with
brine and dried over sodium sulfate. The solution was evaporated
under vacuum to give
tert-butyl2-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate
as a yellow crystalline solid. (4.37 g, 59%); .sup.1H NMR Spectrum:
(CDCl.sub.3) 1.43 (s, 9H), 1.80-2.40 (m, 2H), 3.30-3.65 (m, 4H),
5.20 (bs, 1H), 8.10 (d, 2H), 8.42 (d, 2H).
[0538] A mixture of
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (2.0 g;
prepared as described in Example 2 2-preparation of starting
materials),
tert-butyl-3-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate
(2.4 g) and cesium fluoride (2.9 g) in dimethylformamide (30 ml)
was stirred at room temperature for 18 hours. The reaction mixture
was evaporated under vacuum and partitioned between methylene
chloride and water. The solutions were filtered to remove insoluble
solids and the methylene chloride was washed with water, saturated
brine and adsorbed onto silica. The product was then purified by
column chromatography on silica eluting with increasingly polar
mixtures of methylene chloride/methanol (saturated with ammonia)
(100/0 to 96/4). The fractions containing the required product were
combined and evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[(3S)
1-tert-butoxycarbonylpyrrolidin-3-yloxy]-7-methoxyquinazoline as a
yellow foam (2.9 g, 95%); 3H NMR Spectrum: (DMSO-d.sub.6) 1.40 (s,
9H), 2.00-2.32 (m, 2H), 3.20-3.55 (m, 3H), 3.69 (dd, 1H), 3.92 (s,
3H), 5.00-5.20 (m, 1H), 7.20 (s, 1H), 7.20-7.32 (m, 1H), 7.40-7.57
(m, 2H), 7.80 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum:
(M+H).sup.+ 489.
EXAMPLE 36
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-methylpyrrolidin-2-yl]me-
thoxy}quinazoline
##STR00051##
[0540] Using a similar procedure to that described in Example 34,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-pyrrolidin-2-yl]methoxy-
}quinazoline hydrochloride (300 mg; prepared as described in
Example 31--preparation of starting materials) was reacted with
formaldehyde (2.5 ml) to give the title product (220 mg, 77%);
.sup.1H NMR Spectrum: (DMSO d.sub.6) 1.57-1.76 (m, 3H); 1.96-2.08
(m, 1H); 2.24 (q, 1H): 2.42 (s, 3H); 2.71 (m, 1H); 2.97 (m, 1H);
3.92 (s, 3H); 3.95-4.09 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (m, 1H);
7.42-7.54 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.56 (s, 1H); Mass
Spectrum: (M+H).sup.+ 417.
EXAMPLE 37
4-(3-Chloro-2-fluoroanilino-7-methoxy-7-6-{[1-(methylpyrrolidine)-3-yl]met-
hoxy}quinazoline
##STR00052##
[0542] Using a procedure identical to that described for the
synthesis of Example 34,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazol-
ine hydrochloride (250 mg; prepared as described in Example 3
3-starting material) was reacted with formaldehyde (2.5 ml) to give
the title product (125 mg, 52%); .sup.1H NMR Spectrum: (CDCl.sub.3)
1.61-1.72 (m, 1H); 2.08-2.20 (m, 1H); 2.38 (s, 3Ff); 2.47 (q, 1H);
2.65 (m, 2H); 2.69-2.77 (m, 1H); 2.81-2.88 (m, 1H); 4.01 (s, 3H);
4.06-4.13 (m, 2H); 7.05-7.23 (m, 3H); 7.26 (s, 1H); 7.45 (s, 1H);
8.41-8.47 (m, 1H); 8.68 (s, 1H); Mass Spectrum: (M+H).sup.-
415.
EXAMPLE 38
4-(3-Chloro-2-fluoroanilino)-6-[(3R)-1-acetylpyrrolidin-3-yloxy]-7-methoxy-
quinazoline
##STR00053##
[0544]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyq-
uinazoline (0.22 g, 0.51 mmole)(prepared as described in Example
29-preparation of starting materials) was dissolved in a mixture of
methylene chloride (4 ml), pyridine (1 ml) and
diisopropylethylamine (0.17 ml) under a nitrogen atmosphere. Acetic
anhydride (0.1 ml, 1,0 mmole) was added and the mixture stirred at
ambient temperature for 3 hours. The mixture was then partitioned
between saturated aqueous NaHCO.sub.3 and ethyl acetate. The
organic layer was separated, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatography eluting with methylene chloride/methanol
(saturated with ammonia)(96/4). The fractions containing the
expected product were evaporated and triturated with diethylether.
The solid was filtered and dried under vacuum to give the title
product as a white solid (0.12 g: 55%); .sup.1H NMR Spectrum: (DMSO
d.sub.6) 1.95-1.98 (m, 3H); 2.14-2.40 (m, 2H); 3.53-3.70 (m, 3H);
3.91 (m, 4H); 5.12-5.21 (m, 1H); 7.15-7.30 (m, 2H); 7.4-7.60 (m,
2H); 7.70-7.90 (m, 1H); 8.36-8.37 (d, 1H); 9.60-9.62 (m, 1H); Mass
Spectrum: (M+H).sup.+ 431.
EXAMPLE 39
6-{[(2S)-1-Acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-m-
ethoxyquinazoline
##STR00054##
[0546] Using a similar procedure to that described in Example 38,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]qui-
nazoline hydrochloride (300 mg; 3 prepared as described in Example
31) was reacted with acetic anhydride to give the title product
(280 mg, 92%); .sup.1H NMR Spectrum: (DMSO d.sub.6) 1.89-2.05 (m,
6H); 2.15 (m, 1H); 3.43-3.56 (m, 2H); 3.93 (s, 3H); 4.00-4.11 (m,
1H); 4.17-4.21 (m, 1H); 4.32-4.42 (m, 1H); 7.19-7.29 (m, 2H);
7.41-7.54 (m, 2H); 7.79-7.82 (m, 1H); 8.36-8.37 (m, 1H); 9.52-9.55
(m, 1H); Mass Spectrum: (M+H).sup.+ 445.
EXAMPLE 40
6-{[(2R)-1-Acetylpyrrolidin-2-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-m-
ethoxyquinazoline
[0547] Using a procedure similar to that described in Example 38,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]qui-
nazoline hydrochloride (300) mg; prepared as described in Example 3
2-preparation of starting materials) was reacted with acetic
anhydride to give the title product (203 mg, 66%); .sup.1H NMR
Spectrum (DMSO d.sub.6) 1.89-2.05 (m, 6H); 2.11-2.21 (m, 1H);
3.43-3.56 (m, 2H); 3.94 (s, 3H); 4.00-4.11 (m, 1H); 4.17-4.21 (m,
1H); 4.30-4.37 (m, 1H); 7.19-7.29 (m, 2H); 7.42-7.53 (m, 2H);
7.79-7.82 (m, 1H); 8.37 (s, 1H); 9.54-9.57 (m, 1H); Mass Spectrum:
(M+H).sup.+ 445.
EXAMPLE 41
6-[(1-Acetylpyrrolidin-3-yl)methoxy]-4-(3-chloro-2-fluoroanilino)-7-methox-
yquinazoline
##STR00055##
[0549] Using a procedure similar to that described in Example 38,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(pyrrolidin-3-ylmethoxy)quinazol-
ine hydrochloride (300 mg; prepared as described in Example 3
3-starting material) was reacted with acetic anhydride to give the
title product (194 mg, 63%); .sup.1H NMR Spectrum (DMSO d.sub.6+
CD3COOD) 1.71-1.90 (m, 1H); 1.93-1.94 (m, 3H); 2.00-2.20 (m, 1H);
2.66-2.86 (m, 1H); 3.18-3.31 (m, 1H); 3.43-3.72 (m, 3H); 3.93 (m,
3H); 4.04-4.18 (m, 2H); 7.15-7.32 (m, 2H); 7.42-7.53 (m, 2H);
7.78-7.80 (m, 1H); 8.35-8.37 (m, 1H); Mass Spectrum: (M+H).sup.+
445.
EXAMPLE 42
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(N,N-dimethylsulfamoyl)py-
rrolidin-3-yloxy]quinazoline
##STR00056##
[0551]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-pyrrolidin-3-yloxy]q-
uinazoline hydrochloride (0.21 g, 0.49 mmole; prepared as described
in Example 3 0-preparation of starting materials) was dissolved in
a mixture of methylene chloride (4 ml), pyridine (1 ml) and
di-isopropylethyl amine (0.17 ml) under a nitrogen atmosphere.
Dimethylsulfamoyl chloride (0.08 ml, 0.75 mmole) was added to the
stirred solution. After stirring overnight at ambient temperature,
the reaction mixture was partitioned between ethyl acetate and
saturated aqueous NaHCO.sub.3. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by column chromatography eluting with
methylene chloride/methanol (saturated with ammonia)(98/2). The
fractions containing the expected product were evaporated under
vacuum and the residual gum was triturated with diethylether and
evaporated to give the title product as a dry foam (0.13 g; 53%);
.sup.1H NMR Spectrum: (DMSO d.sub.6) 2.16-2.21 (m, 1H); 2.25-2.38
(m, 1H); 2.76 (s, 6H); 3.41-3.50 (m, 3H); 3.71 (dd, 1H); 3.93 (m,
3H); 5.18 (m, 1H); 7.15-7.35 (m, 2H); 7.44-7.55 (m, 2H); 7.78 (s,
1H); 8.37 (s, 1H); 9.59 (s, 1H); Mass Spectrum; (M+H).sup.+
496.
EXAMPLE 43
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{([2S)-1-(morpholinoacetyl)pyrrol-
idin-2-yl]methoxy}quinazoline
##STR00057##
[0553]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyr-
rolidin-2-yl]methoxy}quinazoline (0.45 g, 0.94 mmole) was dissolved
in morpholine (7.5 ml) and stirred at ambient temperature overnight
in the presence of potassium iodide (10 mg).The solvent was
evaporated and the residue purified by column chromatography
eluting with methylene chloride/methanol (saturated with
ammonia)(98/2). The fractions containing the expected product were
combined and evaporated under vacuum to give the title product as a
foam (0.22 g, 44%); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.91-2.01
(m, 1H); 2.06-2.14 (m, 2H); 2.19-2.27 (m, 1H); 2.48-2.53 (m, 2H);
2.62-2.68 (m, 2H); 3.18 (q, 2H); 3.41-3.52 (m, 1H); 3.56-3.72 (m,
5H); 4.01-4.08 (m, 4H); 4.53 (d, 1H); 4.72 (t, 1H); 7.11-7.28 (m,
3H); 7.96 (m, 1H); 8.36 (s, 1H); 8.60 (s, 1H); 8.63 (s, 1H); Mass
Spectrum: (M-H).sup.- 528.
[0554] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl-
)pyrrolidin-2-yl]methoxy}quinazoline starting material was prepared
as follows:
[0555]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmetho-
xy]quinazoline hydrochloride (1.1 g, 2.5 mmol; prepared as
described in Example 31--starting materials) was dissolved in a
mixture methylene chloride (20 ml) and diisopropylethylamine (1.0
ml) under a nitrogen atmosphere. The solution was cooled in an
ice/water bath to 4.degree. C. and chloroacetyl chloride (0.21 ml,
2.63 mmole) was added. The reaction mixture was stirred cold for
two hours and then partitioned between methylene chloride and
saturated aqueous NaHCO.sub.3. The organic layer was separated,
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated to give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (1.14 g, 94.9%); Mass Spectrum;
(M+H).sup.+ 479.
EXAMPLE 44
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(hydroxyacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline
##STR00058##
[0557]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmetho-
xy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as
described in Example 31--starting materials) was dissolved in a
mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3
ml). The solution was cooled in an ice/water bath to 4.degree. C.
and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) added. The reaction
mixture was stirred cold for two hours and then partitioned between
methylene chloride and saturated aqueous NaHCO.sub.3. The organic
layer was separated, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was
dissolved in methanol (5 ml) containing anhydrous powdered
potassium carbonate (0.2 g). After stirring overnight the solvent
was evaporated and the residue purified by column chromatography
eluting with methylene chloride/isopropanol (96/4)(containing 0.5%
triethylamine). The fractions containing the expected product were
evaporated and the residue was triturated with diethylether to give
the title product as a white solid (0.1 g, 38%); .sup.1H NMR
Spectrum: (CDCl.sub.3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m,
2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H);
7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48
(s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H).sup.+ 461.
EXAMPLE 45
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
##STR00059##
[0559] HCl (4.63 ml, 4 M solution in dioxane) was added to a
mixture of
4-chloro-7-methoxy-6-[1-(tert-butoxycarbonyl)piperidin-3-yloxy)]quinazoli-
ne (2.47 g) and 3-chloro-2-fluoroaniline (1.01 g) in acetonitrile
(40 ml). The mixture was heated to reflux for 1 hour, cooled and
the precipitate collected to give the title product as a
dihydrochloride salt, a white solid (2.51 g, 91%); 3H NMR Spectrum:
(DMSO d.sub.6) 1.9 (m, 2H); 2.0 (m, 1H); 2.2 (m, 1H); 3.0 (m, 1H);
3.2 (m, 2H); 3.5 (m, 1H); 4.0 (s, 3H); 5.0 (m, 1H); 7.4 (m, 1H);
7.5 (m, 1H); 7.6 (s, 1H); 7.6 (m, 1H); 8.8 (s, 1H); 8.9 (s, 1H);
9.2 (br s, 2H); 12.3 (br s, 1H); Mass Spectrum: (M+H): 403.
[0560] The
4-chloro-7-methoxy-6-[1-(tert-butoxycarbonyl)piperidin-3-yloxy)-
]quinazoline starting material was prepared as follows:
[0561] Diethyl azodicarboxylate (9.41 ml, 40% solution in toluene)
was added to a mixture of 4-chloro-6-hydroxy-7-methoxyquinazoline
(2.90 g; prepared as described in Example 16-preparation of
starting materials), triphenylphosphine (5.43 g) and
tert-butoxycarbonyl-3-hydroxypiperidine (4.15 g) in dichloromethane
(75 ml). The resulting solution was heated to 40.degree. C. for 6
hours, and then allowed to stand overnight at room temperature.
This was purified, by flash column chromatography eluting with
isohexane (79%), acetone (20%), and triethylamine (1%) to give
4-chloro-7-methoxy-6-[1-(tert-butoxycarbonyl)piperidin-3-yloxy]quinazolin-
e as a white solid (2.47 g, 53%); .sup.1H NMR Spectrum:
(CDCl.sub.3) 1.5 (m, 9H); 1.6 (m, 1H); 1.9 (m, 2H); 2.1 (m, 1H);
3.5 (m, 1H); 3.6 (m, 1H); 4.0 (s, 3H); 4.2-3.9 (m, 2H); 4.5 (m,
1H); 7.3 (s, 1H); 7.4 (s, 1H); 8.9 (s, 1H):Mass Spectrum: (M+H):
394.
EXAMPLE 46
4-(3-Chloro-2-fluoroanilino)-6-[(2S,4R)-2-(N,N-dimethylcarbamoyl)-1-methyl-
pyrrolidin-4-yloxy]-7-methoxyquinazoline and
4-(3-Chloro-2-fluoroanilino)-6-[(2R,4R)-2-(N,N-dimethylcarbamoyl)-1-methy-
lpyrrolidin-4-yloxy]-7-methoxyquinazoline
##STR00060##
[0563] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) (192 mg, 0.5 mmol) was added to a
stirred solution of
4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-carboxypyrrolidin-4-y-
loxy]-7-methoxyquinazoline (150 mg, 0.336 mmol), dimethylamine
hydrochloride (41 mg, 0.5 mmol) and diisopropyl ethylamine (175
.mu.l, 1.0 mmol) in DMF (5 ml). After 18 hrs the reaction mixture
was evaporated to dryness. The residues were dissolved in methylene
chloride (50 ml) and washed with water (50 ml), dried (MgSO.sub.4),
filtered and concentrated to an orange gum. This was then purified
by flash chromatography on silica eluting with increasingly polar
mixtures of methylene chloride/methanol (100/0 to 90/10) to give
the following diastereoisomers.
[0564] The first eluted product fractions were combined and
evaporated to give a colourless gum that was triturated with
diethylether to yield
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-2-(N,N-dimethylcarbamoyl)-1-methy-
lpyrrolidin-4-yloxy]-7-methoxyquinazoline as a white powder (56.1
mg); .sup.1H NMR Spectrum: (Benzene-d.sub.6) 2.10 (s, 3H), 2.1-2.28
(m, 1H), 2.28-2.45 (m, 6H), 2.65-2.80 (m, 1H), 2.80-2.90 (m, 1H),
3.20 (t, 1H), 3.45 (s, 3H), 3.60-3.75 (m, 1H), 5.70-5.80 (m, 1H),
6.65-6.75 (m, 1H), 6.85-7.00 (m, 1H), 7.55 (s, 1H), 7.93 (t, 1H),
8.05 (s, 1H), 8.93 (s, 1H), 9.08 (s, 1H); Mass Spectrum:
(M+H).sup.+ 474.
[0565] The second eluted product fractions were combined and
evaporated to give
4-(3-chloro-2-fluoroanilino)-6-[(2R,4R)-2-(N,N-dimethylcarbamoyl)-1--
methylpyrrolidin-4-yloxy]-7-methoxyquinazoline as a white foam
(37.8 mg); .sup.1H NMR Spectrum:
(Benzene-d.sub.6+DMSO-d.sub.6+Acetic Acid-d.sub.6) 2.10-2.25 (m,
1H), 2.60 (s, 3H), 2.68 (s, 3H), 2.83 (s, 3H), 3.40-3.60 (m, 1H),
3.83 (s, 3H), 3.90 (dd, 1H), 4.03 (d, 1H), 4.90-5.05 (m, 1H),
5.40-5.55 (m, 1H), 6.89 (t, 1H), 7.10 (t, 1H), 7.65 (t, 1H), 7.92
(s, 1H), 7.95 (s, 1H), 8.80 (s, 1H); Mass Spectrum: (M+H).sup.+
474.
[0566] The
4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-carboxypyrr-
olidin-4-yloxy]-7-methoxyquinazoline starting material was prepared
as follows:
[0567] 4-Nitrobenzenesulfonyl chloride (1.89 g) was added to a
stirred solution of 1-tert-butyl 2-methyl
(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.0 g) and pyridine
(1.29 g) in methylene chloride (30 ml) and stirred at 4.degree. C.
for 16 hours under an atmosphere of nitrogen. The reaction mixture
was washed with citric acid (1.0 M), saturated sodium bicarbonate
and dried over magnesium sulfate. The product was then purified by
column chromatography on silica eluting with increasingly polar
mixtures of methylene chloride/methanol (100/0 to 92/8). The
fractions containing the expected product were combined and
evaporated under vacuum to give 1-tert-butyl 2-methyl
(2S,4S)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1,2-dicarboxyl-
ate as a yellow gum (0.89 g); .sup.1H NMR Spectrum: (DMSO d.sub.6)
1.31-1.42 (m, 9H), 2.12-2.21 (m, 1H), 2.53-2.67 (m, 1H), 3.40-3.50
(m, 1H), 3.58-3.69 (m, 4H), 4.36 (m, 1H), 5.25 (m, 1H), 8.14 (d,
2H), 8.46 (d, 2H).
[0568] Dimethylformamide (15 ml) was added to
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-hydroxyquinazoline (0.66
g; prepared as described in Example 2 2-preparation of starting
materials), 1-tert-butyl 2-methyl
(2S,4S)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1,2-dicarboxylate
(0.889 g) and cesium fluoride (0.941 g). The reaction mixture was
then stirred at room temperature for 16 hours. The reaction mixture
was evaporated under vacuum and the residue partitioned between
ethyl acetate and water. The organics were washed with water and
saturated brine and dried over magnesium sulfate. The product was
then purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride/methanol (100/0 to 95/5). The
fractions containing the expected product were combined and
evaporated under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methox-
ycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a colourless
gum (0.36 g); Mass Spectrum: (M+H).sup.+ 547.
[0569] A solution of
4-(3-Chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-(methox-
ycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (480 mg, 0.88
mmol) in formic acid (50 ml) was reacted with paraformaldehyde (29
mg, 0.97 mmol) and the resulting mixture heated at 85.degree. C.
for 6 hours. The reaction mixture was evaporated and the residues
partitioned between saturated aqueous NaHCO.sub.3 (50 ml) and ethyl
acetate (100 ml). The organic layer was dried over MgSO.sub.4,
filtered and evaporated. The residue was purified by flash
chromatography on silica eluting with increasingly polar mixtures
of methylene chloride/methanol (100/0 to 90/10). The fractions
containing the expected product were combined and evaporated to
give 4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2->
(methoxycarbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline as a
white foam (265 mg); Mass Spectrum: (M+H).sup.+ 461.
[0570] 2 M NaOH (1 ml, 2 mmol) was added to a stirred solution of
4-(3-chloro)-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-(methoxycarbonyl)pyr-
rolidin-4-yloxy]-7-methoxyquinazoline (250 mg, 0.54 mmol) in
methanol (5 ml) and the mixture stirred at room temperature for 18
hours. The reaction mixture was evaporated and the residues
re-dissolved in water (50 ml). This was then washed with ethyl
acetate (25 ml) and the aqueous phase evaporated to dryness and
azeotroped with toluene. The residues were triturated with
methylene chloride/methanol (9/1) (25 ml), filtered and the liquors
evaporated to give
4-(3-chloro-2-fluoroanilino)-6-[(2RS,4R)-1-methyl-2-carboxypyrrolidin-4-y-
loxy]-7-methoxyquinazoline as a white foam (155 mg); Mass Spectrum:
(M+H).sup.+ 447,
EXAMPLE 47
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(2RS,4R)-1-methyl-2-(morpholinoc-
arbonyl)pyrrolidin-4-yloxy]quinazoline
##STR00061##
[0572] A solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S,4R)-1-(tert-butoxycarbonyl)-
-2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline (0.3 g),
formic acid (3.0 ml) and paraformaldehyde (0.047 mg) was stirred at
80.degree. C. for 8 hours. The reaction was cooled, reduced under
vacuum and adsorbed onto silica. The product was eluted with
increasingly polar mixtures of methylene chloride/methanol (100/0
to 90/10). The fractions containing the desired product were
combined and evaporated under vacuum. The product was then
re-purified by preparative HPLC on a reverse phase Hi-Chrom HIRPB
column. The product was eluted with decreasingly polar mixtures of
acetonitrile/water (0.1% trifluoroacetic acid) (20/80 to 50/50).
The fractions containing the desired product were combined and
evaporated under vacuum and the residue dissolved in methylene
chloride/methanol (saturated with ammonia) and adsorbed onto
silica. The product was eluted with increasingly polar mixtures of
methylene chloride/methanol (saturated with ammonia)(100/0 to
90/10). The fractions containing the desired product were combined
and evaporated under vacuum to give the title product as a
colourless foam (0.058 g); .sup.1H NMR Spectrum: (DMSO d.sub.6)
2.10-2.18 (m, 1H), 2.31 (s, 3H), 2.53-2.60 (m, 1H), 3.44-3.67 (m,
10H), 3.72 (t, 1H), 3.92 (s, 3H), 5.10 (m, 1H), 7.21 (s, 1H), 7.28
(t, 1H), 7.46-7.56 (m, 2H), 7.71 (s, 1H), 8.36 (s, 1H), 9.64 (s,
1H); Mass Spectrum: (M+H).sup.+ 516.
[0573] The
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S,4R)-1-(tert-butox-
ycarbonyl)-2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline
starting material was prepared as follows:
[0574] Aqueous sodium hydroxide solution (2 M, 1.0 ml) was added to
a stirred solution of
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tot-butoxycarbonyl)-2-(methoxy-
carbonyl)pyrrolidin-4-yloxy]-7-methoxyquinazoline (prepared as
described in Example 46; preparation of starting materials) in
methanol (8 ml) and THF (3 ml) and the reaction mixture was stirred
at room temperature for 16 hours. The reaction mixture was then
reduced under vacuum and the residue dissolved in water and
adjusted to pH 6 by the addition of hydrochloric acid (2 N). The
product was extracted with ethylacetate/n-propanol and the organic
layer was washed with brine, dried over MgSO.sub.4 and the solvent
removed under vacuum to give
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-carboxy-
pyrrolidin-4-yloxy]-7-methoxyquinazoline as a white powder solid
(0.42 g); Mass Spectrum: (M+H).sup.+ 532.98
[0575] HATU (214 mg) was added to a stirred solution of
4-(3-chloro-2-fluoroanilino)-6-[(2S,4R)-1-(tert-butoxycarbonyl)-2-carboxy-
pyrrolidin-4-yloxy]-7-methoxyquinazoline-(215 mg), morpholine (50
mg) and diisopropylethylamine (200 .mu.l) in DMA (5 ml). After
stirring for 18 hours at ambient temperature, the reaction mixture
was evaporated to dryness. The residues were dissolved in methylene
chloride (50 ml) and washed with water (50 ml), brine (50 ml),
dried (MgSO.sub.4), filtered and the solvent removed under vacuum
to yield
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S,4R)-1-tert-butoxycarbonyl)--
2-(morpholinocarbonyl)pyrrolidin-4-yloxy]quinazoline as a pale
yellow gum (300 mg). The residue was used without further
purification; Mass Spectrum: (M+H).sup.+ 602.08.
EXAMPLE 48
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(pyrrolidin-1-ylacetyl)piperid-
in-3-yloxy]quinazoline
##STR00062##
[0577] Chloroacetyl chloride (89 .mu.l) was added to a solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (469 mg; prepared as described in Example 45) and
diisopropylethylamine (700 .mu.l) in methylene chloride (15 ml)
that was cooled to 0.degree. C. The mixture was stirred at room
temperature for 2 hours to give
6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-meth-
oxyquinazoline; Mass Spectrum: (M+H).sup.+ 479.
[0578] Pyrrolidine (0.5 ml) was then added, and the solution was
further stirred for 1 hour and purified by flash chromatography
eluting with methylene chloride/methanol (containing ammonia 7 N)
(97/3). The fractions containing the expected product were combined
and evaporated under vacuum to give the title product as a
colourless foam (0.327 g); .sup.1H NMR Spectrum: (DMSO dg,
100.degree. C.) 1.50-1.72 (m, 5H), 1.83-1.95 (m, 2H), 2.08-2.18 (m,
1H), 2.40-2.58 (m, 4H), 3.18 (d, 1H), 3.37 (d, 1H) 3.48-3.56 (m,
1H), 3.58-3.64 (m, 1H), 3.68-3.77 (m, 1H), 3.89-3.93 (m, 1H), 3.95
(s, 3H), 4.51-4.59 (m, 1H), 7.23-7.31 (m, 2H % 7.40-7.48 (m, 1H),
7.57-7.64 (m, 1H), 7.90 (s, 1H), 8.41 (s, 1H), 9.25 (br s, 1H);
Mass Spectrum: (M+Ff/514.
EXAMPLE 49
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]-quinazol-
ine
##STR00063##
[0580] HCl (1.0 ml, 4 M solution in dioxane) was added to
4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yloxy]quina-
zoline (0.786 g) and 3-chloro-2-fluoroaniline (0.304 g) dissolved
in acetonitrile (25 ml). The mixture was heated to 60.degree. C.
for 2 hours, cooled and the precipitate collected to give
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine hydrochloride as a white solid (0.577 g, 66%); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.70-1.95 (m, 2H), 1.95-2.10 (m, 1H);
2.10-2.25 (m, 1H), 2.95-3.10 (m, 1H), 3.10-3.30 (m, 2H), 3.45-3.65
(m, 1H); 4.03 (s, 3H); 4.95-5.10 (m, 1H); 7.30-7.45 (m, 1H);
7.45-7.60 (m, 2H); 7.60-7.73 (m, 1H), 8.85 (s, 1H); 8.90 (s, 1H);
9.15 (bs, 2H); 12.3 (bs, 1H); Mass Spectrum: (M+H): 403.
[0581] The
4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-y-
loxy]quinazoline starting material was prepared as follows:
[0582] Diethyl azodicarboxylate (2.76 ml, 40% solution in toluene)
was added to 4-chloro-6-hydroxy-7-methoxyquinazoline (0.89 g;
prepared as described in Example 16), triphenylphosphine (1.66 g)
and (3R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (CAS Registry
No 143900-43-0) (1.28 g) in dichloromethane (25 ml). The resulting
solution was allowed to stir overnight at room temperature. This
was purified by flash column chromatography eluting with an
increasingly polar mixture of acetone/isohexane/triethylamine
(79/20/1 to 64/35/1) to give
4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yloxy)]quin-
azoline as a white solid (0.794 g, 48%); Mass Spectrum:
(M+H)+394.
EXAMPLE 50
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-1-(pyrrolidin-1-ylacetyl)pi-
peridin-3-yloxy]quinazoline
##STR00064##
[0584] Chloroacetyl chloride (66 .mu.l) was added to a solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine hydrochloride (350 mg; prepared according to Example 49) and
diisopropylethylamine (522 .mu.l) in methylene chloride (10 ml)
that was cooled to 0.degree. C. and the mixture was stirred at room
temperature for 30 mins. Pyrrolidine (0.37 ml) was added, and the
solution stirred for 1 hour before being purified by flash column
chromatography eluting with methylene chloride/methanol (containing
ammonia 7 N) (97/3). The fractions containing the expected product
were combined and evaporated to give a foam. This foam was
dissolved in methylene chloride (5 ml) and crystallised by the
addition of isohexane (50 ml) to give the title product (0.206 g);
.sup.1H NMR Spectrum: (DMSO d.sub.6, 100.degree. C.) 1.50-1.72 (m,
5H), 1.83-1.95 (m, 2H), 2.08-2.18 (m, 1H), 2.40-2.58 (m, 4H), 3.18
(d, 1H), 3.37 (d, 1H), 3.48-3.56 (m, 1H), 3.58-3.64 (m, 1H),
3.68-3.77 (m, 1H), 3.89-3.93 (m, 1H), 3.95 (s, 3H), 4.51-4.59 (m,
1H), 7.23-7.31 (m, 2H), 7.40-7.48 (m, 1H), 7.57-7.64 (m, 1H), 7.90
(s, 1H), 8.41 (br s, 1H), 9.25 (br s, 1H); Mass Spectrum:
(M+H).sup.+ 514.
EXAMPLE 51
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N-methylaminoacetyl)pyr-
rolidin-2-yl]methoxy}quinazoline
##STR00065##
[0586] Using a procedure similar to that described for the
synthesis Example 43,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (0.28 g; prepared as described in
Example 43, preparation of starting materials) was reacted with 33%
methylamine in ethanol (5 ml) to give the title product as a foam
(0.131 g, 47%); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.91-2.22 (m,
4H), 2.22 (s, 3H), 2.70-2.90 (m, 1H), 3.28-3.40 (m, 2H), 3.44-3.54
(m, 2H), 3.97-4.09 (m, 4H), 4.47-4.51 (d, 1H), 4.60-4.66 (t, 1H),
7.06-7.20 (m, 2H), 7.24 (s, 1H), 8.07-8.13 (m, 1H), 8.57-8.70 (m,
3H); Mass Spectrum: (M-H).sup.- 472.
EXAMPLE 52
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(N,N-dimethylaminoacetyl-
) pyrrolidin-2-yl]methoxy}quinazoline
##STR00066##
[0588] Using a procedure similar to that described for the
preparation of Example 43,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (0.28 g) was reacted with 33%
dimethylamine in ethanol (5 ml) to give the title product as a foam
(0.165 g, 58%); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.91-2.01 (m,
1H), 2.04-2.11 (m, 2H), 2.14-2.22 (m, 1H), 2.33 (s, 6H), 3.02-3.22
(dd, 2H), 3.40-3.50 (m, 1H), 3.59-3.66 (m, 1H), 4.02 (s, 3H),
4.05-4.09 (m, 1H), 4.51-4.55 (d, 1H), 4.66-4.72 (m, 1H), 7.09-7.21
(m, 2H), 7.23 (s, 1H), 8.00-8.06 (m, 1H), 8.47 (bs, 1H), 8.62 (s,
1H), 8.68 (s, 1H); Mass Spectrum: (M-H) 486.
EXAMPLE 53
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(pyrrolidin-1-ylacetyl)p-
yrrolidin-2-yl]methoxy}quinazoline
##STR00067##
[0590] Using a procedure similar to that described in Example 43,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (0.28 g) was reacted with pyrrolidine
(2.5 ml) to give the title product as a foam (0.151 g, 50%);
.sup.1H NMR Spectrum: (CDCl.sub.3) 1.68-1.75 (m, 4H), 1.90-2.01 (m,
1H), 2.04-2.14 (m, 2H), 2.15-2.23 (m, 1H), 2.51-2.61 (m, 2H),
2.66-2.74 (m, 2H), 3.15-3.21 (d, 1H), 3.38-3.48 (m, 2H), 3.55-3.62
(m, 1H), 4.00-4.08 (m, 4H), 4.52-4.55 (d, 1H), 4.68-4.74 (t, 1H),
7.06-7.27 (m, 3H), 7.90-7.96 (m, 1H), 8.43 (s, 1H), 8.60 (s, 1H),
8.69 (s, 1H); Mass Spectrum: (M-H).sup.- 512.
EXAMPLE 54
4-(3-chloro-2-fluoroanilino)-6-{[(2S)-1-(3,4-methylenedioxypyrrolidin-1-yl-
acetyl)pyrrolidin-2-yl]methoxy}-7-methoxyquinazoline
##STR00068##
[0592] 3,4-methylenedioxypyrrolidine hydrochloride (87 mg) was
added to a stirred solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (0.25 g; prepared as described in
Example 43) and diisopropylethylamine (0.2 ml) in acetonitrile (10
ml) and the mixture heated at reflux for 2 hours. The reaction
mixture was partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatography eluting with increasingly polar mixtures
of methylene chloride/isopropanal/triethylamine (97/2/1) to
(95/4/1). The fractions containing the expected product were
evaporated under vacuum to give the title product as a yellow solid
(0.203 g; 70%); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.92-2.22 (m,
4H), 2.54-2.61 (m, 2H), 3.05-3.15 (m, 2H), 3.26-3.38 (q, 2H),
3.42-3.47 (m, 1H), 3.58-3.65 (m, 1H), 4.00-4.10 (m, 4H), 4.47-4.55
(m, 3H), 4.65-4.72 (m, 1H), 4.84 (s, 1H), 5.02 (s, 1H), 7.11-7.22
(m, 2H), 7.24 (s, 1H), 7.96-8.02 (m, 1H), 8.38 (s, 1H), 8.61 (s,
1H), 8.63 (s, 1H); Mass Spectrum: (M+H).sup.+ 558.
[0593] The 3,4-methylenedioxypyrrolidine hydrochloride used as a
starting material was prepared as follows:--
[0594] A solution of di-tert-butyl dicarbonate (Boc.sub.2O, 78.95
g) in ethyl acetate (125 ml) was added drop wise to a stirred
mixture of 3-pyrroline (25 g; 65% pure containing pyrrolidine) and
ethyl acetate (125 ml) which had been cooled to 0.degree. C. The
reaction temperature was maintained at 5-10.degree. C. during the
addition. The resultant reaction mixture was allowed to warm to
ambient temperature overnight. The reaction mixture was washed
successively with water, 0.1 N aqueous hydrochloric acid solution,
water, a saturated aqueous sodium bicarbonate solution and brine,
dried over magnesium sulphate and evaporated. There was thus
obtained, as a colorless oil (62 g), a 2:1 mixture of tert-butyl
3-pyrroline-1-carboxylate, NMR: (CDCl.sub.3) 1.45 (s, 9H), 4.1 (d,
4H), 6.75 (m, 2H), and tert-butyl pyrrolidine-1-carboxylate, NMR:
(CDCl.sub.3) 1.5 (s, 9H), 1.8 (br s, 4H), 3.3 (br s, 4H).
[0595] A solution of the mixture of materials so obtained in
acetone (500 ml) was added dropwise to a mixture of
N-methylmorpholine-N-oxide (28.45 g), osmium tetroxide (1 g) and
water (500 ml) whilst keeping the reaction temperature below
25.degree. C. The reaction mixture was then stirred at ambient
temperature for 5 hours. The solvent was evaporated and the residue
was partitioned between ethyl acetate and water. The organic phase
was washed with brine, dried over magnesium sulphate and
evaporated. The residue was purified by column chromatography on
silica using increasingly polar mixtures of petroleum ether (b.p.
40-60.degree. C.) and ethyl acetate as eluent and by further column
chromatography on silica using increasingly polar mixtures of
methylene chloride and methanol. There was thus obtained tert-butyl
3,4-dihydroxypyrrolidine-1-carboxylate as an oil (34.6 g); NMR
Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H),
3.6 (m, 2H), 4.25 (m, 2H).
[0596] A solution of tert-butyl
3,4-dihydroxypyrrolidine-1-carboxylate (34.6 g) in DMF (400 ml) was
cooled to 0-5.degree. C. and sodium hydride (60% dispersion in
mineral oil, 0.375 mol) was added portionwise. The reaction mixture
was stirred at 5.degree. C. for 1 hour. Dibromomethane (15.6 ml)
was added and the reaction mixture was stirred at 5.degree. C. for
30 minutes. The reaction mixture was allowed to warm to ambient
temperature and was stirred for 16 hours. The DMF was evaporated
and the residue was partitioned between ethyl acetate and water.
The organic phase was washed with water and with brine, dried over
magnesium sulphate and evaporated. The residue was purified by
column chromatography on silica using increasingly polar mixtures
of petroleum ether (b.p. 40-60.degree. C.) and ethyl acetate as
eluent. There was thus obtained tert-butyl
3,4-methylenedioxypyrrolidine-1-carboxylate as a colourless oil
(19.77 g); NMR Spectrum: (CDCl.sub.3) 1.45 (s, 9H), 3.35 (m, 2H),
3.75 (br s, 2H), 4.65 (m, 2H), 4.9 (s, 1H), 5.1 (s, 1H).
[0597] A cooled 5 M solution of hydrogen chloride in isopropanol
(150 ml) was added to a solution of tert-butyl
3,4-methylenedioxypyrrolidine-1-carboxylate (19.7 g) in methylene
chloride (500 ml) that was cooled in an ice bath. The reaction
mixture was allowed to warm to ambient temperature and was stirred
for 4 hours. The solvent was evaporated and the residue was
triturated under diethyl ether. The precipitate was collected by
filtration, washed with diethyl ether and dried. There was thus
obtained 3,4-methylenedioxypyrrolidine hydrochloride as a beige
solid (13.18 g); NMR Spectrum: (DMSO d.sub.6) 3.15 (m, 2H), 335 (m,
2H), 4.65 (s, 1H), 4.8 (m, 2H), 5.1 (s, 1H).
EXAMPLE 55
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(1-methylpiperazin-4-yla-
cetyl) pyrrolidin-2-yl]methoxy}quinazoline
##STR00069##
[0599] Using a procedure similar to that described in Example 43,
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidi-
n-2-yl]methoxy}quinazoline (0.14 g) was reacted with
1-methylpiperazine (5 ml) to give the title product as a white foam
(0.122 g); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.91-2.01 (m, 1H),
2.04-2.12 (m, 2H), 2.17-2.23 (m, 1H), 2.25 (s, 3H), 2.34-2.45 (m,
3H), 2.49-2.59 (m, 2H), 2.62-2.72 (m, 2H), 3.08-3.26 (q, 2H),
3.40-3.51 (m, 2H), 3.54-3.61 (m, 1H), 4.00-4.08 (m, 4H), 4.50-4.56
(m, 1H), 4.67-4.74 (m, 1H), 7.10-7.24 (m, 2H), 7.23 (s, 1H),
7.91-7.97 (m, 1H), 838 (s, 1H), 8.60 (s, 1H), 8.66 (s, 1H); Mass
Spectrum: (M-H) 541.
EXAMPLE 56
4-(3-Chloro-2-fluoroanilino)-6-[(3R)-1-(hydroxyacetyl)pyrrolidin-3-yloxy]--
7-methoxyquinazoline
##STR00070##
[0601]
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyq-
uinazoline hydrochloride (0.25 g; prepared as described in Example
29) was dissolved in a mixture of methylene chloride (10 ml) and
diisopropylethylamine (0.3 ml). The solution was cooled in an
ice/water bath to 4.degree. C. and acetoxyacetyl chloride (0.069
ml) added. The reaction mixture was stirred cold for two hours and
then partitioned between methylene chloride and saturated aqueous
NaHCO.sub.3. The organic layer was separated, washed with brine,
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was dissolved in 7 M methanolic ammonia (10 ml) and the resulting
solution stirred overnight. The solvent was evaporated and the
residue purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride/methanol (saturated with
ammonia) 98/2 to 92/8 The fractions containing the expected product
were evaporated and the residue was triturated with diethylether to
give the title product as a pale yellow solid (0.161 g, 61%);
.sup.1H NMR Spectrum: (DMSO-d.sub.6 393K, 500 MHz) 2.10-2.40 (m,
2H), 3.50-3.70 (m, 3H), 3.70-3.85 (m, 1H), 3.95 (s, 3H), 4.05 (s,
2H), 5.15 (s, 1H), 7.15-7.30 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.70
(m, 1H), 7.85 (s, 1H), 8.40 (s, 1H), 9.20 (bs, 1H); Mass Spectrum:
(M+H).sup.+ 447.
EXAMPLE 57
6-[(3S)-1-Acetylpiperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyq-
uinazoline
##STR00071##
[0603] A solution of acetic anhydride (42 .mu.l) in methylene
chloride (5 ml) was added dropwise to a stirred solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine hydrochloride (0.175 g, 0.4 mmol; prepared as described in
Example 49) and diisopropylethylamine (208 .mu.l) in methylene
chloride (20 ml) at 0.degree. C. and the mixture was stirred for 2
hours and allowed to warm to room temperature. The reaction mixture
was washed with saturated sodium bicarbonate solution, dried
(MgSO.sub.4), filtered and evaporated to give a white foam. This
was purified by column chromatography eluting with increasingly
polar mixtures of methylene chloride/methanol (100/0 to 95/5). The
fractions containing the desired product were combined and
evaporated under vacuum to give the title product as a colourless
foam (0.117 g, 66%); .sup.1H NMR Spectrum: (DMSO de at 373K)
1.40-1.65 (m, 1H), 1.70-1.94 (m, 2H), 2.00 (s, 3H), 1.95-2.20 (m,
1H), 3.20-3.70 (m, 3H), 3.70-4.10 (m, 1H), 3.95 (s, 3H), 4.40-4.70
(m, 1H), 7.15-7.33 (m, 2H), 7.33-7.50 (m, 1H), 7.50-7.70 (m, 1H),
7.90 (s, 1H), 8.40 (s, 1H), 9.25 (s, 1H); Mass Spectrum:
(M+H).sup.+ 445.
EXAMPLE 58
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(methylsulfonyl)piperidin-3-yloxy]--
7-methoxyquinazoline
##STR00072##
[0605] A solution of methanesulfonyl chloride (34 .mu.l) in
methylene chloride (5 ml) was added dropwise to a stirred solution
of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine hydrochloride (175 mg; prepared as described in Example 49) and
diisopropylethylamine (208 .mu.l) in methylene chloride (20 ml) at
0.degree. C. The reaction mixture was allowed to stir for 2 hours
to room temperature. The reaction mixture was washed with saturated
sodium bicarbonate solution, dried (MgSO.sub.4), filtered and
evaporated to a foam. This was purified by column chromatography
eluting with increasingly polar mixtures of methylene
chloride/methanol (100/0 to 97/3). The fractions containing the
desired product were combined and evaporated under vacuum to give
the title product as a white foam (0.164 g, 85%); .sup.1H NMR
Spectrum: (DMSO ds) 1.5-1.67 (m, 1H), 1.67-1.83 (m, 1H), 1.83-1.95
(m, 1H), 1.95-2.12 (m, 1H), 2.95 (s, 3H), 3.1-3.23 (m, 1H),
3.23-3.45 (m, 2H+ H.sub.2O), 3 3.5-3.65 (m, 1H), 3.95 (s, 3H), 4.70
(m, 1H), 7.18-7.35 (m, 2H), 7.40-7.60 (m, 2H), 7.90 (s, 1H), 8.38
(s, 1H), 9.58 (s, 1H); Mass Spectrum: (M+H).sup.+ 481.
EXAMPLE 59
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(N,N-dimethylaminoacetyl)piperidin--
3-yloxy]-7-methoxyquinazoline
##STR00073##
[0607] N,N-Dimethylaminoacetyl chloride hydrochloride (69 mg) was
added portionwise to a stirred solution of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazol-
ine hydrochloride (175 mg; prepared as described in Example 49) and
diisopropylethylamine (210 pd) in methylene chloride (25 ml) at
0.degree. C. The reaction mixture was allowed to stir for 2 hours
to room temperature. The reaction mixture was washed with saturated
sodium bicarbonate solution, dried (MgSO.sub.4), filtered and
evaporated to a foam. This was purified by column chromatography
eluting with increasingly polar mixtures of methylene
chloride/methanol (saturated with ammonia) (100/0 to 90/10). The
fractions containing the desired product were combined and
evaporated under vacuum to give the title product as a white foam
(0.152 g, 78%); .sup.1H NMR Spectrum: (DMSO d.sub.6 at 100.degree.
C.) 1.40-1.65 (m, 1H); 1.75-1.95 (m, 2H); 2.00-2.30 (m, 7H); 3.05
(dd, 2H); 3.40-3.62 (m, 2H); 3.62-3.75 (m, 1H); 3.88 (dd, 1H); 3.95
(s, 3H); 4.45-4.65 (m, 1H); 7.15-7.30 (m, 2H); 7.30-7.47 (m, 1H);
7.50-7.7 (m, 1H); 7.88 (s, 1H); 8.40 (s, 1H); 9.25 (s, 1H); Mass
Spectrum: (M+H).sup.+ 488.
EXAMPLE 60
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(21S)-1-(2-hydroxyisobutyryl)py-
rrolidin-2-yl]methoxy}quinazoline
##STR00074##
[0609]
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmetho-
xy]quinazoline hydrochloride (0.25 g; prepared as described in
Example 31) was dissolved in a mixture of methylene chloride (5 ml)
and diisopropylethylamine (0.3 ml). The solution was cooled in an
ice/water bath to 4.degree. C. and 2-acetoxyisobutyryl chloride
(0.085 ml) added. The reaction mixture was stirred cold for one
hour and then partitioned between methylene chloride and saturated
aqueous NaHCO.sub.3. The organic layer was separated, washed with
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was dissolved in 7 M Methanolic ammonia (10 ml) and the
resulting solution stirred overnight. The solvent was evaporated
and the residue purified by column chromatography eluting with
increasingly polar mixtures of methylene
chloride/iso-propanol/triethylamine (97/2/1)-(95/4/1). The
fractions containing the expected product were evaporated and the
residue was triturated with diethylether to give the title compound
as a white solid (0.210 g); .sup.1H NMR Spectrum: (CDCl.sub.3) 1.57
(s, 6H), 1.85-2.30 (m, 4H), 3.55-3.75 (m, 1H), 3.75-3.90 (m, 1H),
3.90-4.20 (m, 5H), 4.53 (d, 1H), 4.7-4.85 (m, 1H), 7.05-7.20 (m,
2H), 7.25 (s, 1H), 8.15-8.35 (m, 2H), 8.50 (s, 1H), 8.67 (s, 1H);
Mass Spectrum: (M+H).sup.+ 489.
EXAMPLE 61
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[(2S)-1-methylpyrrolidin-2-ylc-
arbonyl]piperidin-3-yloxy}quinazoline
##STR00075##
[0611] HATU (0.26 g) was added to a solution of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg; prepared as described in Example 45),
diisopropylethylamine (210 .mu.l) and N-methyl-L-proline (0.120 g)
in DMF (7.5 ml) and the mixture was stirred at room temperature for
2.5 hours. The DMF was removed under reduced pressure and the
residue dissolved in methylene chloride (50 ml) and washed with
sodium bicarbonate (50 ml) then water (50 ml). Purification by
flash column chromatography eluting with methylene
chloride/methanol (saturated with ammonia)(96/4). The fractions
containing the expected product were evaporated to give a foam.
This foam was dissolved in methylene chloride (5 ml) and
crystallised by the addition of isohexane (50 ml) to give the title
product as a mixture of two diastereoisomers (0.130 g). .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.43-1.62 (m, 2H), 1.66-1.95 (m, 4H)>
1.96-2.18 (m, 4H), 2.20-2.29 (m, 2H), 2.67-2.80 (m, 1H), 2.96 (m,
1H), 3.03-3.20 (m, 1H), 3.51-3.80 (m, 2H), 3.80-4.05 (m, 4H),
4.51-4.68 (m, 1H), 7.22-7.31 (m, 2H), 7.47-7.59 (m, 2H), 7.89 (m,
1H), 8.39 (s, 1H), 9.55 (m, 1H); Mass Spectrum; (M+H).sup.+
514.
EXAMPLE 62
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(N,N-dimethylcarbamoylmethyl)p-
iperidin-3-yloxy]quinazoline
##STR00076##
[0613] 2-Chloro-N,N-dimethylacetamide (105 mg) was added to a
mixture of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg) and potassium carbonate (1.19 g) in DMF (5
ml). The mixture was stirred at room temperature for 30 mins,
filtered and the solvent evaporated. Purification by flash column
chromatography eluting with methylene chloride/methanol (96/4) gave
a foam. This was triturated with diethyl ether and isohexane to
give the title product as a white solid (105 mg); .sup.1H NMR
Spectrum: (DMSO 4) 1.45 (m, 1H), 1.61 (m, 1H), 1.78 (m, 1H), 2.10
(m, 1H), 2.26 (m, 1H), 2.38 (m, 1H), 2.65-2.77 (m, 1H), 2.75 (s,
3H), 2.99 (s, 3H), 3.04 (m, 1H), 3.22 (s, 2H), 3.94 (s, 3H), 4.62
(m, 1H), 7.21 (s, 1H), 7.29 (m, 1H), 7.47-7.55 (m, 2H), 7.88 (s,
1H), 8.38 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H).sup.+
488.
EXAMPLE 63
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[1-(3,3-difluoropyrolidin-1-ylace-
tyl)piperidin-3-yloxy]quinazoline
##STR00077##
[0615] Chloroacetyl chloride (47 .mu.l) was added to a solution of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg) and diisopropylethylamine (373 .mu.l) in
methylene chloride (10 ml) and the mixture was stirred at room
temperature for 1 hour. 3,3-difluoropyrrolidin hydrochloride
(Synthetic Letters, 1995, 1, 55-57; 328 mg) was added, and the
solution stirred for 1 hour before being washed with saturated
aqueous sodium bicarbonate (10 ml) and purified by flash column
chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol (100/0 to 95/5) to give a foam. This
was dissolved in methylene chloride (5 ml) and crystallised by the
addition of isohexane (50 ml) to give the title product (102 mg).
.sup.1H NMR Spectrum: (DMSO ds) 1.45-1.57 (m, 1H), 1.73-1.95 (m,
2H), 1.98-2.18 (m, 2H), 2.18-2.33 (m, 1H), 2.63-2.75 (m, 1H),
2.77-2.85 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.19 (m, 1H), 3.21-3.29
(m, 1H), 3.37-3.50 (m, 2H), 3.52-3.70 (m, 2H), 3.77-3.99 (m, 4H),
4.63 (m, 1H), 7.21-7.29 (m, 2H), 7.47-7.57 (m, 2H), 7.87 (d, 1H),
8.39 (s, 1H), 9.55 (d, 1H); Mass Spectrum: (M+H).sup.+ 550.
EXAMPLE 64
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[[(3R)-3-hydroxypyrrolidin-1-y-
l]acetyl]piperidin-3-yloxy}quinazoline
##STR00078##
[0617] Chloroacetyl chloride (47 .mu.l) was added to a solution of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg) and diisopropylethylamine (373 .mu.l) in
methylene chloride (10 ml) and the mixture was stirred at room
temperature for 1 hour. (R)-(+)-3-pyrrolidinol (202 mg) was added,
and the solution stirred for 1 hour before being washed with
saturated aqueous sodium bicarbonate (10 ml) and purified by flash
column chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol(saturated with ammonia) (100/0 to 95/5)
to give a foam. This foam was dissolved in methylene chloride (5
ml) and crystallised by the addition of isohexane (50 ml) to give
the title product as a mixture of two diastereoisomers (68 mg);
.sup.1H NMR Spectrum: (DMSO d.sub.6 100.degree. C.) 1.52 (m, 2H),
1.87 (m, 3H), 2.09 (m, 1H), 2.38 (m, 1H), 2.61 (m, 1H), 2.77 (m,
1H), 3.18 (m, 1H), 3.36 (d, 1H), 3.53 (m, 2H), 3.68 (m, 1H), 3.89
(m, 1H), 3.94 (s, 3H), 4.15 (m, 1H), 4.23 (m, 1H), 4.53 (m, 1H),
7.27 (m, 2H), 7.41 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.38 (s,
1H), 9.24 (br s, 1H); Mass Spectrum: (M+H).sup.+ 530.
EXAMPLE 65
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(4-methyl-3-oxopiperazin-1-yl-
)acetyl]piperidin-3-yloxy}quinazoline
##STR00079##
[0619] Chloroacetyl chloride (47 .mu.l) was added to a solution of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg) and diisopropylethylamine (373 .mu.l) in
methylene chloride (10 ml) and the mixture was stirred at room
temperature for 1 hour. 1-Methyl-piperazin-2-one (195 mg) was
added, and the solution stirred for 1 hour before being washed with
saturated aqueous sodium bicarbonate (1.0 ml) and purified by flash
column chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol (100/0 to 95/5) to give a foam. This
foam was dissolved in methylene chloride (5 ml) and crystallised by
the addition of isohexane (50 ml) to give the title compound (177
mg); .sup.1H NMR Spectrum: (DMSO dg, 100.degree. C.) 1.57 (m, 1H),
1.91 (m, 2H), 2.08 (m, 1H), 2.67-2.85 (m, 5H), 3.08 (s, 2H), 3.18
(m, 3H), 3.32 (d, J=15 Hz, 1H), 3.47-3.60 (m, 2H), 3.71-3.83 (m,
2H), 3.95 (s, 3H), 4.57 (m, 1H), 7.27 (m, 2H), 7.42 (m, 1H), 7.60
(m, 1H), 7.89 (s, 1H), 8.40 (s, 1H), 9.23 (br s, 1H); Mass
Spectrum: (M+H).sup.+ 557.
EXAMPLE 66
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{1-[acetylpiperazin-1-yl)acetyl]p-
iperidin-3-yloxy}quinazoline
##STR00080##
[0621] Chloroacetyl chloride (47 .mu.l) was added to a solution of
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline
dihydrochloride (250 mg) and diisopropylethylamine (373 .mu.l) in
methylene chloride (10 ml) and the mixture was stirred at room
temperature for 1 hour. 1-Acetylpiperazine (292 mg) was added, and
the solution stirred for 1 hour before being washed with saturated
aqueous sodium bicarbonate (10 ml) and purified by flash column
chromatography eluting with increasingly polar mixtures of
methylene chloride/methanol (100/0 to 95/5) to give a foam. This
foam was dissolved in methylene chloride (5 ml) and crystallised by
the addition of isohexane (50 ml) to give the title compound (73
mg); .sup.1H NMR Spectrum: (DMSO ds, 100.degree. C.) 1.55 (m, 1H),
1.88 (m, 2H), 1.92 (s, 3H), 2.11 (m, 1H), 2.30-2.48 (m, 4H), 3.10
(d, 1H), 3.28 (d, 1H), 3.34 (m, 4H), 3.56 (m, 2H), 3.73 (m, 1H),
3.88 (m, 1H), 3.94 (s, 3H), 4.56 (m, 1H), 7.27 (m, 2H), 7.41 (m,
1H), 7.60 (m, 1H), 7.90 (s, 1H), 8.38 (s, 1H), 9.27 (m, 1H); Mass
Spectrum: (M+H).sup.+ 571.
EXAMPLE 67
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2R)-1-methylpyrrolidin-2-yl]me-
thoxy}quinazoline
##STR00081##
[0623] A mixture of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2R)-pyrrolidin-2-ylmethoxy]qui-
nazoline hydrochloride (250 mg) (Prepared as described in Example
32), formic acid (5 ml) and formaldehyde (37% w/v in water) (2.5
ml) was heated to 85.degree. C. for one hour. The reaction mixture
was then evaporated under vacuum, azeotroped with toluene and
partitioned between ethyl acetate and saturated aqueous
NaHCO.sub.3. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residues were then
purified by flash chromatography eluting with increasingly polar
mixtures of methylene chloride/methanol (saturated with ammonia)
(98/2-94/6). The fractions containing the desired product were
combined and evaporated to give a colourless gum, which was
triturated with diethylether, filtered and dried under vacuum to
give the title product as a white solid (0.15 g); .sup.1H NMR
Spectrum: (DMSO d.sub.6) 1.55-1.83 (m, 3H); 1.95-2.10 (m, 1H);
2.20-2.35 (m, 1H); 2.45 (s, 3H); 2.68-2.85 (m, 1H); 2.93-3.10 (m,
1H); 3.92 (s, 3H); 3.92-4.15 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (m,
1H); 7.40-7.55 (m, 2H); 7.81 (s, 1H); 8.36 (s, 1H); 9.57 (s, 1H);
Mass Spectrum: (M+H).sup.+ 417.
EXAMPLE 68
Pharmaceutical Compositions
[0624] The following illustrates a representative pharmaceutical
dosage forms of the invention as defined herein (the active
ingredient being termed "Compound X"), for therapeutic or
prophylactic use in humans:
TABLE-US-00006 (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) 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%.
[0625] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. For example the
tablet may be prepared by blending the components together and
compressing the mixture-into a tablet.
REFERENCE EXAMPLE 1
6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
hydrochloride
##STR00082##
[0627] 6-Acetoxy-4-chloro-7-methoxyquinazoline (prepared as
described in Example 25-5 of in WO01/66099, 6.00 g, 23.8 mmol) and
3-chloro-2-fluoroaniline (3.46 g, 23.8 mmol) were suspended in
iso-propanol (200 ml). The mixture was heated to 80.degree. C.
under reflux for 3 hours. The solvent was evaporated; the residue
was crystallised from acetonitrile, giving the product
hydrochloride as a pale pink crystalline solid (8.16 g, 92%);
.sup.1H NMR: 2.37 (s, 3H), 4.00 (s, 3H), 7.34 (ddd, 1H), 7.48 (s,
1H), 7.52 (ddd, 1H), 7.61 (ddd, 1H), 8.62 (s, 1H), 8.86 (s, 1H);
Mass Spectrum: 362.4, 364.4.
REFERENCE EXAMPLE 2
4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
[0628] 6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline
hydrochloride (Reference Example 1, 8.72 g, 21.9 mmol) was
dissolved in methanol (200 ml). Concentrated aqueous ammonia (15
ml) was added, and the solution heated to 50.degree. C. with
stirring for 2 hours, causing precipitation of a cream coloured
solid. The solid was collected by filtration, washed with diethyl
ether (3.times.200 ml), and dried in vacuo at 60.degree. C. over
diphosphorus pentoxide, giving the product as an off white solid
(5.40 g, 77%); .sup.1H NMR: 3.95 (s, 3H), 7.19 (s, 1H), 7.23 (dd,
1H), 7.42 (dd, 1H), 7.50 (dd, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.43
(s, 1H), 9.67 (br.s, 1H); Mass Spectrum: 320.4, 322.4.
REFERENCE EXAMPLE 3
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino-
)-7-methoxyquinazoline
##STR00083##
[0630] 4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
(Reference Example 2, 1870 mg, 5.85 mmol) was dissolved in DMA (50
ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate
(prepared as in Chemical & Pharmaceutical Bulletin 2001, 49(7),
822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol)
were added, and the mixture was heated to 85.degree. C. with
stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl
4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride
were added in the above quantities to the reaction mixture. Heating
was continued at 85.degree. C. for a further 6 hours after the
final addition. The solvent was evaporated, and the residue was
partitioned between DCM (150 ml) and H.sub.2O (150 ml). The aqueous
layer was extracted with DCM (4.times.100 ml), and the extractions
combined with the DCM layer. The combined DCM fractions were dried
over MgSO.sub.4 and evaporated. The residue was purified by
chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated
aqueous NH.sub.4OH) in DCM. The appropriate fractions were combined
and evaporated, giving the product as a light brown foam (2.40 g,
58%, allowing for 2.3 equivalents of residual DMA); .sup.1H NMR:
1.40 (s, 9H), 1.60-1.65 (m, 2H), 1.95-2.00 (m, 2H), 3.20-3.25 (m,
2H), 3.65-3.70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H),
7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36
(s, 1H), 9.53 (s, 1H); Mass Spectrum: 503.5, 505.5
REFERENCE EXAMPLE 4
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]ethoxy}-4-(3-chloro-2-fluoroanil-
ino)-7-methoxyquinazoline
##STR00084##
[0632] 4 (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
(Reference Example 2, 700 mg, 2.19 mmol) was dissolved in DMA (35
ml). Potassium carbonate (1209 mg, 8.76 mmol) and tert-butyl
4-(toluene-4-sulfonyloxymethyl)piperidine-1-carboxylate (prepared
as described in Example 1 in WO 9427965; 808 mg, 2.19 mmol) were
added, and the mixture was stirred at 80.degree. C. for 4 hours.
The solvent was evaporated, and the residue was partitioned between
water (100 ml) and DCM (100 ml). The aqueous layer was extracted
with DCM (3.times.100 ml) and the extractions combined with the DCM
layer. The combined DCM fractions were filtered through a
silicone-treated filter paper, and evaporated, giving the product
as a brown solid (1290 mg, 98%); .sup.1H NMR: 1.20 (m, 2H), 1.39
(s, 9H), 1.82 (m, 2H), 2.03 (br. m, 1H), 2.70-2.85 (br. m, 2H),
3.93 (s, 3H), 3.95-4.05 (br. m, 2H), 3.98 (d, 2H), 7.19 (s, 1H),
7.26 (dd, 1H), 7.46 (dd, 1H), 7.50 (dd, 1H), 7.76 (s, 1H), 8.35 (s,
1H), 9.57 (s, 1H); Mass Spectrum: 517.3, 519.3
REFERENCE EXAMPLE 5
6-{[2-(1-tert-Butoxycarbonyl)piperidin-4-yl]ethoxy}-4-(3-chloro-2-fluoroan-
ilino)-7-methoxyquinazoline
##STR00085##
[0634] 4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
(Reference Example 2, 500 mg, 1.56 mmol) was dissolved in DMA (25
ml). Potassium carbonate (864 mg, 6.26 mmol) and tert-butyl
4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylate (prepared
as described in Example 20 in U.S. Pat. No. 5,252,586; 504 mg, 1.64
mmol) were added, and the mixture was stirred at 60.degree. C. for
16 hours. The solvent was evaporated, and the residue was
partitioned between water (100 ml) and DCM (100 ml). The aqueous
layer was extracted with DCM (3.times.100 ml) and the extractions
combined with the DCM layer. The combined DCM fractions were
filtered through a silicone-treated filter paper, and evaporated,
giving the product as a brown foam (830 mg, 100%); .sup.1H NMR:
1.00-1.18 (m, 2H), 1.38 (s, 9H), 1.65-1.80 (m, 5H), 2.65-2.75 (m,
2H), 3.92 (s, 3H), 3.93 (m, 2H), 4.15 (t, 2H), 7.18 (s, 1H), 7.26
(dd, 1H), 7.46 (dd, 1H), 7.51 (dd, 1H), 7.77 (s, 1H), 8.36 (s, 1H),
9.54 (s, 1H); Mass Spectrum: 531.6, 533.6.
* * * * *